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Zhang Y, Dong D, Zhang J, Cheng K, Zhen F, Li M, Chen B. Pathology and physiology of acid-sensitive ion channels in the bladder. Heliyon 2024; 10:e38031. [PMID: 39347393 PMCID: PMC11437851 DOI: 10.1016/j.heliyon.2024.e38031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/08/2024] [Accepted: 09/16/2024] [Indexed: 10/01/2024] Open
Abstract
Acid-sensitive ion channels (ASICs) are sodium-permeable channels activated by extracellular acidification. They can be activated and trigger the inward flow of Na+ when the extracellular environment is acidic, leading to membrane depolarization and thus inducing action potentials in neurons. There are four ASIC genes in mammals (ASIC1-4). ASIC is widely expressed in humans. It is closely associated with pain, neurological disorders, multiple sclerosis, epilepsy, migraines, and many other disorders. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a specific syndrome characterized by bladder pain. Recent studies have shown that ASICs are closely associated with the development of BPS/IC. A study revealed that ASIC levels are significantly elevated in a BPS/IC model. Additionally, researchers have reported differential changes in ASICs in the bladders of patients with neurogenic lower urinary tract dysfunction (NLUTD) caused by spinal cord injury (SCI). In this review, we summarize the structure and physiological functions of ASICs and focus on the mechanisms by which ASICs mediate bladder disease.
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Affiliation(s)
- Yang Zhang
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Di Dong
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jialong Zhang
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Kang Cheng
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fang Zhen
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Mei Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Binghai Chen
- Department of Urology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Institute of Translational Medicine, Jiangsu University, China
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Homma Y, Akiyama Y, Kim JH, Chuang YC, Jeong SJ, Meng E, Kitta T, Jhang JF, Furuta A, Lee KS, Maeda D. Definition Change and Update of Clinical Guidelines for Interstitial Cystitis and Bladder Pain Syndrome. Low Urin Tract Symptoms 2024; 16:e12532. [PMID: 39267358 DOI: 10.1111/luts.12532] [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: 06/05/2024] [Revised: 07/29/2024] [Accepted: 08/20/2024] [Indexed: 09/17/2024]
Abstract
The clinical guidelines for interstitial cystitis (IC) and bladder pain syndrome (BPS) have been revised by updating our previous guidelines. The symptoms of IC and BPS, collectively called as hypersensitive bladder (HSB) symptoms, are virtually indistinguishable between IC and BPS; however, IC and BPS should be considered as a separate entity of disorders. We define IC as a bladder disease with Hunner lesions, usually associated with HSB symptoms and bladder inflammation, and BPS as a condition with HSB symptoms in the absence of Hunner lesions and any confusable diseases. Pathophysiology totally differs between IC and BPS. IC involves immunological inflammation probably resulting from autoimmunity, while BPS is associated with the interaction of multiple factors such as neurogenic inflammation, exogenous substances, urothelial defects, psychological stress, and neural hyperactivity. Histopathology also differs between IC and BPS. IC is associated with severe inflammation of the whole bladder accompanied by plasma cell infiltration and urothelial denudation, while BPS shows little pathological changes. Management should begin with a differential diagnosis of IC or BPS, which would require cystoscopy to determine the presence or absence of Hunner lesions. The patients should be treated differently based on the diagnosis following the algorithm, although pain management would be common to IC and BPS. Clinical studies are also to be designed and analyzed separately for IC and BPS.
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Affiliation(s)
- Yukio Homma
- Department of Interstitial Cystitis Medicine, Kyorin University, Mitaka, Japan
| | | | - Jang Hwan Kim
- Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yao-Chi Chuang
- Kaohsiung Chang Gang Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | - En Meng
- Tri-Service General Hospital, Taipei, Taiwan
| | | | - Jia-Fong Jhang
- Buddhist Tzu Chi General Hospital and School of Medicine, Hualien, Taiwan
| | - Akira Furuta
- Jikei University School of Medicine, Tokyo, Japan
| | | | - Daichi Maeda
- Department of Cellular and Molecular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Liu L, Zhao Y, An W, Zhao M, Ding N, Liu H, Ge N, Wen J, Zhang X, Zu S, Sun W. Piezo2 Channel Upregulation is Involved in Mechanical Allodynia in CYP-Induced Cystitis Rats. Mol Neurobiol 2023; 60:5000-5012. [PMID: 37227654 PMCID: PMC10415424 DOI: 10.1007/s12035-023-03386-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/13/2023] [Indexed: 05/26/2023]
Abstract
Mechanical sensing Piezo2 channel in primary sensory neurons has been shown contribute to mechanical allodynia in somatic chronic pain conditions. Interstitial cystitis (IC)-associated pain is often triggered by bladder filling, a presentation that mimics the mechanical allodynia. In the present study, we aimed to examine the involvement of sensory Piezo2 channel in IC-associated mechanical allodynia using a commonly employed cyclophosphamide (CYP)-induced IC model rat. Piezo2 channels in dorsal root ganglia (DRGs) was knocked down by intrathecal injections of Piezo2 anti-sense oligodeoxynucleotides (ODNs) in CYP-induced cystitis rats, and mechanical stimulation-evoked referred bladder pain was measured in the lower abdomen overlying the bladder using von Frey filaments. Piezo2 expression at the mRNA, protein, and functional levels in DRG neurons innervating the bladder was detected by RNA-fluorescence in situ hybridization, western blotting, immunofluorescence, and Ca2+ imaging, respectively. We found that Piezo2 channels were expressed on most (> 90%) of the bladder primary afferents, including afferents that express CGRP, TRPV1 and stained with isolectin B4. CYP-induced cystitis was associated with Piezo2 upregulation in bladder afferent neurons at the mRNA, protein, and functional levels. Knockdown of Piezo2 expression in DRG neurons significantly suppressed mechanical stimulation-evoked referred bladder pain as well as bladder hyperactivity in CYP rats compared to CYP rats treated with mismatched ODNs. Our results suggest upregulation of Piezo2 channels is involved in the development of bladder mechanical allodynia and bladder hyperactivity in CYP-induced cystitis. Targeting Piezo2 might be an attractive therapeutic approach for IC-related bladder pain.
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Affiliation(s)
- Lei Liu
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Yan Zhao
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China
| | - Wenhan An
- Department of Rehabilitation, The Second Hospital of Shandong University, Jinan, Shandong, P. R. China
| | - Mengmeng Zhao
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Ning Ding
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Hanwen Liu
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Nan Ge
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Jiliang Wen
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Xiulin Zhang
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Shulu Zu
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China
| | - Wendong Sun
- Department of Urology, The Second Hospital of Shandong University, Jinan, Shandong, 250032, P. R. China.
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Li X, Hu J, Yin P, Liu L, Chen Y. Mechanotransduction in the urothelium: ATP signalling and mechanoreceptors. Heliyon 2023; 9:e19427. [PMID: 37674847 PMCID: PMC10477517 DOI: 10.1016/j.heliyon.2023.e19427] [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: 04/23/2023] [Revised: 08/10/2023] [Accepted: 08/22/2023] [Indexed: 09/08/2023] Open
Abstract
The urothelium, which covers the inner surface of the bladder, is continuously exposed to a complex physical environment where it is stimulated by, and responds to, a wide range of mechanical cues. Mechanically activated ion channels endow the urothelium with functioning in the conversion of mechanical stimuli into biochemical events that influence the surface of the urothelium itself as well as suburothelial tissues, including afferent nerve fibres, interstitial cells of Cajal and detrusor smooth muscle cells, to ensure normal urinary function during the cycle of filling and voiding. However, under prolonged and abnormal loading conditions, the urothelial sensory system can become maladaptive, leading to the development of bladder dysfunction. In this review, we summarize developments in the understanding of urothelial mechanotransduction from two perspectives: first, with regard to the functions of urothelial mechanotransduction, particularly stretch-mediated ATP signalling and the regulation of urothelial surface area; and secondly, with regard to the mechanoreceptors present in the urothelium, primarily transient receptor potential channels and mechanosensitive Piezo channels, and the potential pathophysiological role of these channels in the bladder. A more thorough understanding of urothelial mechanotransduction function may inspire the development of new therapeutic strategies for lower urinary tract diseases.
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Affiliation(s)
| | | | - Ping Yin
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Lumin Liu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Yuelai Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, 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: 29] [Impact Index Per Article: 14.5] [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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Hung CH, Chin Y, Fong YO, Lee CH, Han DS, Lin JH, Sun WH, Chen CC. Acidosis-related pain and its receptors as targets for chronic pain. Pharmacol Ther 2023; 247:108444. [PMID: 37210007 DOI: 10.1016/j.pharmthera.2023.108444] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.
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Affiliation(s)
- Chih-Hsien Hung
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin Chin
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Der-Shen Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Jiann-Her Lin
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.
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7
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Luyts N, Daniluk J, Freitas ACN, Bazeli B, Janssens A, Mulier M, Everaerts W, Voets T. Inhibition of TRPM8 by the urinary tract analgesic drug phenazopyridine. Eur J Pharmacol 2023; 942:175512. [PMID: 36657655 DOI: 10.1016/j.ejphar.2023.175512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023]
Abstract
BACKGROUND and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall. EXPERIMENTAL APPROACH The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice. KEY RESULTS PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC50 values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3. CONCLUSION AND IMPLICATIONS PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP.
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Affiliation(s)
- Noémie Luyts
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Jan Daniluk
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Ana Cristina Nogueira Freitas
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Bahar Bazeli
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Annelies Janssens
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Marie Mulier
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
| | - Wouter Everaerts
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium.
| | - Thomas Voets
- Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
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8
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Jhang JF, Jiang YH, Kuo HC. Current Understanding of the Pathophysiology and Novel Treatments of Interstitial Cystitis/Bladder Pain Syndrome. Biomedicines 2022; 10:biomedicines10102380. [PMID: 36289642 PMCID: PMC9598807 DOI: 10.3390/biomedicines10102380] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/08/2022] [Accepted: 09/17/2022] [Indexed: 12/19/2022] Open
Abstract
The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is multifactorial. Identifying the clinical characteristics and cystoscopic findings of bladder-centered IC/BPS facilitates optimal treatment strategies targeting the diseased urinary bladder. Patients with Hunner’s lesion (HIC) and without Hunner’s lesion (NHIC) should be treated differently. Based on the histopathological findings, NHIC can be treated with intravesical instillation of urothelial protective agents, such as hyaluronic acid, to cover the urothelial defects. In non-responders, chronic inflammation and higher urothelial dysfunction can be treated with intravesical botulinum toxin A injection, platelet-rich plasma injection, or low-energy shock wave treatment to reduce inflammation, increase tissue regeneration, and improve the urothelial barrier. Patients with HIC should be treated with electrocauterization first; augmentation enterocystoplasty should only be used in end-stage HIC when the contracted bladder is refractory to other treatments. The antiviral agent, valacyclovir, can be used in patients with HIC, small bladder capacity, and high-grade glomerulations. In addition, behavioral modification is always recommended from the beginning of treatment. Treatment with cognitive behavioral therapy interventions in combination with bladder therapy can reduce anxiety and improve treatment outcomes. Herein, recent advances in the pathophysiology and novel treatments for IC/BPS are reviewed.
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Affiliation(s)
| | | | - Hann-Chorng Kuo
- Correspondence: ; Tel.: +886-3-8561825 (ext. 2117); Fax: +886-3-8560794
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9
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Perkins ME, Vizzard MA. Transient receptor potential vanilloid type 4 (TRPV4) in urinary bladder structure and function. CURRENT TOPICS IN MEMBRANES 2022; 89:95-138. [PMID: 36210154 PMCID: PMC10486315 DOI: 10.1016/bs.ctm.2022.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a urologic, chronic pelvic pain syndrome characterized by pelvic pain, pressure, or discomfort with urinary symptoms. Symptom exacerbation (flare) is common with multiple, perceived triggers including stress. Multiple transient receptor potential (TRP) channels (TRPA1, TRPV1, TRPV4) expressed in the bladder have specific tissue distributions in the lower urinary tract (LUT) and are implicated in bladder disorders including overactive bladder (OAB) and BPS/IC. TRPV4 channels are strong candidates for mechanosensors in the urinary bladder and TRPV4 antagonists are promising therapeutic agents for OAB. In this perspective piece, we address the current knowledge of TRPV4 distribution and function in the LUT and its plasticity with injury or disease with an emphasis on BPS/IC. We review our studies that extend the knowledge of TRPV4 in urinary bladder function by focusing on (i) TRPV4 involvement in voiding dysfunction, pelvic pain, and non-voiding bladder contractions in NGF-OE mice; (ii) distention-induced luminal ATP release mechanisms and (iii) involvement of TRPV4 and vesicular release mechanisms. Finally, we review our lamina propria studies in postnatal rat studies that demonstrate: (i) the predominance of the TRPV4+ and PDGFRα+ lamina propria cellular network in early postnatal rats; (ii) the ability of exogenous mediators (i.e., ATP, TRPV4 agonist) to activate and increase the number of lamina propria cells exhibiting active Ca2+ events; and (iii) the ability of ATP and TRPV4 agonist to increase the rate of integrated Ca2+ activity corresponding to coupled lamina propria network events and the formation of propagating wavefronts.
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Affiliation(s)
- Megan Elizabeth Perkins
- Department of Neurological Sciences, The Larner College of Medicine, The University of Vermont, Burlington, VT, United States
| | - Margaret A Vizzard
- Department of Neurological Sciences, The Larner College of Medicine, The University of Vermont, Burlington, VT, United States.
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10
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Kamasako T, Kaga K, Inoue KI, Hariyama M, Yamanishi T. Supervised machine learning algorithm identified KRT20, BATF and TP63 as biologically relevant biomarkers for bladder biopsy specimens from interstitial cystitis/bladder pain syndrome patients. Int J Urol 2022; 29:406-412. [PMID: 35102612 DOI: 10.1111/iju.14795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/17/2021] [Accepted: 12/28/2021] [Indexed: 12/22/2022]
Abstract
OBJECTIVES This study was carried out to identify biomarkers that distinguish Hunner-type interstitial cystitis from non-Hunner-type interstitial cystitis patients. METHODS Total ribonucleic acid was purified from 212 punch biopsy specimens of 89 individuals who were diagnosed as interstitial cystitis/bladder pain syndrome. To examine the expression profile of patients' bladder specimens, 68 urothelial master transcription factors and nine known markers (E-cadherin, cytokeratins, uroplakins and sonic hedgehog) were selected. To classify the biopsy samples, principal component analysis was carried out. A decision tree algorithm was adopted to identify critical determinants, in which 102 and 116 bladder specimens were used for learning and validation, respectively. RESULTS Principal component analysis segregated tissues from Hunner-type and non-Hunner-type interstitial cystitis specimens in principal component axes 2 and 4. Principal components 2 and 4 contained urothelial stem/progenitor transcription factors and cytokeratins, respectively. A decision tree identified KRT20, BATF and TP63 to classify non-Hunner-type and Hunner-type interstitial cystitis specimens. KRT20 was lower in tissues from Hunner-type compared with non-Hunner-type interstitial cystitis specimens (P < 0.001). TP63 was lower in Hunner's lesions compared with adjacent mucosa from Hunner-type interstitial cystitis patients (P < 0.001). Blinded validation using additional biopsy specimens verified that the decision tree showed fairly precise concordance with cystoscopic diagnosis. CONCLUSION KRT20, BATF and TP63 were identified as biologically relevant biomarkers to classify tissues from interstitial cystitis/bladder pain syndrome specimens. The biologically explainable determinants could contribute to defining the elusive interstitial cystitis/bladder pain syndrome pathogenesis.
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Affiliation(s)
- Tomohiko Kamasako
- Department of Urology, Continence Center, Dokkyo Medical University, Tochigi, Japan
| | - Kanya Kaga
- Department of Urology, Continence Center, Dokkyo Medical University, Tochigi, Japan
| | - Ken-Ichi Inoue
- Comprehensive Research Facilities for Advanced Medical Science, Research Center for Advanced Medical Science, Dokkyo Medical University, Tochigi, Japan
| | - Masanori Hariyama
- Graduate School of Information Sciences, Tohoku University, Sendai, Japan
| | - Tomonori Yamanishi
- Department of Urology, Continence Center, Dokkyo Medical University, Tochigi, Japan
- Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Aizawa N, Fujita T. The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders. J Smooth Muscle Res 2022; 58:11-21. [PMID: 35354708 PMCID: PMC8961290 DOI: 10.1540/jsmr.58.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the lower urinary tract, transient receptor potential (TRP) channels are primarily involved in physiological function, especially in cellular sensors responding to chemical and physical stimuli. Among TRP channels, TRP melastatin 8 (TRPM8) channels, responding to cold temperature and/or chemical agents, such as menthol or icilin, are mainly expressed in the nerve endings of the primary afferent neurons and in the cell bodies of dorsal root ganglia innervating the urinary bladder (via Aδ- and C-fibers); this suggests that TRPM8 channels primarily contribute to bladder sensory (afferent) function. Storage symptoms of overactive bladder, benign prostatic hyperplasia, and interstitial cystitis are commonly related to sensory function (bladder hypersensitivity); thus, TRPM8 channels may also contribute to the pathophysiology of bladder hypersensitivity. Indeed, it has been reported in a pharmacological investigation using rodents that TRPM8 channels contribute to the pathophysiological bladder afferent hypersensitivity of mechanosensitive C-fibers. Similar findings have also been reported in humans. Therefore, a TRPM8 antagonist would be a promising therapeutic target for bladder hypersensitive disorders, including urinary urgency or nociceptive pain. In this review article, the functional role of the TRPM8 channel in the lower urinary tract and the potential of its antagonist for the treatment of bladder disorders was described.
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Affiliation(s)
- Naoki Aizawa
- Department of Pharmacology and Toxicology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
| | - Tomoe Fujita
- Department of Pharmacology and Toxicology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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12
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Upregulation of TRPM3 in bladder afferents is involved in chronic pain in CYP-induced cystitis. Pain 2022; 163:2200-2212. [DOI: 10.1097/j.pain.0000000000002616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/05/2022] [Indexed: 11/26/2022]
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Low-Energy Shock Wave Plus Intravesical Instillation of Botulinum Toxin A for Interstitial Cystitis/Bladder Pain Syndrome: Pathophysiology and Preliminary Result of a Novel Minimally Invasive Treatment. Biomedicines 2022; 10:biomedicines10020396. [PMID: 35203604 PMCID: PMC8962423 DOI: 10.3390/biomedicines10020396] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 01/27/2023] Open
Abstract
Low-energy shock wave (LESW) therapy is known to facilitate tissue regeneration with analgesic and anti-inflammatory effects. LESW treatment has been demonstrated to be effective in treating chronic prostatitis and pelvic pain syndrome as well as overactive bladder, and it has a potential effect on interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. LESW reduces pain behavior, downregulates nerve growth factor expression, and suppresses bladder overactivity by decreasing the expression of inflammatory proteins. Previous rat IC models have shown that LESW can increase urothelial permeability, facilitate intravesical delivery of botulinum toxin A (BoNT-A), and block acetic acid-induced hyperactive bladder, suggesting that LESW might be a potential therapeutic module for relieving bladder inflammatory conditions, such as bladder oversensitivity, IC/BPS, and overactive bladder. A recent clinical trial showed that LESW monotherapy was associated with a significant reduction in pain scores and IC symptoms. BoNT-A detrusor injection or liposome-encapsulated BoNT-A instillation could also inhibit inflammation and improve IC symptoms. However, BoNT-A injection requires anesthesia and certain complications might occur. Our preliminary study using LESW plus intravesical BoNT-A instillation every week demonstrated an improvement in global response assessment without any adverse events. Moreover, an immunohistochemistry study revealed the presence of cleaved SNAP25 protein in the suburothelium of IC bladder tissue, indicating that BoNT-A could penetrate across the urothelial barrier after application of LESW. These results provide evidence for the efficacy and safety of this novel IC/BPS treatment by LESW plus BoNT-A instillation, without anesthesia, and no bladder injection. This article reviews the current evidence on LESW and LESW plus intravesical therapeutic agents on bladder disorders and the pathophysiology and pharmacological mechanism of this novel, minimally invasive treatment model for IC/BPS.
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14
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[S2K guideline on the diagnosis and treatment of interstitial cystitis (IC/BPS) : Discussion of the current guideline using a case study]. Urologe A 2022; 61:250-259. [PMID: 35037970 DOI: 10.1007/s00120-021-01753-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2021] [Indexed: 10/19/2022]
Abstract
IC/BPS is a chronic progressive disorder that is often difficult and unsatisfactory for the person affected and the treating therapist. Treatment should therefore be comprehensive, interdisciplinary, multimodal and take into account the biopsychosocial model. The guideline forms a thread through the diverse diagnostic and therapeutic options and provides extensive background information on the definition, epidemiology and aetiopathogenesis of this rare disease. However, practice and theory/guideline are different. Adaptation to the individual case is therefore necessary and explicitly desired. The guideline should therefore serve as a source of ideas for colleagues to compile their own standards suitable for their practice. On the one hand, therapy approaches that have been tried and tested in everyday clinical practice are passed on. On the other hand, the frequent lack of evidence should also be viewed critically. Further studies, if possible multi-centre, specifically designed for different aspects of IC/BPS would be desirable. Close networking between therapists in private practice and special centres is essential for the best possible treatment of people with IC/BPS. The guideline is intended to show the limits of what can be done in practices and outpatient clinics and to provide guidance on when patients should be referred to a "Centre for Interstitial Cystitis and Pelvic Pain". Overall, the guideline has improved the presence of this rare disease among colleagues. A comprehensive supplement, update and further substantiation with the state of current research is thus desirable.
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Werneburg GT, Keslar KS, Gotwald P, Doolittle J, Vij SC, Lee BH, Shoskes DA. Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions. Transl Androl Urol 2022; 10:4100-4109. [PMID: 34984176 PMCID: PMC8661250 DOI: 10.21037/tau-21-657] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022] Open
Abstract
Background We sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator. Methods Blood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls. Results Mean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF, CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRP-dependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1. Conclusions Men with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.
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Affiliation(s)
- Glenn T Werneburg
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Karen S Keslar
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Paige Gotwald
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Johnathan Doolittle
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Sarah C Vij
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Byron H Lee
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Daniel A Shoskes
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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Urinary Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome and Its Impact on Therapeutic Outcome. Diagnostics (Basel) 2021; 12:diagnostics12010075. [PMID: 35054241 PMCID: PMC8774507 DOI: 10.3390/diagnostics12010075] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 12/25/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as a chronic bladder disorder with suprapubic pain (pelvic pain) and pressure and/or discomfort related to bladder filling accompanied by lower urinary tract symptoms, such as urinary frequency and urgency without urinary tract infection (UTI) lasting for at least 6 weeks. IC/BPS presents significant bladder pain and frequency urgency symptoms with unknown etiology, and it is without a widely accepted standard in diagnosis. Patients’ pathological features through cystoscopy and histologic features of bladder biopsy determine the presence or absence of Hunner lesions. IC/PBS is categorized into Hunner (ulcerative) type IC/BPS (HIC/BPS) or non-Hunner (nonulcerative) type IC/BPS (NHIC/BPS). The pathophysiology of IC/BPS is composed of multiple possible factors, such as chronic inflammation, autoimmune disorders, neurogenic hyperactivity, urothelial defects, abnormal angiogenesis, oxidative stress, and exogenous urine substances, which play a crucial role in the pathophysiology of IC/BPS. Abnormal expressions of several urine and serum specimens, including growth factor, methylhistamine, glycoprotein, chemokine and cytokines, might be useful as biomarkers for IC/BPS diagnosis. Further studies to identify the key molecules in IC/BPS will help to improve the efficacy of treatment and identify biomarkers of the disease. In this review, we discuss the potential medical therapy and assessment of therapeutic outcome with urinary biomarkers for IC/BPS.
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Biomarkers in Interstitial Cystitis/Bladder Pain Syndrome with and without Hunner Lesion: A Review and Future Perspectives. Diagnostics (Basel) 2021; 11:diagnostics11122238. [PMID: 34943475 PMCID: PMC8700457 DOI: 10.3390/diagnostics11122238] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/27/2021] [Accepted: 11/29/2021] [Indexed: 11/16/2022] Open
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urinary bladder condition that presents with a wide variety of clinical phenotypes. It is commonly characterized by persistent pelvic pain and lower urinary tract symptoms, such as urinary frequency and urgency. Current clinicopathological and genomic evidence has indicated that IC/BPS with Hunner lesions is a clinically relevant distinct subtype with proven bladder pathology of subepithelial chronic inflammatory changes that are characterized by enhanced local immune responses and epithelial denudation. However, other forms of IC/BPS lacking Hunner lesions are a symptom syndrome complex of non-inflammatory conditions with little evidence of bladder etiology, characterized by aberrant neural activity in neurotransmission systems which leads to central nervous sensitization with potential involvement of urothelial malfunction, or clinical presentation of somatic and/or psychological symptoms beyond the bladder. Given such distinct potential pathophysiology between IC/BPS subtypes, disease biomarkers of IC/BPS should be provided separately for subtypes with and without Hunner lesions. Tailored approaches that target characteristic immunological inflammatory processes and epithelial denudation for IC/BPS with Hunner lesions, or the sensitized/altered nervous system, urothelial malfunction, association with other functional somatic syndromes, and psychosocial problems for IC/BPS without Hunner lesions, are essential to identify optimal and reliable disease-specific IC/BPS biomarkers.
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Froehlich JW, Scott Wang HH, Logvinenko T, Kostel S, DiMartino S, van Bokhoven A, Moses MA, Lee RS. "The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study". Mol Cell Proteomics 2021; 21:100176. [PMID: 34774759 PMCID: PMC8733275 DOI: 10.1016/j.mcpro.2021.100176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 10/08/2021] [Accepted: 11/07/2021] [Indexed: 11/27/2022] Open
Abstract
Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 participants was performed. The participants included patients with UCPPS (n = 82), healthy controls (HC) (n = 94), and disparate chronic pain diseases, termed positive controls (PC) (n = 68). Using training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n = 9) and UCPPS from PC (n = 3). The validated UCPPS: HC proteins were predominantly extracellular matrix/extracellular matrix modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by the members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue, and increased bleeding. Comparison with the PC cohort enabled the evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, interleukin-6, epidermal growth factor, and transforming growth factor beta 1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.
The proteomics of urinary chronic pelvic pain syndrome (UCPPS) found altered pathways. Key changes among the extracellular matrix and inflammatory response proteins were found. Several of these pathways and proteins were exclusively altered in UCPPS. These findings may have diagnostic and/or therapeutic potential in the future.
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Affiliation(s)
- John W Froehlich
- Department of Urology, Boston Children's Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Hsin-Hsaio Scott Wang
- Department of Urology, Boston Children's Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Tanya Logvinenko
- Department of Urology, Boston Children's Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
| | - Stephen Kostel
- Department of Urology, Boston Children's Hospital, Boston, MA
| | | | - Adrie van Bokhoven
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Marsha A Moses
- Department of Surgery, Harvard Medical School, Boston, MA; Vascular Biology Program, Boston Children's Hospital, Boston, MA; Department of Surgery, Boston Children's Hospital, Boston, MA
| | - Richard S Lee
- Department of Urology, Boston Children's Hospital, Boston, MA; Department of Surgery, Harvard Medical School, Boston, MA
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Lu K, Wei S, Wang Z, Wu K, Jiang J, Yan Z, Cheng Y. Identification of novel biomarkers in Hunner's interstitial cystitis using the CIBERSORT, an algorithm based on machine learning. BMC Urol 2021; 21:109. [PMID: 34399738 PMCID: PMC8365919 DOI: 10.1186/s12894-021-00875-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/03/2021] [Indexed: 12/20/2022] Open
Abstract
Background Hunner’s interstitial cystitis (HIC) is a complex disorder characterized by pelvic pain, disrupted urine storage, and Hunner lesions seen on cystoscopy. There are few effective diagnostic biomarkers. In the present study, we used the novel machine learning tool CIBERSORT to measure immune cell subset infiltration and potential novel diagnostic biomarkers for HIC. Methods The GSE11783 and GSE57560 datasets were downloaded from the Gene Expression Omnibus for analysis. Ten HIC and six healthy samples from GSE11783 were analyzed using the CIBERSORT algorithm. Gene Set Enrichment Analysis (GSEA) was performed to identify biological processes that occur during HIC pathogenesis. Finally, expression levels of 11 T cell follicular helper cell (Tfh) markers were compared between three healthy individuals and four patients from GSE57560. Results Six types of immune cells in HIC from GSE11783 showed significant differences, including resting mast cells, CD4+ memory-activated T cells (CD3+ CD4+ HLA-DR+ cells), M0 and M2 macrophages, Tfh cells, and activated natural killer cells. Except for plasma cells, there were no significant differences between Hunner’s lesion and non-Hunner’s lesion areas in HIC. The GSEA revealed significantly altered biological processes, including antigen–antibody reactions, autoimmune diseases, and infections of viruses, bacteria, and parasites. There were 11 Tfh cell markers with elevated expression in patients from GSE57560. Conclusion This was the first demonstration of Tfh cells and CD3+ CD4+ HLA-DR+ cells with elevated expression in HIC. These cells might serve as novel diagnostic biomarkers. Supplementary Information The online version contains supplementary material available at 10.1186/s12894-021-00875-8.
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Affiliation(s)
- Kaining Lu
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Shan Wei
- Department of Respiratory and Critical Care Medicine, People's Hospital Affiliated to Ningbo University, Yinzhou People's Hospital, Ningbo, People's Republic of China.,Department of Central Laboratory, People's Hospital Affiliated to Ningbo University, Yinzhou People's Hospital, Ningbo, People's Republic of China
| | - Zhengyi Wang
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Kerong Wu
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Junhui Jiang
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China
| | - Zejun Yan
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China. .,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.
| | - Yue Cheng
- Department of Urology, Ningbo First Hospital, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China. .,Department of Urology and Nephrology, Ningbo First Hospital, Ningbo Hospital of Zhejiang University, 59, Liuting Street, Ningbo, 315010, Zhejiang, People's Republic of China.
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Chess-Williams R, McDermott C, Sellers DJ, West EG, Mills KA. Chronic psychological stress and lower urinary tract symptoms. Low Urin Tract Symptoms 2021; 13:414-424. [PMID: 34132480 DOI: 10.1111/luts.12395] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/30/2022]
Abstract
It is well established that lower urinary tract symptoms (LUTS), particularly urinary urgency and incontinence, cause stress and anxiety for patients. However, there is mounting evidence that the relationship between these two factors is bidirectional and that chronic psychological stress itself can result in the development of symptoms such as urinary frequency, urgency, incontinence, and pelvic pain. This review considers the evidence that such a relationship exists and reviews the literature from clinical and animal studies to identify some of the mechanisms that might be involved. Inflammatory responses induced by chronic stress appear to offer the strongest link to bladder dysfunction. There is overwhelming evidence, both in patients and animal models, for a release of pro-inflammatory cytokines and chemokines during periods of chronic stress. Furthermore, cytokines have been shown to cause bladder dysfunction and pain via actions in the central nervous system and locally in the bladder. In the brain and spinal cord, pro-inflammatory cytokines influence the regulation of micturition pathways by corticotropin-releasing factor (CRF) and its receptors, while peripherally cytokines affect bladder function, directly causing detrusor hypertrophy and afferent nerve hypersensitivity. There is little information on which treatments may have most benefit for stressed/anxious patients with LUTS, but animal studies suggest traditional drugs for overactive bladder (solifenacin, mirabegron) are more effective on LUTS than anxiolytic drugs (fluoxetine, imipramine). The preliminary preclinical data for CRF receptor antagonists is not consistent. A clearer understanding of the mechanisms involved in stress-induced LUTS should provide a basis for improved treatment of this condition.
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Affiliation(s)
- Russ Chess-Williams
- Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Catherine McDermott
- Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Donna J Sellers
- Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Eliza G West
- Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia
| | - Kylie A Mills
- Centre for Urology Research, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia
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21
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Cystoscopic hydrodistention characteristics provide clinical and long-term prognostic features of interstitial cystitis after treatment. Sci Rep 2021; 11:455. [PMID: 33432045 PMCID: PMC7801576 DOI: 10.1038/s41598-020-80252-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022] Open
Abstract
To evaluate the correlations of clinical symptoms, urodynamic parameters, and long-term treatment outcomes with different findings of cystoscopic hydrodistention (HD) in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). This retrospective analysis of 486 patients with IC/BPS investigated baseline clinical symptoms, disease duration, medical comorbidities, urodynamic findings, cystoscopic characteristics [including maximal bladder capacity (MBC) and the presence of glomerulations and Hunner’s lesions], and outcomes according to the five IC/BPS HD subtypes based on the glomerulation grade, MBC, and the presence of Hunner’s lesions. Receiver operation characteristic analysis identified an optimal cutoff value of MBC ≥ 760 ml as a predictor of satisfactory outcomes. Glomerulation grade and MBC were significantly correlated (r = − 0.403, P < 0.001), and both were significantly associated with IC Symptom Index scores. The rate of satisfactory outcomes was better for the patients with low glomerulation grade and MBC ≥ 760 ml (64.2%), and significantly worse for those with Hunner’s lesions (36.8%); no significant differences were noted among the other groups. The results suggested that IC/BPS patients can be classified into the following three distinct subgroups: (1) those with low glomerulation grade and MBC ≥ 760 ml; (2) those with low glomerulation grade and MBC < 760 ml, or with high glomerulation grade regardless of MBC; and (3) those with Hunner’s lesions. The results showed that three IC/BPS subgroups had distinct bladder characteristics and treatment outcomes. The patients with high MBC and low glomerulation grade after HD had more medical comorbidities but a significantly higher rate of satisfactory treatment outcome. IRB: 105-25-B.
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22
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Increased Transient Receptor Potential Melastatin 8 Expression in the Development of Bladder Pain in Patients With Interstitial Cystitis/Bladder Pain Syndrome. Urology 2020; 146:301.e1-301.e6. [PMID: 33045289 DOI: 10.1016/j.urology.2020.09.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To explore the role of transient receptor potential melastatin 8 (TRPM8) in the occurrence and development of bladder pain in interstitial cystitis/bladder pain syndrome (IC/BPS) patients. The differences in the content and location distribution of TRPM8 in bladder were compared between IC/BPS and control group. METHODS All enrolled patients answered questionnaire such as O'leary-Sant symptom index, visual analog scale (VAS), quality of life (QOL), and pelvic pain and urinary urgency frequency (PUF) score, then bladder specimens were collected. Analyses such as qRT-PCR, western blot, and immunofluorescence were performed to determine the changes in TRPM8 content and expression in neurons and sensory nerves between the IC/BPS and control group, and the relationships between TRPM8 and various clinical scores were also analyzed. RESULTS There were significant differences in the O'leary-Sant score, PUF score, VAS, and QOL score between IC/BPS and the control group (P < .05). Compared with the control group, the expression levels of TRPM8 mRNA and protein were significantly increased in the IC/BPS bladder tissues (P < .01). Immunofluorescence examination also revealed that (1) the number of neurons and sensory nerves displayed a significant upward trend in the bladder tissue of IC/BPS patients (2) the expression levels of TRPM8 on neurons and sensory nerves also increased significantly in IC/BPS group. CONCLUSION In IC/BPS patients, TRPM8 content increased significantly and mainly expressed on increased neurons and sensory nerves in bladder tissue. These results may indicate a mechanism by which bladder pain is more easily to spread in IC/BPS patients, and may also indicate an important mechanism for pain sensitization in such patients.
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23
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Kamei J, Aizawa N, Nakagawa T, Kaneko S, Fujimura T, Homma Y, Kume H, Igawa Y. Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide-induced bladder inflammation and its associated hypersensitivity in mice. Int J Urol 2020; 28:107-114. [PMID: 33026125 DOI: 10.1111/iju.14389] [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: 05/12/2020] [Accepted: 09/02/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To study the role of transient receptor potential melastatin 2 in bladder function and inflammation-associated hypersensitivity. METHODS We evaluated physiological function of the bladder and intravesical lipopolysaccharide-induced inflammatory nociceptive responses in female wild-type and transient receptor potential melastatin 2-knockout mice. In vivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as in vitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0 mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain-like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation. RESULTS Few phenotypic differences in in vivo and in vitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24-48 h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin 2-knockout mice, whereas an increased voiding frequency was observed in wild-type mice. At 24 h after intravesical lipopolysaccharide instillation, the numbers of bladder pain-like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild-type mice compared with those in both transient receptor potential melastatin 2-knockout mice and in wild-type mice treated with saline instillation. CONCLUSIONS Although the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin 2-knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin 2 channels in these processes.
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Affiliation(s)
- Jun Kamei
- Department of Urology, Jichi Medical University, Tochigi, Japan.,Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Naoki Aizawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Department of Pharmacology and Toxicology, Dokkyo Medical University, Tochigi, Japan
| | - Takayuki Nakagawa
- Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.,Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | | | - Yukio Homma
- Department of Urology, Japan Red Cross Hospital, Tokyo, Japan
| | - Haruki Kume
- Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Igawa
- Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.,Department of Urology, Nagano Prefectural Medical Center, Suzaka, Japan
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24
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Huo Y, Chen W, Zheng X, Zhao J, Zhang Q, Hou Y, Cai Y, Lu X, Jin X. The protective effect of EGF-activated ROS in human corneal epithelial cells by inducing mitochondrial autophagy via activation TRPM2. J Cell Physiol 2020; 235:7018-7029. [PMID: 32083315 DOI: 10.1002/jcp.29597] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 01/16/2020] [Indexed: 01/03/2023]
Abstract
Oxidative stress is a major pathogenesis of some ocular surface diseases. Our previous study demonstrated that epidermal growth factor (EGF)-activated reactive oxygen species (ROS) could protect against human corneal epithelial cell (HCE) injury. In the present study, we aimed to explore the role and mechanisms of oxidative stress and mitochondrial autophagy in HCE cells subjected to scratch injury. CCK-8 assays, EdU assays, Western blot analysis, wound-healing assays, and flow cytometry were conducted to determine cell viability, proliferation, protein expression, cell apoptosis, and intracellular ROS levels, respectively. The results showed that EGF could promote damage repair and inhibit cell apoptosis in scratch injured HCE cells by upregulating ROS (**p < .01, ***p < .001). EGF also induced mitochondrial autophagy and alleviated mitochondrial damage. Interestingly, the combination of the mitochondrial autophagy inhibitor and mitochondrial division inhibitor 1 (MDIVI-1) with EGF could reduce cell proliferation, viability, and the ROS level (*p < .05, **p < .01, ***p < .001). Treatment using the ROS inhibitor N-acetyl- l-cysteine abrogated the increase in mitochondrial membrane potential after EGF treatment. (*p < .05). Taken together, these findings indicated that EGF plays an important role in HCE damage repair and could activate ROS to protect against HCE injury by inducing mitochondrial autophagy via activation of TRPM2.
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Affiliation(s)
- Yanan Huo
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wei Chen
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaoxiao Zheng
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jinchuan Zhao
- Zhejiang Institute of Medical Device Supervision and Testing, Hangzhou, Zhejiang, China
| | - Qi Zhang
- Zhejiang Institute of Medical Device Supervision and Testing, Hangzhou, Zhejiang, China
| | - Yuerou Hou
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ying Cai
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xuemei Lu
- Department of Medical Oncology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiuming Jin
- Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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25
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Dalghi MG, Montalbetti N, Carattino MD, Apodaca G. The Urothelium: Life in a Liquid Environment. Physiol Rev 2020; 100:1621-1705. [PMID: 32191559 PMCID: PMC7717127 DOI: 10.1152/physrev.00041.2019] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/02/2020] [Accepted: 03/14/2020] [Indexed: 02/08/2023] Open
Abstract
The urothelium, which lines the renal pelvis, ureters, urinary bladder, and proximal urethra, forms a high-resistance but adaptable barrier that surveils its mechanochemical environment and communicates changes to underlying tissues including afferent nerve fibers and the smooth muscle. The goal of this review is to summarize new insights into urothelial biology and function that have occurred in the past decade. After familiarizing the reader with key aspects of urothelial histology, we describe new insights into urothelial development and regeneration. This is followed by an extended discussion of urothelial barrier function, including information about the roles of the glycocalyx, ion and water transport, tight junctions, and the cellular and tissue shape changes and other adaptations that accompany expansion and contraction of the lower urinary tract. We also explore evidence that the urothelium can alter the water and solute composition of urine during normal physiology and in response to overdistension. We complete the review by providing an overview of our current knowledge about the urothelial environment, discussing the sensor and transducer functions of the urothelium, exploring the role of circadian rhythms in urothelial gene expression, and describing novel research tools that are likely to further advance our understanding of urothelial biology.
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Affiliation(s)
- Marianela G Dalghi
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nicolas Montalbetti
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Marcelo D Carattino
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Gerard Apodaca
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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26
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Bschleipfer T. Interstitielle Zystitis/Blasenschmerzsyndrom (IC/BPS). Urologe A 2020; 59:1123-1134. [DOI: 10.1007/s00120-020-01309-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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27
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Homma Y. Interstitial cystitis, bladder pain syndrome, hypersensitive bladder, and interstitial cystitis/bladder pain syndrome - clarification of definitions and relationships. Int J Urol 2020; 26 Suppl 1:20-24. [PMID: 31144731 DOI: 10.1111/iju.13970] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/18/2019] [Indexed: 12/23/2022]
Abstract
Interstitial cystitis and interstitial cystitis-related conditions such as bladder pain syndrome and hypersensitive bladder have a similar symptomatic profile but probably different etiologies. A meaningful classification of these diseases/conditions is mandatory for clinical and investigational progress. The condition with Hunner lesions (Hunner type interstitial cystitis) is distinct from other categories in terms of histopathology, gene expression, and clinical management. Classification should clearly differentiate the presence or absence of Hunner lesions. The term covering patients as a whole should contain interstitial cystitis, since interstitial cystitis is historically a well-known name and used for insurance reimbursement. The proposed taxonomy features an umbrella term (interstitial cystitis/bladder pain syndrome) and two subgroups, Hunner type interstitial cystitis (with Hunner lesions) and bladder pain syndrome (without Hunner lesions). Interstitial cystitis/bladder pain syndrome is convenient for initial management, and subgroups can categorize the patients for specific management. The characteristic symptom profile is to be collectively termed as hypersensitive bladder symptoms.
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Affiliation(s)
- Yukio Homma
- Japanese Red Cross Medical Center, Shibuyaku, Tokyo, Japan
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28
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Immunomodulatory Therapies for Interstitial Cystitis/Bladder Pain Syndrome. CURRENT BLADDER DYSFUNCTION REPORTS 2020. [DOI: 10.1007/s11884-020-00593-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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29
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Cho KJ, Lee KS, Choi JB, Koh JS, Kim JC. Changes in uroplakin expression in the urothelium of patients with ulcerative interstitial cystitis/bladder pain syndrome. Investig Clin Urol 2020; 61:304-309. [PMID: 32377607 PMCID: PMC7189107 DOI: 10.4111/icu.2020.61.3.304] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/29/2020] [Indexed: 01/24/2023] Open
Abstract
Purpose We evaluated changes in the expression of uroplakin (UP) in the urothelium of patients with ulcerative interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and Methods Bladder samples were collected from 19 patients with ulcerative IC/BPS who were treated with augmentation ileocystoplasty and from 5 control patients. Frequency-volume charts, the pain visual analogue scale (VAS), and the O'Leary-Sant interstitial cystitis symptom index (ICSI) and problem index (ICPI) were used to evaluate the patients' symptoms preoperatively. The expression levels of UP-Ib and UP-III in the urothelium were compared between the IC/BPS patients and control patients. Results Sixteen women and three men with IC/BPS were evaluated. Their values for preoperative mean voiding frequency, number of nocturia episodes, and functional bladder capacity as recorded in frequency-volume charts were 21.1±12.8, 5.9±4.2, and 151.1±62.7 mL, respectively. The mean pain VAS, ICSI, and ICPI scores were 8.4±1.3, 17.7±2.2, and 14.7±1.8, respectively. Immunofluorescence staining showed that UP-Ib and UP-III were localized in the urothelium. Upon Western blot analysis, the expression of UP-III was significantly increased in the IC/BPS group compared with the control group. However, expression of UP-Ib did not differ significantly between the IC/BPS and control groups. Conclusions UP-III was significantly upregulated in patients with ulcerative IC/BPS. UP-III is a potential biomarker for the diagnosis of ulcerative IC/BPS.
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Affiliation(s)
- Kang Jun Cho
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyu-Sung Lee
- Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Bong Choi
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jun Sung Koh
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Joon Chul Kim
- Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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30
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Homma Y, Akiyama Y, Tomoe H, Furuta A, Ueda T, Maeda D, Lin ATL, Kuo H, Lee M, Oh S, Kim JC, Lee K. Clinical guidelines for interstitial cystitis/bladder pain syndrome. Int J Urol 2020; 27:578-589. [DOI: 10.1111/iju.14234] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/27/2020] [Indexed: 12/19/2022]
Affiliation(s)
- Yukio Homma
- Department of Urology Japanese Red Cross Medical Center Tokyo Japan
| | - Yoshiyuki Akiyama
- Department of Urology Graduate School of Medicine The University of Tokyo Tokyo Japan
| | - Hikaru Tomoe
- Department of Urology Tokyo Women’s Medical University Medical Center East Tokyo Japan
| | - Akira Furuta
- Department of Urology Jikei University School of Medicine Tokyo Japan
| | | | - Daichi Maeda
- Department of Clinical Genomics Graduate School of Medicine Osaka University Osaka Japan
| | - Alex TL Lin
- Department of Urology Taipei Veterans General Hospital National Yang Ming University Taipei Taiwan
| | - Hann‐Chorng Kuo
- Department of Urology School of Medicine Buddhist Tzu Chi General Hospital Tzu Chi University Hualien Taiwan
| | - Ming‐Huei Lee
- Department of Urology Feng‐Yuan Hospital Taichung Taiwan
| | - Seung‐June Oh
- Department of Urology Seoul National University Seoul Korea
| | - Joon Chul Kim
- Department of Urology The Catholic University of Korea Seoul Korea
| | - Kyu‐Sung Lee
- Department of Urology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea
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31
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Akiyama Y, Luo Y, Hanno PM, Maeda D, Homma Y. Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives. Int J Urol 2020; 27:491-503. [PMID: 32246572 DOI: 10.1111/iju.14229] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/24/2020] [Indexed: 12/30/2022]
Abstract
Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.
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Affiliation(s)
- Yoshiyuki Akiyama
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Urology, University of Iowa, Iowa City, Iowa, USA
| | - Yi Luo
- Department of Urology, University of Iowa, Iowa City, Iowa, USA
| | - Philip M Hanno
- Department of Urology, Stanford University School of Medicine, Stanford, California, USA
| | - Daichi Maeda
- Department of Clinical Genomics, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yukio Homma
- Japanese Red Cross Medical Center, Tokyo, Japan
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Wei X, Sun C, Zhou RP, Ma GG, Yang Y, Lu C, Hu W. Nerve growth factor promotes ASIC1a expression via the NF-κB pathway and enhances acid-induced chondrocyte apoptosis. Int Immunopharmacol 2020; 82:106340. [PMID: 32146316 DOI: 10.1016/j.intimp.2020.106340] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/02/2020] [Accepted: 02/21/2020] [Indexed: 12/15/2022]
Abstract
Nerve growth factor (NGF) is a neurotrophic factor that is thought to have a broad role in the nervous system and tumors, and has recently been described as a mediator of inflammation. It is not clear whether or not NGF participates in apoptosis of articular chondrocytes. In this study, we determined if NGF affects ASIC1a expression and NF-κB P65 activation in rat chondrocytes, and measured the effectiveness of NGF on apoptotic protein expression in acid-induced chondrocytes. NGF was shown to up-regulate the level of ASIC1a in a dose- and time-dependent fashion. Simultaneously, NGF activated NF-κB P65 in chondrocytes. Additionally, the elevated ASIC1a expression induced by NGF was eliminated by the NF-κB inhibitor (PDTC) in chondrocytes. Moreover, NGF reduced cell viability and induced LDH release under the premise of acid-induced articular chondrocytes. Furthermore, NGF could enhance cleaved-caspase 9 and cleaved-PARP expression in acid-pretreated chondrocytes, and which could be inhibited by using psalmotoxin 1(PcTX1) or PDTC. Together, these results indicated that NGF may up-regulate ASIC1a expression through the NF-κB signaling pathway, and further promote acid-induced apoptosis of chondrocytes.
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Affiliation(s)
- Xin Wei
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Cheng Sun
- Department of Pharmacology, Zhongda Hospital Southeast University, Nanjing 210009, China
| | - Ren-Peng Zhou
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Gang-Gang Ma
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Yang Yang
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Chao Lu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Wei Hu
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China.
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Update on the Pathophysiology of Interstitial Cystitis /Bladder Pain Syndrome. CURRENT BLADDER DYSFUNCTION REPORTS 2020. [DOI: 10.1007/s11884-019-00569-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Chen JL, Kuo HC. Clinical application of intravesical botulinum toxin type A for overactive bladder and interstitial cystitis. Investig Clin Urol 2019; 61:S33-S42. [PMID: 32055752 PMCID: PMC7004832 DOI: 10.4111/icu.2020.61.s1.s33] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/25/2019] [Indexed: 01/30/2023] Open
Abstract
After decades of clinical and basic science research, the clinical application of botulinum toxin A (Botox) in urology has been extended to neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity, refractory overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), lower urinary tract symptoms, benign prostatic hyperplasia, and neurogenic or non-neurogenic lower urinary tract dysfunction in children. Botox selectively disrupts and modulates neurotransmission, suppresses detrusor overactivity, and modulates sensory function, inflammation, and glandular function. In addition to motor effects, Botox has been found to have sensory inhibitory effects and anti-inflammatory effects; therefore, it has been used to treat IC/BPS and OAB. Currently, Botox has been approved for the treatment of NDO and OAB. Recent clinical trials on Botox for the treatment of IC/BPS have reported promising therapeutic effects, including reduced bladder pain. Additionally, the therapeutic duration was found to be longer with repeated Botox injections than with a single injection. However, the use of Botox for IC/BPS has not been approved. This paper reviews the recent advances in intravesical Botox treatment for OAB and IC/BPS.
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Affiliation(s)
- Jing-Liang Chen
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Hann-Chorng Kuo
- Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
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Homma Y, Akiyama Y, Niimi A, Nomiya A, Igawa Y. Classification, Characterization, and Sub-Grouping of Interstitial Cystitis. CURRENT BLADDER DYSFUNCTION REPORTS 2019. [DOI: 10.1007/s11884-019-00542-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Girard BM, Campbell SE, Perkins M, Hsiang H, Tooke K, Drescher C, Hennig GW, Heppner TJ, Nelson MT, Vizzard MA. TRPV4 blockade reduces voiding frequency, ATP release, and pelvic sensitivity in mice with chronic urothelial overexpression of NGF. Am J Physiol Renal Physiol 2019; 317:F1695-F1706. [PMID: 31630542 DOI: 10.1152/ajprenal.00147.2019] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 μM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly (P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly (P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly (P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.
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Affiliation(s)
- Beatrice M Girard
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Susan E Campbell
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Megan Perkins
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Harrison Hsiang
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Katharine Tooke
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Carolyn Drescher
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Grant W Hennig
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Thomas J Heppner
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Mark T Nelson
- Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont
| | - Margaret A Vizzard
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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Factors affecting the symptom-free period after hydrodistention in females with interstitial cystitis and painful bladder syndrome. J INCL PHENOM MACRO 2019. [DOI: 10.1007/s10847-019-00923-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Majima T, Mori K, Kadekawa K, Takai S, Funahashi Y, Reinhart B, Goins WF, Gotoh M, Glorioso JC, Yoshimura N. The effect of herpes simplex virus vector‐mediated gene therapy of
protein phosphatase 1α
on bladder overactivity and nociception. Neurourol Urodyn 2018; 38:582-590. [DOI: 10.1002/nau.23882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 09/30/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Tsuyoshi Majima
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
- Department of UrologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Kenichi Mori
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
| | - Katsumi Kadekawa
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
| | - Shun Takai
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
- Department of UrologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Yasuhito Funahashi
- Department of UrologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Bonnie Reinhart
- Departments of Microbiology and Molecular GeneticsUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
| | - William F. Goins
- Departments of Microbiology and Molecular GeneticsUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
| | - Momokazu Gotoh
- Department of UrologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Joseph C. Glorioso
- Departments of Microbiology and Molecular GeneticsUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
| | - Naoki Yoshimura
- Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvania
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Barrett KT, Roy A, Rivard KB, Wilson RJ, Scantlebury MH. Vagal TRPV1 activation exacerbates thermal hyperpnea and increases susceptibility to experimental febrile seizures in immature rats. Neurobiol Dis 2018; 119:172-189. [DOI: 10.1016/j.nbd.2018.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/20/2018] [Accepted: 08/07/2018] [Indexed: 12/22/2022] Open
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Attenuated lipopolysaccharide-induced inflammatory bladder hypersensitivity in mice deficient of transient receptor potential ankilin1. Sci Rep 2018; 8:15622. [PMID: 30353098 PMCID: PMC6199359 DOI: 10.1038/s41598-018-33967-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 10/09/2018] [Indexed: 11/08/2022] Open
Abstract
Transient receptor potential ankyrin 1 (TRPA1) channel expressed by urothelial cells and bladder sensory nerve fibers might act as a bladder mechanosensor and nociceptive transducer. To disclose the role of TRPA1 in bladder function and inflammation-associated hypersensitivity, we evaluated in vitro and in vivo bladder function and inflammatory mechanosensory and nociceptive responses to intravesical lipopolysaccharide (LPS)-instillation in wild type (WT) and TRPA1-knock out (KO) mice. At baseline before treatment, no significant differences were observed in frequency volume variables, in vitro detrusor contractility, and cystometric parameters between the two groups in either sex. LPS-instillation significantly increased voiding frequency and decreased mean voided volume at 24-48 hours after instillation in WT but not in TRPA1-KO mice. LPS-instillation also significantly increased the number of pain-like behavior at 24 hours after instillation in WT mice, but not in TRPA1-KO mice. Cystometry 24 hours after LPS-instillation revealed shorter inter-contraction intervals in the WT mice compared with TRPA1-KO mice. In contrast, inflammatory cell infiltration in the bladder suburothelial layer was not significantly different between the two groups. These results indicate that TRPA1 channels are involved in bladder mechanosensory and nociceptive hypersensitivity accompanied with inflammation but not in physiological bladder function or development of bladder inflammation.
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Clodfelder-Miller BJ, Kanda H, Gu JG, Creighton JR, Ness TJ, DeBerry JJ. Urothelial bladder afferent neurons in the rat are anatomically and neurochemically distinct from non-urothelial afferents. Brain Res 2017; 1689:45-53. [PMID: 29291392 DOI: 10.1016/j.brainres.2017.12.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/09/2017] [Accepted: 12/18/2017] [Indexed: 12/11/2022]
Abstract
There is mounting evidence underscoring a role for the urothelium in urinary bladder sensation. Previous functional studies have identified bladder primary afferents with mechanosensitive properties suggesting urothelial innervation and/or communication. The current study identifies a group of urothelium-innervating afferent neurons in rat, and characterizes and compares the properties of these and non-urothelial afferent neuron populations. Lumbosacral (LS) primary afferent neurons were retrogradely labeled using intraparenchymal (IPar) microinjection or intravesical (IVes) infusion of tracer into the bladder. Using these techniques, separate populations of neurons were differentiated by dorsal root ganglion (DRG) somata labeling and dye distribution within the bladder. IPar- and IVes-labeled neurons accounted for 85.0% and 14.4% of labeled L6-S1 neurons (P < .001), respectively, with only 0.6% of neurons labeled by both techniques. Following IVes labeling, dye was contained only within the periurothelial bladder region in contrast to non-urothelial distribution of dye after IPar labeling. Electrophysiological characterization by in situ patch-clamp recordings from whole-mount DRG preparations indicated no significant difference in passive or active membrane properties of IPar and IVes DRG neurons. However, calcium imaging of isolated neurons indicates that a greater proportion of IPar- than IVes-labeled neurons express functional TRPA1 (45.7% versus 25.6%, respectively; P < .05). This study demonstrates that two anatomically distinct groups of LS bladder afferents can be identified in rat. Further studies of urothelial afferents and the phenotypic differences between non-/urothelial afferents may have important implications for normal and pathophysiological bladder sensory processing.
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Affiliation(s)
- Buffie J Clodfelder-Miller
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Hirosato Kanda
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jianguo G Gu
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Judy R Creighton
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Timothy J Ness
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jennifer J DeBerry
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
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Kitamura N, Nishino M, Fujii A, Hashizume K, Nakamura J, Kondo H, Ohuchi A, Hase T, Murase T. Perilla extract improves frequent urination in spontaneously hypertensive rats with enhancement of the urothelial presence and anti-inflammatory effects. Int J Urol 2017; 25:298-304. [PMID: 29268303 DOI: 10.1111/iju.13516] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 11/16/2017] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To investigate the effects of perilla extract on urinary symptoms in spontaneously hypertensive rats as a model of spontaneous overactive bladder. METHODS Spontaneously hypertensive rats were randomly divided into two groups and fed either a control diet or a perilla extract-containing diet. Cystometry, gene expression and histological analyses were carried out to evaluate the effects of perilla extract after 2-week feeding of either the control or the perilla extract diet. The expression of inflammation-related genes in the human urothelial cell line HT-1376 and the normal human bladder epithelial cell was measured after the treatment with perillaldehyde, the main component of perilla extract, or perillic acid, the final metabolite of perillaldehyde. RESULTS A significant 27% increase in the micturition interval and decreased expression of nerve growth factor, tumor necrosis factor-α, interleukin-1β and transient receptor potential V1 were observed in the perilla group compared with the control group. The level of uroplakin 3A was 40% higher in the perilla group than in the control group. The urothelium in the control group was thin or defective, but it was almost completely intact in the perilla group. Perillaldehyde and perillic acid suppressed the induction of nerve growth factor and tumor necrosis factor-α by interleukin-1β in HT-1376 and normal human bladder epithelial cells. CONCLUSIONS The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti-inflammatory effects of perilla.
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Affiliation(s)
- Naoya Kitamura
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | - Machiko Nishino
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | - Akihiko Fujii
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | | | - Junji Nakamura
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | - Hidehiko Kondo
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | - Atsushi Ohuchi
- Biological Science Research, Kao Corporation, Tochigi, Japan
| | - Tadashi Hase
- Biological Science Research, Kao Corporation, Tochigi, Japan
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Oyama S, Dogishi K, Kodera M, Kakae M, Nagayasu K, Shirakawa H, Nakagawa T, Kaneko S. Pathophysiological Role of Transient Receptor Potential Ankyrin 1 in a Mouse Long-Lasting Cystitis Model Induced by an Intravesical Injection of Hydrogen Peroxide. Front Physiol 2017; 8:877. [PMID: 29249972 PMCID: PMC5715365 DOI: 10.3389/fphys.2017.00877] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 10/18/2017] [Indexed: 01/23/2023] Open
Abstract
Chronic inflammatory bladder disorders, such as interstitial cystitis/bladder pain syndrome, are associated with poor quality of life. The exact pathological processes remain unclear, but accumulating evidence suggests that reactive oxidative species (ROS) are involved in urinary bladder disorders. Transient receptor potential ankyrin 1 (TRPA1), the most sensitive TRP channel to ROS, was shown to be responsible for urinary bladder abnormalities and hyperalgesia in an acute cystitis model. However, the roles of TRPA1 in chronic inflammatory bladder are not fully understood. We previously established a novel mouse cystitis model induced by intravesical injection of hydrogen peroxide (H2O2), resulting in long-lasting frequent urination, bladder inflammation, pain-related behavior, and histopathological changes. In the present study, we investigated the pathophysiological role of TRPA1 in the H2O2-induced long-lasting cystitis mouse model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female wild-type (WT) and TRPA1-knockout mice and maintained for 30 min. This increased the number of voids in WT mice at 1 and 7 days after injection, but reduced the number in TRPA1-knockout mice at 1 day but not 7 days after injection. Spontaneous locomotor activities (increase in freezing time and decrease in distance moved) were reduced at 3 h after injection in WT mice, whereas the spontaneous visceral pain-related behaviors were attenuated in TRPA1-knockout mice. Furthermore, upregulation of c-fos mRNA in the spinal cord at 1 day after injection was observed in WT but not TRPA1-knockout mice. However, there was no difference in histopathological changes in the urinary bladder, such as edematous thickening in the submucosa, between WT and TRPA1-knockout mice at 1 or 7 days after injection. Finally, Trpa1 mRNA levels in the L5-S1 dorsal root ganglion were not altered, but levels in the urinary bladder were drastically increased at 1 and 7 days after injection. Taken together, these results suggest that TRPA1 contributes to acute bladder hyperactivity such as frequent urination and bladder pain, but does not appear to play a major role in the pathological processes of long-lasting cystitis.
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Affiliation(s)
- Shohei Oyama
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Koji Dogishi
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Mizuki Kodera
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Masashi Kakae
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuki Nagayasu
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Hisashi Shirakawa
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Takayuki Nakagawa
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Shuji Kaneko
- Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
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Effects of herpes simplex virus vectors encoding poreless TRPV1 or protein phosphatase 1α in a rat cystitis model induced by hydrogen peroxide. Gene Ther 2017; 25:20-26. [PMID: 29057994 PMCID: PMC5814327 DOI: 10.1038/gt.2017.94] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 08/30/2017] [Accepted: 09/29/2017] [Indexed: 02/08/2023]
Abstract
Enhanced afferent excitability is considered to be an important pathophysiological basis of interstitial cystitis/bladder pain syndrome (IC/BPS). In addition, transient receptor potential vanilloid-1 (TRPV1) receptors are known to be involved in afferent sensitization. Animals with hydrogen peroxide (HP)-induced cystitis have been used as a model exhibiting pathologic characteristics of chronic inflammatory condition of the bladder. This study investigated the effect of gene therapy with replication-defective herpes simplex virus (HSV) vectors encoding poreless TRPV1 (PL) or protein phosphatase 1 α (PP1α), a negative regulator of TRPV1, using a HP-induced rat model of cystitis. HSV vectors encoding green fluorescent protein, PL or PP1α were inoculated into the bladder wall of female rats. After 1 week, 1% HP or normal saline was administered into the bladder, and the evaluations were performed 2 weeks after viral inoculation. In HP-induced cystitis rats, gene delivery of PL or PP1α decreased pain behavior as well as a reduction in the intercontraction interval. Also, both treatments reduced nerve growth factor expression in the bladder mucosa, reduced bladder inflammation characterized by infiltration of inflammatory cells and increased bladder weight. Taken together, HSV-mediated gene therapy targeting TRPV1 receptors could be effective for the treatment of IC/BPS.
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Shimura H, Mitsui T, Tsuchiya S, Miyamoto T, Ihara T, Kira S, Nakagomi H, Sawada N, Imai Y, Mochizuki T, Takeda M. Development of novel and non-invasive diagnostic markers for lower urinary tract symptoms using urothelial cells in voided urine. Neurourol Urodyn 2017; 37:1137-1143. [PMID: 29044760 DOI: 10.1002/nau.23436] [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: 08/10/2017] [Accepted: 09/25/2017] [Indexed: 12/23/2022]
Abstract
OBJECTIVES We evaluated the association between lower urinary tract symptoms (LUTS) and the expression of connexin (Cx) and transient receptor potential (TRP) channel on urothelial cells non-invasively collected from voided urine in humans. METHODS A total of 55 patients (36 males and 19 females, median age: 71 years old), who were followed up at University of Yamanashi Hospital, were enrolled in the present study. Urothelial cells were collected from voided urine of patients, and the mRNA expression of each subtype of Cxs and TRP channels was measured using quantitive real-time reverse transcription polymerase chain reaction. We then analyzed the correlation between the expression of Cxs and TRP channels and symptom scores in International Prostate Symptom Scoreand Overactive Bladder Symptom Score, in addition to Interstitial Cystitis Symptom Index (ICSI) from only interstitial cystitis (IC) patients. RESULTS Non-adjusted statistical procedure using Spearman's rank-correlation showed that there were significant correlations between the following expressions and symptom scores; (positive correlations) Cx26 versus urgency score, Cx40 versus nocturia, TRPM2 versus intermittency, TRPV1 versus urge incontinence, (negative correlation) Cx40 versus intermittency, TRPM7 versus pollakisuria. However, a multiple comparison adjustment using Bonferroni correction showed that only Cx40 had a trend of correlation with nocturia in ICSI. CONCLUSIONS The expressions of Cxs and TRP channels on urothelial cells in voided urine could be related to LUTS. Further analysis of urothelial cells in voided urine has the potential to reveal the mechanism of the LUTS and develop new markers with non-invasive methods.
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Affiliation(s)
- Hiroshi Shimura
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Takahiko Mitsui
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Sachiko Tsuchiya
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Tatsuya Miyamoto
- Department of Urology, Fujiyoshida Municipal Medical Center, Fujiyoshida, Yamanashi, Japan
| | - Tatsuya Ihara
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Satoru Kira
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Hiroshi Nakagomi
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Norifumi Sawada
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Yuki Imai
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Takanori Mochizuki
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
| | - Masayuki Takeda
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Yamanashi, Japan
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Significant Linkage Evidence for Interstitial Cystitis/Painful Bladder Syndrome on Chromosome 3. J Urol 2017; 199:172-177. [PMID: 28734863 DOI: 10.1016/j.juro.2017.07.068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2017] [Indexed: 11/23/2022]
Abstract
PURPOSE Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis. MATERIALS AND METHODS We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed. RESULTS Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity θ logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree θ logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model. CONCLUSIONS While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome.
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Dagher A, Curatolo A, Sachdev M, Stephens AJ, Mullins C, Landis JR, van Bokhoven A, El-Hayek A, Froehlich JW, Briscoe AC, Roy R, Yang J, Pontari MA, Zurakowski D, Lee RS, Moses MA. Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. BJU Int 2017; 120:130-142. [PMID: 28263447 PMCID: PMC5951631 DOI: 10.1111/bju.13832] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. METHODS Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression. RESULTS Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1. CONCLUSION Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.
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Affiliation(s)
- Adelle Dagher
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Adam Curatolo
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Monisha Sachdev
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
| | - Alisa J Stephens
- Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Chris Mullins
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - J Richard Landis
- Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Adrie van Bokhoven
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew El-Hayek
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - John W Froehlich
- Department of Urology, Boston Children's Hospital, Boston, MA, USA
| | - Andrew C Briscoe
- Department of Urology, Boston Children's Hospital, Boston, MA, USA
| | - Roopali Roy
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Jiang Yang
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Michel A Pontari
- Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - David Zurakowski
- Department of Surgery, Harvard Medical School, Boston, MA, USA
- Department of Anesthesia, Boston Children's Hospital, Boston, MA, USA
| | - Richard S Lee
- Department of Urology, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Marsha A Moses
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
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48
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Majima T, Tyagi P, Dogishi K, Kashyap M, Funahashi Y, Gotoh M, Chancellor MB, Yoshimura N. Effect of Intravesical Liposome-Based Nerve Growth Factor Antisense Therapy on Bladder Overactivity and Nociception in a Rat Model of Cystitis Induced by Hydrogen Peroxide. Hum Gene Ther 2017; 28:598-609. [PMID: 28446032 DOI: 10.1089/hum.2016.121] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The aim of this study was to evaluate whether liposome-based local suppression of nerve growth factor (NGF) in the bladder has effects on bladder hypersensitivity in a rat cystitis model induced by intravesical instillation of hydrogen peroxide (HP). HP (1.5%) was intravesically administered to adult female Sprague-Dawley rats. Liposomes complexed with NGF antisense oligonucleotide (OND) labeled with TYE563 fluorescent tag were intravesically instilled on day 2. Red fluorescence from the TYE 563 tag was observed with fluorescent microscopy on day 3. Four separate groups of rats were used in the following experiments: (a) sham-liposome group, (b) sham-OND group, (c) cystitis-liposome group, and (d) cystitis-OND group. Saline or 1.5% HP was intravesically administered on day 0. Empty liposomes or liposomes-antisense OND were instilled into the bladder on day 2. The following experiments were conducted to evaluate the effect of NGF antisense treatment on day 7: (a) continuous cystometry was performed in an awake condition; (b) pain behavior induced by instillation of resiniferatoxin into the bladder, including licking behavior (lower abdominal licking) and freezing behavior (motionless head-turning toward lower abdomen), was observed; (c) immunohistochemical staining of the bladder and L6 DRG for NGF was performed; (d) the expression of several genes in the bladder was analyzed by reverse transcription polymerase chain reaction (RT-PCR); and (e) after Fast Blue was injected into the bladder wall, Fast Blue-positive or -negative cells in DRG neurons were separately collected by using a laser-capture microdissection method 7 days later. RT-PCR was performed to evaluate gene expressions in captured neuronal cells. The expression of TYE563 was identified only in the urothelial layer. In cystometric investigation, intercontraction intervals (ICI) were significantly (p = 0.001) shorter in the cystitis-liposome group in comparison to the sham-liposome group. ICI was significantly (p = 0.007) longer in the cystitis-OND group compared to the cystitis-liposome group. Comparisons of the sham-liposome and the sham-OND groups showed no significant difference in ICI (p = 0.56). Licking events did not significantly differ among the four groups. In contrast, the cystitis-liposome group showed significantly more freezing events than the sham-liposome group did (p = 0.002). A significant reduction in the number of freezing events was observed in the cystitis-OND group compared to the cystitis-liposome group (p = 0.04). Immunofluorescence staining demonstrated that NGF expression in the mucosa (p = 0.02) and L6 DRG (p = 0.01) was significantly higher in the cystitis-liposome group than it was in the sham-liposome group. The expression of NGF was significantly lower in the mucosa (p = 0.002) and L6 DRG (p = 0.01) in the cystitis-OND group compared to the cystitis-liposome group. RT-PCR showed that the expression of NGF and TRPV1 mRNA in the mucosa was significantly higher in the cystitis-liposome group than it was in the sham-liposome group (p = 0.001 and 0.03, respectively). On the other hand, these gene expressions were significantly lower in the cystitis-OND group than they were in the cystitis-liposome group (p = 0.007 and 0.02, respectively). The cystitis-liposome group showed significantly higher expression of TRPA1, P2X3, and BDNF mRNA in labeled bladder afferent neurons than the sham-liposome group did (p = 0.03, 0.01, and 0.001, respectively). These gene expressions were significantly lower in the cystitis-OND group compared to the cystitis-liposome group (p = 0.04, 0.006, and 0.03, respectively). The study indicated that intravesical application of liposome-NGF antisense OND significantly improved bladder hypersensitivity induced by chemical cystitis in rats. Intravesical treatment with liposome-OND conjugates could be a novel local therapy of hypersensitive bladder disorders such as bladder pain syndrome/interstitial cystitis.
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Affiliation(s)
- Tsuyoshi Majima
- 1 Department of Urology, Nagoya University Graduate School of Medicine , Nagoya, Japan .,2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- 2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Koji Dogishi
- 2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.,3 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University , Kyoto, Japan
| | - Mahendra Kashyap
- 2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
| | - Yasuhito Funahashi
- 1 Department of Urology, Nagoya University Graduate School of Medicine , Nagoya, Japan
| | - Momokazu Gotoh
- 1 Department of Urology, Nagoya University Graduate School of Medicine , Nagoya, Japan
| | - Michael B Chancellor
- 4 Department of Urology, Oakland University William Beaumont School of Medicine , Royal Oak, Michigan
| | - Naoki Yoshimura
- 2 Department of Urology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania
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Sakakibara A, Sakakibara S, Kusumoto J, Takeda D, Hasegawa T, Akashi M, Minamikawa T, Hashikawa K, Terashi H, Komori T. Upregulated Expression of Transient Receptor Potential Cation Channel Subfamily V Receptors in Mucosae of Patients with Oral Squamous Cell Carcinoma and Patients with a History of Alcohol Consumption or Smoking. PLoS One 2017; 12:e0169723. [PMID: 28081185 PMCID: PMC5230781 DOI: 10.1371/journal.pone.0169723] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 12/07/2016] [Indexed: 01/06/2023] Open
Abstract
Objectives Transient receptor potential cation channel (subfamily V, members 1–4) (TRPV1–4) are expressed in skin and neurons and activated by external stimuli in normal mucosae of all oral cavity sites. The oral cavity is exposed to various stimuli, including temperature, mechanical stimuli, chemical substances, and changes in pH, and, notably, the risk factors for oncogenic transformation in oral squamous epithelium are the same as the external stimuli received by TRPV1–4 receptors. Hence, we examined the relationship between oral squamous cell carcinoma (SCC) and TRPV1–4 expression. Materials and Methods Oral SCC patients (n = 37) who underwent surgical resection were included in this study. We investigated the expression of TRPV1–4 by immunohistochemical staining and quantification of TRPV1–4 mRNA in human oral mucosa. In addition, we compared the TRPV1–4 levels in mucosa from patients with SCC to those in normal oral mucosa. Results The receptors were expressed in oral mucosa at all sites (tongue, buccal mucosa, gingiva, and oral floor) and the expression was stronger in epithelia from patients with SCC than in normal epithelia. Furthermore, alcohol consumption and tobacco use were strongly associated with the occurrence of oral cancer and were found to have a remarkable influence on TRPV1–4 receptor expression in normal oral mucosa. In particular, patients with a history of alcohol consumption demonstrated significantly higher expression levels. Conclusion Various external stimuli may influence the behavior of cancer cells. Overexpression of TRPV1-4 is likely to be a factor in enhanced sensitivity to external stimuli. These findings could contribute to the establishment of novel strategies for cancer therapy or prevention.
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Affiliation(s)
- Akiko Sakakibara
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
- * E-mail:
| | - Shunsuke Sakakibara
- Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Junya Kusumoto
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Daisuke Takeda
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takumi Hasegawa
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masaya Akashi
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tsutomu Minamikawa
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazunobu Hashikawa
- Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroto Terashi
- Department of Plastic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takahide Komori
- Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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50
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Matos R, Cordeiro JM, Coelho A, Ferreira S, Silva C, Igawa Y, Cruz F, Charrua A. Bladder pain induced by prolonged peripheral alpha 1A adrenoceptor stimulation involves the enhancement of transient receptor potential vanilloid 1 activity and an increase of urothelial adenosine triphosphate release. Acta Physiol (Oxf) 2016; 218:265-275. [PMID: 27370818 DOI: 10.1111/apha.12744] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/22/2016] [Accepted: 06/28/2016] [Indexed: 12/24/2022]
Abstract
AIM Pathophysiological mechanisms of chronic visceral pain (CVP) are unknown. This study explores the association between the sympathetic system and bladder nociceptors activity by testing the effect of a prolonged adrenergic stimulation on transient receptor potential vanilloid 1 (TRPV1) activity and on urothelial adenosine triphosphate (ATP) release. METHODS Female Wistar rats received saline, phenylephrine (PHE), PHE + silodosin, PHE + naftopidil or PHE + prazosin. TRPV1 knockout and wild-type mice received saline or PHE. Visceral pain behaviour tests were performed before and after treatment. Cystometry was performed, during saline and capsaicin infusion. Fos immunoreactivity was assessed in L6 spinal cord segment. Human urothelial ATP release induced by mechanical and thermal stimulation was evaluated. RESULTS Subcutaneous, but not intrathecal, PHE administration induced pain, which was reversed by silodosin, a selective alpha 1A adrenoceptor antagonist, but not by naftopidil, a relatively selective antagonist for alpha 1D adrenoceptor. Silodosin also reversed PHE-induced bladder hyperactivity and L6 spinal cord Fos expression. Thus, in subsequent experiments, only silodosin was used. Wild-type, but not TRPV1 knockout, mice exhibited phenylephrine-induced pain. Capsaicin induced a greater increase in voiding contractions in PHE-treated rats than in control animals, and silodosin reversed this effect. When treated with PHE, ATP release from human urothelial cells was enhanced either by mechanical stimulation or by lowering the thermal threshold of urothelial TRPV1, which becomes abnormally responsive at body temperature. CONCLUSION This study suggests that the activation of peripheral alpha 1A adrenoceptors induces CVP, probably through its interaction with TRPV1 and ATP release.
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Affiliation(s)
- R. Matos
- i3S - Instituto de Investigação e Inovação em Saúde; Universidade do Porto; Porto Portugal
- IBMC - Instituto de Biologia Molecular e Celular; University of Porto; Porto Portugal
- Department of Experimental Biology; Faculty of Medicine of University of Porto; Porto Portugal
| | - J. M. Cordeiro
- CIMAR/CIIMAR-Interdisciplinary Centre of Marine and Environmental Research; University of Porto; Porto Portugal
| | - A. Coelho
- i3S - Instituto de Investigação e Inovação em Saúde; Universidade do Porto; Porto Portugal
- IBMC - Instituto de Biologia Molecular e Celular; University of Porto; Porto Portugal
- Department of Experimental Biology; Faculty of Medicine of University of Porto; Porto Portugal
- Department of Renal, Urologic and Infectious diseases; Faculty of Medicine of University of Porto; Porto Portugal
| | - S. Ferreira
- Department of Experimental Biology; Faculty of Medicine of University of Porto; Porto Portugal
| | - C. Silva
- i3S - Instituto de Investigação e Inovação em Saúde; Universidade do Porto; Porto Portugal
- IBMC - Instituto de Biologia Molecular e Celular; University of Porto; Porto Portugal
- Department of Renal, Urologic and Infectious diseases; Faculty of Medicine of University of Porto; Porto Portugal
- Department of Urology; Hospital S. João; Porto Portugal
| | - Y. Igawa
- Department of Continence Medicine; The University of Tokyo Graduate School of Medicine; Tokyo Japan
| | - F. Cruz
- i3S - Instituto de Investigação e Inovação em Saúde; Universidade do Porto; Porto Portugal
- IBMC - Instituto de Biologia Molecular e Celular; University of Porto; Porto Portugal
- Department of Renal, Urologic and Infectious diseases; Faculty of Medicine of University of Porto; Porto Portugal
- Department of Urology; Hospital S. João; Porto Portugal
| | - A. Charrua
- i3S - Instituto de Investigação e Inovação em Saúde; Universidade do Porto; Porto Portugal
- IBMC - Instituto de Biologia Molecular e Celular; University of Porto; Porto Portugal
- Department of Experimental Biology; Faculty of Medicine of University of Porto; Porto Portugal
- Department of Renal, Urologic and Infectious diseases; Faculty of Medicine of University of Porto; Porto Portugal
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