|Ahead of print publication
Potential urine biomarkers in bladder outlet obstruction-related detrusor underactivity
Yuan-Hong Jiang1, Jia-Fong Jhang1, Yung-Hsiang Hsu2, Han-Chen Ho3, Hann-Chorng Kuo1
1 Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
2 Department of Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
3 Department of Anatomy, Tzu Chi University, Hualien, Taiwan
|Date of Submission||18-Dec-2020|
|Date of Decision||27-Dec-2020|
|Date of Acceptance||30-Dec-2020|
|Date of Web Publication||05-Apr-2021|
Department of Urology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 707, Section 3, Chung-Yang Road, Hualien
Source of Support: None, Conflict of Interest: None
Detrusor underactivity (DU), an important but under-researched issue, is thought to be complex and multifactorial in etiology, pathophysiology, and diagnosis. Bladder outlet obstruction (BOO) is one of the important known etiologies of DU, with significant morphologic and physiologic changes of the urothelium, suburothelium, and detrusor muscle in the urinary bladder. Chronic urinary bladder ischemia and repeated cycles of ischemia and reperfusion injury cause excessive oxidative stress, and it is thought to be responsible for the development of DU. DU might be the late phase or decompensated status of BOO, with the possible mechanisms of afferent nervous dysfunction, increased inflammation, denervation of the detrusor muscle, and myogenic failure. Prostaglandin E2 (PGE2) involves in the physiological detrusor contraction, and might provide the prognostic value for the recoverability of DU. Neurotrophins, including nerve growth factor and brain-derived neurotrophic factor, involve in the neuroplastic changes in many inflammatory bladder diseases, including BOO and DU. Oxidative stress biomarkers, including 8-hydroxy-2-deoxyguanosine, F2-isoprostane, and the involved pro-inflammatory cytokines, have been applied in BOO due to their involvements in chronic bladder ischemia. PGE2, neurotrophins, inflammatory cytokines, and oxidative stress biomarkers are the potential urine biomarkers in BOO-related DU.
Keywords: Bladder outlet obstruction, Detrusor underactivity, Neurotrophin, Oxidative stress, Urine biomarker
|How to cite this URL:|
Jiang YH, Jhang JF, Hsu YH, Ho HC, Kuo HC. Potential urine biomarkers in bladder outlet obstruction-related detrusor underactivity. Tzu Chi Med J [Epub ahead of print] [cited 2021 Jul 24]. Available from: https://www.tcmjmed.com/preprintarticle.asp?id=313011
| Introduction|| |
Definition and clinical characteristics of detrusor underactivity
Detrusor underactivity (DU) is an important and gradually emphasized issue. DU is defined as “a contraction of reduced strength or duration resulting in prolonged or incomplete emptying of the bladder or both” by the International Continence Society . DU is an urodynamic diagnosis, however, there is no consensus about the specific thresholds of “reduced strength or duration” or “prolonged or incomplete emptying” in urodynamic studies. The lack of standardized definition hinders the advancement in the clinical research of DU, which becomes an important but under-researched issue. In the elderly population (age over 65-year-old), DU is a common etiology of lower urinary tract symptoms, in 40.2% of men and 13.3% of women . Underactive bladder (UAB) is a symptom complex suggestive of DU, and is defined by slow urinary stream, hesitancy and straining to void, with or without a feeling of incomplete bladder emptying and sometimes with storage symptoms . In general, DU is a urodynamic term, and UAB is its clinical correlate. UAB might be received as the symptom of DU, although not all DU patients may have UAB symptoms. The correlation between DU and UAB is analogous to detrusor overactivity (DO) and overactive bladder (OAB) .
Currently, both DU and UAB are thought to be complex and multifactorial in etiology, pathophysiology, and diagnosis. Several causes of DU/UAB have been reported, including aging , diabetes mellitus (DM) , bladder outlet obstruction (BOO) , peripheral nervous system disorders (e.g., pelvic surgery, pelvic fracture, spinal stenosis, and herpes zoster), and central nervous system disorders (e.g., cerebrovascular accident, traumatic brain injury, Parkinson's disease, spinal cord injury, and multiple sclerosis) [8-10].
DU is a status of a contraction of reduced strength or duration in urodynamic study. However, it is an intuitive but incorrect linkage to “detrusor muscle failure.” Up to present, the pathophysiology of DU has included afferent nervous dysfunction, efferent nervous dysfunction, and myogenic failure, and the role of afferent nervous dysfunction in DU is increasingly recognized ,. Several causes, contributing factors, and diverse pathophysiology of DU have been reported, and BOO is one of the important etiologies of DU. The understanding of progressive bladder remodeling in BOO  is more clear than other etiologies of DU, which makes BOO to be a better research model and encourages the further research in DU.
| Pathophysiology of Bladder Outlet Obstruction|| |
LUTS is highly prevalent and affects >60% of men aged over than 40 years . BOO is the most common cause (69.6%) of male LUTS, and benign prostatic hyperplasia/benign prostatic obstruction is the most common etiology (46.8%) of BOO . BOO might lead to progressive bladder tissue remodeling and subsequent serious impairments of upper urinary tract ,.
The general urodynamic state of BOO is high detrusor pressure and low urinary flow rate during voiding phase . Increased detrusor voiding pressure may result in the reduction of blood flow and chronic ischemia in urinary bladder . Such ischemia status during voiding is followed by an increase in bladder blood flow after micturition, which induces the next step of reperfusion injury. Such cyclic ischemia-reperfusion injury may give rise to the increased oxidative stress and hypoxia-related inflammation, which result in the structural and functional damages of urinary bladder thereafter ,. In BOO, available evidences demonstrate that the effects of hypoxia involve in not only increased inflammation, but also the alternations on human bladder smooth muscle cells (HBSMC) proliferation and differentiation . Hypoxia induces a time-dependent increased expression of inflammatory cytokines, including transforming growth factor-beta (protein and mRNA), interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNFα) (mRNA), and decreased expression of anti-inflammatory cytokines IL-10. In addition, hypoxia inhibits the proliferation of HBSMC, induces the de-differentiation of HBSMC with increased αSMA, vimentin, and desmin, and elicits the profibrotic changes with a time-dependent increase of total collagen proteins . In summary, the hypoxic cascade of HBSMC results in a potent inflammation, de-differentiation of smooth muscle cells, and increased extracellular matrix expression.
| Pathophysiology of Bladder Outlet Obstruction Related Detrusor Underactivity|| |
BOO is one of the important known etiologies of DU, with significant morphologic and physiologic changes of the urothelium, suburothelium, and detrusor muscle in the urinary bladder ,. Chronic urinary bladder ischemia and repeated cycles of ischemia and reperfusion injury cause excessive oxidative stress, and it is thought to be responsible for the development of DU .
A hypothesis of 3 morpho-functional stages for BOO-induced bladder remodeling in human has been proposed recently . The 3 phases comprise hypertrophy, compensation, and decompensation. Increased intravesical pressure during bladder voiding is considered as the “primum movens.” Hypertrophy and hyperplasia of HBSMC, mediated by the increased of muscarinic receptor expression, are induced by increased hydrostatic pressure ,. Subsequently, tissue hypoxia intervenes as the next critical stress factor. Compensatory response to hypoxia includes hypoxia induced pathway with hypoxia-inducible factor and vascular endothelial growth factor. Persistent hypoxia inhibits HBSMC proliferation with the transition from hypertrophy to compensation phase, and promotes the progression of extracellular matrix deposition. High levels of extracellular matrix deposition with the alternations of mechanical properties of bladder, resulting in decreased bladder compliance and contractility, characterizes the transition from compensation to decompensation phase. The histological and molecular characteristics in decompensation phase include urothelial dysfunction, neuron degeneration, and smooth muscle cell degeneration. DU is thought to be the decompensation phase or late phase of BOO related bladder dysfunction.
In BOO, urothelial dysfunction with low expression of E-cadherin, increased suburothelial inflammation, and increased cellular apoptosis are noted in the bladder urothelium of male BOO patients . In addition, alternations of sensory proteins with increased expressions of P2X3 and M2 muscarinic receptors, and decreased expressions of M3 muscarinic receptors are explored, which indicates the prominent bladder dysfunction secondary to BOO. In patients with BOO related DU, increased expressions of β3 adrenoreceptors and lower expressions of inducible nitric oxide synthase are detected, which reflects the impaired sensory transduction . In DU, decreased bladder urothelial-afferent signaling has an important role in its pathophysiology and accounts for the clinical presentation of hyposensitivity of DU . In summary, DU might be the late phase or decompensated status of BOO, with the possible mechanisms of afferent nervous dysfunction (urothelial dysfunction and alternations of sensory proteins) , increased inflammation, denervation of the detrusor muscle , and myogenic failure .
| Potential Urine Biomarkers of Bladder Outlet Obstruction Related Detrusor Underactivity|| |
Until now, the relationship about the levels of the selected target between bladder tissue and urine is still under-researched. Nevertheless, noninvasive approach to urine cytokine analysis might provide important information regarding the different pathological bladder conditions without the invasive bladder biopsy procedures. Potential urine biomarkers of BOO-related DU are summarized in [Table 1].
|Table 1: Summary of potential urine biomarkers in bladder outlet obstruction related detrusor underactivity|
Click here to view
Prostaglandin E2 (PGE2), one of the prostanoids, is synthesized by COX-1 and COX-2 locally in urothelium, interstitial cells, and smooth muscle, and released during detrusor contraction/and under basal physiological conditions . PGE2 is believed to be responsible for the spontaneous detrusor contractions necessary for potentiating afferent transmission.
Benign prostatic hyperplasia patients with OAB symptoms have significantly higher urinary PGE2 levels than those without OAB symptoms and normal controls, and urinary PGE2 level decreases with the relief of the OAB symptoms after treatment . In OAB patients, urinary PGE2 level is higher than in controls with positive correlation to both the volume at first desire to void and maximum cystometric capacity . However, urinary PGE2 level is decreased in OAB patients with concurrent DU compared with those without concurrent DU . Lower urinary PGE2 level with upregulation of the associated EP1 and EP3 receptors in DM-induced hyposensitive UAB is recently revealed in a rat study . Therefore, replenishing PGE2 is thought to be one of the treatment strategies to UAB/DU, and experimental instillation of PGE2 into urinary bladder has been tried ,.
DU, a dynamic bladder condition, may change with time or after treatment. In our recent study, DU patients with bladder function recovery after treatment had significantly higher urine PGE2 levels than DO patients and controls at baseline . However, DU patients without bladder function recovery had low urine PGE2 levels, which were similar to controls. It suggested that urine PGE2 level might provide the prognostic value and have a potential role for the recoverability of DU. PGE2 involves in the physiological detrusor contraction, and it might be the core urine biomarker of DU.
Neurotrophins and inflammatory cytokines
Neurotrophins including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have attracted considerable attention in the urologic community, because of the recognition of their ability to induce plastic changes of the neuronal circuits that govern bladder function . Urinary neurotrophins have been considered as putative and important urinary biomarkers for bladder dysfunction . In many inflammatory bladder diseases, such as OAB and interstitial cystitis, urinary symptoms reflect abnormal activity of bladder sensory afferents that results from neuroplastic changes, which indicates the important role of neurotrophins and their link to the inflamed bladder . Recently, impaired urothelial signaling, increased suburothelial inflammation, and altered sensory transduction pathways are also observed in the urinary bladder of BOO with different bladder dysfunctions  and DU . Accordingly, neurotrophins are considered to be have important roles in the pathophysiology of BOO with bladder dysfunctions and even DU.
In urinary bladder, NGF and BDNF are expressed in the urothelium, suburothelial tissue, and bladder smooth muscles, and function as governing innervation during development, growth, and injury, which influences urinary symptoms in bladder diseases . Also, increased NGF and BDNF levels can eventually be founded in urine. In female patients with BOO resulting from pelvic organ prolapse, urine NGF levels significantly increased before treatment and then decreased after surgical treatment for BOO . In BOO patients with OAB symptoms or DO, urine NGF levels significantly increased compared with controls, and these levels returned to normal levels after successful medical treatment of OAB symptoms . It suggested that urine NGF level was a potential biomarker of BOO with OAB or DO, and it might be applied to the future investigation of DU, the late phase of BOO related bladder dysfunction.
In a recent study in rats, DM induced hyposensitive UAB is characterized by increased inflammatory reaction and apoptosis, lower bladder NGF level, and increased urine NGF level . In our recent study, DU patients had significantly higher urine NGF and BDNF levels than controls . More importantly, urine baseline BDNF level was significantly higher in DU patients with bladder function recovery after treatment, but not in those without recovery compared with that in controls. However, there was no difference in urine NGF levels between DU patients with and without bladder function recovery. It suggested that different neurotrophins might have the important but varied roles in DU, and urine BDNF level probably had more prognostic value than urine NGF level. Chronic bladder inflammation is an important pathophysiology of BOO-related bladder dysfunctions and DU, and the analysis of neurotrophins and inflammation-related cytokines and proteins in urine might be with the potential to monitoring the diseased status and the activity of the inflammation in bladder tissue in a non-invasive approach.
Oxidative stress biomarkers in bladder outlet obstruction and bladder outlet obstruction-related detrusor underactivity
Excessive oxidative stress and hypoxia-related inflammation resulting from cyclic ischemia-reperfusion injury are thought to play important and critical roles in BOO progression and the associated bladder dysfunctions, including DU ,.
Reactive oxygen species (ROS) are by-products of aerobic metabolism and can induce pathologic conditions by damaging lipids, proteins, and DNA . In addition, ROS serve as signaling molecules to regulate biological and physiological processes . However, excessive production of ROS can cause oxidative stress that may damage cellular lipids, proteins, and DNA, thereby changing the structure and function of target tissue [42-44]. Oxidative stress is regulated by the balance between pro-oxidative and anti-oxidative factors, and endogenous anti-oxidants act as scavengers under physiologic conditions. Cyclic ischemia-and-reperfusion injury in BOO generates ROS, that induce the elevation of oxidative stress and play important roles in bladder dysfunctions ,. Numerous oxidative stress biomarkers are reported ,, and some are used to evaluate the degree of oxidative stress in BOO, including 8-hydroxy-2-deoxyguanosine (8-OHdG), F2-isoprostane, and malondialdehyde . Various endogenous anti-oxidative defense systems protect against harmful activities caused by oxidative stress, and total antioxidant capacity reflect the cumulative effect of all antioxidants ,. At present, the evidence from many animal studies discloses the application of oxidative stress and antioxidant biomarkers in BOO , and these targets might also become the potential biomarkers in human BOO related DU.
Eight-OHdG, a stable end product of DNA oxidation, is the mostly used oxidative marker, and the levels are not influenced by a long-term storage of urine specimen at −20°C ,. In an animal study with rabbits, the levels of 8-OHdG in urine, plasma, and tissue were all increased under partial BOO, and all of them returned toward the control levels after the reversal of obstruction . In addition, plasma total antioxidant capacity levels decreased under partial BOO and returned toward control levels after the reversal of obstruction. The results suggested that the imbalance of increased oxidative stress and decreased antioxidant capacity of the plasma and urine was detected in BOO, and it was reversible if early reversal happens. However, there was scarce evidence of 8-OHdG in human BOO subjects, which merely demonstrated the reverse of urinary levels of 8-OHdG after medical treatment .
F2-isoprostane, formed by free radical-induced peroxidation of arachidonic acid, is also a reliable indicator of oxidative stress ,. F2-isoprostatne is chemically stable compounds, sensitive, not affected by dietary intake of lipids, and detectable in all normal biological fluids, and tissue. In the animal study with mice, the levels of F2-isoprostanes significantly elevated in bladder tissue after partial BOO, which suggested the usefulness of F2-isoprostanes as an oxidative stress biomarker of BOO .
ROS is required for the release of pro-inflammatory cytokines (IL-1β, TNFα, IL-6, IL-8, interferon beta) to affect an appropriate immune response . In an BOO rat model, bladder weight, the levels of oxidative stress biomarkers in urine (8-OHdG), and the levels of proinflammatory cytokine (IL-1β, and TNFα) in tissue all increased in BOO and these changes were suppressed after Eviprostat treatment . It suggested that oxidative stress and the related pro-inflammatory cytokines were responsible for BOO, and antioxidant and anti-inflammatory activities (from Eviprostat) might contribute to the protection of bladder function. In a rat model of atherosclerosis-induced chronic bladder ischemia, bladder oxidative stress biomarkers (8-OHdG in urine, and malondialdehyde in bladder tissue) and proinflammatory cytokines (TNFα, IL-6, and IL-8) were significantly higher in study group . It indicated that oxidative stress and inflammation might be the key factors in the development of bladder dysfunction in chronic bladder ischemia.
Tissue hypoxia plays the critical role in the disease progression of BOO, and is essential to the pathophysiology of BOO related DU. Oxidative stress biomarkers including 8-OHdG, F2-isoprostane, and the involved pro-inflammatory cytokines have the potential of clinical application in BOO-related DU.
| Conclusions|| |
BOO is one of the important known etiologies of DU. Chronic urinary bladder ischemia and repeated cycles of ischemia and reperfusion injury cause excessive oxidative stress, and it is thought to be responsible for the development of DU. PGE2, neurotrophins, inflammatory cytokines, and oxidative stress biomarkers are the potential urine biomarkers in BOO-related DU.
Financial support and sponsorship
This study was funded by TCMMP 109-02-03, Buddhist Tzu Chi Medical Foundation.
Conflicts of interest
Dr. Yuan-Hong Jiang, Dr. Yung-Hsiang Hsu, Dr. Han-Chen Ho, and Dr. Hann-Chorng Kuo are editoiral board members at Tzu Chi Medical Journal, had no roles in the peer review process of or decision to publish this article. The other author declared no conflict of interest in writing this paper.
| References|| |
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167-78.
Jeong SJ, Kim HJ, Lee YJ, Lee JK, Lee BK, Choo YM, et al. Prevalence and Clinical Features of Detrusor Underactivity among Elderly with Lower Urinary Tract Symptoms: A Comparison between Men and Women. Korean J Urol 2012;53:342-8.
Chapple CR, Osman NI, Birder L, Dmochowski R, Drake MJ, van Koeveringe G, et al. Terminology report from the International Continence Society (ICS) Working Group on Underactive Bladder (UAB). Neurourol Urodyn 2018;37:2928-31.
Abrams P. Describing bladder storage function: Overactive bladder syndrome and detrusor overactivity. Urology 2003;62:28-37.
Smith PP. Aging and the underactive detrusor: A failure of activity or activation? Neurourol Urodyn 2010;29:408-12.
Sasaki K, Yoshimura N, Chancellor MB. Implications of diabetes mellitus in urology. Urol Clin North Am 2003;30:1-12.
Jiang YH, Lee CL, Kuo HC. Urothelial dysfunction, suburothelial inflammation and altered sensory protein expression in men with bladder outlet obstruction and various bladder dysfunctions: Correlation with urodynamics. J Urol 2016;196:831-7.
Miyazato M, Yoshimura N, Chancellor MB. The other bladder syndrome: Underactive bladder. Rev Urol 2013;15:11-22.
Aizawa N, Igawa Y. Pathophysiology of the underactive bladder. Investig Clin Urol 2017;58:S82-S89.
Chou YC, Jiang YH, Harnod T, Lee HT, Kuo HC. Stroke and lower urinary tract symptoms: A neurosurgical view. Urol Sci 2019;30:8-13. [Full text]
Drake MJ, Williams J, Bijos DA. Voiding dysfunction due to detrusor underactivity: An overview. Nat Rev Urol 2014;11:454-64.
Fusco F, Creta M, De Nunzio C, Iacovelli V, Mangiapia F, Li Marzi V, et al. Progressive bladder remodeling due to bladder outlet obstruction: A systematic review of morphological and molecular evidences in humans. BMC Urol 2018;18:15.
Liu SP, Chuang YC, Sumarsono B, Chang HC. The prevalence and bother of lower urinary tract symptoms in men and women aged 40 years or over in Taiwan. J Formos Med Assoc 2019;118:170-8.
Lee CL, Kuo HC. Videourodynamic analysis in men with lower urinary tract symptoms: Correlation between age and prostate size with lower urinary tract dysfunction. UrolSci 2016;27:21-5.
Mirone V, Imbimbo C, Longo N, Fusco F. The detrusor muscle: An innocent victim of bladder outlet obstruction. Eur Urol 2007;51:57-66.
Nitti VW. Pressure flow urodynamic studies: The gold standard for diagnosing bladder outlet obstruction. Rev Urol 2005;7(Suppl 6):S14-21.
Azadzoi KM, Pontari M, Vlachiotis J, Siroky MB. Canine bladder blood flow and oxygenation: Changes induced by filling, contraction and outlet obstruction. J Urol 1996;155:1459-65.
Wiafe B, Adesida A, Churchill T, Adewuyi EE, Li Z, Metcalfe P. Hypoxia-increased expression of genes involved in inflammation, dedifferentiation, pro-fibrosis, and extracellular matrix remodeling of human bladder smooth muscle cells. In vitro
Cell Dev Biol Anim 2017;53:58-66.
Yamaguchi O, Nomiya M, Andersson KE. Functional consequences of chronic bladder ischemia. Neurourol Urodyn 2014;33:54-8.
Lee SD, Akbal C, Jung C, Kaefer M. Intravesical pressure induces hyperplasia and hypertrophy of human bladder smooth muscle cells mediated by muscarinic receptors. J Pediatr Urol 2006;2:271-6.
Lee SD, Misseri R, Akbal C, Jung C, Rink RC, Kaefer M. Muscarinic receptor expression increases following exposure to intravesical pressures of<or=40 cm-H2O: A possible mechanism for pressure-induced cell proliferation. World J Urol 2008;26:387-93.
Jiang YH, Kuo HC. Urothelial barrier deficits, suburothelial inflammation and altered sensory protein expression in detrusor underactivity. J Urol 2017;197:197-203.
Chung DE, Dillon B, Kurta J, Maschino A, Cronin A, Sandhu JS. Detrusor underactivity is prevalent after radical prostatectomy: A urodynamic study including risk factors. Can Urol Assoc J 2013;7:E33-7.
Kim JC, Park EY, Hong SH, Seo SI, Park YH, Hwang TK. Changes of urinary nerve growth factor and prostaglandins in male patients with overactive bladder symptom. Int J Urol 2005;12:875-80.
Chen SF, Jiang YH, Kuo HC. Urinary biomarkers in patients with detrusor underactivity with and without bladder function recovery. Int Urol Nephrol 2017;49:1763-70.
Nirmal J, Tyagi P, Chuang YC, Lee WC, Yoshimura N, Huang CC, et al. Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat. PLoS One 2014;9:e102644.
Chan R, Munoz A, Wenker EP, Stewart J, Boone T, Khavari R. The association of urinary nerve growth factor levels with bladder outlet obstruction in women. Female Pelvic Med Reconstr Surg 2015;21:111-5.
Liu HT, Kuo HC. Urinary nerve growth factor levels are increased in patients with bladder outlet obstruction with overactive bladder symptoms and reduced after successful medical treatment. Urology 2008;72:104-8.
Matsumoto S, Hanai T, Matsui T, Oka M, Tanaka M, Uemura H. Eviprostat suppresses urinary oxidative stress in a rabbit model of partial bladder outlet obstruction and in patients with benign prostatic hyperplasia. Phytother Res 2010;24:301-3.
Lin WY, Wu SB, Lin YP, Chang PJ, Levin RM, Wei YH. Reversing bladder outlet obstruction attenuates systemic and tissue oxidative stress. BJU Int 2012;110:1208-13.
Clayton DB, Stephany HA, Ching CB, Rahman SA, Tanaka ST, Thomas JC, et al. F2-isoprostanes as a biomarker of oxidative stress in the mouse bladder. J Urol 2014;191:1597-601.
Rahnama'i MS, van Kerrebroeck PE, de Wachter SG, van Koeveringe GA. The role of prostanoids in urinary bladder physiology. Nat Rev Urol 2012;9:283-90.
Zhang YJ, Bai Q. Urinary prostaglandins E2 correlates to overactive bladder symptoms in patients with benign prostatic hyperplasia. Zhonghua Nan Ke Xue 2014;20:244-8.
Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandins in the urine of female patients with overactive bladder. J Urol 2006;175:1773-6.
Desmond AD, Bultitude MI, Hills NH, Shuttleworth KE. Clinical experience with intravesical prostaglandin E2. A prospective study of 36 patients. Br J Urol 1980;52:357-66.
Smith PP, Tyagi P, Kuchel GA, Pore S, Chermansky C, Chancellor M, et al. Advanced therapeutic directions to treat the underactive bladder. Int Urol Nephrol 2014;46(Suppl 1):S35-44.
Cruz CD. Neurotrophins in bladder function: What do we know and where do we go from here? Neurourol Urodyn 2014;33:39-45.
Ochodnický P, Cruz CD, Yoshimura N, Michel MC. Nerve growth factor in bladder dysfunction: Contributing factor, biomarker, and therapeutic target. Neurourol Urodyn 2011;30:1227-41.
Miyata Y, Matsuo T, Mitsunari K, Asai A, Ohba K, Sakai H. A review of oxidative stress and urinary dysfunction caused by bladder outlet obstruction and treatments using antioxidants. Antioxidants (Basel) 2019;8:132.
Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol 2014;24:R453-62.
Finkel T. Signal transduction by reactive oxygen species. J Cell Biol 2011;194:7-15.
D'Autréaux B, Toledano MB. ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 2007;8:813-24.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
Brown DI, Griendling KK. Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 2015;116:531-49.
Lin AT, Yang CH, Chen KK, Chang LS. Detrusor mitochondrial lipid peroxidation and superoxide dismutase activity in partial bladder outlet obstruction of rabbits. Neurourol Urodyn 2005;24:282-7.
Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. Biomarkers of oxidative damage in human disease. Clin Chem 2006;52:601-23.
Il'yasova D, Scarbrough P, Spasojevic I. Urinary biomarkers of oxidative status. Clin Chim Acta 2012;413:1446-53.
Fraga CG, Oteiza PI, Galleano M. In vitro
measurements and interpretation of total antioxidant capacity. Biochim Biophys Acta 2014;1840:931-4.
Loft S, Svoboda P, Kasai H, Tjønneland A, Vogel U, Møller P, et al. Prospective study of 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion and the risk of lung cancer. Carcinogenesis 2006;27:1245-50.
Roberts LJ, Morrow JD. Measurement of F (2)-isoprostanes as an index of oxidative stress in vivo
. Free Radic Biol Med 2000;28:505-13.
Oka M, Fukui T, Ueda M, Tagaya M, Oyama T, Tanaka M. Suppression of bladder oxidative stress and inflammation by a phytotherapeutic agent in a rat model of partial bladder outlet obstruction. J Urol 2009;182:382-90.
Nomiya M, Sagawa K, Yazaki J, Takahashi N, Kushida N, Haga N, et al. Increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosis-induced chronic bladder ischemia. Neurourol Urodyn 2012;31:185-9.