Naoki Yoshimura

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (415)1385.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Interstitial cystitis or bladder pain syndrome (IC/BPS) is a debilitating chronic disease characterized by suprapubic pain and lower urinary tract symptoms: however, the etiology is still unknown. Therefore, the long-lasting, effective treatments of IC/BPS are still not established, and the treatment is sometimes empirically selected depending on practitioners' experience and preference. Area covered: In this review we focus on the current treatments, ongoing clinical trials, and several potential new drugs based on the results of basic and clinical research studies. First, we discuss the potential etiologies of IC/BPS that include altered barrier lining, afferent and/or central nervous system abnormalities, possible contribution of inflammation or infection and abnormal urothelial signaling. Then, the current therapies of IC/BPS, either systemic or local, are reviewed by critical evaluation of the efficacy and shortcomings of each treatment. Finally, based on proposed etiologies of the disease, potential emerging drugs and treatments are discussed. Expert opinion: Current therapies often fail to control the symptoms of IC/BPS. Several interventions including sustained drug release and retaining techniques, and drugs that act on afferent neural pathways are emerging and may be promising. In addition, phenotyping of IC/BPS patients based on cystoscopic findings (e.g., Hunner vs. non-Hunner lesion) or patients' symptoms would be important for further investigation of IC/BPS etiology and the evaluation of efficacy of new treatments.
    Expert Opinion on Emerging Drugs 11/2015; DOI:10.1517/14728214.2015.1105216 · 3.06 Impact Factor
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    ABSTRACT: Objective: To investigate the time dependent changes in expression of cytokines that characterizes the spontaneous recovery of reflex voiding after spinal cord injury (SCI). SCI is known to reorganize the neural circuitry of micturition reflex after injury. Methods: Under isoflurane anesthesia, spinal cord of 18 adult female Sprague-Dawley rats was completely transected at the Th9/10 level. Awake cystometry was performed on controls and 6 SCI animals at each time point of 4, 8 and 12 weeks and bladder was then harvested for analysis of 29 proteins Millipore kit or ELISA. Prophylactic dose of ampicillin 100mg/kg was administered periodically to all SCI animals. Results: Spontaneous recovery of voiding after SCI at 12 weeks was evident from increased intercontractile interval and voiding efficiency during cystometry. Expression of pro-inflammatory interleukins (IL-1α and IL-1β, IL-2 IL-5, IL-6, IL-18, TNF- α) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1 and CCL2 showed significant elevation at 4 and 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory interleukin IL-10 and neuroprotective factors, BDNF,CXCL-5 and Leptin was elevated at 8 and 12 weeks (p<0.05). In contrast, expression of CCL3, CCL5 and growth factors VEGF, NGF, EGF, G-CSF, GM-CSF did not show any significant temporal change after SCI. Conclusions: Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors BDNF, CXCL-5 and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI.
    Urology 11/2015; DOI:10.1016/j.urology.2015.10.017 · 2.19 Impact Factor
  • Pradeep Tyagi · Mahendra Kashyap · Harvey Hensley · Naoki Yoshimura ·
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    ABSTRACT: Introduction: Intravesical therapy is a valuable option in the clinical management of urinary tract disorders such as interstitial cystitis/ painful bladder syndrome (IC/PBS) and refractory overactive bladder. This review will cover the latest advances in this field using polymer and liposomes as delivery platform for drugs, protein and nucleic acids. Areas covered: This review summarizes the significance of intravesical therapy for lower urinary tract disorders. The recent advancement of liposomes as a drug delivery platform for botulinum toxin, tacrolimus and small interfering RNA is discussed. The importance of polymers forming indwelling devices and hydrogels are also discussed, where all preparations improved efficacy parameters in rodent models. Clinical experience of treating IC/PBS with indwelling devices and liposomes are summarized and preclinical evidence about the downregulation of target gene expression in rodent bladder with liposomes complexed with siRNA is also reviewed. Expert opinion: There have been several advances in the field of intravesical therapy for improving clinical outcomes. One of the most promising research avenues is the repurposing of drugs, given previously by other routes of administration, such as tacrolimus. Intravesical therapy also opens up novel therapeutic targets with improved efficacy and safety for underactive bladder.
    Expert Opinion on Drug Delivery 10/2015; DOI:10.1517/17425247.2016.1100166 · 4.84 Impact Factor
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    ABSTRACT: To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction. Female SD rats of three different ages were used: 8 weeks old (8W; n = 5), 9 months old (9M; n = 5), and 15 months old (15M; n = 5). After cystometry, the expression levels of AT1R, connexin43 (Cx43), MAP kinase (MAPK), collagen1, AT2R, PPAR-γ, adiponectin (Adipo), and adiponectin receptor (Adipo-R) were investigated in the bladder. Pressure threshold, post-void residual volume and the number of non-voiding contractions were significantly increased in 15M versus 8W rats (P < 0.01). Maximum voiding pressure was significantly decreased in 15M versus 8W rats (P < 0.05). There was no significant difference in CMG parameters between 8W and 9M rats. In the bladder, the mRNA expression of AT1R, Cx43, MAPK, collagen 1, AT2R, PPAR-γ, Adipo, and Adipo-R were significantly higher in 15M than in 8W rats. The relative expression ratio of AT1R protein against AT2R protein in the mucosa and detrusor was significantly increased in 15M versus 8W rats. These results indicate that matured rats exhibit not only bladder overactivity but also impaired voiding, which are associated with upregulation of AT1R. The upregulation of AT2R also may play a significant role in the suppressing of AT1R induced remodelling. However, because AT1R upregulation is more dominant than AT2R increases, AT2R activation may not be sufficient to suppress AT1R stimulation in matured rats. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Neurourology and Urodynamics 08/2015; DOI:10.1002/nau.22849 · 2.87 Impact Factor
  • Z Jallah · R Liang · A Feola · W Barone · S Palcsey · SD Abramowitch · N Yoshimura · P Moalli ·
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    ABSTRACT: To evaluate the impact of prolapse meshes on vaginal smooth muscle structure (VaSM) and function, and to evaluate these outcomes in the context of the mechanical and textile properties of the mesh. Three months following the implantation of three polypropylene prolapse meshes with distinct textile and mechanical properties, mesh tissue explants were evaluated for smooth muscle contraction, innervation, receptor function, and innervation density. Magee-Womens Research Institute at the University of Pittsburgh. Thirty-four parous rhesus macaques of similar age, parity, and pelvic organ prolapse quantification (POP–Q) scores. Macaques were implanted with mesh via sacrocolpopexy. The impact of Gynemesh™ PS (Ethicon; n = 7), Restorelle® (Coloplast; n = 7), UltraPro™ parallel and UltraPro™ perpendicular (Ethicon; n = 6 and 7, respectively) were compared with sham-operated controls (n = 7). Outcomes were analysed by Kruskal–Wallis ANOVA, Mann–Whitney U–tests and multiple regression analysis (P < 0.05). Vaginal tissue explants were evaluated for the maximum contractile force generated following muscle, nerve, and receptor stimulation, and for peripheral nerve density. Muscle myofibre, nerve, and receptor-mediated contractions were negatively affected by mesh only in the grafted region (P < 0.001, P = 0.002, and P = 0.008, respectively), whereas cholinergic and adrenergic nerve densities were affected in the grafted (P = 0.090 and P = 0.008, respectively) and non-grafted (P = 0.009 and P = 0.005, respectively) regions. The impact varied by mesh property, as mesh stiffness was a significant predictor of the negative affect on muscle function and nerve density (P < 0.001 and P = 0.013, respectively), whereas mesh and weight was a predictor of receptor function (P < 0.001). Mesh has an overall negative impact on VaSM, and the effects are a function of mesh properties, most notably, mesh stiffness. Prolapse mesh affects vaginal smooth muscle.
    BJOG An International Journal of Obstetrics & Gynaecology 08/2015; DOI:10.1111/1471-0528.13514 · 3.45 Impact Factor
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    ABSTRACT: Increased afferent excitability has been proposed as an important pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder (OAB). In this study, we investigated whether herpes simplex virus (HSV) vectors encoding poreless TRPV1, in which the segment in C terminus of TRPV1 receptor is deleted, suppress bladder overactivity and pain behavior using a rat model of chemical cystitis. Replication-defective HSV vectors encoding poreless TRPV1 were injected into the bladder wall of adult female Sprague-Dawley rats. Additionally, vHG vectors were injected as control. Cystometry (CMG) under urethane anesthesia was performed 1 week after viral injection to evaluate bladder overactivity induced by resiniferatoxin (RTx, a TRPV1 agonist). RTx-induced nociceptive behavior such as licking (lower abdominal licking) and freezing (motionless head-turning) was observed 2 weeks after viral injection. GFP expression in L4/L6/S1 dorsal root ganglia and the bladder as well as c-Fos positive cells in the L6 spinal cord dorsal horn were also evaluated 2 weeks after viral injection. In CMG, the poreless TRPV1 vector-treated group showed a significantly smaller reduction in intercontraction intervals and voided volume after RTx infusion than the vHG-treated control group. The number of the RTx-induced freezing events was significantly decreased in the poreless TRPV1 group than in the vHG group whereas there was no significant difference of the number of RTx-induced licking events between groups. The number of c-Fos positive cells in the DCM and SPN regions of the L6 spinal dorsal horn was significantly smaller in the poreless TRPV1 group than in the vHG group. Our results indicated that HSV vector-mediated gene delivery of poreless TRPV1 had a therapeutic effect on TRPV1-mediated bladder overactivity and pain behavior. Thus, the HSV vector mediated gene therapy targeting TRPV1 receptors could be a novel modality for the treatment of OAB and/or hypersensitive bladder disorders such as IC/BPS.
    Human gene therapy 07/2015; DOI:10.1089/hum.2015.026 · 3.76 Impact Factor
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    07/2015; 2(2):15. DOI:10.14440/bladder.2015.44
  • William C de Groat · Naoki Yoshimura ·
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    ABSTRACT: Functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. Neural control of micturition is organized as a hierarchic system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily during the early postnatal period, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults cause re-emergence of involuntary micturition, leading to urinary incontinence. The mechanisms underlying these pathologic changes are discussed. © 2015 Elsevier B.V. All rights reserved.
    Handbook of Clinical Neurology 05/2015; 130:61-108. DOI:10.1016/B978-0-444-63247-0.00005-5
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    ABSTRACT: Background There is mounting evidence to support the role of inflammation in benign prostate hyperplasia (BPH), and a recent study reported expression of inflammasome derived cytokine IL-18 in prostate biopsy of BPH patients. Here we examined the expression of inflammasome-derived cytokines and activation of nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP) 1 inflammasome in a rat model of prostatic inflammation relevant to BPH. Methods Prostatic inflammation was experimentally induced in three-month-old male Sprague–Dawley rats by intraprostatic injection (50 μL) of either 5 % formalin or saline (sham) into the ventral lobes of prostate. 7 days later, prostate and bladder tissue was harvested for analysis of inflammasome by Western blot, immunohistochemistry and downstream cytokine production by Milliplex. Results Expression of interleukins, CXC and CC chemokines were elevated 2-15 fold in formalin injected prostate relative to sham. Significant expression of NLRP1 inflammasome components and caspase-1 in prostate were associated with significant elevation of pro and cleaved forms of IL-1β (25.50 ± 1.16 vs 3.05 ± 0.65 pg/mg of protein) and IL-18 (1646.15 ± 182.61 vs 304.67 ± 103.95 pg/mg of protein). Relative to prostate tissue, the cytokine expression in bladder tissue was much lower and did not involve inflammasome activation. Conclusions Significant upregulation of NLRP1, caspase-1 and downstream cytokines (IL-18 and IL-1β) suggests that a NLRP1 inflammasome is assembled and activated in prostate tissue of this rat model. Recapitulation of findings from human BPH specimens suggests that the inflammasome may perpetuate the inflammatory state associated with BPH. Further clarification of these pathways may offer innovative therapeutic targets for BPH-related inflammation.
    Journal of Inflammation 05/2015; 12(1). DOI:10.1186/s12950-015-0082-3 · 2.02 Impact Factor
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    ABSTRACT: High prevalence of lower urinary tract symptoms (LUTS) consistent with benign prostate hyperplasia (BPH) is associated with obesity and prostatic inflammation. Here, we investigated whether chemokines associated with obesity and prostatic inflammation can be measured in normally voided urine of BPH/LUTS patients to demonstrate the mechanistic association between obesity and BPH/LUTS. Frozen urine specimens of BPH/LUTS patients enrolled in the Nashville Men's Health Study were sent for blinded analysis to University of Pittsburgh. Thirty patients were blocked by their AUA-SI (>7 or ≤7) and prostatic enlargement (<40, 40-60, >60 cc). Clinical parameters including age, prostate size, and medications were derived from chart review. CXC chemokines (CXCL-1, CXCL-8, and CXCL-10), CC chemokines (CCL2 and CCL3), and sIL-1ra were measured in thawed urine using Luminex™ xMAP(®) technology and ELISA for NGF. Urinary CCL2 levels were several fold higher compared with the other six proteins, of which CCL3 was detectable in less than one-fourth of patients. Urine levels of sIL-1ra and CXCL-8 were significantly associated with increasing BMI and waist circumference in BPH patients. CXCL-8 showed a marginal association with overall AUA-SI scores, as well as obstructive (p = 0.08) symptom subscores. Prostate volume was inversely and marginally associated with urinary CXCL-10 (p = 0.09). Urine levels of CXCL-8, CXCL-10, and sIL-1ra were associated with varying degrees with LUTS severity, prostate size, and obesity, respectively. These findings in urine are consistent with past studies of chemokine levels from expressed prostatic secretions and demonstrate the potential of noninvasively measured chemokine in urine to objectively classify BPH/LUTS patients.
    International Urology and Nephrology 04/2015; 47(7). DOI:10.1007/s11255-015-0992-2 · 1.52 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e331. DOI:10.1016/j.juro.2015.02.1288 · 4.47 Impact Factor
  • Pradeep Tyagi · Mahendra Kashyap · Subrata Pore · Zhou Wang · Naoki Yoshimura ·

    The Journal of Urology 04/2015; 193(4):e360-e361. DOI:10.1016/j.juro.2015.02.1368 · 4.47 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e134-e135. DOI:10.1016/j.juro.2015.02.793 · 4.47 Impact Factor

  • European Urology Supplements 04/2015; 14(2):e1089. DOI:10.1016/S1569-9056(15)61077-6 · 3.37 Impact Factor
  • Pradeep Tyagi · Mahendra Kashyap · Subrata Pore · Zhou Wang · Naoki Yoshimura ·

    The Journal of Urology 04/2015; 193(4):e287. DOI:10.1016/j.juro.2015.02.1210 · 4.47 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e286. DOI:10.1016/j.juro.2015.02.1208 · 4.47 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e575-e576. DOI:10.1016/j.juro.2015.02.455 · 4.47 Impact Factor

  • The Journal of Urology 04/2015; 193(4):e831. DOI:10.1016/j.juro.2015.02.2399 · 4.47 Impact Factor

  • The Journal of Urology 04/2015; 193(4):e234. DOI:10.1016/j.juro.2015.02.957 · 4.47 Impact Factor

  • The Journal of Urology 04/2015; 193(4):e132. DOI:10.1016/j.juro.2015.02.787 · 4.47 Impact Factor

Publication Stats

8k Citations
1,385.52 Total Impact Points


  • 1994-2015
    • University of Pittsburgh
      • • Department of Urology
      • • Department of Pharmacology and Chemical Biology
      • • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2014
    • Kaohsiung Municipal Ta-Tung Hospital, Taiwan
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2013
    • Tottori University
      • Division of Urology
      Tottori, Tottori-ken, Japan
  • 2006
    • Chang Gung University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2003
    • Pittsburg State University
      Питсбург, Kansas, United States
  • 2001
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
    • Okayama University
      • Department of Urology
      Okayama, Okayama, Japan
  • 1987-2001
    • Kyoto University
      • • Department of Urology
      • • Department of Pharmacology
      Kioto, Kyōto, Japan
  • 1991
    • Rakuwakai Otowa Hospital
      Kioto, Kyōto, Japan
    • Osaka Saiseikai Nakatsu Hospital
      Ōsaka, Ōsaka, Japan