Publications by authors named "Wei-Chia Lee"

54 Publications

Low Energy Shock Wave Therapy Attenuates Mitochondrial Dysfunction and Improves Bladder Function in HCl induced Cystitis in Rats.

Biomed J 2021 Jul 2. Epub 2021 Jul 2.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan. Electronic address:

Background: We examine the effects of low energy shock wave (LESW)) on bladder and mitochondrial function in a rat model of HCl induced cystitis, and the influence of dynamic bladder filling volume on LESW responses. Dysregulation of mitochondria function may impact the urothelial barrier and contribute to bladder dysfunction in patients with Interstitial cystitis/bladder pain syndrome (IC/BPS).

Materials And Methods: Female Sprague-Dawley rats underwent urethral catheterization and intravesical instillation of 0.2 ml of 0.4N HCl (N=32) or 0.2 ml saline (N=8) kept for 90 s. After HCl instillation, the bladder received LESW treatment while filled with 0 ml, 0.2 ml or 0.4 ml saline or no LESW treatment. Continuous cystometry (CMG) was performed on day 8. The bladder was harvested after CMG for histology and Western blotting.

Results: HCl provoked bladder overactivity, bladder wall inflammation marked by infiltration of mast cells, increased bax/bcl2 ratio consistent with increased TUNEL staining and increased release of mitochondrial-integrity markers (cleaved caspase 3 and Cytochrome c). LESW treatment suppressed HCl provoked bladder overactivity in association with lower inflammatory reaction, mast cells infiltration, and a lower bax/bcl2 ratio also reflected by reduced TUNEL staining and mitochondrial-integrity markers irrespective of the volume of saline in bladder at the time of LESW.

Conclusions: These findings support that antiinflammatory effect of LESW in chemical cystitis is associated with the reversal of the molecular-cellular perturbations in mitochondrial dependent intrinsic apoptotic pathway.
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http://dx.doi.org/10.1016/j.bj.2021.06.006DOI Listing
July 2021

Comparative safety review of current pharmacological treatments for interstitial cystitis/ bladder pain syndrome.

Expert Opin Drug Saf 2021 May 19:1-11. Epub 2021 May 19.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a frustrating disease of chronic bladder pain associated with lower urinary tract symptoms. Although there are many proposed treatment algorithms, the uncertainty as to their etiology has a negative impact on the therapeutic outcome. Oftentimes combination therapy of drugs with different mechanisms of action will be utilized to relieve the symptoms. With the various treatment options available to patients and providers, there is an ever-growing need to implement drug efficacy as well as safety to promote best practice in use of the approved drug.: This review will focus on guideline-based pharmacotherapies as described by the AUA and EAU, specifically oral, and intravesical therapies with the most up-to-date published literature. Pharmacotherapies targeting bladder, and/or systemic factors in the overall treatment of IC/BPS are discussed with a particular focus on efficacy and drug safety evaluation.: IC/BPS is a syndrome that requires bladder targeting agents to restore the urothelium barrier function and inhibit bladder hypersensitivity as well as various drugs with anti-inflammatory effects, and immune modulation effects. Current pharmacotherapies for IC/BPS have various therapeutic effects and adverse effects depending on the dose and individual response.
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http://dx.doi.org/10.1080/14740338.2021.1921733DOI Listing
May 2021

Tadalafil ameliorates bladder overactivity by restoring insulin-activated detrusor relaxation via the bladder mucosal IRS/PI3K/AKT/eNOS pathway in fructose-fed rats.

Sci Rep 2021 Apr 15;11(1):8202. Epub 2021 Apr 15.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Rd., Niao Song Qu, Kaohsiung, Taiwan, Republic of China.

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration-response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1 and pIRS2 and downregulation of PI3K/pPI3K, AKT/pAKT, and eNOS/peNOS in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.
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http://dx.doi.org/10.1038/s41598-021-87505-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050041PMC
April 2021

Improves symptoms and urinary biomarkers in refractory interstitial cystitis/bladder pain syndrome patients randomized to extracorporeal shock wave therapy versus placebo.

Sci Rep 2021 Apr 6;11(1):7558. Epub 2021 Apr 6.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Song District, Kaohsiung, Taiwan.

Extracorporeal shock wave therapy (ESWT) has been shown to improve symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS); however, there is a lack of objective evidence. We measured change of urinary biomarker levels in 25 patients with IC/BPS received ESWT or placebo once a week for 4 weeks. Urines were collected from participants at baseline, 4 and 12 weeks post treatment. A representative 41 inflammatory growth factors, cytokines, and chemokines in urine were measured using a MILLIPLEX immunoassay kit. Symptom bother was assessed by O'Leary-Sant symptom scores (OSS), and visual analog scale (VAS) for pain. The ESWT group exhibited a significant reduction in the OSS and VAS compared to the placebo group 4 weeks post-treatment (P < 0.05), and the effects were persistent at 12 weeks. The difference in urinary markers change in ESWT versus placebo was P = 0.054 for IL4, P = 0.013 for VEGF, and P = 0.039 for IL9 at 4 weeks. The change of urine biomarker was not significant in other biomarkers or all the measured proteins at 12 weeks. The current data suggest that IL4, IL9, and VEGF mediation may be involved in its pathophysiologic mechanisms and response to LESW treatment.
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http://dx.doi.org/10.1038/s41598-021-87040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024394PMC
April 2021

Altered Gut Microbiota and Its Metabolites in Hypertension of Developmental Origins: Exploring Differences between Fructose and Antibiotics Exposure.

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied ( = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera , , and . Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin-angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.
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http://dx.doi.org/10.3390/ijms22052674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961901PMC
March 2021

New Frontiers or the Treatment of Interstitial Cystitis/Bladder Pain Syndrome - Focused on Stem Cells, Platelet-Rich Plasma, and Low-Energy Shock Wave.

Int Neurourol J 2020 Sep 30;24(3):211-221. Epub 2020 Sep 30.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Interstitial cystitis/bladder pain syndrome (IC/BPS), which is characterized by bladder pain and irritative voiding symptoms, is a frustrating disease without effective treatment. The cause is still largely not understood, although urothelium ischemia/hypoxia, apoptosis, denudation, and infiltration of inflammatory cells are common histopathological findings. The current uncertainty regarding the etiology and pathology of IC/BPS has a negative impact on its timely and successful treatment; therefore, the development of new treatment modalities is urgently needed. Herein, we present advances in our knowledge on this topic and review the potential application of regenerative medicine for the treatment of IC/BPS. This article provides information on the basic characteristics and clinical evidence of stem cells, platelet-rich plasma (PRP), and low-energy shock waves (LESWs) based on a literature review with a search strategy for articles related to IC/BPS, stem cells, PRP, and LESW published in MEDLINE and PubMed. Stem cells, PRP, and LESW, which modulate inflammatory processes and promote tissue repair, have been proven to improve bladder regeneration, relieve bladder pain, inhibit bladder inflammation, and increase bladder capacity in some preclinical studies. However, clinical studies are still in their infancy. Based on the mechanisms of action of stem cells, PRP, and LESW documented in many preclinical studies, the potential applications of regenerative medicine for the treatment of IC/BPS is an emerging frontier of interest. However, solid evidence from clinical studies remains to be obtained.
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http://dx.doi.org/10.5213/inj.2040104.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538293PMC
September 2020

Targeting on Gut Microbiota-Derived Metabolite Trimethylamine to Protect Adult Male Rat Offspring against Hypertension Programmed by Combined Maternal High-Fructose Intake and Dioxin Exposure.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied ( = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.
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http://dx.doi.org/10.3390/ijms21155488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432895PMC
July 2020

Anomalous AMPK-regulated angiotensin ATR expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure.

J Biomed Sci 2020 May 23;27(1):68. Epub 2020 May 23.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan.

Background: Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (ATR) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring.

Methods: Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, ATR, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction.

Results: Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of ATR and pg91 subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in ATR and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension.

Conclusion: Dysfunction of AMPK-regulated ATR expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.
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http://dx.doi.org/10.1186/s12929-020-00660-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245869PMC
May 2020

Therapeutic Efficacy of onabotulinumtoxinA Delivered Using Various Approaches in Sensory Bladder Disorder.

Toxins (Basel) 2020 01 23;12(2). Epub 2020 Jan 23.

Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

Cystoscopic onabotulinumtoxinA (onaBoNTA) intradetrusor injection is an efficient and durable modality for treating sensory bladder disorders. However, the inconvenience of using the cystoscopic technique and anesthesia, and the adverse effects of direct needle injection (e.g., haematuria, pain, and infections) have motivated researchers and clinicians to develop diverse injection-free procedures to improve accessibility and prevent adverse effects. However, determining suitable approaches to transfer onaBoNTA, a large molecular and hydrophilic protein, through the impermeable urothelium to reach therapeutic efficacy remains an unmet medical need. Researchers have provided potential solutions in three categories: To disrupt the barrier of the urothelium (e.g., protamine sulfate), to increase the permeability of the urothelium (e.g., electromotive drug delivery and low-energy shock wave), and to create a carrier for transportation (e.g., liposomes, thermosensitive hydrogel, and hyaluronan-phosphatidylethanolamine). Thus far, most of these novel administration techniques have not been well established in their long-term efficacy; therefore, additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques. Finally, researchers may make progress with new combinations or biomaterials to change clinical practices in the future.
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http://dx.doi.org/10.3390/toxins12020075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076745PMC
January 2020

The role of intravesical prostatic protrusion in the evaluation of overactive bladder in male patients with LUTS.

Int Urol Nephrol 2020 May 2;52(5):815-820. Epub 2020 Jan 2.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Song District, Kaohsiung, Taiwan.

Purpose: To evaluate the association of intravesical prostatic protrusion (IPP) and overactive bladder (OAB) in male patients with lower urinary tract symptoms (LUTS). IPP has been suggested to correlate with storage symptoms in addition to bladder outlet obstruction.

Methods: This was an open-labeled, single-center, prospective study involving 128 men older than 40 years presenting with LUTS. We analyzed the relationship of IPP with age, prostate volume, uroflowmetry, post-void residual urine volume (PVR), International Prostate Symptom Score (IPSS), urgency severity scale (USS), and OAB symptom score (OABSS). The patients with an urgency score of ≥ 2 (OABSS question 2) and sum score of ≥ 3 were considered to have OAB. IPP was measured in the mid-sagittal section using transrectal ultrasound. The degree of IPP was classified as grade 1 (≤ 5 mm), grade 2 (> 5-10 mm), and grade 3 (> 10 mm).

Results: The mean age of the patients was 64.9 ± 9.2 years, and 101 patients were diagnosed with OAB (79%). Mean IPPs were 2.4 ± 1.4 mm (grade 1, n = 77), 7.6 ± 1.4 mm (grade 2, n = 27), and 14.8 ± 4.4 mm (grade 3, n = 24). IPP was positively correlated with age, prostate size, PSA, PVR, and OABSS nocturia subscore, but not correlated with the presence or severity of OAB. Areas under the receiver-operating characteristic (ROC) curves for the diagnosis of OAB were 0.807 and 0.604 for IPSS-storage subscore and IPP, respectively.

Conclusion: IPP is not a good predictor of OAB in men presenting with LUTS. However, grade 3 IPP indicates higher frequency of nocturia.
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http://dx.doi.org/10.1007/s11255-019-02370-4DOI Listing
May 2020

Effect of mirabegron on erectile function in sexually active men with bothersome overactive bladder symptoms.

J Chin Med Assoc 2020 Jan;83(1):55-59

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.

Background: To evaluate the change of erectile function (EF) in sexually active male overactive bladder (OAB) patients treated with Mirabegron. Mirabegron, a selective β3 adrenoceptor agonist, approved for the treatment of OAB, has been reported to relax human and rat corpus cavernosum and might have beneficial effect on EF.

Methods: A total of 128 consecutive men with lower urinary tract symptoms attended urology outpatient clinic were evaluated for OAB and EF. Thirty-four sexually active OAB patients were prospectively enrolled in this study and received mirabegron 50 mg oral once a day. The evaluation of EF and OAB was based on a self-administered questionnaire containing International Index of Erectile Function (IIEF-5) and OAB symptom score (OABSS), respectively. Men with an OABSS urgency score of ≥2 and sum score of ≥3 were considered to have OAB. The therapeutic outcomes were assessed at baseline, 4, and 12 weeks.

Results: Mirabegron usage was associated with a statistically significant improvement of OAB symptoms (OABSS 32.1% decrease) at 4-week follow-up and the therapeutic effects were maintained at 12-week follow-up. Mirabegron usage did not improve EF (IIEF-5 4.9% decrease at 4-week; p = 0.106, and 9.1% decrease at 12-week follow-up; p = 0.077). However, the IIEF-5 was significantly decreased in the higher baseline IIEF-5 (≥17) group (11.7% decrease; p = 0.044), noncoronary artery disease (13.2%; p = 0.007), or non-DM group (13.9% decrease; p = 0.021) at 12-week follow-up.

Conclusion: This preliminary study demonstrates that mirabegron treatment of men with OAB improved OAB symptoms, but has no beneficial effect on EF.
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http://dx.doi.org/10.1097/JCMA.0000000000000208DOI Listing
January 2020

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

Neurourol Urodyn 2019 11 20;38(8):2159-2169. Epub 2019 Sep 20.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.

Aim: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model.

Methods: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out.

Results: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M - and M -muscarinic receptors) and detrusor (M - and M -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-β1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups.

Conclusion: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.
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http://dx.doi.org/10.1002/nau.24165DOI Listing
November 2019

The Impact of Maternal Fructose Exposure on Angiogenic Activity of Endothelial Progenitor Cells and Blood Flow Recovery After Critical Limb Ischemia in Rat Offspring.

Int J Mol Sci 2019 May 16;20(10). Epub 2019 May 16.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.

Adult metabolic syndrome is considered to be elicited by the developmental programming which is regulated by the prenatal environment. The maternal excess intake of fructose, a wildly used food additive, is found to be associated with developmental programing-associated cardiovascular diseases. To investigate the effect of maternal fructose exposure (MFE) on endothelial function and repair, which participate in the initiation and progress of cardiovascular disease, we applied a rat model with maternal fructose excess intake during gestational and lactational stage and examined the number and function of endothelial progenitor cells (EPCs) in 3-month-old male offspring with induction of critical limb ischemia (CLI). Results showed that the circulating levels of c-Kit+/CD31+ and Sca-1+/KDR+ EPC were reduced by MFE. In vitro angiogenesis analysis indicated the angiogenic activity of bone marrow-derived EPC, including tube formation and cellular migration, was reduced by MFE. Western blots further indicated the phosphorylated levels of ERK1/2, p38-MAPK, and JNK in circulating peripheral blood mononuclear cells were up-regulated by MFE. Fourteen days after CLI, the reduced blood flow recovery, lowered capillary density, and increased fibrotic area in quadriceps were observed in offspring with MFE. Moreover, the aortic endothelium-mediated vasorelaxant response in offspring was impaired by MFE. In conclusion, maternal fructose intake during gestational and lactational stage modulates the number and angiogenic activity of EPCs and results in poor blood flow recovery after ischemic injury.
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http://dx.doi.org/10.3390/ijms20102429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566409PMC
May 2019

Long-term functional change of cryoinjury-induced detrusor underactivity and effects of extracorporeal shock wave therapy in a rat model.

Int Urol Nephrol 2019 Apr 22;51(4):617-626. Epub 2019 Feb 22.

Department of Urology, Oakland University-William Beaumont School of Medicine, Detroit, USA.

Purpose: To investigate the long-term functional change of cryoinjury-induced detrusor underactivity (DU) and the therapeutic potential of repeated low-energy shock wave therapy (LESW).

Methods: Fifty-six female Sprague-Dawley rats were assigned into sham and cryoinjury of bladder with or without LESW (0.05 or 0.12 mJ/mm; 200 pulses; twice a week for 2 weeks after cryoinjury). Under halothane anesthesia, an incision was made in lower abdomen, and cryoinjury was provoked by bilateral placement of a chilled aluminum rod on the bladder filled with 1 ml saline. Measurement of contractile responses to KCl and carbachol in vitro, conscious voiding, and histological and protein changes were performed on week 1, 2, and 4 after cryoinjury.

Results: Cryoinjury of bladder induced a significant decrease in the detrusor contraction amplitude at week 1 (55.0%) and week 2 (57.2%), but the decrease in the contractile response to KCl and carbachol was only noted at week 1. At week 1, significantly increased COX-2 and TGF-β1 expression accompanied a decrease of VEGF and CGRP expression. At week 4, there was a partial recovery of voiding function and a significant increase in the Ki-67 staining. LESW treatment at higher energy level further amplified the Ki-67 staining and improved the recovery of contraction amplitude and the expression of TGF-β1 and VEGF.

Conclusions: Cryoinjury of detrusor induces DU/UAB with functional impairment lasting for up to 4 weeks, but the associated molecular changes are restored by 2 weeks. LESW improved bladder wall composition, and hastened functional recovery from cryoinjury.
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http://dx.doi.org/10.1007/s11255-019-02095-4DOI Listing
April 2019

Pioglitazone reversed the fructose-programmed astrocytic glycolysis and oxidative phosphorylation of female rat offspring.

Am J Physiol Endocrinol Metab 2019 04 22;316(4):E622-E634. Epub 2019 Jan 22.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.

Excessive maternal high-fructose diet (HFD) during pregnancy and lactation has been reported to cause metabolic disorders in the offspring. Whether the infant's brain metabolism is disturbed by maternal HFD is largely unknown. Brain energy metabolism is elevated dramatically during fetal and postnatal development, whereby maternal nutrition is a key factor that determines cellular metabolism. Astrocytes, a nonneuronal cell type in the brain, are considered to support the high-energy demands of neurons by supplying lactate. In this study, the effects of maternal HFD on astrocytic glucose metabolism were investigated using hippocampal primary cultures of female infants. We found that glycolytic capacity and mitochondrial respiration and electron transport chain were suppressed by maternal HFD. Mitochondrial DNA copy number and mitochondrial transcription factor A expression were suppressed by maternal HFD. Western blots and immunofluorescent images further indicated that the glucose transporter 1 was downregulated whereas the insulin receptor-α, phospho-insulin receptor substrate-1 (Y612) and the p85 subunit of phosphatidylinositide 3-kinase were upregulated in the HFD group. Pioglitazone, which is known to increase astrocytic glucose metabolism, effectively reversed the suppressed glycolysis, and lactate release was restored. Moreover, pioglitazone also normalized oxidative phosphorylation with an increase of cytosolic ATP. Together, these results suggest that maternal HFD impairs astrocytic energy metabolic pathways that were reversed by pioglitazone.
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http://dx.doi.org/10.1152/ajpendo.00408.2018DOI Listing
April 2019

Alterations of Renal Epithelial Glucose and Uric Acid Transporters in Fructose Induced Metabolic Syndrome.

Kidney Blood Press Res 2018 7;43(6):1822-1831. Epub 2018 Dec 7.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan,

Background/aims: Hyperglycemia and hyperuricemia are two major disorders of Metabolic syndrome. Kidney plays a crucial role in maintaining the homeostasis of uric acid and glucose. The aim of the study was to examine the changes of renal glucose and uric acid transporters in animals with metabolic syndrome.

Methods: Sprague-Dawley rats were fed with high fructose diet (60%) for 3 months (FR-3) and 5 months (FR-5). At the end study, serum and urine biochemical data were compared. Gene expression and protein abundance of renal GLUT1, GLUT2, GLUT9, SGLT1, SGLT2, UAT and URAT1 was investigated by using RT-PCR and immunohistochemical staining.

Results: Metabolic syndrome was induced by high-fructose diet. Systolic blood pressure and proteinuria was significantly increased in FR-5 animals. In kidney tissue, gene expression of GLUT2 and SGLT2 increased significantly in a time dependent manner. GLUT9, SGLT1 and UAT were also significantly upregulated in FR-5. Immunohistochemical study showed a significant increase of SGLT1 in both FR-3 (413.5 ± 88.3% of control, p< 0.001) and FR-5 (677.6 ± 26.5% of control, p< 0.001). Also, SGLT2 protein was increased in both FR-3 (643.1 ± 41.3% of control, p< 0.001) and FR-5 (563.3 ± 21.7% of control, p< 0.001). Fructose rich food also induced increase of UAT by nearly 5-fold in both FR-3 and FR-5 (both p< 0.05) and more than 3-fold of GLUT-9 in FR-3 and FR-5 (both p< 0.05).

Conclusion: Long term high fructose diet induced metabolic syndrome with increased blood pressure and proteinuria in rats. Metabolic syndrome was associated with dual increase in renal glucose and uric acid transporters, including SGLT1, SGLT2, GLUT2, GLUT9 and UAT.
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http://dx.doi.org/10.1159/000495814DOI Listing
February 2019

Tract creation using plasma vaporization versus metal dilatation in percutaneous nephrolithotomy: A propensity score-matched analysis.

Int J Urol 2019 02 14;26(2):223-228. Epub 2018 Nov 14.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Objectives: To share our 10-year experience of tract creation by using plasma vaporization compared with metal dilatation in percutaneous nephrolithotomy.

Methods: We retrospectively reviewed the medical records of 230 patients who had undergone 244 percutaneous nephrolithotomy procedures at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, from January 2007 to December 2016, and divided the patients into the plasma (n = 130) and metal (n = 114) groups. All patients underwent percutaneous nephrolithotomy by either a bipolar resectoscope mounted with a plasma vaporization button electrode or metal dilatation for tract creation. Propensity score matching was applied to reduce selection bias. Perioperative and postoperative data analysis included procedure time, length of hospital stay, blood transfusion rate, any early and late complications, stone-free rate, renal function, and time of need for pain control.

Results: Before propensity score matching, there were significantly shorter hospital stay (2.6 vs 3.8 days, P < 0.01), less operating time (66.1 vs 108.1 min, P < 0.01) and no blood transfusion rate (0 vs 4 [3.5%], P = 0.031) in the plasma vaporization group. After propensity score matching, there was no statistically significant difference in the patients' baseline characteristics. There were significantly shorter hospital stay (odds ratio 0.46, 95% confidence interval 0.32-0.66; P < 0.001) and shorter average operating time (odds ratio 0.98, 95% confidence interval 0.97-0.99, P < 0.001) in the plasma vaporization group.

Conclusions: In comparison with metal dilatation, the plasma vaporization technique is a safe and effective method for creating the nephrostomy tract for percutaneous nephrolithotomy, based on shorter postoperative stay, less operating time, zero blood transfusion rate, acceptable stone-free rate and no major complications.
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http://dx.doi.org/10.1111/iju.13843DOI Listing
February 2019

Translational insights on developmental origins of metabolic syndrome: Focus on fructose consumption.

Biomed J 2018 04;41(2):96-101

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Metabolic syndrome (MetS) is a highly prevalent complex trait despite recent advances in pathophysiology and pharmacological treatment. MetS can begin in early life by so-called the developmental origins of health and disease (DOHaD). The DOHaD concept offers a novel approach to prevent MetS through reprogramming. High fructose (HF) intake has been associated with increased risk of MetS. HF diet becomes one of the most commonly used animal model to induce MetS. This review discusses the maternal HF diet induced programming process and reprogramming strategy to prevent MetS of developmental origin, with an emphasis on: (1) an overview of metabolic effects of fructose consumption on MetS; (2) insight from maternal HF animal models on MetS-related phenotypes; (3) impact of HF consumption induces organ-specific transcriptome changes; and (4) application of reprogramming strategy to prevent maternal HF consumption-induced MetS. Research into the preventions and treatments of MetS that begin early in life will have a lifelong impact and profound savings in disease burden and financial costs.
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http://dx.doi.org/10.1016/j.bj.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138777PMC
April 2018

Resveratrol Prevents the Development of Hypertension Programmed by Maternal Plus Post-Weaning High-Fructose Consumption through Modulation of Oxidative Stress, Nutrient-Sensing Signals, and Gut Microbiota.

Mol Nutr Food Res 2018 Apr 30:e1800066. Epub 2018 Apr 30.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, 833, Taiwan.

Scope: High-fructose (HF) intake, oxidative stress, nutrient-sensing signals, and gut microbiota dysbiosis are closely related to the development of hypertension. It was investigated whether resveratrol can prevent hypertension induced by maternal plus post-weaning HF diets in adult offspring via the above-mentioned mechanisms.

Methods And Results: Female Sprague-Dawley rats received either a normal (ND) or 60% high-fructose (HF) diet during gestation and lactation. Male offspring were assigned to five groups (maternal diet/post-weaning diet; n = 8 per group): ND/ND, ND/HF, HF/ND, HF/HF, and HF/HF+ Resveratrol. Resveratrol (50 mg L ) was administered in drinking water from weaning to 3 months of age. It was found that HF/HF induced hypertension in adult offspring. Maternal HF diet altered gut microbiota composition in adult offspring, including decreasing the abundance of genera Bacteroides, Dysgonomonas, and Turicibacter, while increasing phylum Verrucomicrobia and Akkermansia muciniphila. Additionally, HF/HF diets increased oxidative stress and decreased renal mRNA expression of Prkaa2, Prkag2, Ppara, Pparb, Ppargc1a, and Sirt4. Resveratrol reduced renal oxidative stress, activated nutrient-sensing signals, modulated gut microbiota, and prevented associated HF/HF-induced programmed hypertension.

Conclusion: Targeting oxidative stress, nutrient-sensing signals, and gut microbiota by resveratrol might be a useful therapeutic strategy for the treatment of hypertension induced by excessive consumption of fructose in the adult rat offspring.
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http://dx.doi.org/10.1002/mnfr.201800066DOI Listing
April 2018

Potential Orphan Drug Therapy of Intravesical Liposomal Onabotulinumtoxin-A for Ketamine-Induced Cystitis by Mucosal Protection and Anti-inflammation in a Rat Model.

Sci Rep 2018 04 11;8(1):5795. Epub 2018 Apr 11.

Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Ketamine abusers may develop ulcerative cystitis and severe lower urinary tract symptoms, which is a medical dilemma. Recently, researchers have found the endemic of ketamine-induced cystitis worldwide. The intravesical administration of liposome-encapsulated onabotulinumtoxinA (Lipotoxin) might facilitate the healing of the damaged urothelium from liposomes, and reduce the urinary symptoms by onabotulinumtoxinA-induced chemo-denervation. Using female Sprague-Dawley rats, we investigated the effects of Lipotoxin on ketamine-induced cystitis. Functional magnetic resonance imaging, metabolic cage study, and cystometry were conducted. Paraffin-embedded sections were stained. The bladder mucosa and muscle proteins were assessed through Western blotting. We observed that repeated intravesical Lipotoxin instillation could improve suburothelial hemorrhage, recover the urothelial tight junction and adhesion proteins (zonula occludens-1 and E-cadherin), ensure less substance P in the urothelium, inhibit the overexpression of inflammatory mediators (IL-6, TNF-α, nuclear NF-κB, and COX-2) in the detrusor, suppress the upregulation of the mucosal TRPV1 and detrusor M-mAChR, and ameliorate bladder overactivity in the ketamine-treated rats. These data reveal the mechanisms underlying the action of Lipotoxin in ketamine-induced cystitis of rats, which provide a basis of Lipotoxin for further treating ketamine-induced cystitis in humans.
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http://dx.doi.org/10.1038/s41598-018-24239-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895575PMC
April 2018

Maternal Melatonin Therapy Attenuated Maternal High-Fructose Combined with Post-Weaning High-Salt Diets-Induced Hypertension in Adult Male Rat Offspring.

Molecules 2018 Apr 11;23(4). Epub 2018 Apr 11.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Consumption of food high in fructose and salt is associated with the epidemic of hypertension. Hypertension can originate from early life. Melatonin, a pleiotropic hormone, regulates blood pressure. We examined whether maternal melatonin therapy can prevent maternal high-fructose combined with post-weaning high-salt diet-induced programmed hypertension in adult offspring. Pregnant Sprague-Dawley rats received either a normal diet (ND) or a 60% fructose diet (HF) during pregnancy and the lactation period. Male offspring were on either the ND or a high-salt diet (HS, 1% NaCl) from weaning to 12 weeks of age and were assigned to five groups (n = 8/group): ND/ND, HF/ND, ND/HS, HF/HS, and HF/HS+melatonin. Melatonin (0.01% in drinking water) was administered during pregnancy and lactation. We observed that maternal HF combined with post-weaning HS diets induced hypertension in male adult offspring, which was attenuated by maternal melatonin therapy. The beneficial effects of maternal melatonin therapy on HF/HS-induced hypertension related to regulating several nutrient-sensing signals, including , , , , , and . Additionally, melatonin increased protein levels of mammalian targets of rapamycin (mTOR), decreased plasma asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine levels, and increased the l-arginine-to-ADMA ratio. The reprogramming effects by which maternal melatonin therapy protects against hypertension of developmental origin awaits further elucidation.
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http://dx.doi.org/10.3390/molecules23040886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017187PMC
April 2018

Prenatal Metformin Therapy Attenuates Hypertension of Developmental Origin in Male Adult Offspring Exposed to Maternal High-Fructose and Post-Weaning High-Fat Diets.

Int J Mol Sci 2018 Apr 3;19(4). Epub 2018 Apr 3.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Widespread consumption of a Western diet, comprised of highly refined carbohydrates and fat, may play a role in the epidemic of hypertension. Hypertension can take origin from early life. Metformin is the preferred treatment for type 2 diabetes. We examined whether prenatal metformin therapy can prevent maternal high-fructose plus post-weaning high-fat diets-induced hypertension of developmental origins via regulation of nutrient sensing signals, uric acid, oxidative stress, and the nitric oxide (NO) pathway. Gestating Sprague-Dawley rats received regular chow (ND) or chow supplemented with 60% fructose diet (HFR) throughout pregnancy and lactation. Male offspring were onto either the ND or high-fat diet (HFA) from weaning to 12 weeks of age. A total of 40 male offspring were assigned to five groups ( = 8/group): ND/ND, HFR/ND, ND/HFA, HFR/HFA, and HFR/HFA+metformin. Metformin (500 mg/kg/day) was administered via gastric gavage for three weeks during the pregnancy period. Combined maternal HFR plus post-weaning HFA induced hypertension in male adult offspring, which prenatal metformin therapy prevented. The protective effects of prenatal metformin therapy on HFR/HFA-induced hypertension, including downregulation of the renin-angiotensin system, decrease in uric acid level, and reduction of oxidative stress. Our results highlighted that the programming effects of metformin administered prenatally might be different from those reported in adults, and that deserves further elucidation.
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http://dx.doi.org/10.3390/ijms19041066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979307PMC
April 2018

Maternal High Fructose Intake Increases the Vulnerability to Post-Weaning High-Fat Diet-Induced Programmed Hypertension in Male Offspring.

Nutrients 2018 Jan 9;10(1). Epub 2018 Jan 9.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.

Widespread consumption of high-fructose and high-fat diets relates to the global epidemic of hypertension. Hypertension may originate from early life by a combination of prenatal and postnatal nutritional insults. We examined whether maternal high-fructose diet increases vulnerability to post-weaning high-fructose or high-fat diets induced hypertension in adult offspring and determined the underlying mechanisms. Pregnant Sprague-Dawley rats received regular chow (ND) or chow supplemented with 60% fructose (HFR) during the entire pregnancy and lactation periods. Male offspring were onto either the regular chow, 60% fructose, or high-fat diet (HFA) from weaning to 12 weeks of age and assigned to four groups: ND/ND, HFR/ND, HFR/HFR, and HFR/HFA. Maternal high-fructose diet exacerbates post-weaning high-fat diet-induced programmed hypertension. Post-weaning high-fructose and high-fat diets similarly reduced , , , , , and mRNA expression in offspring kidneys exposed to maternal high-fructose intake. Additionally, post-weaning high-fat diet significantly reduced renal mRNA levels of , , and and induced greater oxidative stress than did high-fructose diet. Although maternal high-fructose intake increases soluble epoxide hydrolase (SEH) expression in the kidney, which was restored by post-weaning high-fructose and high-fat diets. Maternal high-fructose diet programs differential vulnerability to developing hypertension in male offspring in response to post-weaning high-fructose and high-fat diets. Our data implicated that specific therapy targeting on nutrient sensing signals, oxidative stress, and SEH may be a promising approach to prevent hypertension in children and mothers exposed to high-fructose and high-fat consumption.
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http://dx.doi.org/10.3390/nu10010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793284PMC
January 2018

Effects of low energy shock wave therapy on inflammatory moleculars, bladder pain, and bladder function in a rat cystitis model.

Neurourol Urodyn 2017 Aug 30;36(6):1440-1447. Epub 2016 Dec 30.

Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Aims: Low energy shock wave (LESW) is known to facilitate tissue regeneration with analgesic and anti-inflammatory effects. We examined the effects of LESW on the expression of inflammatory molecules, pain behavior, and bladder function in a rat cystitis model.

Methods: Control and experimental animals were injected with saline or cyclophosphamide (CYP; 75 mg/kg intraperitoneally) on day 1 and 4. After lower midline incision, the bladders were exposed to LESW (300 pulses, 0.12 mJ/mm ) or sham operation on day 2. In study 1 (N = 12, 4 for each group), the nociceptive effects of CYP were evaluated for 30 min by behavioral assessment on day 4 one hour after CYP injection. In study 2 (N = 21, 7 for each group), continuous cystometry (CMG) was performed on day 8. The bladder was harvested after behavioral assessment or CMG for histology and Western blotting.

Results: CYP-induced upregulation of COX2 and IL6 expression, caused pain behavior (eye closing and hypolocomotion), and bladder inflammation was noted on days 4 and 8 along with bladder hyperactivity. LESW treatment reduced pain behavior and downregulated the NGF expression (33.3%, P < 0.05) on day 4 and IL6 (40.9%, P < 0.05). LESW treatment suppressed bladder overactivity (intercontraction interval 77.8% increase, P < 0.05) by decreasing inflammation and COX2 (38.6%, P < 0.05) expression and NGF expression (25.2%, P = 0.0812).

Conclusions: CYP-induced bladder pain, inflammation, and overactivity involves activation of IL6, NGF, and COX2 expression. These changes are suppressed by LESW, indicating it as a potential candidate for relieving bladder inflammatory conditions and overactivity.
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http://dx.doi.org/10.1002/nau.23141DOI Listing
August 2017

Developmental programming of the metabolic syndrome: Next-generation sequencing analysis of transcriptome expression in a rat model of maternal high fructose intake.

Sheng Li Xue Bao 2016 Oct;68(5):557-567

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Kaohsiung 83301.

Excessive fructose intake is related to a high prevalence of metabolic syndrome, while little attention has been paid to the impact of maternal high-fructose (HF) intake on the development of metabolic syndrome and organ-specific transcriptome alterations in the offspring. We utilized RNA next-generation sequencing (NGS) technology to analyze the transcriptome expression in four organs (kidney, brain, heart, and urinary bladder) from 1-day, 3-week, and 3-month-old male offspring exposed to maternal HF diet. Maternal HF induced various phenotypes of metabolic syndrome in adult male offspring. We observed that maternal HF exposure induces long-term alterations of gene expression in the brain, heart, kidney, and urinary bladder in adult offspring. Different organs do not respond similarly to maternal HF intake. We found that changes in expression of Errfi1 and Ctgf were shared by four organs at 1 day of age. Also, a number of genes regulating fructose metabolism, glycolysis/gluconeogenesis, fatty acid metabolism, and insulin signalling appear to be regulated by maternal HF intake in different organs at 1 day of age. Our NGS results are of significance to the development of maternal interventions in the prevention of maternal HF-induced organ-specific programming, in order to reduce the global burden of metabolic syndrome.
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October 2016

Targeting arachidonic acid pathway to prevent programmed hypertension in maternal fructose-fed male adult rat offspring.

J Nutr Biochem 2016 12 7;38:86-92. Epub 2016 Sep 7.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan. Electronic address:

Hypertension can be programmed in response to nutritional insults in early life. Maternal high-fructose (HF) intake induced programmed hypertension in adult male offspring, which is associated with renal programming and arachidonic acid metabolism pathway. We examined whether early treatment with a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-Deoxy-Δ-prostagandin J (15dPGJ) can prevent HF-induced programmed hypertension. Pregnant Sprague Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) during the whole period of pregnancy and lactation. Four groups of male offspring were studied: control, HF, HF+AUDA and HF+15dPGJ In HF+AUDA group, mother rats received AUDA 25 mg/L in drinking water during lactation. In the HF+15dPGJ group, male offspring received 15dPGJ 1.5 mg/kg body weight by subcutaneous injection once daily for 1 week after birth. Rats were sacrificed at 12 weeks of age. Maternal HF-induced programmed hypertension is associated with increased renal protein level of SEH and oxidative stress, which early AUDA therapy prevents. Comparison of AUDA and 15dPGJ treatments demonstrated that AUDA was more effective in preventing HF-induced programmed hypertension. AUDA therapy increases angiotensin converting enzyme-2 (ACE2) protein levels and PGE levels in adult offspring kidney exposed to maternal HF. 15dPGJ therapy increases plasma asymmetric dimethylarginine (ADMA) levels and decreases L-arginine-to-ADMA ratio. Better understanding of the impact of arachidonic acid pathway, especially inhibition of SEH, on renal programming may aid in developing reprogramming strategy to prevent programmed hypertension in children exposed to antenatal HF intake.
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http://dx.doi.org/10.1016/j.jnutbio.2016.08.006DOI Listing
December 2016

Maternal Fructose Exposure Programs Metabolic Syndrome-Associated Bladder Overactivity in Young Adult Offspring.

Sci Rep 2016 10 5;6:34669. Epub 2016 Oct 5.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Maternal fructose exposure (MFE) programs the development of metabolic syndrome (MetS) in young adult offspring. Epidemiological data indicate that MetS may increase the risks of overactive bladder (OAB) symptoms. However, it remains unknown whether MFE programs MetS-associated bladder dysfunction in adult offspring. Using Sprague-Dawley rats, we investigated the effects of MFE during pregnancy and lactation on developmental programming of MetS-associated bladder dysfunction. In addition, next generation sequencing technology was used to identify potential transcripts involved in the programmed bladder dysfunction in adult male offspring to MFE. We found that MFE programmed the MetS-associated OAB symptoms (i.e., an increase in micturition frequency and a shortened mean inter-contractile interval) in young adult male offspring, alongside significant alterations in bladder transcripts, including Chrm2, Chrm3, P2rx1, Trpv4, and Vipr2 gene expression. At protein level, the expressions of M-, M-muscarinic and P2X receptor proteins were upregulated in the MFE bladder. Functionally, the carbachol-induced detrusor contractility was reduced in the MFE offspring. These data suggest that alterations in the bladder transcripts and impairment of the bladder cholinergic pathways may underlie the pathophysiology of programmed bladder dysfunction in adult offspring to MFE.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050417PMC
http://dx.doi.org/10.1038/srep34669DOI Listing
October 2016

Aliskiren Administration during Early Postnatal Life Sex-Specifically Alleviates Hypertension Programmed by Maternal High Fructose Consumption.

Front Physiol 2016 12;7:299. Epub 2016 Jul 12.

Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan; Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan.

Unlabelled: Key points summary Maternal high-fructose (HF) induces programmed hypertension in adult offspring.Early aliskiren administration prevents HF-induced hypertension in both sexes of adult offspring.HF regulates RAS components in the offspring kidney in a sex-specific manner.HF alters renal transcriptome, with female offspring being more sensitive.Deprogramming strategy to prevent hypertension might be sex-specific.

Background: Maternal high fructose (HF) intake induced renal programming and hypertension in male adult offspring. We examined whether maternal HF intake causes programmed hypertension and whether aliskiren administration confers protection against the process in a sex-specific manner, with a focus on the transcriptome changes in the kidney using next-generation RNA sequencing (NGS) technology and renin-angiotensin system (RAS).

Methods: Pregnant Sprague-Dawley rats received regular chow or chow supplemented with 60% fructose throughout pregnancy and lactation. Offspring were assigned to six groups: male control, male HF (MHF), MHF+Aliskiren, female control, female HF (FHF), and FHF+Aliskiren. Oral aliskiren 10 mg/kg/day was administered via gastric gavage between 2 and 4 weeks of age. Rats were sacrificed at 12 weeks of age.

Results: Maternal HF intake induced programmed hypertension in 12-week-old offspring of both sexes. HF regulated renal transcriptome and RAS components in the offspring kidney in a sex-specific manner. Aliskiren administration prevented HF-induced programmed hypertension in both sexes of adult offspring. Aliskiren administration increased ACE2 and MAS protein levels in female kidneys exposed to maternal HF intake.

Conclusion: Maternal HF induced programmed hypertension in both sexes of adult offspring, which was sex-specifically mitigated by early aliskiren administration. Better understanding of the sex-dependent mechanisms that underlie maternal HF-induced renal programming will help develop a novel sex-specific strategy to prevent programmed hypertension.
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http://dx.doi.org/10.3389/fphys.2016.00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941125PMC
July 2016

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate cyclophosphamide-induced ongoing bladder overactivity and acidic adenosine triphosphate solution-induced hyperactivity on rats prestimulated bladder.

J Ethnopharmacol 2016 May 21;184:1-9. Epub 2015 Dec 21.

Division of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. Electronic address:

Ethnopharmacological Relevance: Ba-Wei-Die-Huang-Wan (BWDHW) is the traditional Chinese medicine formula containing eight ingredients, namely Rehmannia glutinosa (Gaetn.) DC., root, steamed & dried; Cornus officinalis Siebold & Zucc., fructus, dried; Dioscorea oppositifolia L., root, dried; Alisma plantago-aquatica, subsp. orientale (Sam.) Sam., tuber, dried; Poria cocos (Fr.) Wolf., sclerotium, dried; Paeonia×suffruticosa Andrews, bark, dried; Cinnamomum cassia (Nees & T.Nees) J. Presl, bark, dried; Aconitum carmichaeli Debeaux, lateral root, dried & processed. It has been used for diabetes and urinary frequency treatments.

Aim Of The Study: We investigate effects of BWDHW on cyclophosphamide (CYP)-induced ongoing bladder overactivity and acidic adenosine triphosphate (ATP) solution-induced hyperactivity on rat's prestimulated bladder.

Material And Methods: Female Wistar rats were injected with intraperitoneal CYP (100mg/kg) or saline respectively. Rats were treated with BWDHW (90mg/kg/day) or vehicle for the next five days. After treatments animals were evaluated both in metabolic cage model and then by cystometry. Acidic ATP solution (5mM, pH 3.3) was instilled to provoke bladder hyperactivity. Bladder mucosa and muscle proteins were assessed by Western blotting.

Results: As compared to the controls, the CYP group showed significantly decreased mean cystometric intercontractile interval and increased micturition frequency, whereas the CYP/BWDWH group did not. The CYP group had significant protein overexpression in mucosal M2, M3, P2X2, and P2X3 receptors as well as detrusor M2 and M3 receptors. However, the CYP/BWDWH group had insignificant changes from controls. In the provoking test, the control/BWDHW and CYP/BWDHW groups were less affected by acidic ATP stimulation of intercontractile interval changes than the control group. Compared to the control group, the control/BWDHW group showed significantly lower mucosal P2X3 protein expression and the CYP group showed significant mucosal TRPV1 protein upregulation after the provoking test.

Conclusion: BWDHW treatment can ameliorate CYP-induced ongoing bladder overactivity and suppress mucosal P2X2, P2X3, M2, and M3 receptor protein overexpression, as well as detrusor M2 and M3 receptor protein overexpression. BWDHW pretreatment can reduce acidic ATP solution-provoked hyperactivity by preventing TRPV1 receptor overexpression in CYP-treated bladder mucosa and inhibiting P2X3 receptor overexpression in naïve bladder mucosa.
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http://dx.doi.org/10.1016/j.jep.2015.12.026DOI Listing
May 2016

Maternal fructose-intake-induced renal programming in adult male offspring.

J Nutr Biochem 2015 Jun 26;26(6):642-50. Epub 2015 Feb 26.

Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan. Electronic address:

Nutrition in pregnancy can elicit long-term effects on the health of offspring. Although fructose consumption has increased globally and is linked to metabolic syndrome, little is known about the long-term effects of maternal high-fructose (HF) exposure during gestation and lactation, especially on renal programming. We examined potential key genes and pathways that are associated with HF-induced renal programming using whole-genome RNA next-generation sequencing (NGS) to quantify the abundance of RNA transcripts in kidneys from 1-day-, 3-week-, and 3-month-old male offspring. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with HF (60% diet by weight) during the entire period of pregnancy and lactation. Male offspring exhibited programmed hypertension at 3 months of age. Maternal HF intake modified over 200 renal transcripts from nephrogenesis stage to adulthood. We observed that 20 differentially expressed genes identified in 1-day-old kidney are related to regulation of blood pressure. Among them, Hmox1, Bdkrb2, Adra2b, Ptgs2, Col1a2 and Tbxa2r are associated with endothelium-derived hyperpolarizing factor (EDHF). NGS also identified genes in arachidonic acid metabolism (Cyp2c23, Hpgds, Ptgds and Ptges) that may be potential key genes/pathways contributing to renal programming and hypertension. Collectively, our NGS data suggest that maternal HF intake elicits a defective adaptation of interrelated EDHFs during nephrogenesis which may lead to renal programming and hypertension in later life. Moreover, our results highlight genes and pathways involved in renal programming as potential targets for therapeutic approaches to prevent metabolic-syndrome-related comorbidities in children with HF exposure in early life.
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http://dx.doi.org/10.1016/j.jnutbio.2014.12.017DOI Listing
June 2015
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