Search

Objective: We investigated the association between overactive bladder (OAB) and urinary metabolites in men. Methods: This prospective observational study included 42 men aged 65–80 years. The 3-day frequency volume chart (FVC), International Prostate Symptom Score (IPSS), and quality of life score were adapted to assess the micturition behavior. Participants with IPSS urgency score ≥2 were included in the OAB group, and those with IPSS urgency score t test and Fisher’s exact test in a nonadjusted analysis. Multivariable logistic regression analysis was performed to investigate the association between OAB and the metabolites. Results: Overall, 23 men were included in the OAB group and 19 in the control group. There were no differences in the background factors except age between the groups. FVC analysis demonstrated that nocturnal urine volume, 24-h micturition frequency, and nocturnal micturition frequency were significantly higher, and the maximum voided volume was significantly lower in the OAB group than in the controls. Metabolomic analysis revealed 14 metabolites that were differentially expressed between the groups. Multivariate analysis indicated that an increase in the levels of 5-iso prostaglandin F2α-VI (5-iPF2a-VI) and 5-methoxyindoleacetic acid was associated with OAB. Conclusion: Abnormal urinary metabolites, including metabolites in the tryptophan (5-methoxyindoleacetic acid, 3-indoleacetonitrile, and 3-hydroxyanthranilic acid) and arachidonic acid (5-iPF2a-VI) pathways, play a role in the pathogenesis of OAB in older men.

OBJECTIVE To evaluate the efficacy and safety of onabotulinumtoxinA (botulinum toxin type A) 100 U in patients with overactive bladder and urinary incontinence. METHODS This was a phase III, randomized, double-blind, placebo-controlled trial in Japanese patients who were inadequately managed with overactive bladder medications (anticholinergics and/or β3 -adrenergic receptor agonists). Eligible patients were randomized 1:1 to receive a single dose of either onabotulinumtoxinA or placebo into the detrusor muscle (n = 124 each). The primary end-point was the change in the number of daily urinary incontinence episodes at week 12 from baseline. Secondary end-points included volume voided per micturition, other symptomatic measures (urinary urgency incontinence, micturition, urgency and nocturia) and patient-reported outcomes. RESULTS In the onabotulinumtoxinA group, there was a significantly greater decrease from baseline in the mean number of daily urinary incontinence episodes compared with the placebo group (2.16; P

To investigate the association between nocturia and urinary metabolites in elderly men using metabolomic analysis. We recruited 66 men aged 65–80 years. The 3-day frequency volume chart (FCV), International Prostate Symptom Score (IPSS), and quality of life score were used to assess micturition behavior. Participants with the total IPSS > 0 and ≥ 1.5 micturition on an average for three nights were included in the nocturia group. Participants with the total IPSS

Purpose Several complications of robot-assisted partial nephrectomy (RAPN) have been reported; however, there are limited data on thoracic findings and complications. We investigated the risk factors for atelectasis or pneumomediastinum after robot-assisted partial nephrectomy. Methods This retrospective cohort study included 84 consecutive patients who underwent robot-assisted partial nephrectomy with the da Vinci Si System and the AirSealTM Insufflation System. Based on chest radiography findings obtained postoperatively in the operating room, patients with and without atelectasis or pneumomediastinum were categorized into Groups A and B, respectively. Patient characteristics (age, sex, body mass index (BMI), RENAL nephrometry score, tumor size, and surgical approach) and perioperative outcomes (total operative time, console time, warm ischemic time, and estimated blood loss) were compared using the Mann-Whitney U test and chi-square test. A multivariate logistic regression analysis was performed to identify the risk factors associated with atelectasis or pneumomediastinum. Results Groups A and B included 31 and 53 patients, respectively. Although the rate of the retroperitoneal approach was significantly higher in Group A than in Group B, the other parameters and perioperative outcomes did not differ. The multivariate logistic regression analysis showed that the retroperitoneal approach and high body mass index were risk factors for atelectasis or pneumomediastinum after robot-assisted partial nephrectomy. However, these abnormal findings disappeared spontaneously without requiring postoperative treatment. Conclusions The retroperitoneal approach and high body mass index may be risk factors for atelectasis or pneumomediastinum after robot-assisted partial nephrectomy.

Background: Laparoscopic adrenalectomy (LA) is the standard treatment for adrenal benign tumors, including primary aldosteronism (PA) or Cushing's syndrome (CS). Several obesity-related factors wer...

The present study was conducted to identify metabolites using a metabolomics approach and investigate the relationship between these metabolites and urgency as a major symptom of overactive bladder (OAB). In 47 male participants without any apparent neurological disease, OAB was defined as an urgency score on the International Prostate Symptom Score of 2 and higher (OAB group, n = 26), while patients with a score of 1 or 0 were placed in a control group (n = 21). A comprehensive study on plasma metabolites was conducted, and metabolites were compared between the OAB and control groups. Age was significantly higher in the OAB group, while prostate volume did not differ between the groups. A 24-h bladder diary revealed that nocturnal urine volume, 24-h micturition frequency, nocturnal micturition frequency, and the nocturnal index were significantly higher in the OAB group, whereas maximum voided volume was significantly lower in this group. The metabolomics analysis identified 79 metabolites from the plasma of participants. The multivariate analysis showed that increases in the fatty acids (22:1), erucic acid and palmitoleic acid, and a decrease in cholic acid correlated with incidence of male OAB. A decrease in acylcarnitine (18:2)-3 and an increase in cis-11-eicosenoic acid also appeared to be associated with OAB in males. OAB in males may occur through the abnormal metabolism of fatty acids and bile acids. Further studies on these pathways will contribute to the detection of new biomarkers and development of potential targets for novel treatments.

Intermittent stress disrupts the circadian rhythm in clock genes such as Per2 only in peripheral organs without any effect on the central circadian clock in the suprachiasmatic nucleus. Here, the effect of restraint stress (RS) on circadian bladder function was investigated based on urination behavior and gene expression rhythms. Furthermore, PF670462 (PF), a Per2 phosphorylation enzyme inhibitor, was administered to investigate the effects on circadian bladder re-alignment after RS. Two-hour RS during the light (sleep) phase was applied to mice (RS mice) for 5 days. The following parameters were then examined: urination behaviors; clock gene expression rhythms and urinary sensory-related molecules such as piezo type mechanosensitive ion channel component 1 (Piezo1), transient receptor potential cation channel subfamily V member 4 (TRPV4), and Connexin26 (Cx26) in the bladder mucosa; Per2 expression in the excised bladder of Per2luciferase knock-in mice (Per2::luc); in vivo Per2 expression rhythms in the bladder of Per2::luc mice. Control mice did not show altered urination behavior in the light phase, whereas RS mice exhibited a higher voiding frequency and lower bladder capacity. In the bladder mucosa, RS mice also showed abrogated or misaligned Piezo1, TRPV4, Connexin26, and clock gene expression. The rhythmic expression of Per2 was also altered in RS mice both in excised- and in vivo bladder, compared with control mice. After PF administration, voiding frequency was reduced and bladder capacity was increased during the light phase in RS mice; the in vivo Per2 expression rhythm was also fully restored. Therefore, RS can alter circadian gene expression in the bladder during the light phase and might cause nocturia via changes in circadian bladder function due the dysregulation of clock genes. Amending the circadian rhythm therapeutically could be applied for nocturia.

Objectives Nocturia is a major problem in geriatric patients. Clock genes regulate circadian bladder function and Piezo type mechanosensitive ion channel component 1 (Piezo1) that senses bladder fullness. We utilized WT and Clock mutant (ClockΔ19/Δ19: nocturia phenotype) mice to determine if the effects of GsMTx4, a Piezo1 inhibitor, is dependent on circadian Piezo1 expression in the bladder. Methods We compared voiding behavior in mice after the administration of vehicle, low dose, or high dose of GsMTx4. Intraperitoneal injections (IP) were performed at Zeitgeber time (ZT) 0, lower Piezo1 expression phase (ZT0-IP) and ZT12, higher Piezo1 expression phase (ZT12-IP). Urine volume (Uvol), voiding frequency (VF), and urine volume per void (Uvol/v) were measured using metabolic cages. Results VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in ClockΔ19/Δ19 mice. VF decreased significantly at ZT0-IP in WT mice after both doses, but only decreased after high dose in ClockΔ19/Δ19 mice. Uvol/v increased in WT mice at ZT0-IP after both doses and at ZT12-IP after high dose. Uvol/v increased in ClockΔ19/Δ19 mice only at ZT0-IP after high dose. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP. Conclusions The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level. The maximum effect occurred during sleep phase in WT. These results may lead to new therapeutic strategies against nocturia.

Distant urethral metastasis of the castration-resistant prostate cancer (CRPC) is very rare. In this case report, we present a 69-year-old man who was first diagnosed prostate cancer from the sessile papillary tumor in the prostatic urethra which recurred after surgery and androgen deprivation therapy and finally treated with CyberKnife radiosurgery. There has been no recurrence for 50 months. To the best of our knowledge, there is no case of urethral metastasis of the CRPC successfully controlled with CyberKnife radiosurgery in the literature.

INTRODUCTION AND OBJECTIVE:It is reported that the bladder functions are under the regulation of clock genes, which regulate circadian rhythm in organisms, and dysregulation of circadian bladder fu...

A thirty-eight-year-old man presented with acute urinary retention due to a long complicated strictures between the meatus and the bulbar urethra. During the first surgery, in addition to the penile skin flap, the flap of the incised skin at 10mm outside the scrotum strip-like tissue was moved medially and sutured onto the incised urethra. After 12 months of the first surgery, we performed the urethroplasty from the bulbar urethra to the meatus. Postoperatively, the patient voided without complications. Thus, this technique using a skin flap outside the scrotum is effective in long complicated urethral strictures.

Aims The sensation of bladder fullness (SBF) is triggered by the release of ATP. Therefore, the aim of this study was to investigate whether time-dependent changes in the levels of stretch-released ATP in mouse primary-cultured urothelial cells (MPCUCs) is regulated by circadian rhythm via clock genes. Methods MPCUCs were derived from wild-type and Clock mutant mice (ClockΔ19/Δ19 ), presenting a nocturia phenotype. They were cultured in elastic silicone chambers. Stretch-released ATP was quantified every 4 h by ATP photon count. An experiment was also performed to determine whether ATP release correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Connexin26 (Cx26) in MPCUCs regulated by clock genes with circadian rhythms. MPCUCs were treated with carbenoxolone, an inhibitor of gap junction protein; were derived from VNUT-KO mice; or treated with Piezo1-siRNA, TRPV4-siRNA, and Cx26-siRNA. Results Stretch-released ATP showed time-dependent changes in wild-type mice and correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Cx26. However, these rhythms were disrupted in ClockΔ19/Δ19 mice. Carbenoxolone eliminated the rhythmicity of ATP release in wild-type mice. However, time-dependent ATP release changes were maintained when a single gene was deficient such as VNUT-KO, Piezo1-, TRPV4-, and Cx26-siRNA. Conclusions ATP release in the bladder urothelium induces SBF and may have a circadian rhythm regulated by the clock genes. In the bladder urothelium, clock gene abnormalities may disrupt circadian ATP release by inducing Piezo1, TRPV4, VNUT, and Cx26. All these genes can trigger nocturia.

Objectives To identify metabolites that are associated with an overactive bladder (OAB) using metabolomics. Materials and Methods A total of 58 male patients without apparent neurologic disease completed 24-hour bladder diaries of their micturition behavior and International Prostate Symptom Score (IPSS) for the assessment of micturition behavior and lower urinary tract symptoms. Urgency was defined as an IPSS urgency score of ≥2 (OAB group), and patients with IPSS urgency scores of ≤1 belonged to the control group. A comprehensive study of plasma metabolites was also conducted using capillary electrophoresis time-of-flight mass spectrometry. Metabolite levels were compared between the control and OAB groups using the Mann-Whitney U test. Potential metabolite biomarkers were selected using multivariate logistic regression analysis. Results Of the 58 subjects, the control and OAB groups consisted of 32 and 26 male patients, respectively. Nocturnal urinary volume, 24-hour micturition frequency, nocturnal micturition frequency, and the nocturia index were significantly higher in the OAB group. Metabolomic analysis revealed 60 metabolites in the subjects' plasma. The levels of 11 metabolites differed between the control and OAB groups. Multivariate analysis showed that an increased glutamate level and reduced arginine, glutamine, and inosine monophosphate levels are significantly associated with OAB in male patients. Reduced levels of asparagine and hydroxyproline could also be associated with OAB. Conclusions Urgency is associated with abnormal metabolism. Analyses of amino acid profiles might aid the search for new treatment targets for OAB.

We previously showed that bladder functions are controlled by clock genes with circadian rhythm. The sensation of bladder fullness (SBF) is sensed by mechano-sensor such as Piezo1 and TRPV4 in the mouse bladder urothelium. However, functional circadian rhythms of such mechano-sensors remain unknown. To investigate functional circadian changes of these mechano-sensors, we measured circadian changes in stretch-evoked intracellular Ca2+ influx ([Ca2+] i ) using mouse primary cultured urothelial cells (MPCUCs). Using Ca2+ imaging, stretch-evoked [Ca2+] i was quantified every 4 h in MPCUCs derived from wild-type (WT) and Clock Δ19/Δ19 mice, which showed a nocturia phenotype. Furthermore, a Piezo1 inhibitor GsMTx4 and a TRPV4 inhibitor Ruthenium Red were applied and stretch-evoked [Ca2+] i in MPCUCs was measured to investigate their contribution to SBF. Stretch-evoked [Ca2+] i showed a circadian rhythm in the WT mice. In contrast, Clock Δ19/Δ19 mice showed disrupted circadian rhythm. The administration of both GsMTx4 and Ruthenium Red eliminated the circadian rhythm of stretch-evoked [Ca2+] i in WT mice. We conclude that SBF may have a circadian rhythm, which is created by functional circadian changes of Piezo1 and TRPV4 being controlled by clock genes to be active during wakefulness and inactive during sleep. Abnormalities of clock genes disrupt SBF, and induce nocturia.

Aims To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. Methods PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques. We also evaluated stretch-induced changes in ATP concentration in the mouse bladder in the presence or absence of 100 µM tadalafil. Results Immunochemistry and western blot analyses demonstrated that PDE5 is abundantly expressed in the bladder urothelium and in primary rat urothelial cells. Ca2+ influx induced by hypotonic stimulation, GSK1016790A, or cannabidiol was significantly inhibited by tadalafil, whereas ATP-induced Ca2+ influx was unaffected by tadalafil. PIP2 did not induce Ca2+ influx. ATP release in tadalafil-pretreated bladders significantly decreased compared to control bladders. Conclusions Tadalafil attenuates Ca2+ influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction.

Introduction: To investigate the association between bladder capacity and the urine production rate in aged men with or without nocturia using a frequency volume chart (FVC). Materials and Methods: One-hundred and thirty-eight men aged 65–80 years were enrolled. After the International Prostate Symptom Score (IPSS) and 3 consecutive days FVC were evaluated, men were divided into 2 groups: Nocturia group, with any total IPSS, and ≥1.5 micturition on average at night; and Control group, with total IPSS < 8 and < 1.5 micturition on average at night. Each parameter was compared between the 2 groups using unpaired t tests. Linear and multiple regression analyses were performed between the urine production rate and volume/voids. Results: Men numbering 45 and 21 were assigned to the Nocturia and Control groups respectively. There were no differences in background factors between the 2 groups. Volume/voids positively correlated with the urine production rate in both groups for day and night. A multivariate regression model also showed the same results. In the Control group, the degree of slope at night was higher than that during the day. However, in the Nocturia group, there were no differences in the degree of slope between day and night. Conclusions: This novel finding has led to a possibility for resolving nocturia.

Aims To investigate circadian gene expressions in the mouse bladder urothelium to establish an experimental model and study the functions of the circadian rhythm. Methods The gene expression rhythms of the clock genes, mechano-sensors such as Piezo1 and TRPV4, ATP release mediated molecules (ARMM) such as Cx26 and VNUT were investigated in mouse primary cultured urothelial cells (UCs) of wild-type (WT) and Clock mutant (ClockΔ19/Δ19) mice using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis. The long-term oscillation of the clock genes in UC was investigated by measuring bioluminescence from UC isolated from Period2luciferase knock-in mice (Per2::luc) and Per2::luc with ClockΔ19/Δ19 using a luminometer. The mRNA expression rhythms after treatment with Clock short interfering RNA (siRNA) were also measured to compare differences between Clock point mutations and Clock deficiency. Results The UCs from WT mice showed the time-dependent gene expressions for clock genes, mechano-sensors, and ARMM. The abundances of the products of these genes also correlated with the mRNA expression rhythms in UCs. The bioluminescence of Per2::Luc in UCs showed a circadian rhythm. By contrast, all the gene expressions rhythms observed in WT mice were abrogated in the ClockΔ19/Δ19 mice. Transfection with Clock siRNA in UCs had the same effect as the Clock mutation. Conclusions We demonstrated that the time-dependent gene expressions, including clock genes, mechano-sensors, and ARMM, were reproducible in UCs. These findings demonstrated that UCs have the potential to progress research into the circadian functions of the lower urinary tract regulated by clock genes.

We encountered a 12-year-old boy who had lower urinary tract dysfunction and high-grade vesicoureteral reflux (VUR) in a bilateral duplex system. Since febrile urinary tract infections (f-UTI) frequently occurred even after intermittent catheterization, we performed bladder augmentation and an anti-reflux procedure, reimplanting the four dilated ureters into the afferent ileal limb without creating a submucosal tunnel. The VUR was improved, and no f-UTI were seen after the surgery. The described anti-reflux procedure, which is based on bowel peristalsis, seems to be a feasible treatment for VUR in patients who undergo augmentation cystoplasty. Keywords: Augmentation, VUR, Bowel peristalsis

Background To investigate the feasibility of the fourth arm of the da Vinci Si system for robot-assisted partial nephrectomy (RAPN). Methods Fifty-eight consecutive patients underwent RAPN with the same port placements. After reviewing the surgical videos and records, 38 patients showing usefulness of the fourth arm were categorized into Group A and those not showing usefulness into Group B. The background data, tumor characteristics, and perioperative outcomes were compared between the groups. Results Group B had a larger proportion of tumors located on the inner side of the kidney, and the console time was significantly longer. Multivariable logistic regression analysis showed that tumors located on the inner side of the kidney were associated with the non-use of the fourth arm of the da Vinci Si system during RAPN. Conclusions Our findings suggested that use of fourth arm in RAPN by da Vinci Si should be considered for each tumor location.

Gap junctions (Gjs), formed by specific protein termed connexins (Cxs), regulate many important cellular processes in cellular immunity. However, little is known about their effects on humoral immunity. Here we tested whether and how Gj protein connexin43 (Cx43) affected antibody production in spleen cells. Detection of IgG in mouse tissues and serum revealed that wild-type (Cx43+/+) mouse had a significantly higher level of IgG than Cx43 heterozygous (Cx43+/&minus, ) mouse. Consistently, spleen cells from Cx43+/+ mouse produced more IgG under both basal and lipopolysaccharide (LPS)-stimulated conditions. Further analysis showed that LPS induced a more dramatic activation of ERK and cell proliferation in Cx43+/+ spleen cells, which was associated with a higher pro-oxidative state, as indicated by the increased NADPH oxidase 2 (NOX2), TXNIP, p38 activation and protein carbonylation. In support of a role of the oxidative state in the control of lymphocyte activation, exposure of spleen cells to exogenous superoxide induced Cx43 expression, p38 activation and IgG production. On the contrary, inhibition of NOX attenuated the effects of LPS. Collectively, our study characterized Cx43 as a novel molecule involved in the control of spleen cell activation and IgG production. Targeting Cx43 could be developed to treat certain antibody-related immune diseases.

INTRODUCTION AND OBJECTIVES:The objective of this study was to evaluate the influence of ingested L-citrulline and L-arginine on the progression of bladder dysfunction in rats with chronic pelvic i...

Background: Our aim was to investigate the association between serum metabolites and nocturia. Methods: A total of 66 males aged 65–80 years were enrolled in this study and stratified according to micturition behavior, which was characterized in terms of the 24 h frequency volume chart (FVC) for 3 consecutive days, the International Prostate Symptom Score (IPSS), and quality-of-life score. The nocturia group included participants with any total IPSS and ⩾1.5 micturitions/night as the mean of 3 nights, while the control group included participants with total IPSS < 8 and Results: Of 66 participants, 45 were included in the nocturia group and 21 in the control group. There were no differences in background factors between the two groups. FVC analysis revealed that urine production during night-time, as well as micturition frequency during daytime and night-time were significantly higher in the nocturia group. CE-TOFMS identified eight metabolites whose plasma levels differed between the two groups. Multivariate analysis indicated that increased levels of lauric acid and imidazolelactic acid, as well as decreased levels of thiaproline and glycerol, contribute to the etiology of nocturia in aged men. Conclusions: Our findings suggest that abnormal serum levels of metabolites in several pathways play a role in the pathogenesis of nocturia in aged men.

Aims The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (ClockΔ19/Δ19) mice in order to determine the effects of clock genes on NOC/NP. Methods Male C57BL/6 mice aged 8–12 weeks (WT) and male C57BL/6 ClockΔ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods. Results No significant differences were observed in behavior patterns between ClockΔ19/Δ19 and WT mice. ClockΔ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in ClockΔ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in ClockΔ19/Δ19 mice than in WT mice. Conclusions We demonstrated that ClockΔ19/Δ19 mice showed the phenotype of NOC/NP. The ClockΔ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. © 2016 Wiley Periodicals, Inc.

Background: Bilateral adrenal tumors are not common in clinical practice, but are an important source of ectopic adrenocorticotropic hormone (ACTH) secretion. Standard operative management for bilateral pheochromocytomas might dictate the removal of the involved adrenal gland and the removal of the contralateral adrenal gland. We present a case of bilateral ACTH-secreting pheochromocytoma treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy. Case Presentation: A 58-year-old male with elevated hyperglycemia and general fatigue was hospitalized for pneumonia. CT incidentally revealed bilateral adrenal tumor. Biochemical examination was significant for elevated urinary metanephrine and normetanephrines, and plasma catecholamine level. CT scan of the head, neck, thorax, and pelvis was normal. Under the clinical diagnosis of ACTH-dependent pheochromocytoma, laparoscopic right total adrenalectomy was performed. As endocrinologic examination showed residual ACTH-dependent pheochromocytoma after surgery, laparoscopic left subtotal adrenalectomy was performed. Pathology analysis revealed pheochromocytoma with stained ACTH lesions in both adrenal tumors. Conclusion: This is a rare case of ACTH-secreting bilateral pheochromocytoma effectively treated with staged laparoscopic unilateral total and contralateral subtotal adrenalectomy, in which the production of ACTH was confirmed by immunohistochemical staining.

Hydrogen sulfide (H2S) is a gaseous mediator with multifaceted biological activities. It has anti-inflammatory and anti-oxidative effects. Currently, the mechanisms are not fully understood. Given that Trx/ASK1/P38 signaling pathway mediates many oxidative cell responses, we tested whether and how H2S affected this pathway. Exposure of podocytes to Adriamycin (ADR), an antitumor drug, led to a P38-mediated oxidative cell injury, as evidenced by the increased protein carbonylation, oxidative activation of P38, and prevention of the cell death by antioxidants, NADPH oxidase inhibitor and P38 inhibitor. In the presence of H2S donor NaHS, however, the podocyte injury was largely prevented. NaHS also significantly prevented cell death elicited by H2O2, menadione, and thioredoxin (Trx) inhibitors. These effects of H2S were also associated with a potent inhibition of P38. Further analysis revealed that H2S did not affect the protein level of TXNIP and Trx, two pivotal regulators of ASK1/P38 activation, but it promoted the dissociation of Trx from TXNIP. Moreover, it disrupted the H2O2-initiated polymerization of Trx and converted Trx from the oxidized to the reduced form. In HepG2 cells, inhibition of H2S-producing enzyme cystathionine γ-lyase (CSE) increased Trx oxidation, promoted Trx binding to TXNIP and exaggerated cell injury caused by Trx inhibition. Collectively, our results indicate that H2S exerted its antioxidative effects through the regulation of the redox state of Trx and interference with Trx/ASK1/P38 signaling pathway. Given the importance of the pathway in the mediation of multiple oxidative cell responses, our study thus provides novel mechanistic insight into the action of H2S.