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Background Patients with cancer are treated with chemotherapeutics that cause adverse effects, including erectile dysfunction (ED). Objectives We investigated erectile function in rats after the administration of anticancer agents based on data retrieved through mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database. Materials and methods The statistical signal strength for the association between anticancer drugs and ED was calculated using the reporting odds ratio (ROR). A drug-event combination was detected when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1.00. Rats were administered anticancer agents detected in the FDA AERS analysis. Erectile function was assessed using intracavernous pressure (ICP) and mean arterial pressure (MAP) analysis after electrical stimulation of the cavernous nerve. Statistical significance was determined using Welch's t-test or two-way ANOVA. Results Melphalan (L-PAM; ROR = 4.72, 95% CI = 2.78-8.00), vincristine (VCR; ROR = 2.47, 95% CI = 1.54-3.97), docetaxel (DTX; ROR = 2.25, 95% CI = 1.28-3.95), methotrexate (MTX; ROR = 1.96, 95% CI = 1.39-2.75), and doxorubicin (DOX; ROR = 1.82, 95% CI = 1.07-3.19) enhanced ED risk. L-PAM and MTX decreased the ICP/MAP ratio 1 week after administration. VCR and DOX decreased erectile function 4 weeks after administration. DTX decreased erectile function at all assessed time points. Discussion and conclusion Certain anticancer agents should be considered risk factors for ED. Our results provide possible treatment strategies for maintaining erectile function in cancer survivors, including careful erectile function monitoring after treatment.

We aimed to investigate detrusor function in a previously developed rat neurogenic voiding dysfunction model that we have developed previously. We performed sham or bilateral accessory nerve injury (BACNI) surgeries on ten-week-old male Wistar/ST rats. One week after surgery, we evaluated detrusor contractility in the bladder using isometric tension and mRNA expression assays. Cholinergic contraction was attenuated in the injury model, whereas carbachol-evoked contraction was enhanced, and mRNA expression of the cholinergic receptor increased. These findings suggest that there was a reduction in neurotransmitter release causing detrusor underactivity.

Purpose Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three‐dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the status of regulatory signals for such abnormality are also performed. Methods To analyze the 3D structure of sinusoid, 3D reconstruction from serial sections of murine CC were performed. Histological analyses between young (2 months old) and aged (14 months old) CC were performed. As for chondrogenic signaling status of aged CC, SOX9 and RBPJK staining was examined. Results Sinusoids prominently developed in the outer regions of CC adjacent to tunica albuginea. Aged CC samples contained ectopic chondrocytes in such regions. Associating with the appearance of chondrocytes, the expression of SOX9, chondrogenic regulator, was upregulated. The expression of RBPJK, one of the Notch signal regulators, was downregulated in the aged CC. Conclusions Prominent sinusoids distribute in the outer region of CC which may possess important roles for erection. A possibility of ectopic chondrogenesis induced by alteration of SOX9/Notch signaling with aging is indicated.

Male penis is required to become erect during copulation. In the upper (dorsal) part of penis, the erectile tissue termed corpus cavernosum (CC) plays fundamental roles for erection by regulating the inner blood flow. When blood flows into the CC, the microvascular complex termed sinusoidal space is reported to expand during erection. A novel in vitro explant system to analyze the dynamic erectile responses during contraction/relaxation is established. The current data show regulatory contraction/relaxation processes induced by phenylephrine (PE) and nitric oxide (NO) donor mimicking dynamic erectile responses by in vitro CC explants. Two-photon excitation microscopy (TPEM) observation shows the synchronous movement of sinusoidal space and the entire CC. By taking advantages of the CC explant system, tadalafil (Cialis) was shown to increase sinusoidal relaxation. Histopathological changes have been generally reported associating with erection in several pathological conditions. Various stressed statuses have been suggested to occur in the erectile responses by previous studies. The current CC explant model enables to analyze such conditions through directly manipulating CC in the repeated contraction/relaxation processes. Expression of oxidative stress marker and contraction-related genes, Hypoxia-inducible factor 1-alpha (Hif1a), glutathione peroxidase 1 (Gpx1), Ras homolog family member A (RhoA), and Rho-associated protein kinase (Rock), was significantly increased in such repeated contraction/relaxation. Altogether, it is suggested that the system is valuable for analyzing structural changes and physiological responses to several regulators in the field of penile medicine.

AIMS To investigate the relationship between lower urinary tract function and the accessory nerve (ACN) arising from the major pelvic ganglion (MPG). METHODS Ten-week-old male Wistar/ST rats were randomly divided into eight groups according to the type of treatment (sham or bilateral accessory nerve injury [BACNI]) and the duration of observation (3 days, 1 week, 2 weeks, or 4 weeks: Sham-3d, Sham-1w, Sham-2w, Sham-4w, BACNI-3d, BACNI-1w, BACNI-2ws, and BACNI-4w. BACNI was induced in the following manner: the ACN was crushed for 1 min (2 mm away from the MPG) using reverse-action tweezers. The same procedure was performed on both sides. On the last day of each observation period, the bladder function was measured by awake cystometry, and histological evaluation was performed. RESULTS All rats in the Sham groups micturated normally. In the BACNI-3d and BACNI-1w groups, all rats showed symptoms of overflow urinary incontinence (OUI). This OUI improved gradually over time. The bladder's size in the BACNI group was significantly larger than that in the Sham group (p

AIMS To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P

Stress is a risk factor for erectile dysfunction (ED); however, the pathology of stress‐induced ED remains unclear. Accordingly, in this study, we investigated the mechanisms of stress‐induced ED using a rat model. Ten‐week‐old male Wistar/ST rats were maintained in a cage filled with water to a height of 2 cm (stress group) or a normal cage (control group). We found that water immersion stress significantly enhanced the contractile response to noradrenaline in the corpus cavernosum (CC) (p, Water immersion stress significantly enhanced contractile response in the corpus cavernosum (CC), decreased erectile function, and also upregulated RhoA/Rho kinase pathway in the CC. Fasudil, a Rho kinase inhibitor, improved erectile function. Our findings suggest that RhoA/Rho kinase pathway may be associated with stress‐induced erectile dysfunction via contraction of CC.

During chemotherapy, hyponatremia is one of the most frequently encountered adverse effects. This study aimed to investigate the prognostic impact of hyponatremia induced by systemic chemotherapy (HIC) using a propensity matching method in cumulative pooled data. Between January 2011 and July 2017, 2129 patients were administered systemic chemotherapy for malignancy in various organs at Nagoya City University Hospital. Patients were divided into two groups: a grade 0–1 group (control group) and a grade 3–4 group (severe group) according to the severity of HIC appearing within 30 days after starting treatment. Kaplan–Meier curves were used for survival and recurrence analyses using a propensity case-matched analysis. The number of severe HIC patients was 93 (4.4%). In platinum-containing regimens, HIC appeared at higher frequencies. In the 21.2 months median follow-up period, the median OS (mOS) in the severe group was 49.1 months, which was significantly worse than the mOS in the control group; the OS in the control group did not reach the median. Univariate and multivariate analyses of associated factors in patients with grade 3–4 HIC revealed that renal dysfunction, cisplatin-containing regimen, and infusion of more than 5000 mL fluid was associated with HIC. This study suggests that severe HIC in the first treatment cycle affects survival time. Chemotherapy patients receiving extensive hydration should be required to undergo frequent monitoring of serum sodium levels, especially patients receiving platinum-containing regimens.

Introduction Testosterone deficiency is known to induce endothelial dysfunction, which can lead to erectile dysfunction and/or vascular dysfunction. In some basic and clinical reports, testosterone has been shown to regulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and thereby influence endothelial function and endothelial progenitor cells (EPCs), which are key for the endothelial repair system. Aim To review the association between testosterone and endothelial dysfunction focusing on NO and EPCs. Methods A review of relevant literature up to September 2018 was performed via PubMed. Main Outcome Measures We reviewed the association between testosterone and endothelial dysfunction focusing on NO derived from endothelial NO synthase, phosphodiesterase type 5 (PDE-5), asymmetric dimethylarginine (ADMA), inflammation, and EPCs. Results Numerous articles describing the association between testosterone deficiency and endothelial dysfunction have been published. Some reports have shown that testosterone deficiency decreases NO production by altering the expression and activity of NO synthase and by regulating ADMA expression. Testosterone also regulates the expression of phosphodiesterase type 5. In addition, some basic and clinical studies have shown that testosterone affects the function and number of EPCs. However, some inconsistencies among these reports have been noted. Conclusion Testosterone deficiency might cause endothelial dysfunction by decreasing NO levels through regulating the expression and activity of NO synthase and increasing ADMA expression. In addition, testosterone might affect the endothelial repair system by regulating the proliferation and migration of EPCs. Testosterone replacement therapy might be useful for treating endothelial dysfunction, considering that some reports have shown that this therapy improved NO bioavailability and EPC function. Hotta Y, Kataoka T, Kimura K. Testosterone Deficiency and Endothelial Dysfunction: Nitric Oxide, Asymmetric Dimethylarginine, and Endothelial Progenitor Cells. Sex Med Rev 2019;7:661–668.

The photochemically-induced thrombosis(photothrombosis) method can create focal cerebral infarcts anywhere in the relatively superficial layers of the cerebrum; it is easy to implement and minimally invasive. Taking advantage of this versatility, we aimed to establish a new rat model of urinary frequency with focal cerebral infarction, which was characterized by its simplicity, nonlethal nature, and high reproducibility. The prefrontal cortex and the anterior cingulate cortex, which are urinary centers, were targeted for focal cerebral infarction, and urinary parameters were measured by cystometrogram. Cystometric analysis indicated that micturition intervals significantly shortened in photothrombosis-treated rats compared with those in the sham operative group on Days 1 and 7 (P < 0.01), but prolonged after 14 days, with no difference between the two groups. Immunopathological evaluation showed an accumulation of activated microglia, followed by an increase in reactive astrocytes at the peri-infarct zone after photothrombotic stroke. Throughout this study, all postphotothrombosis rats showed cerebral infarction in the prefrontal cortex and anterior cingulate cortex; there were no cases of rats with fatal cerebral infarction. This model corresponded to the clinical presentation, in that the micturition status changed after stroke. In conclusion, this novel model combining nonlethality and high reproducibility may be a suitable model of urinary frequency after focal cerebral infarction.

Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). Results AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. Conclusion This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.

High salt intake has been reported as a risk factor for urinary storage symptoms. However, the association between high salt intake and detrusor muscle contraction is not clear. Therefore, we investigated the effects of high salt intake on the components of detrusor muscle contraction in rats. Six-week-old male Dahl salt-resistant (DR, n = 5) and Dahl salt-sensitive (DS, n = 5) rats were fed a high salt (8% NaCl) diet for one week. The contractile responses of the detrusor muscle to the cumulative administration of carbachol and electrical field stimulation (EFS) with and without suramin and atropine were evaluated via isometric tension study. The concentration–response curves of carbachol were shifted more to the left in the DS group than those in the DR group. Contractile responses to EFS were more enhanced in the DS group than those in the DR group (p &lt, 0.05). Cholinergic component-induced responses were more enhanced in the DS group than those in the DR group (p &lt, 0.05). High salt intake might cause urinary storage symptoms via abnormalities in detrusor muscle contraction and the enhancement of cholinergic signals. Excessive salt intake should be avoided to preserve bladder function.

Androgens are essential for male physical activity. Age-related androgen deficiency, known as late-onset hypogonadism (LOH), is considered a risk factor for several diseases. There are many men’s health supplements on the market. Therefore, the purpose of this review is to summarize the food ingredients that have been suggested in published literature to increase testosterone levels. A review of previously reported animal studies suggested that 5 representative nutritional components, 7 food ingredients, and 25 supplements were associated with testosterone. Some food and supplements influence testosterone levels in various animals by directly increasing testosterone or suppressing the decrease in testosterone production due to testicular toxicity. There are three mechanisms by which foods or supplements increase testosterone production: 1) regulating luteinizing hormone, the hormone that stimulates testosterone production, 2) regulating testosterone synthase in the testis, and 3) regulating testosterone-degrading enzymes. In contrast, suppressing the decrease in testosterone depends on the antioxidant effect of the foods. Although detailed mechanistic studies and clinical trials are required to validate these findings, the use of food to regulate testosterone levels is a promising therapeutic option.

The photochemically-induced thrombosis (photothrombosis) method can create focal cerebral infarcts anywhere in the relatively superficial layers of the cerebrum; it is easy to implement and minimally invasive. Taking advantage of this versatility, we aimed to establish a new rat model of urinary frequency with focal cerebral infarction, which was characterized by its simplicity, nonlethal nature, and high reproducibility. The prefrontal cortex and the anterior cingulate cortex, which are involved in lower urinary tract control, were targeted for focal cerebral infarction, and urinary parameters were measured by cystometrogram. Cystometric analysis indicated that micturition intervals significantly shortened in photothrombosis-treated rats compared with those in the sham operative group on Days 1 and 7 (P < 0.01), but prolonged after 14 days, with no difference between the two groups. Immunopathological evaluation showed an accumulation of activated microglia, followed by an increase in reactive astrocytes at the peri-infarct zone after photothrombotic stroke. Throughout this study, all postphotothrombosis rats showed cerebral infarction in the prefrontal cortex and anterior cingulate cortex; there were no cases of rats with fatal cerebral infarction. This model corresponded to the clinical presentation, in that the micturition status changed after stroke. In conclusion, this novel model combining nonlethality and high reproducibility may be a suitable model of urinary frequency after focal cerebral infarction.

Background Chemotherapeutics, one of the standard treatment options for cancer worldwide, have various adverse effects, including erectile dysfunction (ED). Aim To investigate erectile function in an animal model after administration of the anticancer agent oxaliplatin (L-OHP). Methods Male Wistar/ST rats were divided into 2 groups: L-OHP rats (n = 21), which were intravenously administered L-OHP (4 mg/kg; twice a week for 4 weeks), and Control rats (n = 21), which were injected with the same volume of 5% glucose solution, using the same dosing schedule. At the end of the study period, erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation (n = 9–10). Endothelial function was evaluated with an isometric tension study using corpus cavernosum strips (n = 11). Western blot analysis was used to assess neuronal nitric oxide (nNOS) and endothelial NO synthase (eNOS) protein levels (n = 7). Real-time quantitative polymerase chain reaction (qRT-PCR) was used to assess the expression of inflammation- and oxidative stress-related markers (nicotinamide adenine dinucleotide phosphate oxidase-1, p22phox, interleukin [IL]-6, and nuclear factor-kappa B) (n = 6). Statistical significance was determined using the Student’s t-test. Outcomes The L-OHP group had a significantly lower ICP:MAP ratio than the control group (P < .05). Compared to the Control group, the L-OHP group exhibited significantly lower responses to ACh and eNOS protein levels and significantly higher inflammatory biomarker levels. Clinical Translation The results based on this animal model indicate that use of the anticancer agent L-OHP should be considered as a risk factor for ED occurring via reduction of NO bioavailability in humans; our results provide possible treatment strategies for maintaining the erectile function of cancer survivors. Strengths and limitations Our study showed that the anticancer agent L-OHP has the propensity to cause ED in rats. A major limitation of this study is the lack of an established cure for ED associated with L-OHP and the lack of clinical evidence. CONCLUSIONS L-OHP causes ED in rats via reduction of NO bioavailability caused by endothelial dysfunction.

Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU–based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy. Significance: Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.

Phosphodiesterase 5 inhibitors are widely used to treat erectile dysfunction and lower urinary tract symptoms with benign prostatic hyperplasia. Recent studies have indicated the renoprotective effects of this class of compounds. Whether renoprotection depends on blood pressure reduction remains controversial. In this study, we investigated the renoprotective effects of the phosphodiesterase 5 inhibitor, tadalafil, in a rat model of high‐salt induced kidney injury with hypertension. Dahl salt‐sensitive rats were fed a normal diet, high‐salt (8% sodium chloride) diet, or high‐salt diet with oral administration of either low‐ or high‐dose tadalafil (1 and 10 mg kg−1 day−1, respectively). Serum creatinine, urinary protein, and blood pressure were measured at baseline and after 8 weeks, at which point the rats were examined for glomerular injury and fibrosis. PAI1 mRNA levels were also evaluated. After 8 weeks, blood pressure, serum creatinine, and urinary protein levels were significantly higher in the high‐salt group than those in the normal‐salt group. Serum creatinine and urinary protein were significantly lower in both tadalafil groups than those in the high‐salt group, while only high‐dose tadalafil affected blood pressure. In addition, glomerulosclerosis and α‐smooth muscle actin expression significantly decreased in both tadalafil treatment groups. PAI1 mRNA increased significantly in the high‐salt group but decreased in both tadalafil‐treated groups. Our results indicated that both low‐ and high‐dose tadalafil prevented fibrosis and glomerular injury in a chronic kidney disease rat model. Mechanistically, these effects may be associated with PAI1 expression and glomerular structure protection., A PDE5 inhibitor, Tadalafil is renoprotective by preventing glomerular injury and fibrosis from high blood pressure. This study suggest that Inhibition of PDE5 might be effective to delay the CKD progression.

Background Cancer-related neuropathic pain is sometimes unresponsive to multidrug treatment. Novel drugs are required to treat such severe pain without necessitating the use of adjuvant analgesics. Tapentadol is a new drug that has a dual mechanism as both an opioid agonist and noradrenalin reuptake inhibitor. The study objective was to investigate the effectiveness of oral tapentadol for relieving cancer-related neuropathic pain. Methods A retrospective, single-center, open, non-randomized study was conducted at the Nagoya City University Hospital. The study included 38 Japanese patients with advanced cancer who received opioids, such as tramadol, oral oxycodone and transdermal fentanyl, with or without adjuvant analgesics. Eastern Cooperative Oncology Group performance status, Numerical Rating Scale, primary tumor type, primary opioid and tapentadol doses, adjuvant analgesic prescriptions, outcomes and adverse events of opioid switching were assessed for 7 days. Results Eighteen (47.3%) out of 38 patients were enrolled in this study. The average performance status was 2.13 ± 0.94 (mean ± standard deviation). After switching to oral tapentadol, the pain score decreased from 3.78 to 2.78. The patients who had clinically improved effective pain scores had a higher percentage of prior opioid use for more than 2 months. After switching to tapentadol, adverse events were usually mild, with a grade of 1-2 by the Common Terminology Criteria for Adverse Events v4.03. Conclusions Tapentadol appears to have an acceptable safety margin and promising efficacy to relieve cancer-related neuropathic pain that is refractory to first-line opioid treatment.

Composite analysis was conducted using high-frequency radar data obtained during 2006–2015 in order to gain a better understanding of the current field in the Ariake Sea. The seasonally averaged surface current in the Ariake Sea was directed southward in all seasons, except around river mouths during summer. Heavy rainfall enhanced the outflow along the eastern coast of the Shimabara Peninsula from Isahaya Bay to the southern area 2–5 days after heavy rainfall. Spring–neap differences were clearly seen in the southward current along the Shimabara Peninsula. Interannual variation in the M2 tidal current amplitude was synchronized with the lunar nodal cycle.

Background Testosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear. Aim To investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency. Methods Rats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle. Outcomes Erectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation. Results In the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P < .01). Testosterone injection significantly improved each of these parameters (P < .01). Clinical Translation The present results provide scientific evidence of the effect of testosterone deficiency on erectile function and the effect of testosterone replacement therapy. Strengths and Limitations This study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation. Conclusion Testosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction.

We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCα in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCα protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction.

Background: It is difficult to objectively evaluate chemotherapy-related adverse events early in elderly patients with urothelial carcinoma. A delayed response causes a reduction in quality of life (QoL). Wearable activity systems that objectively record life logs have recently been used. Objectives: This study was undertaken to verify the reliability and effectiveness of a wearable activity system (Fitbit) to monitor subjective symptoms in an objective manner during chemotherapy for elderly patients with urothelial cancer (UC). Materials and Methods: This was a cohort prospective study. Elderly patients with UC were enrolled who received short hydration gemcitabine and cisplatin (shGC) combination therapy at Nagoya City University Hospital from January 2018 to March 2020. A Fitbit was used to monitor heart rate, distance moved, and cardio zone time. Heart rate was also monitored by an oscillometric method. The relationship between Fitbit recordings and perceived adverse events, such as fatigue, constipation and nausea, observed during chemotherapy was investigated using a general linear mixed effects model. Results: Twenty-one of 28 inpatients were enrolled and observed for a total of 824 days. A significant, moderately strong correlation was found between two measurements of heart rate (Pearson's r = 0.65, p < 0.05). The measurement of fatigue using Fitbit was effective (p = 0.03). Conclusion: Fitbit monitoring can measure the QoL of a patient and was useful for monitoring elderly patients with UC undergoing shGC therapy in an outpatient setting. Fitbit may be useful for monitoring outpatients and their QoL during chemotherapy.

Purpose: To investigate whether relaxation of the rat penile corpus cavernosum could be controlled with NOBL-1, a novel, lightcontrollable nitric oxide (NO) releaser. Materials and Methods: Fifteen-week-old male Wistar-ST rats were used. The penile corpus cavernosum was prepared and used in an isometric tension study. After noradrenaline (10−5 M) achieved precontraction, the penile corpus cavernosum was irradiated by light (470–500 nm) with and without NOBL-1 (10−6 M). In addition, we noted rats’ responses to light with vardenafil (10−6 M), a phosphodiesterase-5 (PDE-5) inhibitor. Next, responses to light in the presence of a guanylate cyclase inhibitor, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (10−5 M), were measured. All measurements were performed in pretreated L-NAME (10−4 M) conditions to inhibit endogenous NO production. Results: Corpus cavernosal smooth muscle, precontracted with noradrenaline, was unchanged by light irradiation in the absence of NOBL-1. However, in the presence of NOBL-1, corpus cavernosal smooth muscle, precontracted with noradrenaline, relaxed in response to light irradiation. After blue light irradiation ceased, tension returned. In addition, the light response was obviously enhanced in the presence of a PDE-5 inhibitor. Conclusions: This study showed that rat corpus cavernosal smooth muscle relaxation can be light-controlled using NOBL-1, a novel, light sensitive NO releaser. Though further in vivo studies are needed to investigate possible usefulness, NOBL-1 may be prove to be a useful tool for erectile dysfunction therapy, specifically in the field of penile rehabilitation.

We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10–12-week-old, male Sprague–Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.

There is no established chemotherapy regimen in metastatic primary urethral cancer (mPUC). The efficacy of a cisplatin (CDDP)-based regimen has been reported, however, when the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs, the chemotherapy regimen should be changed to another platinum compound. In this report, we describe a 66-year-old woman who was diagnosed as mPUC with, CDDP-induced SIADH. After switching her to CBDCA and careful managing her sodium balance, three courses of the chemotherapy regimen were completed.

Introduction Nitric oxide (NO) is known as the key factor involved in initiating and maintaining an erection. Therefore, NO supplementation may be a target for erectile dysfunction. However, the use of NO donors carries the risk of systemic side effects. Recently, novel NO donors, such as a light-controllable NO donor or NO donor in nanoparticles, have been developed. In this review, we introduce such novel compounds and methods. Aim To review light-controllable and nanotechnological NO donors for the treatment of erectile dysfunction. Methods We conducted a review of relevant articles via PubMed in December 2018. Main Outcome Measures In this study, we reviewed novel NO donors, such as light-controllable NO donors and nanotechnological NO donors. Results Some light-controllable NO donors have been already reported. A light-controllable NO donor without metal has also been recently developed. Light-controllable NO donors and light irradiation can control the release of NO spatiotemporally. In an isometric tension study, a relaxing response of the aortic tissue and penile corpus cavernosum was observed under light irradiation with a light-controllable NO donor. In addition, the effects of nanoparticles and nanoemulsions containing sodium nitrate on erectile function have been reported. The nanoformulation containing an NO donor can likely be absorbed percutaneously and, thus, enhance erectile function. Conclusions A light-controllable NO donor might be useful for treating erectile dysfunction because light irradiation is a convenient method to be applied for patients. However, light permeability might be an issue that needs to be solved. Nanoformulation is also likely to be a useful, non-invasive approach. The application of these procedures and compounds may help in the development of future treatments for erectile dysfunction. Hotta Y, Kataoka T, Taiki Mori T, et al. Review of a Potential Novel Approach for Erectile Dysfunction: Light-Controllable Nitric Oxide Donors and Nanoformulations. Sex Med Rev 2020;8:297–302.

Methylmalonic acidemia (MMA) is an inherited metabolic disease. In this condition, metabolism from methylmalonyl coenzyme A (CoA) to succinyl-CoA is inhibited because of either low methylmalonyl-CoA mutase (MCM) activity or adenosylcobalamin deficiency owing to altered vitamin B12 metabolism. A high-precision assay for detecting MCM activity would facilitate not only MMA diagnosis but also the ability to determine the severity of MMA. We developed an MCM assay method based on ultrahigh-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) that involves the determination of succinyl-CoA, which is formed in an enzyme reaction, using peripheral lymphocytes. Using 0.05, 0.5, and 5 μmol/L succinyl-CoA, the intra-assay coefficient of variation (CV) was less than 5.2 % and the inter-assay CV was less than 8.7 %. The MCM activities of five healthy individuals and four patients were investigated with this assay. The MCM activities of the patients were very low in relation to those of healthy individuals. Together, these results show that the UPLC–MS/MS method is useful for a detailed MCM activity assay.

We conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database on spontaneously reported adverse events to evaluate the association between anticancer drug therapy and hepatitis B infection. Reports of hepatitis B infection were retrieved from the FAERS database. The reporting odds ratio (ROR) was used to estimate the association between hepatitis B infection and various anticancer agents and drug combinations. We detected statistically significant risk signals of hepatitis B for 33 of 64 anticancer agents by ROR (26 cytotoxicity drugs and seven molecular‐targeted drugs). We focused on molecular‐targeted drugs and assessed the risk of hepatitis B from specific anticancer drug combinations. The frequency of hepatitis B infection was significantly high for drugs such as rituximab, bortezomib, imatinib, and everolimus. The addition of cyclophosphamide, doxorubicin, and fludarabine to drug combinations additively enhanced the frequency of hepatitis B infection. There were no reports on hepatitis B infection associated with trastuzumab or azacitidine monotherapy. However, trastuzumab‐containing regimens (e.g., combinations with docetaxel or paclitaxel) were correlated with the incidence of hepatitis B infection, similar to azacitidine monotherapy. Our findings suggest that the concomitant use of anticancer drugs, such as trastuzumab, taxane, and azacitidine, may contribute to the risk of hepatitis B infection. The unique signals detected from the public database might provide clues to eliminate the threat of HBV in oncology.

Objectives To investigate the efficacy of oral l-citrulline for erectile dysfunction and penile structure disruption in a rat model. Methods Male Wistar-ST rats aged 15 weeks were randomly divided into three groups as follows: sham-operated rats (control group), surgically castrated rats (castrated group) and surgically castrated rats subsequently treated with 2% l-citrulline water (castrated + l-citrulline). At 4 weeks postoperative, erectile function was assessed based on intracavernous pressure changes, followed by electrostimulation of cavernous nerves and calculation of maximum intracavernous pressure/mean arterial pressure. Penile structure was evaluated by Masson's trichrome staining and the smooth muscle-to-collagen ratio was calculated. The serum bioavailable testosterone, l-arginine, l-citrulline, NG,NG-dimethylarginine and nitrogen oxide levels were evaluated. Results The bioavailable testosterone concentrations were decreased in the castrated and castrated + l-citrulline groups compared with the control group at 4 weeks after surgery. The intracavernous pressure-to-mean arterial pressure and smooth muscle-to-collagen ratios were significantly decreased in the castrated group compared with the control group, but significantly increased in the castrated + l-citrulline group compared with the castrated group. The serum l-citrulline, l-arginine and NG,NG-dimethylarginine levels, and the l-arginine-to-NG,NG-dimethylarginine ratios were significantly increased in the castrated + l-citrulline group compared with the castrated group. The serum nitrogen oxide levels were increased in the castrated + l-citrulline group compared with the castrated group. Conclusions Oral l-citrulline can improve the erectile response to electric stimulation of cavernous nerve and penile structure in castrated rats.

Oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine itself and increases nitric oxide (NO) production.To investigate whether oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction (ED).We divided 8-week-old male Wistar-ST rats into 3 groups: sham-operated rats (control group), arteriogenic ED rats who underwent ligation of both internal iliac arteries (ligation group), and arteriogenic ED rats receiving oral 2% L-citrulline water supplementation (citrulline group). Citrulline water was given to arteriogenic ED rats for 3 weeks from 1 week after surgery. Erectile function was evaluated by maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios via cavernous nerve stimulation at 4 weeks after surgery. Then, the penises were resected, stained with Masson's trichrome, and observed microscopically. Serum nitrogen oxides (NOx) levels were measured by high-performance liquid chromatography. Bonferroni's multiple t-test was used for statistical analysis.The main outcome measures were changes in ICP/MAP, smooth muscle (SM)/collagen ratios, and NOx levels following L-citrulline supplementation.The ICP/MAP ratio in the ligation group was significantly lower than that in the control group (P0.05), denoting ED. The ICP/MAP ratio of the citrulline group was significantly higher than that of the ligation group (P0.05), indicating ED amelioration. Levels of NOx in the ligation group were significantly lower than in the control group (P0.05), while those in the citrulline group were significantly higher than in the ligation group (P0.05). SM/collagen ratios in the ligation group were significantly lower than in the control group (P0.05), while ratios in the citrulline group were significantly higher than those in the ligation group (P0.05).Oral L-citrulline supplementation improved ICP/MAP and SM/collagen ratios and increased NOx. Therefore, oral L-citrulline supplementation might be a useful novel therapy for acute arteriogenic ED.

Some studies suggest that high-estrogen levels lead to erectile dysfunction (ED); high-estrogen levels are known to decrease testosterone levels. However, no study has examined whether testosterone replacement can improve the ED induced by high-estrogen levels. We investigated the effects of testosterone on ED caused by high-estrogen levels in rats. Rats were distributed in the following groups: (1) control (vehicle for 2 weeks), (2) the estrogen-treated group (ES; estradiol (3 μg kg(-1) day(-1)) for 2 weeks), and (3) the estrogen- and testosterone-treated group (ES+TE; estradiol (3 μg kg(-1) day(-1)) and testosterone (3 mg kg(-1) day(-1)) for 2 weeks). We measured smooth muscle function via isometric tension and erectile function by measuring the intracavernosal pressure on cavernous nerve stimulation. In the ES group, the contraction of the corpus cavernosum smooth muscle increased in response to noradrenalin, and its relaxation decreased in response to the nitric oxide donor, sodium nitroprusside. Further, the erectile function was significantly decreased. In the ES+TE group, neither smooth muscle function nor erectile function was significantly improved. In conclusion, a high-estrogen milieu affected erectile function in rats, and testosterone treatment did not improve the ED caused by high-estrogen levels.

Propionic acidemia (PA) is an inherited metabolic disease caused by low activity of propionyl coenzyme A (CoA) carboxylase (PCC), which metabolizes propionyl-CoA into methylmalonyl-CoA. Although many patients with PA have been identified by tandem mass spectrometry since the test was first included in neonatal mass screening in the 1990s, the disease severity varies. Thus, determining the specific level of PCC activity is considered to be helpful to grasp the severity of PA. We developed a new PCC assay method by the determination of methylmalonyl-CoA, which is formed by an enzyme reaction using peripheral lymphocytes, based on ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). With methylmalonyl-CoA concentrations of 0.05, 0.5, and 5μmol/L, the intra-assay coefficients of variation (CVs) were 8.2%, 8.7%, and 5.1%, respectively, and the inter-assay CVs were 13.6%, 10.5%, and 5.9%, respectively. The PCC activities of 20 healthy individuals and 6 PA patients were investigated with this assay. Methylmalonyl-CoA was not detected in one PA patient with a severe form of the disease, but the remaining PA patients with mild disease showed residual activities (3.3-7.8%). These results demonstrate that determination of PCC activity with this assay would be useful to distinguish between mild and severe cases of PA to help choose an appropriate treatment plan.

In our previous study, chronic vardenafil treatment improved erectile function soon after the end of the treatment in rats with acute arteriogenic erectile dysfunction (ED).The aim of this study is to evaluate whether the effects of chronic vardenafil treatment persist after the end of treatment using rats with acute arteriogenic ED.Rats were randomly divided into three groups: (i) control; (ii) ligation; and (iii) vardenafil + no treatment. Rats in the ligation and vardenafil + no treatment groups underwent ligature of the bilateral internal iliac arteries to induce acute arteriogenic ED and were subsequently treated with vehicle or vardenafil (4.0 mg/kg/day), respectively, for 3 weeks. Subsequently, all rats were kept for a further 2 weeks with no treatment. Rats in the control group underwent sham surgery.Erectile function was assessed by changes in intracavernous pressure (ICP). Smooth muscle (SM)/collagen ratios in corpus cavernosum were analyzed by Masson trichrome staining. Transforming growth factor-β1 (TGF-β1 ) mRNA and protein levels in corpus cavernosum (CC) were, respectively, evaluated by real-time polymerase chain reaction (PCR) analysis and Western blotting analysis.ICP/mean arterial pressure (MAP) in the ligation group remained significantly lower than that in control group (P 0.01). Despite no treatment for 2 weeks, ICP/MAP in the var + no treatment group remained significantly higher than that in ligation group (P 0.05). SM/collagen ratio in the ligation group remained significantly lower when compared with the control group (P 0.01). The ratio in the var + no treatment group remained significantly higher when compared with the ligation group at 2 weeks after the end of treatment (P 0.05). TGF-β(1) mRNA and protein levels did not differ among the groups.The effects of chronic vardenafil treatment on erectile function and penile structure persist, even after the end of treatment, in acute arteriogenic ED rats.