Erectile Function and Sexual Activity Are Declining in the Younger Generation: Results from a National Survey in Japan.

PURPOSE: Twenty five years have passed since the first national survey on erectile dysfunction (ED) in Japan. The Japanese Society for Sexual Medicine conducted a nationwide survey on the actual status of sexual function targeting men over 20 years old in Japan using validated questionnaires commonly used in clinical practice. MATERIALS AND METHODS: Japanese men aged 20 to 79 years participated in our online epidemiological study on sexual dysfunction. Erectile status was assessed by direct questioning and specific questionnaires. Risk factors and frequencies of sexual intercourse, masturbation, nocturnal erections, and feeling sexual desire were assessed. The prevalence of these risk factors was compared between men with and without ED. Prevalence and frequencies were calculated for each 5-year age group. Main outcomes were the prevalence and number of patients with ED and simultaneous evaluation of age-related variations. RESULTS: Direct questioning of the men revealed that 13.0% felt troubled by ED. Although 81.0% of them had at least some ED symptoms based on a Sexual Health Inventory For Men score of ≤21, the prevalence of men with ED by Erection Hardness Score (EHS), the most appropriate questionnaire for Japanese with low sexual activity, was 30.9%, indicating that 14,012,596 men have ED. Most risk factors were related with ED, whereas frequencies of sexual intercourse, masturbation, nocturnal erections, and feeling sexual desire were affected by aging. However, the low frequency of these factors in the young generation was surprising. CONCLUSIONS: The EHS-based assessment revealed a prevalence of ED of 30.9%, which affected approximately 14 million men, and that the sexual desire, erection stiffness, orgasms, and satisfaction were lower than expected in young Japanese men, especially those aged 20 to 24 years, although those factors tended to worsen with aging. We believe that these findings actually reveal the current sexual status of men in Japan.

The Effects of a Red-Light Controllable Nitric Oxide Donor, NORD-1, on Erectile Dysfunction in Rats with Streptozotocin Induced Diabetes Mellitus.

PURPOSE: Patients with diabetes mellitus (DM) often exhibit refractory erectile dysfunction (ED). Red-light-controllable nitric oxide donor (NORD-1) and red-light irradiation have successfully enhanced erectile function in intact rats. In this study, we investigated whether the combination of NORD-1 and red-light irradiation effectively treated ED in streptozotocin (STZ)-treated rats with DM. MATERIALS AND METHODS: Seven-week-old male Sprague-Dawley rats were used in this study. Rats in the DM and sham groups received intravenous STZ (50 mg/kg) and saline, respectively. One week after treatment, the blood glucose level of rats in the DM group was >250 mg/dL. Five weeks after the treatment, we performed a functional study by measuring intracavernous pressure (ICP) under cavernous nerve stimulation before and after NORD-1 treatment with and without light irradiation. Additionally, we performed an isometric tension study using the corpus cavernosum of rats treated with NORD-1 or the control compound, SiR650. RESULTS: The ICP/mean arterial pressure (MAP) ratio was significantly lower in the DM group than in the sham group before and after NORD-1 treatment without light irradiation (both p<0.05). After NORD-1 treatment with light irradiation, the ICP/MAP ratio in the sham and DM groups was significantly enhanced than before and after NORD-1 treatment without light irradiation (all p<0.05). The ICP/MAP ratio in the DM group after NORD-1 with light irradiation was similar to that in the sham group under normal conditions before NORD-1 treatment. Moreover, the systemic blood pressure was not affected by NORD-1 or light irradiation. In the tension study, the corpus cavernosum of rats treated with SiR650 was not changed by red light in the sham or DM groups. However, the rats treated with NORD-1 were strongly relaxed by red light in both groups. CONCLUSIONS: NORD-1 and red-light irradiation could improve ED in the presence of DM without lowering blood pressure.

A BODIPY-picolinium-cation conjugate as a blue-light-responsive caged group.

Caged compounds protected with photolabile protecting groups (PPGs) are useful for controlling various biological events with high spatiotemporal resolution. Most of the commonly used PPGs are controlled by ultraviolet light irradiation, but it is desirable to have PPGs controlled by visible light irradiation in order to minimize tissue damage. Here, we describe a boron-dipyrromethene (BODIPY)-picolinium conjugate (BPc group) that functions as a blue-light-controllable PPG. ESR experiments indicate that the photolysis mechanism is based on intramolecular photoinduced electron transfer. We illustrate the applicability of the BPc group to biologically active compounds by employing it firstly to photocontrol release of histamine, and secondly to photocontrol release of a soluble guanylyl cyclase (sGC) activator, GSK2181236A, which induces photovasodilation. The BPc group is expected to be a useful PPG for controlling various biological events with blue light irradiation.

The Relationship between Changes in Serum Element Concentrations and Pathological Condition and Disease Status in Japanese Multiple Myeloma Patients: A Pilot Study and Literature Review.

BACKGROUND: Multiple myeloma (MM) is a rare cancer, and information on its pathological condition and serum element levels is lacking. In this pilot study, we examined serum element concentrations in Japanese patients with MM by a comprehensive multi-element analysis. METHODS: This is a case-control study of 12 Japanese patients diagnosed with MM at the Nagoya City University Hospital between 2008 and 2013. Blood samples were taken, at the initial diagnosis and at relapse. The serum concentrations of 12 elements were analyzed by inductively coupled plasma mass spectrometry and compared between MM patients and non-MM volunteers. We also analyzed the correlation between serum element concentrations and laboratory values related to disease status and tumor volume of MM. RESULTS: We found that serum chromium (Cr), copper (Cu), molybdenum (Mo), and barium (Ba) concentrations were significantly increased in MM patients. Ba was significantly increased in MM patients, suggesting an association with bone lesions. There was no consistent trend between these elements and existing indices related to MM tumor volume and disease status. CONCLUSIONS: Although this is a pilot study, serum Cr, Cu, Mo, and Ba concentrations were found to be significantly elevated in MM patients. Further studies with large sample sizes are needed, since the changes in serum concentrations of these elements may reflect the pathological condition of MM.

Elevated eosinophils proportion as predictor of immune-related adverse events after ipilimumab and nivolumab treatment of advanced and metastatic renal cell carcinoma.

OBJECTIVES: Ipilimumab and nivolumab treatment against advanced and metastatic renal cell carcinoma (RCC) causes severe and lethal immune-related adverse events (irAEs). Predicting irAEs might improve clinical outcomes, however no practical biomarkers exist. This study examined whether eosinophils could be effective biomarkers for ≥grade 2 irAEs in RCC. METHODS: We retrospectively analyzed 75 patients with RCC treated with ipilimumab and nivolumab between August 2018 and March 2021 in a multicenter study. Eosinophils were examined before and 2 weeks after treatment, and immediately after irAEs development. The optimal cut-off value for ≥grade 2 irAEs was determined by a receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were undertaken to identify predictors of ≥grade 2 irAEs. RESULTS: Two weeks after treatment, eosinophils were significantly upregulated in patients who had experienced ≥grade 2 irAEs than in those who had not experienced irAEs (mean, 5.7% vs. 3.2%; p < 0.05). The optimal cut-off value for eosinophils against ≥grade 2 irAEs was 3.0% (area under the curve = 0.69). In multivariate analyses, an eosinophil level ≥ 3.0% was a risk factor for ≥grade 2 irAEs (odds ratio 4.18, 95% confidence interval 1.16-15.1). The eosinophil level 2 weeks after treatment was upregulated by the onset of any type of irAEs including endocrine, gastrointestinal, pulmonary and skin disorders. CONCLUSIONS: An increased eosinophil level 2 weeks after treatment might be an effective biomarker for ≥grade 2 irAEs in patients with RCC treated with ipilimumab and nivolumab.

Determination of dietary essential fatty acids in a deep-sea fish, the splendid alfonsino Beryx splendens: functional characterization of enzymes involved in long-chain polyunsaturated fatty acid biosynthesis.

The splendid alfonsino Beryx splendens is a commercially important deep-sea fish in East Asian countries. Because the wild stock of this species has been declining, there is an urgent need to develop aquaculture systems. In the present study, we investigated the long-chain polyunsaturated fatty acid (LC-PUFA) requirements of B. splendens, which are known as essential dietary components in many carnivorous marine fish species. The fatty acid profiles of the muscles, liver, and stomach contents of B. splendens suggested that it acquires substantial levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from its natural diet. The functional characterization of a fatty acid desaturase (Fads2) and three elongases (Elovl5, Elovl4a, and Elovl4b) from B. splendens confirmed their enzymatic capabilities in LC-PUFA biosynthesis. Fads2 showed Δ6 and Δ8 bifunctional desaturase activities. Elovl5 showed preferential elongase activities toward C18 and C20 PUFA substrates, whereas Elovl4a and Elovl4b showed activities toward various C18-22 substrates. Given that Fads2 showed no Δ5 desaturase activity and no other fads-like sequence was found in the B. splendens genome, EPA and arachidonic acid cannot be synthesized from C18 precursors; hence, they can be categorized as dietary essential fatty acids in B. splendens. EPA can be converted into DHA in B. splendens via the so-called Sprecher pathway. However, given that fads2 is only expressed in the brain, it is unlikely that the capacity of B. splendens to biosynthesize DHA from EPA can fulfill its physiological requirements. These results will be useful to researchers developing B. splendens aquaculture methods.

Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

A review of experimental techniques for erectile function researches and development of medical technology using animal erectile dysfunction models in sexual and reproductive medicine.

Background: Erectile dysfunction (ED) is one of the causes of male infertility and is a disease that requires treatment. The first-line drugs for ED are phosphodiesterase 5 (PDE-5) inhibitors, and further treatment options are currently limited. Medical technologies, such as genetic control and regenerative medicine, are developing rapidly. Research on erectile function is progressing rapidly, coupled with technological innovations in other areas. Methods: A PubMed search using the keywords "animal (rat, mouse, rabbit, dog, and monkey)" and "erectile" was conducted, and all relevant peer-reviewed English results were evaluated. Main findings: The methods for evaluating erectile function include intracavernous pressure (ICP) measurements, isometric tension studies, and dynamic infusion cavernosometry. Papers also reported various disease model animals for the study of diabetes mellitus, cavernous nerve injury, and drug-induced ED. Conclusion: Basic research on ED treatment has progressed rapidly over the past 20 years. In particular, research on the mechanism of ED has been accelerated by the publication of a study on the evaluation of erectile function using ICP measurements in rats. In addition, molecular biological experimental methods such as polymerase chain reaction (PCR) and western blotting have become relatively easy to perform due to technological progress, thus advancing research development.

High preoperative serum strontium levels increase the risk of acute kidney injury after cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgeries. The incidence of AKI after cardiac surgeries using cardiopulmonary bypass (CPB-AKI) is high, emphasizing the need to determine strategies to prevent CPB-AKI. This study investigates the correlation between CPB-AKI and trace metal levels in clinical and animal studies. METHODS: Samples and clinical data were obtained from 74 patients from the Nagoya City University Hospital and Okazaki City Hospital. Blood samples were collected before, immediately after, and 2 h after CPB withdrawal. Trace metal levels were measured using inductively coupled plasma mass spectrometry. Sr or vehicle treatment was orally administered to the rats to determine if Sr was associated with CPB-AKI. After the treatment, ischemia-reperfusion (IR) injury was induced, and serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. RESULTS: In this clinical study, the incidence of CPB-AKI was found to be 28% (21/74). The body mass index and estimated glomerular filtration rate were significantly different in patients with AKI. The intensive care unit and hospital stay were longer in AKI patients than in non-AKI patients. The Na, Fe, and Sr levels were significantly higher in AKI patients before CPB. Also, Fe and Sr were higher immediately after CPB withdrawal, and Sr was higher 2 h after CPB withdrawal in AKI patients. Animal studies showed that Sr-treated rats had significantly increased SCr and BUN levels than vehicle-treated rats at 24 h post-IR injury. CONCLUSIONS: High preoperative serum Sr levels may be associated with CPB-AKI.

Changes in zinc and manganese concentrations in cisplatin-induced acute kidney injury.

Cisplatin (CDDP) is a widely used anticancer drug, but acute kidney injury (AKI) is one of the most important dose-limiting factors. Trace metal elements are present in various concentrations in the body and play an important role in maintaining normal vital functions. However, the relationship between CDDP-induced AKI and trace metal elements is unknown. In this study, we cultured human renal proximal tubular epithelial cells in the presence of CDDP (0, 12.5, 25, 50 µM) and analyzed the concentration of trace elements in medium after 24 h. We found that CDDP significantly increased the concentrations of zinc (Zn) and manganese (Mn) in medium and significantly decreased them in lysate. Therefore, we examined the effects of CDDP (3 mg/kg, i.p.) administration on serum and urinary Zn and Mn concentrations in rats. The results showed that urinary excretion of Zn and Mn increased in CDDP-treated rats 5 days after administration. Also, 5 days after administration, pyknosis, nuclear loss, loss of the brush border membrane, and DNA fragmentation were observed, and serum creatinine and blood urea nitrogen levels were found to be significantly increased. These data suggested that 24-h excretion of Zn and Mn might reflect on CDDP induced nephropathy. Monitoring urinary Zn and Mn excretion may be beneficial in detecting AKI, but further studies are needed for clinical application.

Efficacy of a Red-Light Controllable Nitric Oxide Releaser for Neurogenic Erectile Dysfunction: A Study Using a Rat Model of Cavernous Nerve Injury.

PURPOSE: Neurogenic erectile dysfunction (ED) is a common side effect of radical prostatectomy (RP) because of cavernous nerve damage. In these patients, the production of nitric oxide (NO), which is important for erection, is decreased in the corpus cavernosum. Therefore, NO donors are useful for post-RP ED. However, short half-life and systemic side effects are problems of NO application in ED therapy. To avert these problems, we developed a red-light controllable NO releaser, NORD-1. This study aimed to investigate the effect of NORD-1 and red-light irradiation on neurogenic ED using a rat model of bilateral cavernous nerve injury (BCNI). MATERIALS AND METHODS: BCNI and sham operations were conducted on 8-week-old rats. After 4 weeks, erectile function was evaluated using changes in intracavernous pressure (ICP) during electrostimulation of the cavernous nerve. ICP was measured under three conditions; without NORD-1 and red-light irradiation, with NORD-1 and without red-light irradiation, and with NORD-1 and red-light irradiation. SiR650 which absorbs red-light but does not release NO was used for the negative control. After the experiment, localization of NORD-1 was observed using a microscope. RESULTS: Erectile function in a BCNI rat model was significantly decreased compared to sham-operated rats (p<0.05). After injecting NORD-1 into the penis, erectile function did not change without red-light irradiation. However, the combination of NORD-1 and red-light irradiation significantly improved erectile function (p<0.05) without affecting systemic arterial pressure. In contrast, when SiR650 was used, erectile function did not change in all three conditions. NORD-1 was detected only in the corpus cavernosum and not in the urethra and dorsal vein. CONCLUSIONS: NORD-1 combined with red-light irradiation is effective for ED induced by cavernous nerve injury. This treatment may have low risks of hypotension and urinary incontinence, and it can replace the current treatment for post-RP ED.

Clinical Usefulness of the "MN Criteria" - the Clostridioides difficile Infection Severity Scoring System - in the Japanese Setting.

Objective The severity of Clostridioides difficile infection (CDI) is an important prognostic factor. The "MN criteria," proposed in Japan in 2017, attempted to remedy the shortfalls in the reported guidelines proposed globally to determine CDI severity. We therefore assessed the accuracy of the MN criteria and validated the important factors associated with predicting CDI severity. Methods Sixty-six CDI cases were investigated retrospectively at a Japanese University Hospital from January 2015 to December 2018. The fulminant cases were screened out, and the non-fulminant cases were classified according to their severity stages using the nine variables included in the MN criteria. Clinical events, such as death within 28 days, colectomy, and admission to the intensive care unit, were evaluated. First, the sensitivity and specificity of the MN criteria for predicting clinical events were determined. The relationships between clinical events and the explanatory variables were then evaluated through univariate and multivariate analyses. Results The screening of the fulminant cases and classification of the non-fulminant cases into mild/moderate and severe/super severe cases resulted in a sensitivity of 1.00 and a specificity of 0.89. Univariate and multivariate analyses revealed a significant association of the serum albumin (Alb) level as well as white blood cell (WBC) count with clinical events. Conclusion The findings provide evidence supporting the accuracy of the MN criteria in predicting CDI severity and show that the Alb and WBC are important variables in predicting CDI severity.

A Simple Colorimetric Assay of Bleomycin-Mediated DNA Cleavage Utilizing Double-Stranded DNA-Modified Gold Nanoparticles.

A colorimetric assay of DNA cleavage by bleomycin (BLM) derivatives was developed utilizing high colloidal stability on double-stranded (ds) DNA-modified gold nanoparticles (dsDNA-AuNPs) possessing a cleavage site. The assay was performed using dsDNA-AuNPs treated with inactive BLM or activated BLM (Fe(II)⋅BLM). A 10-min exposure in dsDNA-AuNPs with inactive BLM treatment resulted in a rapid color change from red to purple because of salt-induced non-crosslinking aggregation of dsDNA-AuNPs. In contrast, the addition of active Fe(II)⋅BLM retained the red color, probably because of the formation of protruding structures at the outermost phase of dsDNA-AuNPs caused by BLM-mediated DNA cleavage. Furthermore, the results of our model experiments indicate that oxidative base release and DNA-cleavage pathways could be visually distinguished with color change. The present methodology was also applicable to model screening assays using several drugs with different mechanisms related to antitumor activity. These results strongly suggest that this assay with a rapid color change could lead to simple and efficient screening of potent antitumor agents.

Development and Evaluation of a Novel Software Program, SAKURA-TDM, for Area Under the Concentration-Time Curve-Guided Vancomycin Dosing: A Short Communication.

BACKGROUND: The area under the concentration-time curve (AUC)-guided dosing of vancomycin has been introduced in Japan; however, the optimal dosing method remains controversial. Here, a novel software program was developed for AUC-guided vancomycin dosing and to estimate the theoretical threshold of the steady-state AUC 24 that could reduce the risk of renal injury. METHODS: A single-center, retrospective, observational study was conducted to develop a novel software program (SAKURA-TDM ver.1.0) for AUC-guided dosing. The estimation accuracy of pharmacokinetic parameters determined using SAKURA-TDM was compared with that of clinically available software programs and assessed with Bland-Altman analysis. In addition, theoretical cutoff points of the steady-state AUC 24 and the predicted trough values were estimated using Youden J statistic approach. RESULTS: The estimation accuracy of pharmacokinetic parameters and AUC determined using SAKURA-TDM was comparable to that of other TDM software programs. Of note, despite a good relationship between the predicted AUC 24 and trough values, the correlation between the predicted AUC 24 and measured trough values was not strong. The cutoff values of the steady-state AUC 24 and the predicted trough value for reducing the probability of a measured trough value of >20 mcg/mL were 513.1 mg·h/L and 15.6 mcg/mL, respectively. CONCLUSIONS: We demonstrated the equivalence of the estimated PK parameters between SAKURA-TDM and other TDM software programs available in Japan. Considering the threshold of both trough values and the steady-state AUC and monitoring of the AUC in a non-steady state, it would be possible to reduce the risk of vancomycin-associated renal injury.

Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells.

In the field of cosmetic research, there is a growing interest in alternatives to animal experiments, such as in vitro models using cultured cells. The trend is spreading to the field of food and drugs. Although various types of cells are used as in vitro models, the effect of cellular senescence on the expression and function of transporters in these models is unclear. In the present study, we examined the effect of replicative senescence (by passage culture) on the expression and function of transporters in renal proximal tubular epithelial cells (RPTECs). The increase in senescence-associated-ß-galactosidase (SA-ß-gal)-positive cells, cell cycle arrest markers, and senescence-associated secretory phenotype (SASP) markers was associated with an increase in passage numbers of RPTECs. Gene expression of various transporters in RPTEC was also altered. The mRNA level of organic cation transporter 2 decreased most rapidly with passage numbers among the transporters. The uptake of fluorescent cationic substrates in SA-ß-gal-positive RPTECs was less than that in SA-ß-gal-negative RPTECs. However, these changes in the expression of transporters seem to be significantly different from those observed in rodents and human kidneys in many aspects. As cellular senescence is observed in various situations, especially in RPTECs, it may be necessary to exclude it from toxicological and pharmacokinetic evaluations using in vitro models as much as possible. Additionally, when discussing cellular senescence, it is important to note the differences between aging in cells and aging and senescence in individuals.

Testosterone improved erectile function by upregulating transcriptional expression of growth factors in late androgen replacement therapy model rats.

We previously showed that castration of rats reduced erectile function over time; when testosterone replacement therapy was started 4 weeks after castration, erectile function improved. In this study, we examined the mechanism of improvement in erectile function following testosterone replacement therapy in rats. Thirty 12-week-old rats were divided into castrated (Cast), castrated with subcutaneous administration of testosterone (Cast + T), and sham (Sham) groups. Erectile function and mRNA and protein expression were evaluated in the rats by using standard methods. To assess erectile function, we measured the intracavernosal pressure, mean arterial pressure, mRNA expression of endothelial growth factors, and protein expression of endothelial nitric oxide synthase (eNOS). The intracavernosal pressure/mean arterial pressure ratio was significantly lower in the Cast group, and testosterone administration significantly improved (P = 0.017). Compared to the Cast group, the Cast+T group exhibited significantly increased mRNA expressions of vascular endothelial growth factor A (VEGF-A), intercellular adhesion molecule 1 (ICAM-1), transforming growth factor-ß (TGF-ß), nerve growth factor (NGF), α-smooth muscle actin (α-SMA), caveolae associated protein 1 (Cavin-1), Cavin-2, Cavin-3, sirtuin 1 (Sirt-1), sphingosine-1-phosphate 1 (S1P1), S1P2, and S1P3 and eNOS protein expression. Testosterone replacement therapy improved erectile function in castrated rats by increasing growth factors and eNOS protein.

Effect of High Testosterone Levels on Endothelial Function in Aorta and Erectile Function in Rats.

BACKGROUND: Testosterone is an important hormone for the physical and mental health of men; however testosterone administration has also been suggested to adversely affect the cardiovascular system. AIM: To investigate the effects of excessive testosterone administration on vascular endothelial and erectile function in rats. METHODS: A total of seventy-five 12-week-old rats were divided into the following groups: Sham, castrated (Cast), castrated with subcutaneous administration of 100 mg/kg/month testosterone (Cast + T1), and castrated with subcutaneous administration of 100 mg/kg/week testosterone (Cast + T4). To observe the changes in testosterone level after the administration, rats were further divided into the following groups: control; T(6.25), wherein the rats were subcutaneously injected with 6.25 mg/kg testosterone; T(25) per week, wherein the rats were subcutaneously injected with 25 mg/kg testosterone per week; and T(100), wherein the rats were subcutaneously injected with 100 mg/kg testosterone per week. The relaxation responses of aorta were measured in these rats using standardized methods, and their erectile function was also evaluated. Statistical analysis of the obtained data was performed using two-way analysis of variance (ANOVA), Tukey-Kramer's multiple comparison test, or Student's t-test. OUTCOMES: At the end of the study period, endothelial function was evaluated through measurement of isometric tension, while erectile function was assessed using intracavernosal pressure (ICP), mean arterial pressure (MAP), and the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), sirtuin 1 (Sirt1) and vascular endothelial growth factor A. RESULTS: The ICP/MAP ratio in the Cast group (0.42 ± 0.04) was significantly lower than that in the Sham group (0.79 ± 0.07). The ICP/MAP ratio in the Cast + T1 group (0.73 ± 0.06) was significantly higher than that in the Cast group (P < .01) and that of the Cast + T4 (0.38 ± 0.01) group was unchanged (P > .05). The T(25) and T(100) groups exhibited significantly lower responses to ACh than the control group at 4 weeks (P < .01). Meanwhile, the ICP/MAP ratios in the T(25) group (0.44 ± 0.07) and T(100) group (0.47 ± 0.03) were significantly lower than that in the control group (0.67 ± 0.05) at stimulation frequencies of 16 Hz (P < .05). The expression of androgen receptor, Sirt1, and eNOS were significantly lower while that of iNOS was higher in the T(25) group compared with the control group (P < .05). CLINICAL TRANSLATION: The results based on this animal model indicate that extremely high testosterone levels may affect endothelial and erectile function. STRENGTHS AND LIMITATIONS: We found that high-dose testosterone administration decreased endothelial function in aorta and erectile function in rats. A major limitation of this study is that the blood concentration may not be representative of that in humans, and further research is needed. CONCLUSION: The findings suggest that high doses of testosterone may cause endothelial dysfunction in the aorta and erectile dysfunction in rats and that the blood concentration should be monitored after testosterone administration. Kataoka T, Fukamoto A, Hotta Y, et al. Effect of High Testosterone Levels on Endothelial Function in Aorta and Erectile Function in Rats. Sex Med 2022;10:100550.

Ascorbate-assisted nitric oxide release from photocontrollable nitrosonium ion releasers for potent ex vivo photovasodilation.

We found that N-nitrosoaminoanisole derivatives tethered to dyes work as photocontrollable nitrosonium cation releasers and are converted to potent nitric oxide releasers in the presence of sodium ascorbate. The N-nitrosoaminoanisole derivative 2 worked as a more potent photovasodilating reagent ex vivo than previously reported nitric oxide releasers.

[A novel approach to treating erectile dysfunction with a light-controlled nitric oxide donor].

It has long been known that nitric oxide (NO) is involved in the initiation and maintenance of erection. For this reason, NO supplementation has been considered a useful target for the treatment of erectile dysfunction (ED), and many studies have been conducted. However, to date, no compounds have been launched for a variety of reasons. One of the reasons is the systemic adverse reactions. In order to solve this problem, we focused on light-controlled NO donors and investigate their potential application in ED treatment. Light-controlled NO donors have three main characteristics: first, they release NO only at the site of light irradiation, second, they release NO only during the time of light irradiation, and third, the amount of NO released can be controlled according to the light intensity. These features suggest that light-responsive NO donors may be useful for ED therapy. Our group has been working on the development of light-controlled NO donors, and has so far developed the blue light-controlled NO donor "NOBL-1", the yellowish-green light-controlled NO donor "NO-Rosa", and the red light-controlled NO donor "NORD-1". Our recent studies have shown that NORD-1 and red light can enhance the erectile response in rats at the in vivo level. Next, we examined the effects of NORD-1 and red light using a neurogenic ED model, which is believed to be less effective than existing ED drugs. The results showed that red light irradiation after NORD-1 administration enhanced the erectile response and improved ED in the neurogenic ED model. These results suggest that NORD-1, a light-controlled NO donor, and red light can enhance the erectile response in rats and may have potential as an ED drug. Although optimization of the compound is essential, it is expected that a new therapeutic approach called photobiotherapy for ED will be developed in the future.

Protective effects of tadalafil on damaged podocytes in an adriamycin-induced nephrotic syndrome model.

Podocyte injury is responsible for nephrotic syndrome. Previously, we found that tadalafil, a phosphodiesterase 5 inhibitor, might have protective effects on podocytes. Here, we investigated the effects of tadalafil in a nephrotic syndrome model and human podocyte cells. We divided adriamycin (ADR)-induced nephrotic syndrome model rats into the following groups: control + vehicle, control + tadalafil, ADR + vehicle, and ADR + tadalafil. The tadalafil-treated groups were orally administered 10 mg/kg tadalafil for 2 weeks. Renal parameters were measured. Immunohistology and immunofluorescence assays of glomerular injury were performed. Human primary podocytes were treated with or without tadalafil, and ADR. Cell viability and permeability assays were performed. ADR + vehicle exhibited severe proteinuria compared with control + vehicle and control + tadalafil. ADR + tadalafil attenuated proteinuria compared with ADR + vehicle. Wilms' tumor 1 (WT1) immunostaining revealed that the number of WT1-positive cells was decreased by ADR; however, this decrease was prevented by ADR + tadalafil. In human podocytes, tadalafil increased the viability of ADR-treated cells, which was abrogated by KT5823, a cGMP-dependent protein kinase (PKG) inhibitor. Moreover, tadalafil prevented albumin permeability in ADR-treated cells. ADR treatment alone increased the permeability of albumin compared with the control. Tadalafil might inhibit kidney injury progression by preventing damage to podocytes and dysfunction of the glomerular filtration barrier.