Riboflavin Inhibits Histamine-Dependent Itch by Modulating Transient Receptor Potential Vanilloid 1 (TRPV1).

Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.

The epidemiology and role of surgery in the treatment of urethral clear cell carcinoma.

PURPOSE: To perform a retrospective analysis of the epidemiology and role of surgery on survival in patients with urethral clear cell carcinoma (UCCC) using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. METHODS: UCCC cases diagnosed from January 1, 1973, to December 31, 2014, were extracted from SEER. Descriptive statistics were calculated for all variables. Univariate analysis to assess for differences in survival with respect to covariates was performed using the log-rank test. Multivariate analysis was performed with Cox proportional hazards regression models to determine the predictive performance of covariates with respect to overall survival (OS) and disease-specific survival (DSS), reported as hazard ratio (HR) with 95% CIs. Comparisons were considered statistically significant at P < 0.05. RESULTS: Sixty-one cases were extracted for analysis. Mean age ± SD was 63.0 ± 13.9 years. Fifty (82%), 18 (29.5%), and 14 (23.0%) patients underwent surgery, radiation, and chemotherapy, respectively. On univariate analysis, the following covariates were associated with both OS and DSS: age, stage, and surgery (all P < 0.001). On multivariate analysis, surgery was a predictor for improved OS and DSS (HR, 0.178; 95% CI [0.068; 0.464]) and HR, 0.166; 95% CI [0.057; 0.484], respectively). Neither radiation nor chemotherapy was significantly associated with OS or DSS. CONCLUSION: Surgery was associated with improved OS and DSS in patients with UCCC. While neither radiation nor chemotherapy was significantly associated with survival, additional studies are necessary to determine how these therapeutic interventions may impact prognosis.

Patient Demographics and Extracorporeal Membranous Oxygenation (ECMO)-Related Complications Associated With Survival to Discharge or 30-Day Survival in Adult Patients Receiving Venoarterial (VA) and Venovenous (VV) ECMO in a Quaternary Care Urban Center.

OBJECTIVE: Investigate how a multitude of patient demographics and extracorporeal membranous oxygenation (ECMO)-related complications affect 30-day survival or survival to discharge. DESIGN: Retrospective observational study. SETTING: Urban university hospital, quaternary care center. PARTICIPANTS: Patients who underwent ECMO circulatory support from January 2012 to May 2016. INTERVENTIONS: Date-based data extraction, univariate and multivariate regression analysis. MEASUREMENTS AND MAIN RESULTS: The hospital database contained complete data for 235 adult patients who received venoarterial ECMO (74.04 %) and venovenous ECMO (25.96 %); 106 patients (45.11%) survived. The independent predictors significant in the odds of in-hospital mortality in a multiregression model were age (odds ratio [OR] = 1.028, p = 0.008), extracorporeal cardiopulmonary resuscitation (ECPR) after unsuccessful high-quality CPR (OR = 7.93, p =0.002), cardiogenic shock as the primary indication for circulatory support (OR = 2.58, p = 0.02), acute kidney injury (AKI) before ECMO initiation (OR = 7.53, p < 0.001), time spent on ECMO in days (OR = 1.08, p = 0.03), and limb ischemia (OR = 3.18, p = 0.047). CONCLUSION: The most significant findings of advancing age, time spent on ECMO, AKI, ECMO use in the setting of cardiogenic shock, ECPR, and limb ischemia as a complication of ECMO all independently increase the odds of in-hospital and 30-day mortality. To the best of the authors' knowledge, this study is the first to demonstrate a significant relationship between limb ischemia and mortality.

DAMGO modulates two-pore domain K(+) channels in the substantia gelatinosa neurons of rat spinal cord.

The analgesic mechanism of opioids is known to decrease the excitability of substantia gelatinosa (SG) neurons receiving the synaptic inputs from primary nociceptive afferent fiber by increasing inwardly rectifying K(+) current. In this study, we examined whether a µ-opioid agonist, [D-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), affects the two-pore domain K(+) channel (K2P) current in rat SG neurons using a slice whole-cell patch clamp technique. Also we confirmed which subtypes of K2P channels were associated with DAMGO-induced currents, measuring the expression of K2P channel in whole spinal cord and SG region. DAMGO caused a robust hyperpolarization and outward current in the SG neurons, which developed almost instantaneously and did not show any time-dependent inactivation. Half of the SG neurons exhibited a linear I~V relationship of the DAMGO-induced current, whereas rest of the neurons displayed inward rectification. In SG neurons with a linear I~V relationship of DAMGO-induced current, the reversal potential was close to the K(+) equilibrium potentials. The mRNA expression of TWIK (tandem of pore domains in a weak inwardly rectifying K(+) channel) related acid-sensitive K(+) channel (TASK) 1 and 3 was found in the SG region and a low pH (6.4) significantly blocked the DAMGO-induced K(+) current. Taken together, the DAMGO-induced hyperpolarization at resting membrane potential and subsequent decrease in excitability of SG neurons can be carried by the two-pore domain K(+) channel (TASK1 and 3) in addition to inwardly rectifying K(+) channel.

SUMO proteins are involved in the stress response during spermatogenesis and are localized to DNA double-strand breaks in germ cells.

Small ubiquitin-like modifiers (SUMO) proteins have been implicated in cellular stress response in different tissues, but whether sumoylation has a similar role during spermatogenesis is currently unknown. In this study, changes in the levels of both free SUMO isoforms and high-molecular weight (HMW) SUMO conjugates were monitored before and after the induction of different types of cellular stresses. Using cell lines and primary cells freshly isolated from mouse testes, significant changes were detected in the levels of SUMO1 and SUMO2/3 conjugates following short exposure of the cells to heat stress and oxidative stress. While high concentrations of H(2)O(2) caused an increase in protein sumoylation, low concentrations of H(2)O(2) mostly caused protein desumoylation. Immunofluorescence studies localized SUMO to the sites of DNA double-strand breaks in stressed germ cells and during meiotic recombination. To study the effect of oxidative stress in vivo, animals exposed to tobacco smoke for 12 weeks were used. Changes in sumoylation of HMW proteins were consistent with their oxidative damage in the tobacco-exposed mice. Our results are consistent with the important roles of different SUMO isoforms in stress responses in germ cells. Furthermore, this study identified topoisomerase 2 alpha as one of the targets of sumoylation during normal spermatogenesis and under stress.