The Suppression of Ubiquitin C-Terminal Hydrolase L1 Promotes the Transdifferentiation of Auditory Supporting Cells into Hair Cells by Regulating the mTOR Pathway.

In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.

Validity analysis of respiratory events of polysomnography using a plethysmography chest and abdominal belt.

PURPOSE: Respiratory inductive plethysmography (RIP) is recommended as an alternative respiratory sensor for the identification of each apnea and hypopnea event in polysomnography. Using this sensor, the cumulative RIP results from the chest and abdomen (RIP sum) and time-derived results of the RIP sum (RIP flow) are calculated to track respiratory flow. However, the effectiveness of this sensor and the calculated respiratory results is still unclear, and validation studies for the scoring of respiratory events in polysomnography are rare. METHODS: Two hundred subjects were selected according to the severity of obstructive sleep apnea. A sleep specialist re-evaluated the respiratory events based on RIP flow data in a single-blind study. Statistical analysis was conducted with paired respiratory events scored in each of the RIP flow and polysomnography datasets. RESULTS: All respiratory events scored from the RIP flow were strongly correlated with those identified with standard sensors of polysomnography, regardless of disease severity. Most of the respiratory parameters from RIP flow trended toward underestimation. The RIP flow obtained from the alternative RIP sensor was appropriate for the diagnosis of obstructive sleep apnea based on a receiver operating characteristic curve. CONCLUSIONS: Scored respiratory events from RIP flow data effectively reflected the respiratory flow and statistically correlated with the results from standard polysomnography sensors. Therefore, analyzing RIP flow utilizing an RIP sensor is considered a reliable method for respiratory event scoring.

Food- and gender-dependent pharmacokinetics of paeoniflorin after oral administration with Samul-tang in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Samul-tang (Si-Wu-tang in Chinese, Shimotsu-to in Japanese), widely used in eastern Asia, is composed of Angelica gigas (Angelicae Gigantis Radix), Cnidium officinale (Cnidii Rhizoma), Paeonia lactiflora (Paeonia Radix) and Rehmannia glutinosa (Rehmanniae Radix Preparata). Paeoniflorin, one of active components in Samul-tang has anti-platelet, anti-inflammation, anti-cancer and neuroprotective properties. However, there is no information about the effects of gender and food intake on the pharmacokinetics of paeoniflorin till now. AIM OF THE STUDY: This study was conducted to investigate whether food and gender could influence pharmacokinetic profiles of paeoniflorin after oral administration of Samul-tang. MATERIALS AND METHODS: Male and female rats were administered with a single oral dose of Samul-tang equivalent to 80 mg/kg of paeoniflorin. Plasma concentrations of paeoniflorin were measured by high-performance liquid chromatography. The statistical differences of each group were evaluated using the analysis of variance (ANOVA) or Student t-test. RESULTS: The pharmacokinetic parameters of paeoniflorin were not significant different by gender difference. However, the maximum plasma concentration (C(max), 0.47±0.29 µg/mL versus 1.10±0.35 µg/mL), area under the concentration-time curve (AUC(0→∞), 1.41±0.89 h · µg/mL versus 3.12±1.61 h · µg/mL) and relative bioavailability (F(rel)=2.21) of fed rats were significantly increased in comparison with those of fasted rats (P<0.05). CONCLUSION: Taken together, food intake can affect both the rate and extent of absorption of paeoniflorin when Samul-tang was administered orally. Furthermore, this study demonstrates a readily preparative HPLC method in the research of traditional herbal medicine.