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We examined the effects of empagliflozin, a selective inhibitor of Na+-glucose cotransporter 2, on mitochondrial quality control and autophagy in renal tubular cells in a diabetic environment in vivo and in vitro. Human renal proximal tubular cells (hRPTCs) were incubated under high-glucose conditions. Diabetes was induced with streptozotocin in male C57BL/6J mice. Improvements in mitochondrial biogenesis and balanced fusion-fission protein expression were noted in hRPTCs after treatment with empagliflozin in high-glucose media. Empagliflozin also increased autophagic activities in renal tubular cells in the high-glucose environment, which was accompanied with mammalian target of rapamycin inhibition. Moreover, reduced mitochondrial reactive oxygen species production and decreased apoptotic and fibrotic protein expression were observed in hRPTCs after treatment with empagliflozin, even in the hyperglycemic circumstance. Importantly, empagliflozin restored AMP-activated protein kinase-α phosphorylation and normalized levels of AMP-to-ATP ratios in hRPTCs subjected to a high-glucose environment, which suggests the way that empagliflozin is involved in mitochondrial quality control. Empagliflozin effectively suppressed Na+-glucose cotransporter 2 expression and ameliorated renal morphological changes in the kidneys of streptozotocin-induced diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased and 8-hydroxy-2′-deoxyguanosine content was low in renal tubular cells of empagliflozin treatment groups compared with those of the diabetic control group. We suggest one mechanism related to the renoprotective actions of empagliflozin, which reverse mitochondrial dynamics and autophagy.

Address for correspondence Won Chul Shin, MD, PhD Department of Neurology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6166 Fax: +82-2-440-7262 E-mail: shin1chul@gmail.com Objectives: Obstructive sleep apnea-hypopnea syndrome (OSAHS) and insomnia are two of the most common sleep disorders in the general population. Because OSAHS patients with insomnia may have difficulty in adapting to the sleep breathing medical equipment, it is necessary to pay special attention to the diagnosis and treatment of comorbid insomnia. This study is to investigate the emotion and personality in OSAHS patients with insomnia complaints by using Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Methods: We reviewed the results of the standardized questionnaires assessing sleep-related variables, MMPI, and polysomnographic findings of the patients diagnosed as OSAHS. Results: 145 subjects were 49.05±11.83 years of age. The mean Respiratory Disturbance Index was 33.57±19.91 and the mean score of Insomnia Severity Index (ISI) was 11.52±6.49. The mean scores of the Beck Depression Inventory (BDI) and MMPI-2 were within normal ranges. We divided the patients into two groups based on the scores of the ISI, OSAHS with insomnia (n=109) and OSAHS without insomnia (n=36). OSAHS patients with insomnia symptoms had significantly higher scores of hypochondriasis, hysteria, psychasthenia, schizophrenia, paranoia and psychopathic deviate scales and BDI than those without insomnia. Conclusions: Our results suggest that insomnia complaints are very common in OSAHS patients and the psychological problems are more frequently found in OSAHS patients with insomnia symptom than those without it. J Sleep Med 2015;12(2):59-63

We investigated the effects of chloroquine (CQ) and amodiaquine (AQ) on AMPK phosphorylation in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether CQ- or AQ-mediated AMPK activity restoration attenuated diabetic tubulopathy by normalizing mitochondrial fragmentation. Human renal proximal epithelial cells (HKC8) were incubated in high-glucose conditions. Diabetes was induced with streptozotocin in male C57/BL6J mice. Treatment with CQ or AQ abolished high-glucose-induced phospho-AMPK and phosph-PGC1α down-regulation in HKC8 cells. Improvements in functional mitochondrial mass and balanced fusion/fission protein expression were observed in HKC8 cells after treatment with CQ or AQ in high-glucose conditions. Moreover, decreased mitochondrial ROS production and reduced apoptotic and fibrotic protein expression were noted in HKC8 cells after treatment with CQ or AQ, even in high-glucose conditions. CQ and AQ treatment effectively mitigated albuminuria and renal histopathologic changes and increased AMPK activity in the kidneys of diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased, and 8-OHdG content was low in the renal tubular cells of the CQ and AQ treatment groups compared with those of the diabetic control group. Our results suggest that CQ and AQ may be useful treatments for patients with diabetic kidney disease.

Thirty subjects were recruited in this study and were randomly divided into two groups, indigo blanket and placebo asked to complete the sleep questionnaires [Insomnia Severity Index, Pittsburgh Sleep Quality Index, World Health Organization (WHO)-5 Well-Being Index] and to record the sleep diary before and after they use the blanket. The effects of each blanket was evaluated by sleep quality improvement and sleep satisfaction during their use of blanket, based on the sleep diary and sleep questionnaires.

Address for correspondence Won Chul Shin, MD Department of Neurology, Kyung Hee University College of Medicine, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 134-727, Korea Tel: +82-2-440-6166 Fax: +82-2-440-7262 E-mail: shinwc@khu.ac.kr Objectives: Sleeping problems and disorders generally increase with aging, and these changes influence elderly functioning and well-being. We studied the clinical characteristics of the elderly patients with insomnia symptoms for the appropriate diagnosis in Korea. Methods: Patients aged over 65 years with insomnia symptoms were recruited from Sleep Center of Kyung Hee University Hospital at Gangdong, from January 2010 to April 2013. General characteristics of sleep patterns, past medical history, previous medication related sleep, sleep diary, and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) were analyzed to understand the sleep pattern and the clinical characteristics in the elderly patients with insomnia symptoms. Results: The study population included 143 patients (45 men, 98 female), and their mean age was 71.41±5.32 years. These patients were classified according to the cause of insomnia symptoms, the primary cause was 39.1% (92.8% psychophysiological insomnia, 7.2% paradoxical insomnia), the secondary cause was 34.2% (depression, anxiety, associated medical illness, obstructive sleep apnea syndrome, restless legs syndrome), and circadian rhythm sleep disorder was 26.6%. The MMPI-2 profiles were not significant differences in the study population. Conclusions: The clinical characteristics in our study population were different in variable parameters from the general population. It is necessary to understand these differences in the elderly patients for approaching the appropriate diagnosis and medical care. J Korean Sleep Res Soc 2013;10:25-30

This study examined the effect of rosiglitazone, an oral antidiabetic drug, on human ether-a-gogo-related gene (HERG) channels expressed in human embryonic kidney (HEK293) cells. Using the whole-cell patch-clamp technique, interaction between rosiglitazone and HERG in HEK293 cells was studied. Rosiglitazone inhibited HERG channels in a concentration-dependent manner, with an IC 50 value of 18.8 μM and a Hill coefficient of 1.0. These effects were reversible after wash-out of the drug. The rosiglitazone-induced inhibition of HERG channels was voltagedependent, with a steep increase in inhibition over the voltage range of channel opening. However, inhibition was voltage-independent over the voltage range in which channels are fully activated. Rosiglitazone did not change the steady-state activation or inactivation curves or the activation or deactivation kinetics, implying that rosiglitazone blocks HERG channels predominantly in the open and inactivated state rather than in the closed state. The present study suggests that rosiglitazone blocks HERG channels by binding to activated and inactivated channels, and rosiglitazone use should thus be carefully monitored in patients with pre-existing QT prolongation.

The effects of paroxetine, a selective serotonin reuptake inhibitor, on human ether-a-go-go-related gene (HERG) channels were investigated using the whole-cell patch-clamp technique. The HERG channels were stably expressed in human embryonic kidney cells. Paroxetine inhibited the peak tail currents of the HERG channel in a concentration-dependent manner, with an IC50 value of 0.45 µM and a Hill coefficient of 0.85. These effects were reversible after wash-out of the drug. The paroxetine-induced inhibition of the HERG channels was voltage-dependent. There was a steep increase in inhibition over the voltage range of the channel opening. Also, a shallow voltage-dependent inhibition was detected over the voltage range in which the channels were fully activated. The fractional electrical distance was estimated to be 0.11. Paroxetine induced a leftward shift in the voltage-dependence of the steady-state activation of the HERG channels. Before and after application of the 1 µM paroxetine, the half-maximum activation was -14.21 mV and -27.04 mV, respectively, with no shift in the slope value. The HERG channel block was not use-dependent. The characteristics of the block were dependent on open and inactivated channel states rather than closed state. Paroxetine had no effect on activation and deactivation kinetics, steady-state inactivation. These results suggest that paroxetine blocks the HERG channels by binding to these channels in the open and inactivated states.

The psoralen, a furocoumarin derivative, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Psoralen reduced Kv3.1 whole-cell currents in a reversible concentration-dependent manner, with an IC50 value and a Hill coefficient of 2.3 +/- 0.03 microM and 0.9 +/- 0.08, respectively. Psoralen accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The psoralen-induced inhibition of Kv3.1 channels was voltage-dependent, with a steep increase over the voltage range of channel opening. However, the inhibition exhibited voltage independence over the voltage range in which channels are fully activated. Psoralen slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of psoralen, were superimposed. Inhibition of Kv3.1 by psoralen was use-dependent at a frequency of 1 Hz. The present results suggest that psoralen acts on Kv3.1 currents as an open-channel blocker.

The action of fluoxetine, a serotonin reuptake inhibitor, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Fluoxetine reduced Kv3.1 whole-cell currents in a reversible, concentration-dependent manner, with an IC50value and a Hill coefficient of 13.4 μ M and 1.4, respectively. Fluoxetine accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The inhibition increased steeply between 0 and +30 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +30 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance δ of 0.38. The binding (k+1) and dissociation (k−1) rate constants for fluoxetine-induced block of Kv3.1 were 5.7 μ M−1s−1and 53.5 s−1, respectively. The theoretical KDvalue derived by k− 1/k+1yielded 9.3 μ M. Fluoxetine did not affect the ion selectivity of Kv3.1. Fluoxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of fluoxetine, were superimposed. Inhibition of Kv3.1 by fluoxetine was use-dependent. The present results suggest that fluoxetine acts on Kv3.1 currents as an open-channel blocker. Keywords:: fluoxetine, serotonin reuptake inhibitor, Kv3.1, Shaw-type K+channel, open channel block