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While liver histopathology is heterogeneous in diabetes, the underlying mechanisms remain unclear. We investigated whether glycemic variation resulting from differential diets can induce heterogeneity in diabetic liver and the underlying molecular mechanisms. We generated end-stage non-obese diabetic model rats by subtotal-pancreatectomy in male Sprague- Dawley rats and ad libitum diet for 7 weeks (n = 33). The rats were then divided into three groups, and fed a standard- or a low-protein diet (18 or 6 kcal%, respectively), for another 7 weeks: to maintain hyperglycemia, 11 rats were fed ad libitum (18AL group); to achieve euglycemia, 11 were calorierestricted (18R group), and 11 were both calorie- and proteinrestricted with the low-protein diet (6R group). Overnightfasted liver samples were collected after the differential diets together with sham-control (18S group), and histology and molecular changes were compared. Hyperglycemic-18AL showed glycogenic hepatopathy (GH) without steatosis, with the highest GSK-3β inactivation because of Akt activation during hyperglycemia; mitochondrial function was not impaired, compared to the 18S group. Euglycemic-18R showed neither GH nor steatosis, with intermediate GSK-3β activation and mitochondrial dysfunction. However, euglycemic-6R showed both GH and steatosis despite the highest GSK-3β activity and no molecular evidence of increased lipogenesis or decreased ApoB expression, where mitochondrial dysfunction was highest among the groups. In conclusion, heterogeneous liver histopathology developed in end-stage non-obese diabetic rats as the glycemic levels varied with differential diets, in which protein content in the diets as well as glycemic levels differentially influenced GSK-3β activity and mitochondrial function in insulin-deficient state. [BMB Reports 2020; 53(2): 100-105].

Alzheimer's disease (AD) is a chronic neurodegenerative disease, and typical pathologic findings include abnormally hyperphosphorylated tau aggregation and neurofibrillary tangles. Insulin resistance and hyperglycaemia have been proposed as risk factors for AD development. As the maintenance of optimal blood glucose level is an important indicator of diabetes mellitus (DM) treatment, diet control is essential. AMPK is a crucial sensor of cellular bioenergetics for controlling anabolic and catabolic metabolism. Since AMPK is a direct regulator of tau phosphorylation, we hypothesized that strict diet control to achieve euglycaemia affects tau protein phosphorylation through increased AMPK activity in the hippocampus of DM rats. To test this hypothesis, we generated insulin-deficient DM rats by subtotal pancreatectomy and the animals were categorized into the diet-restriction (R) group and ad libitum (AL) feeding group. We found that tau phosphorylation was significantly higher in the R group than that in the sham-control (C) or AL group. AMPK activity in the R group was significantly higher than that in the C or AL group, as expected. Furthermore, the R group showed more critical tau pathology in the hippocampus than the other groups. These results suggest that diet control to achieve euglycaemia in an insulin-deficient DM condition may be harmful because of the greater possibility of AD development through increased tau phosphorylation by AMPK activation in the hippocampus.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia, and it corresponds highly with exercise intensity. Here, we induced AF in mice using acetylcholine (ACh)-CaCl

Oxidative stress is associated with many cardiovascular diseases, such as hypertension and arteriosclerosis. Oxidative stress reportedly activates the L-type voltage-gated calcium channel (VDCCL) and elevates [Ca2+]i in many cells. However, how oxidative stress activates VDCCL under clinical setting and the consequence for arteries are unclear. Here, we examined the hypothesis that hydrogen peroxide (H2O2) regulates membrane potential (Em) by altering Na+ influx through cation channels, which consequently activates VDCCL to induce vasoconstriction in rat mesenteric arteries. To measure the tone of the endothelium-denuded arteries, a conventional isometric organ chamber was used. Membrane currents and Em were recorded by the patch-clamp technique. [Ca2+]i and [Na+]i were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that H2O2 (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of H2O2 on isometric contraction. H2O2 increased [Ca2+]i as well as [Na+]i, and depolarised Em. Gd3+ (1 µM) blocked all these H2O2-induced effects including Em depolarisation and increases in [Ca2+]i and [Na+]i. Although both nifedipine (30 nM) and low Na+ bath solution completely prevented the H2O2-induced increase in [Na+], they only partly inhibited the H2O2-induced effects on [Ca2+]i and Em. Taken together, the results suggested that H2O2 constricts rat arteries by causing Em depolarisation and VDCCL activation through activating Gd3+-and nifedipine-sensitive, Na+-permeable channels as well as Gd3+-sensitive Ca2+-permeable cation channels. We suggest that unidentified Na+-permeable cation channels as well as Ca2+-permeable cation channels may function as important mediators for oxidative stress-induced vascular dysfunction.

The Article Abstract is not available.

MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HT2ARs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HT2AR signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HT2AR signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5-HT2AR-mediated response. Using isometric organ bath experiments with arterial rings and conventional whole-cell patch-clamp recording of Chinese hamster ovary (CHO) cells ectopically overexpressing Kv1.5, we examined the effect of ketamine and MK801 on 5-HT2AR-mediated vasocontraction and Kv1.5 channels. Both ketamine and MK801 potentiated 5-HT2AR-mediated vasocontraction. This potentiation of 5-HT2AR function occurred in a membrane potential-dependent manner, indicating the involvement of ion channel(s). Both ketamine and MK801 rapidly and directly inhibited Kv1.5 channels from the extracellular side independently of NMDArs. The potencies of MK801 in facilitating the 5-HT2AR-mediated response and blocking Kv1.5 were higher than those of ketamine. Our data demonstrated the direct inhibition of Kv1.5 channels by MK801/ketamine and indicated that this inhibition may potentiate the functions of 5-HT2ARs. We suggest that 5-HT2AR-Kv1.5 may serve as a receptor-effector module in response to 5-HT and is a promising target in the pathogenesis of MK801-/ketamine-induced disease states such as hypertension and schizophrenia.

Activation of L-type voltage-dependent Ca2+ channels (VDCCL) by membrane stretch contributes to many biological responses such as myogenic contraction of arteries. However, mechanism for the stretch-induced VDCCL activation is unclear. In this study, we examined the hypothesis that caveolar remodeling and its related signaling cascade contribute to the stretch-induced activation of VDCCL in rat mesenteric arterial smooth muscle cells. The VDCCL currents were recorded with nystatin-perforated or with conventional whole-cell patch-clamp technique. Hypotonic (~230 mOsm) swelling-induced membrane stretch reversibly increased the VDCCL currents. Electron microscope and confocal imaging analysis revealed that both hypotonic swelling and cholesterol depletion by methyl-β-cychlodextrin (MβCD) similarly disrupted the caveolae structure and translocated caveolin-1 (Cav-1) from membrane to cytosolic space. Accordingly, MβCD also increased VDCCL currents. Moreover, subsequent hypotonic swelling after MβCD treatment failed to increase the VDCCL currents further. Western blotting experiments revealed that hypotonic swelling phosphorylated Cav-1 and JNK. Inhibitors of tyrosine kinases (genistein) and JNK (SP00125) prevented the swelling-induced facilitation of VDCCL currents. Knockdown of Cav-1 by small interfering RNA blocked both the VDCCL current facilitation by stretch and the related phosphorylation of JNK. Taken together, the results suggest that membrane stretch is transduced to the facilitation of VDCCL currents via caveolar structure-dependent tyrosine phosphorylation of Cav-1 and subsequent activation of JNK in rat mesenteric arterial myocytes.

Oxidative stress is associated with many cardiovascular diseases, such as hypertension and arteriosclerosis. Oxidative stress reportedly activates the L-type voltage-gated calcium channel (VDCC

Exercise-induced rhabdomyolysis (exRML), a pathophysiological condition of skeletal muscle cell damage that may cause acute renal failure and in some cases death. Increased Ca2+ level in cells along with functional degradation of cell signaling system and cell matrix have been suggested as the major pathological mechanisms associated with exRML. The onset of exRML may be exhibited in athletes as well as in general population. Previous studies have reported that possible causes of exRML were associated with excessive eccentric contractions in high temperature, abnormal electrolytes balance, and nutritional deficiencies possible genetic defects. However, the underlying mechanisms of exRML have not been clearly established among health professionals or sports medicine personnel. Therefore, we reviewed the possible mechanisms and correlated prevention of exRML, while providing useful and practical information for the athlete and general exercising population.

Aim: Alcohol consumption among adolescents is a serious public health problem in South Korea. Our study examined the relationship between alcohol consumption and academic achievement in Korean adolescents. In 2011, 75,643 students from seventh to twelfth grade participated in the Seventh Korea Youth Risk Behaviour Web-based Survey (KYRBWS-VII). Method: We performed multivariate logistic regression analysis to examine the associations between alcohol consumption, frequency of severe alcohol intoxication, and academic achievement for both girls and boys. Results: Compared to non-drinkers, the odds of achieving average or higher academic performance significantly decreased for both boys and girls with increasing number of days per month with reported alcohol consumption (p≤0.008). Further, odds of achieving average or higher academic performance significantly decreased with increasing amounts of alcohol consumed compared to non-drinkers (p≤0.026). Additionally, the odds of achieving average or higher academic performance according to the frequency of severe alcohol intoxication were only significantly decreased for 1-2 days per month of severe intoxication (p

This study was conducted on Korean male high school soccer players who underwent anterior cruciate ligament reconstruction (ACLR) to identify the effects of an accelerated rehabilitation exercise (ARE) program on knee joint isometric strength, thigh circumference, Lysholm score, and active balance agility. We assigned eight test participants each to a physical therapy group (PTG) and an accelerated rehabilitation exercise group (AREG), and compared differences between the groups. Both the PTG and AREG showed significant increases in 30° away and 60° toward isometric strength after treatment. In addition, significant differences were observed in these strength tests between the two groups. Both groups also showed significant increases in thigh circumference, Lysholm score, and active balance agility after treatment, but no significant differences were observed between the two groups. We conclude that the ARE treatment was more effective for improving isometric strength of the knee joint than that of physical therapy, and that an active rehabilitation exercise program after ACLR had positive effects on recovery performance of patients with an ACL injury and their return to the playing field.

The purpose of this cross-sectional study was to determine the differences in areal bone mineral density (aBMD) based on alcohol consumption behaviors, bone-loading history as assessed by a bone-specific physical activity questionnaire (BPAQ), and the body mass index (BMI). College-aged female students (N = 112) were recruited from the universities in Seoul and Gyeonggi province, South Korea. The aBMD of the lumbar spine and non-dominant side of the proximal femur (total hip, TH, femoral neck, FN, femoral trochanter, FT) were measured using dual energy X-ray absorptiometry (DXA). Alcohol consumption was determined by the frequency and amount of alcohol intake during the past 12 months using a self-reported questionnaire. The X-scan plus II was used to measure height (cm), body mass (kg), fat-free mass (FFM, kg), and % body fat. Drinking two or more times alcohol per week was associated with greater aBMD of the TH (p = 0.04&ndash, 0.002) and FN (p = 0.043) compared to a lower frequency of alcohol consumption and 2&ndash, 4 times per month, respectively. Based on the drinking amount per occasion, there were no significant group differences (p &gt, 0.05) in aBMD at any of the sites. The highest group of total BPAQ had greater aBMD of the TH, FN, and FT versus the lowest (p = 0.023&ndash, 0.009) and mid of total BPAQ groups (p = 0.004&ndash, 0.009). Additionally, the highest group had greater aBMD of the lumbar spine compared to the mid group (p = 0.001). No significant group differences in aBMD at any of the sites were noted based on the BMI (p &gt, 0.05). Young college-aged women with greater bone-loading physical activity showed greater aBMD at the TH, FN, FT, and lumbar spine, while a moderate alcohol intake was associated with greater aBMD of the TH and FN. These findings have clinical implications for young women who may not participate in high-impact physical activity and are binge drinkers.

Transcranial direct current stimulation (tDCS) is a technique used to modulate neuronal excitability through non-invasive brain stimulation that can enhance exercise performance. We hypothesize that tDCS would improve submaximal running time to exhaustion (TTE) and delay the increase in the rating of perceived exertion (RPE) over time. We also hypothesize that tDCS would not lead to difference in cardiorespiratory responses. We employed a randomized, single-blinded, and counterbalanced design in which 10 trained men participated. After receiving either 20 min of 1.98 mA anodal tDCS applied over the primary motor cortex (M1) or sham-operated control on separate days, participants completed a constant-load test involving running at a speed equivalent to 80% of their own maximum oxygen consumption (VO2max). During this constant-load test, RPE, heart rate (HR), VO2, pulmonary ventilation (VE), respiratory exchange ratio (RER), and ventilatory threshold (VT) were continuously monitored. TTE was recorded at the end of the test. TTEs were significantly longer in the tDCS than in the sham conditions (21.18 ± 7.13 min; 18.44 ± 6.32 min; p = 0.011). For TTE, no significant differences were found in RPE between conditions at isotime. In addition, no significant differences in HR, VO2, VE, RER, and VT were found during TTE between the two stimulation conditions at any time point. These results indicate that the application of tDCS does not induce a change of the exercise performance-related index; however, it can affect the increase of the exercise duration due to the stimuli in the M1 area.

Muscle damage is induced by both high-intensity resistance and endurance exercise. Creatine is a widely used dietary supplement to improve exercise performance by reducing exercise-induced muscle damage. Many researchers have suggested that taking creatine reduces muscle damage by decreasing the inflammatory response and oxidative stress, regulating calcium homeostasis, and activating satellite cells. However, the underlying mechanisms of creatine and muscle damage have not been clarified. Therefore, this review discusses the regulatory effects of creatine on muscle damage by compiling the information collected from basic science and sports science research.

Pancreatic β-cells are critical in the regulation of glucose homeostasis by controlled secretion of insulin in mammals. Activation of protein kinase A by cAMP is shown to be responsible for enhancing this pathway, which is countered by phosphodiesterase (PDE) that converts cAMP to AMP and turns off the signal. Salt-inducible kinases (SIKs) were also known to inhibit cAMP signaling, mostly by promoting inhibitory phosphorylation on CREB-regulated transcription coactivators. Here, we showed that SIK1 regulates insulin secretion in β-cells by modulating PDE4D and cAMP concentrations. Haploinsufficiency of SIK1 led to the improved glucose tolerance due to the increased glucose-stimulated insulin secretion. Depletion of SIK1 promoted higher cAMP concentration and increased insulin secretion from primary islets, suggesting that SIK1 controls insulin secretion through the regulation of cAMP signaling. By using a consensus phosphorylation site of SIK1, we identified PDE4D as a new substrate for this kinase family. In vitro kinase assay as well as mass spectrometry analysis revealed that the predicted Ser136 and the adjacent Ser141 of PDE4D are critical in SIK1-mediated phosphorylation. We found that overexpression of either SIK1 or PDE4D in β-cells reduced insulin secretion, while inhibition of PDE4 activity by rolipram or knockdown of PDE4D restored it, showing indeed that SIK1-dependent phosphorylation of PDE4D is critical in reducing cAMP concentration and insulin secretion from β-cells. Taken together, we propose that SIK1 serves as a part of a self-regulatory circuit to modulate insulin secretion from pancreatic β-cells by controlling cAMP concentration through modulation of PDE4D activity.

[Purpose] This study was performed to determine whether certain lifestyle factors are associated with hypertension in community-dwelling Korean adults. [Subjects and Methods] The subjects were 586 males and 1,135 females > 20 years old who had visited a public health promotion center in Seoul, Republic of Korea to take a survey related to lifestyle factors. Hypertension status was defined according to the criteria of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VII report. [Results] The relationships between lifestyle factors and hypertension status were assessed using multivariate logistic regression analysis after adjusting for age and gender. Only mental stress and economic status significantly predicted hypertension status. [Conclusion] We conclude that sleep duration, education level, frequency of drinking and smoking status were not associated with hypertension status. However, economic status and mental stress were significantly associated with hypertension in community-dwelling Korean adults, regardless of age or gender.

MK801 (dizocilpine), a phencyclidine (PCP) derivative, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). Another PCP derivative, ketamine, was reported to block voltage-gated K+ (Kv) channels, which was independent of NMDAr function. Kv currents are major regulators of the membrane potential (E-m) and excitability of muscles and neurons. Here, we investigated the effect of MK801 on the Kv channels and E-m in rat mesenteric arterial smooth muscle cells (RMASMCs). We used the whole-cell patch clamp technique to analyze the effect of MK801 enantiomers on Kv channels and E-m. (+)MK801 inhibited Kv channels in a concentration-dependent manner (IC50 of 89.1 +/- 13.1 mu M. Hill coefficient of 1.05 +/- 0.08). The inhibition was voltage- and state- independent. (+)MK801 didn't influence steady-state activation and inactivation of Kv channels. (+)MK801 treatment depolarized E-m in a concentration-dependent manner and concomitantly decreased membrane conductance. (-)MK801 also similarly inhibited the Kv channels (IC50 of 134.0 +/- 17.5 mu M, Hill coefficient of 0.87 +/- 0.09). These results indicate that MK801 directly inhibits the Kv channel in a state-independent manner in RMASMCs. This MK801-mediated inhibition of Kv channels should be considered when assessing the various pharmacological effects produced by MK801, such as schizophrenia, neuroprotection, and hypertension. (C) 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V.

MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HT2ARs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HT2AR signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HT2AR signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5-HT2AR-mediated response. Using isometric organ bath experiments with arterial rings and conventional whole-cell patch-clamp recording of Chinese hamster ovary (CHO) cells ectopically overexpressing Kv1.5, we examined the effect of ketamine and MK801 on 5-HT2AR-mediated vasocontraction and Kv1.5 channels. Both ketamine and MK801 potentiated 5-HT2AR-mediated vasocontraction. This potentiation of 5-HT2AR function occurred in a membrane potential-dependent manner, indicating the involvement of ion channel(s). Both ketamine and MK801 rapidly and directly inhibited Kv1.5 channels from the extracellular side independently of NMDArs. The potencies of MK801 in facilitating the 5-HT2AR-mediated response and blocking Kv1.5 were higher than those of ketamine. Our data demonstrated the direct inhibition of Kv1.5 channels by MK801/ketamine and indicated that this inhibition may potentiate the functions of 5-HT2ARs. We suggest that 5-HT2AR-Kv1.5 may serve as a receptor-effector module in response to 5-HT and is a promising target in the pathogenesis of MK801-/ketamine-induced disease states such as hypertension and schizophrenia., Serotonin: Flipping a cellular switch The drugs ketamine and MK801, which are derivatives of phencyclidine (PCP, or angel dust), may provide clues to treatment of schizophrenia and hypertension. Both ketamine and MK801 have been reported to induce symptoms of schizophrenia and hypertension, and are used as to study these illnesses. The two drugs are known to affect serotonin receptors, but the mechanism remains unclear. Young Min Bae at Konkuk University School of Medicine, Chungju, South Korea, and colleagues investigated how ketamine and MK801 interact with a type of electrically activated biological switch known as a voltage-gated ion channel to influence serotonin receptors. They found that both ketamine and MK801 blocked the switch and enhanced activity of serotonin receptors, with MK801 having a stronger effect than ketamine. These results may help identify drug targets for treating hypertension and schizophrenia.

Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca2+-activated K+ channels and inward rectifier K+ channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2. Electronic supplementary material The online version of this article (doi:10.1007/s00424-014-1513-3) contains supplementary material, which is available to authorized users.

The inward rectifier Kir2.1 current (IKir2.1) was reported to be facilitated by fluid flow. However, the mechanism underlying this facilitation remains uncertain. We hypothesized that during K+ influx or efflux, [K+] adjacent to the outer mouth of the Kir2.1 channel might decrease or increase, respectively, compared with the average [K+] of the bulk extracellular solution, and that fluid flow could restore the original [K+] and result in the apparent facilitation of IKir2.1. We recorded the IKir2.1 in RBL-2H3 cells and HEK293T cells that were ectopically over-expressed with Kir2.1 channels by using the whole-cell patch-clamp technique. Fluid-flow application immediately increased the IKir2.1, which was not prevented by either the pretreatment with inhibitors of various protein kinases or the modulation of the cytoskeleton and caveolae. The magnitudes of the increases of IKir2.1 by fluid flow were driving force-dependent. Simulations performed using the Nernst-Planck mass equation indicated that [K+] near the membrane surface fell markedly below the average [K+] of the bulk extracellular solution during K+ influx, and, notably, that fluid flow restored the decreased [K+] at the cell surface in a flow rate-dependent manner. These results support the “convection-regulation hypothesis” and define a novel interpretation of fluid flow-induced modulation of ion channels.