The thermal sensation threshold and its reliability induced by the exposure to 28 GHz millimeter-wave.

The application of 28 GHz millimeter-wave is prevalent owing to the global spread of fifth-generation wireless communication systems. Its thermal effect is a dominant factor which potentially causes pain and tissue damage to the body parts exposed to the millimeter waves. However, the threshold of this thermal sensation, that is, the degree of change in skin temperature from the baseline at which the first subjective response to the thermal effects of the millimeter waves occurs, remains unclear. Here, we investigated the thermal sensation threshold and assessed its reliability when exposed to millimeter waves. Twenty healthy adults were exposed to 28 GHz millimeter-wave on their left middle fingertip at five levels of antenna input power: 0.2, 1.1, 1.6, 2.1, and 3.4 W (incident power density: 27-399 mW/cm2). This measurement session was repeated twice on the same day to evaluate the threshold reliability. The intraclass correlation coefficient (ICC) and Bland-Altman analysis were used as proxies for the relative and absolute reliability, respectively. The number of participants who perceived a sensation during the two sessions at each exposure level was also counted as the perception rate. Mean thermal sensation thresholds were within 0.9°C-1.0°C for the 126-399 mW/cm2 conditions, while that was 0.2°C for the 27 mW/cm2 condition. The ICCs for the threshold at 27 and 126 mW/cm2 were interpreted as poor and fair, respectively, while those at higher exposure levels were moderate to substantial. Apart from a proportional bias in the 191 mW/cm2 condition, there was no fixed bias. All participants perceived a thermal sensation at 399 mW/cm2 in both sessions, and the perception rate gradually decreased with lower exposure levels. Importantly, two-thirds of the participants answered that they felt a thermal sensation in both or one of the sessions at 27 mW/cm2, despite the low-temperature increase. These results suggest that the thermal sensation threshold is around 1.0°C, consistent across exposure levels, while its reliability increases with higher exposure levels. Furthermore, the perception of thermal sensation may be inherently ambiguous owing to the nature of human perception.

Gamified exercise for the distal upper extremity in people with post-stroke hemiparesis: feasibility study on subjective perspectives during daily continuous training.

INTRODUCTION: Dose (number of repetitions) has been suggested as a key element in the effectiveness of rehabilitation exercises to promote motor recovery of the hemiparetic upper limb. However, rehabilitation exercises tend to be monotonous and require significant motivation to continue, making it difficult to increase the exercise dose. To address this issue, gamification technology has been implemented in exercises to promote self-engagement for people with hemiparesis in continuing monotonous repetitive movements. This study aimed to investigate how subjective perspectives, specifically enjoyability, motivation to continue, and expectancy of effectiveness, change through continuous daily exercise using a developed gamified exercise system. MATERIALS AND METHOD: Ten people with stroke suffering upper limb dysfunction underwent daily gamified exercise for seven days. The gamified exercise consisted of an electromyography (EMG)-controlled operating system that enabled users to play virtual games using repetitive finger movements. The participants performed conventional self-exercise on the same day as the control exercise, and rated their subjective perspectives on both exercises on a numerical rating scale on each exercise day. RESULTS: Ratings for enjoyability and motivation to continue consistently showed significantly higher scores for the gamified exercise than for conventional self-exercise on all exercise days. A similar trend was observed in the ratings for the expectancy of effectiveness. No changes over time were found in any of the ratings throughout the exercise period. CONCLUSIONS: Exercise using the developed EMG-controlled gamified system may have the potential to maintain motivation and enjoyment in people with stroke to continue monotonous repetitive finger movements.

Although dose (number of repetitions) has been suggested as a key element in the effectiveness of rehabilitation exercises to promote motor recovery of the hemiparetic upper limb, rehabilitation exercises tend to be monotonous and require significant motivation to continue.Gamification technology has been implemented in exercises to promote self-engagement for people with hemiparesis in continuing monotonous repetitive movements.Exercises using the developed EMG-controlled gamified system may have the potential to maintain motivation and enjoyment in people with stroke to continue monotonous repetitive finger movements.

The suppression of the differentiation of adipocytes with Mallotus furetianus is regulated through the posttranslational modifications of C/EBPß.

Obesity is a major risk factor for various chronic diseases, especially lifestyle-related diseases. Therefore, finding a protective substance against obesity and elucidating its molecular mechanism is one of the most important problems for improving human health. In this study, we investigated the antiobesity effect of Mallotus furetianus extract (MFE). The aim of the study was to examine the in vivo and in vitro effects of MFE on lipid synthesis. We examined the effect using an in vivo experimental system with obesity model mice and an in vitro experimental system with 3T3-L1 preadipocytes. We found that the treatment of MFE significantly suppressed the increase in body weight and adipose tissue weight and morphological changes in the liver and adipose tissue of the obesity model mice. In the in vitro experimental system, we revealed that MFE treatment suppressed the expression of transcription factors such as C/EBPα, C/EBPß, and PPARγ, which are involved in the early differentiation of 3T3-L1 preadipocytes. As a result, the ability to synthesize triacylglycerol was suppressed. An interesting finding in this study was the clarification that MFE decreases the expression of C/EBPß through post-translation modifications (PTMs), followed by the transcriptional suppression of PPAR𝛾 and C/EBP𝛼.

Direction-dependent differences in the quality and quantity of horizontal reaching in people after stroke.

Arm reaching is often impaired in individuals with stroke. Nonetheless, how aiming directions influence reaching performance and how such differences change with motor recovery over time remain unclear. Here, we elucidated kinematic parameters of reaching toward various directions in people with poststroke hemiparesis in the subacute phase. A total of 13 and 15 participants with mild and moderate-to-severe hemiparesis, respectively, performed horizontal reaching in eight directions with their more-affected and less-affected sides using an exoskeleton robotic device at the time of admission to and discharge from the rehabilitation ward of the hospital. The movement time, path length, and number of velocity peaks were computed for the mild group (participants able to reach toward all eight directions). In addition, the total amount of displacement (i.e., movement quantity) toward two simplified directions (mediolateral or anteroposterior) was evaluated for the moderate-to-severe group (participants who showed difficulty in completing the reaching task). Motor recovery was evaluated using the Fugl-Meyer assessment. The mild group showed worse values of movement parameters during reaching in the anteroposterior direction, irrespective of the side of the arm or motor recovery achieved. The moderate-to-severe group exhibited less movement toward the anteroposterior direction than toward the mediolateral direction at admission; however, this direction-dependent bias in movement quantity decreased, with the movement expanding toward the anteroposterior direction with motor recovery at discharge. These results suggest that direction-dependent differences in the quality and quantity of reaching performance exist in people after stroke, regardless of the presence or severity of hemiparesis. This highlights the need to consider the task work area when designing rehabilitative training.NEW & NOTEWORTHY Arm reaching, a fundamental function required for the upper extremities, is often impaired after stroke due to muscle weakness and abnormal synergies. Nonetheless, how aiming directions influence performance remains unclear. Here, we report that direction-dependent differences in the quality and quantity of reaching performance exist, surprisingly regardless of the presence or severity of hemiparesis. This result highlights the need to consider the task work area when designing rehabilitative training.

Kaempferia galanga L. extract and its main component, ethyl p-methoxycinnamate, inhibit the proliferation of Ehrlich ascites tumor cells by suppressing TFAM expression.

Kaempferia galanga L. shows anti-cancer effects; however, the underling mechanism remains unclear. In this study, we explored the underlying mechanism of the anti-cancer effects of Kaempferia galanga L. Kaempferia galanga L. rhizome extracts (KGEs) suppressed Ehrlich ascites tumor cell (EATC) proliferation by inhibiting S-phase progression. The main component of KGE is ethyl p-methoxycinnamate (EMC), which exhibits the same anti-proliferative effect as KGE. Furthermore, EMC induced the downregulation of cyclin D1 and upregulation of p21. EMC also decreased the expression of mitochondrial transcription factor A (TFAM) but did not significantly change mitochondrial DNA copy number and membrane potential. Phosphorylation at Ser62 of c-Myc, a transcription factor of TFAM, was decreased by EMC treatment, which might be due to the suppression of H-ras expression. These results indicate that EMC is the active compound responsible for the anti-cancer effect of KGE and suppresses EATC proliferation by regulating the protein expression of cyclin D1 and p21; TFAM may also regulate the expression of these genes. In addition, we investigated the anticancer effects of KGE and EMC in vivo using EATC bearing mice. The volume of ascites fluid was significantly increased by intraperitoneal administration of EATC. However, the increase in the volume of ascites fluid was suppressed by oral administration of EMC and KGE. This study provides novel insights into the association between the anti-cancer effects of natural compounds and TFAM, indicating that TFAM might be a potential therapeutic target.

Characteristics of current perception produced by intermediate-frequency contact currents in healthy adults.

Introduction: Contact electrical currents in humans stimulate peripheral nerves at frequencies of <100 kHz, producing sensations such as tingling. At frequencies above 100 kHz, heating becomes dominant, resulting in a sensation of warmth. When the current amplitude exceeds the threshold, the sensation results in discomfort or pain. In international guidelines and standards for human protection from electromagnetic fields, the limit for the contact current amplitude has been prescribed. Although the types of sensations produced by contact current at low frequencies, i.e., approximately 50-60 Hz, and the corresponding perception thresholds have been investigated, there is a lack of knowledge about those in the intermediate-frequency band-particularly from 100 kHz to 10 MHz. Methods: In this study, we investigated the current-perception threshold and types of sensations for 88 healthy adults (range: 20-79 years old) with a fingertip exposed to contact currents at 100 kHz, 300 kHz, 1 MHz, 3 MHz, and 10 MHz. Results: The current perception thresholds at frequencies ranging from 300 kHz to 10 MHz were 20-30% higher than those at 100 kHz (p < 0.001). In addition, a statistical analysis revealed that the perception thresholds were correlated with the age or finger circumference: older participants and those with larger finger circumferences exhibited higher thresholds. At frequencies of ≥300 kHz, the contact current mainly produced a warmth sensation, which differed from the tingling/pricking sensation produced by the current at 100 kHz. Discussion: These results indicate that there exists a transition of the produced sensations and their perception threshold between 100 kHz and 300 kHz. The findings of this study are useful for revising the international guidelines and standards for contact currents at intermediate frequencies. Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000045660, identifier UMIN 000045213.

Glyoxylic Acid, an α-Keto Acid Metabolite Derived from Glycine, Promotes Myogenesis in C2C12 Cells.

α-Keto acids may help prevent malnutrition in patients with chronic kidney disease (CKD), who consume protein-restricted diets, because they serve as amino acid sources without producing nitrogenous waste compounds. However, the physiological roles of α-keto acids, especially those derived from non-essential amino acids, remain unclear. In this study, we examined the effect of glyoxylic acid (GA), an α-keto acid metabolite derived from glycine, on myogenesis in C2C12 cells. Differentiation and mitochondrial biogenesis were used as myogenesis indicators. Treatment with GA for 6 d resulted in an increase in the expression of differentiation markers (myosin heavy chain II and myogenic regulatory factors), mitochondrial biogenesis, and intracellular amounts of amino acids (glycine, serine, and alanine) and their metabolites (citric acid and succinic acid). In addition, GA treatment suppressed the 2.5-µM dexamethasone (Dex)-induced increase in mRNA levels of ubiquitin ligases (Trim63 and Fbxo32), muscle atrophy markers. These results indicate that GA promotes myogenesis, suppresses Dex-induced muscle atrophy, and is metabolized to amino acids in muscle cells. Although further in vivo experiments are needed, GA may be a beneficial nutrient for ameliorating the loss of muscle mass, strength, and function in patients with CKD on a strict dietary protein restriction.

Effects of trunk neuromuscular electrical stimulation on the motor circuits of able-bodied individuals.

Upper- and lower-limb neuromuscular electrical stimulation (NMES) is known to modulate the excitability of the neural motor circuits. However, it remains unclear whether short-duration trunk muscle NMES could achieve similar neuromodulation effects. We assessed motor evoked potentials (MEPs) elicited through transcranial magnetic stimulation of the primary motor cortex representation of the trunk extensor muscles to evaluate corticospinal excitability. Moreover, cervicomedullary motor evoked potentials (CMEPs) were assessed through cervicomedullary junction magnetic stimulation to evaluate subcortical excitability. Twelve able-bodied individuals participated in the MEP study, and another twelve in the CMEP study. During the interventions, NMES was applied bilaterally to activate the erector spinae muscle and produce intermittent contractions (20 s ON/20 s OFF) for a total of 20 min while participants remained seated. Assessments were performed: (i) before; (ii) during (in brief periods when NMES was OFF); and (iii) immediately after the interventions to compare MEP or CMEP excitability. Our results showed that MEP responses were not affected by trunk NMES, while CMEP responses were facilitated for approximately 8 min during the intervention, and returned to baseline before the end of the 20 min stimulating period. Our findings therefore suggest that short-duration NMES of the trunk extensor muscles likely does not affect the corticospinal excitability, but it has a potential to facilitate subcortical neural circuits immediately after starting the intervention. These findings indicate that short-duration application of NEMS may be helpful in rehabilitation to enhance neuromodulation of the trunk subcortical neural motor circuits.

Electromyography-controlled gamified exercise system for the distal upper extremity: a usability assessment in subacute post-stroke patients.

PURPOSE: Movement repetition is known to play a key role in promoting functional improvements or maintaining functional levels in post-stroke hemiparetic patients. However, repetitive movements tend to be monotonous, making it challenging for patients to continue. Here, we developed a new gamified system to allow patients perform repetitive movements with enjoyment. The present study aimed to examine the usability of the system in subacute stroke patients. METHOD: The exercise system comprised an electromyography-controlled operating system that enabled users to play a virtual game by repetitive finger and wrist movements on the affected side. A total of 13 patients with upper-limb hemiparesis underwent a single bout of exercise using the system and assessed its usability, satisfactoriness, enjoyability, etc. using the System Usability Scale (SUS), Quebec User Evaluation of Satisfaction with assistive Technology (QUEST)-like questionnaire, and numerical rating scale (NRS). RESULTS: All the participants, who had a wide range of paretic levels, were able to perform the exercise using the system. Participants scored the system a median of 85.0 for SUS and 4.2 for the QUEST-like questionnaire, with an "excellent" in usability and "satisfied" in user satisfaction with the system. The median NRS scores for enjoyability, potential for continuous use, and effectiveness were 8.0, 9.0, and 9.0, respectively, which were greater than the scores for usual rehabilitation training for the upper extremity. CONCLUSIONS: The novel electromyography-controlled gamified exercise system may have sufficient usability and enjoyability to motivate patients with a wide range of paretic levels to perform repetitive finger and wrist movements.IMPLICATIONS FOR REHABILITATIONThe electromyography-controlled gamified exercise system had overall positive perspectives on the usability of the system.This exercise system could help motivate patients with a wide range of paretic levels to perform repetitive finger and wrist movements.

Systematic determination of muscle groups and optimal stimulation intensity for simultaneous TMS mapping of multiple muscles in the upper limb.

Transcranial magnetic stimulation has been used to assess plastic changes in the cortical motor representations of targeted muscles. The present study explored the optimal settings and stimulation intensity for simultaneous motor mapping of multiple upper-limb muscles across segments. In 15 healthy volunteers, we evaluated cortical representations simultaneously from one muscle in the shoulder, two in the upper arm, two in the forearm, and two intrinsic hand muscles, using five stimulation intensities, ranging from 40% to 100% of the maximum stimulator output. We represented the motor map area acquired at each intensity as a percentage of the maximum for each muscle. We defined a motor map area between 25% and 75% of the maximum as the optimal area size with sufficient scope for both up- and down-regulation, and stimulation intensities producing the map area size within this range as the optimal intensities. We found that motor maps with optimal area sizes could be produced simultaneously for the four distal muscles of the forearm and hand in most participants when the stimulation intensity was set at 120-140% of the resting motor threshold (RMT) of the first dorsal interosseous. For the remaining three proximal muscles, motor maps with optimal area sizes were produced only in a few participants, even when using a higher intensity (180-220% RMT). These findings suggest that cortical representations can be assessed simultaneously in a group of distal muscles using a relatively low stimulation intensity, while a separate operation is required to assess that of the proximal muscles.

Effects of cerebellar transcranial direct current stimulation on upper limb motor function after stroke: study protocol for the pilot of a randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a technique that can noninvasively modulate neural states in a targeted brain region. As cerebellar activity levels are associated with upper limb motor improvement after stroke, the cerebellum is a plausible target of tDCS. However, the effect of tDCS remains unclear. Here, we designed a pilot study to assess: (1) the feasibility of a study that aims to examine the effects of cerebellar tDCS combined with an intensive rehabilitation approach based on the concept of constraint-induced movement therapy (CIMT) and (2) the preliminary outcome of the combined approach on upper limb motor function in patients with stroke in the chronic stage. METHODS: This pilot study has a double-blind randomized controlled design. Twenty-four chronic stroke patients with mild to moderate levels of upper limb motor impairment will be randomly assigned to an active or sham tDCS group. The participants will receive 20 min of active or sham tDCS to the contralesional cerebellum at the commencement of 4 h of daily intensive training, repeatedly for 5 days per week for 2 weeks. The primary outcomes are recruitment, enrollment, protocol adherence, and retention rates and measures to evaluate the feasibility of the study. The secondary outcome is upper limb motor function which will be evaluated using the Action Research Arm Test, Fugl-Meyer Assessment, for the upper extremity and the Motor Activity Log. Additionally, neurophysiological and neuroanatomical assessments of the cerebellum will be performed using transcranial magnetic stimulation and magnetic resonance imaging. These assessments will be conducted before, at the middle, and after the 2-week intervention, and finally, 1 month after the intervention. Any adverse events that occur during the study will be recorded. DISCUSSION: Cerebellar tDCS combined with intensive upper limb training may increase the gains of motor improvement when compared to the sham condition. The present study should provide valuable evidence regarding the feasibility of the design and the efficacy of cerebellar tDCS for upper limb motor function in patients with stroke before a future large trial is conducted. TRIAL REGISTRATION: This study has been registered at the Japan Registry of Clinical Trials ( jRCTs042200078 ). Registered 17 December 2020.

Effective corticospinal excitability neuromodulation elicited by short-duration concurrent and synchronized associative cortical and neuromuscular stimulations.

Optimal parameters of combined repetitive associative transcranial magnetic stimulation (rTMS) and neuromuscular electrical stimulation (NMES) for neuromodulation of central nervous system (CNS) excitability are not well understood. We examined corticospinal excitability after short-duration concurrent and synchronized associative stimulation applied using primary motor cortex rTMS and upper-limb NMES. Intermittent theta burst stimulation (iTBS) was delivered with burst at 50 Hz and repeated at 5 Hz over the course of 192 s as an established cortical facilitation rTMS protocol. NMES was applied to activate the extensor carpi radialis muscle over the same 192 s duration. Four interventions were compared: (1) iTBS with concurrent and synchronized 50 Hz NMES; (2) iTBS with concurrent and synchronized 5 Hz NMES; (3) iTBS with concurrent and asynchronized 41 Hz NMES; (4) iTBS with 5 s delayed and synchronized 50 Hz NMES. Single-pulse motor evoked potential (MEP) responses elicited by transcranial magnetic stimulation of the primary motor cortex and maximum motor responses (Mmax) elicited by radial nerve stimulation were compared before and for 30 min after each intervention. Our results showed that corticospinal excitability (MEP/Mmax) was only facilitated after the iTBS and concurrent 50 Hz NMES intervention, but the responses returned to baseline within 10 min of completing the intervention. This result demonstrates that short-duration concurrent and synchronized stimulation could be applied to effectively neuromodulate corticospinal excitability. Therefore, repetitive synchronized associative stimulation of the primary motor cortical networks and sensorimotor peripheral circuits may be enhanced using synchronized 50 Hz frequency of activation during concurrent stimulation.

Phosphodiesterase 4 mRNA Level Suppression is Important for Extract of Black Carrot to Protect Against Hepatic Injury Induced by Ethanol.

Excessive alcohol use often results in alcoholic liver disease (ALD). An early change in the liver due to excessive drinking is hepatic steatosis, which may ultimately progress to hepatitis, liver fibrosis, cirrhosis, and liver cancer. Among these debilitating processes, hepatic steatosis is reversible with the appropriate treatment. Therefore, it is important to find treatments and foods that reverse hepatic steatosis. Black carrot has antioxidant and anti-inflammatory effects. In this study, we examined the effectiveness of black carrot extract (BCE) on hepatic steatosis in in vivo and in vitro ethanol-induced liver injury models. For the in vivo experiments, serum aminotransferase activities enhanced by ethanol- and carbon tetrachloride were significantly suppressed by the BCE diet. Furthermore, morphological changes in the liver hepatic steatosis and fibrosis were observed in the in vivo ethanol-induced liver injury model, however, BCE feeding resulted in the recovery to an almost normal liver morphology. In the in vitro experiments, ethanol treatment induced reactive oxygen species (ROS) levels in hepatocytes at 9 h. Conversely, ROS production was suppressed to control levels and hepatic steatosis was suppressed when hepatocyte culture with ethanol were treated with BCE. Furthermore, we investigated enzyme activities, enzyme protein levels, and messenger RNA levels of alcohol dehydrogenase (ADH), cytochrome p450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) using enzyme assays, western blot, and quantitative reverse transcription-polymerase chain reaction analyses. We found that the activities of ADH, CYP2E1, and ALDH were regulated through the cAMP-PKA pathway at different levels, namely, translational, posttranslational, and transcriptional levels, respectively. The most interesting finding of this study is that BCE increases cAMP levels by suppressing the Pde4b mRNA and PDE4b protein levels in ethanol-treated hepatocytes, suggesting that BCE may prevent ALD.

Black carrot extract protects against hepatic injury through epigenetic modifications.

We studied the epigenetic regulation of how black carrot extract (BCE) protects against ethanol-induced hepatic damage. We have shown that the butanol-extracted fraction of BCE (BCE-BuOH) increased intracellular cyclic adenosine monophosphate (cAMP) levels by suppressing the expression of phosphodiesterase 4b (PDE4b); however, the detailed mechanism remains to be elucidated. We focused on changes in histone modifications involved in the suppression of pde4 expression. The methylation level of histone H3 lysine 9 (H3K9), which regulates gene expression of PDE4b, decreased after treatment with 100 mM ethanol but was significantly increased by treatment with 400 µg/ml BCE-BuOH. In contrast, ethanol induced an increase in H3K9 acetylation. However, treatment with BCE-BuOH inhibited the increase in acetylation through an increase in Sirtuin 1 (Sirt1), a histone deacetylase. Furthermore, BCE-BuOH treatment increased the level of methionine adenosyltransferase (MAT) 2a mRNA and increased intracellular S-adenosylmethionine. The present results indicate that BCE-BuOH is useful for protection against alcohol-induced hepatic injury. PRACTICAL APPLICATIONS: We have reported that black carrot extract (BCE) suppressed liver steatosis and liver fibrosis on a rat alcoholic liver disease model. The results from this study have shown that BCE regulated the alcoholic-induced hepatic injury at the level of epigenetic modifications. These results suggested that BCE is useful for protection against alcoholic-induced hepatic injury.

Short-term facilitation effects elicited by cortical priming through theta burst stimulation and functional electrical stimulation of upper-limb muscles.

Non-invasive theta burst stimulation (TBS) can elicit facilitatory or inhibitory changes in the central nervous system when applied intermittently (iTBS) or continuously (cTBS). Conversely, neuromuscular electrical stimulation (NMES) can activate the muscles to send a sensory volley, which is also known to affect the excitability of the central nervous system. We investigated whether cortical iTBS (facilitatory) or cTBS (inhibitory) priming can affect subsequent NMES-induced corticospinal excitability. A total of six interventions were tested, each with 11 able-bodied participants: cortical priming followed by NMES (iTBS + NMES and cTBS + NMES), NMES only (iTBSsham + NMES and cTBSsham + NMES), and cortical priming only (iTBS + rest and cTBS + rest). After iTBS or cTBS priming, NMES was used to activate right extensor capri radialis (ECR) muscle intermittently for 10 min (5 s ON/5 s OFF). Single-pulse transcranial magnetic stimulation motor evoked potentials (MEPs) and maximum motor response (Mmax) elicited by radial nerve stimulation were compared before and after each intervention for 30 min. Our results showed that associative facilitatory iTBS + NMES intervention elicited greater MEP facilitation that lasted for at least 30 min after the intervention, while none of the interventions alone were effective to produce effects. We conclude that facilitatory iTBS priming can make the central nervous system more susceptible to changes elicited by NMES through sensory recruitment to enhance facilitation of corticospinal plasticity, while cTBS inhibitory priming efficacy could not be confirmed.

Ursolic acid improves the indoxyl sulfate-induced impairment of mitochondrial biogenesis in C2C12 cells.

BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis. MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 µM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells. CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.

Corticospinal excitability and somatosensory information processing of the lower limb muscle during upper limb voluntary or electrically induced muscle contractions.

Neural interactions between upper and lower limbs underlie motor coordination in humans. Specifically, upper limb voluntary muscle contraction can facilitate spinal and corticospinal excitability of the lower limb muscles. However, little remains known on the involvement of somatosensory information in arm-leg neural interactions. Here, we investigated effects of voluntary and electrically induced wrist flexion on corticospinal excitability and somatosensory information processing of the lower limbs. In Experiment 1, we measured transcranial magnetic stimulation (TMS)-evoked motor evoked potentials (MEPs) of the resting soleus (SOL) muscle at rest or during voluntary or neuromuscular electrical stimulation (NMES)-induced wrist flexion. The wrist flexion force was matched to 10% of the maximum voluntary contraction (MVC). We found that SOL MEPs were significantly increased during voluntary, but not NMES-induced, wrist flexion, compared to the rest (P < .001). In Experiment 2, we examined somatosensory evoked potentials (SEPs) following tibial nerve stimulation under the same conditions. The results showed that SEPs were unchanged during both voluntary and NMES-induced wrist flexion. In Experiment 3, we examined the modulation of SEPs during 10%, 20% and 30% MVC voluntary wrist flexion. During 30% MVC voluntary wrist flexion, P50-N70 SEP component was significantly attenuated compared to the rest (P = .003). Our results propose that the somatosensory information generated by NMES-induced upper limb muscle contractions may have a limited effect on corticospinal excitability and somatosensory information processing of the lower limbs. However, voluntary wrist flexion modulated corticospinal excitability and somatosensory information processing of the lower limbs via motor areas.

Carob pod polyphenols suppress the differentiation of adipocytes through posttranscriptional regulation of C/EBPß.

Obesity is a major risk factor for various chronic diseases such as diabetes, cardiovascular disease, and cancer; hence, there is an urgent need for an effective strategy to prevent this disorder. Currently, the anti-obesity effects of food ingredients are drawing attention. Therefore, we focused on carob, which has high antioxidant capacity and various physiological effects, and examined its anti-obesity effect. Carob is cultivated in the Mediterranean region, and its roasted powder is used as a substitute for cocoa powder. We investigated the effect of carob pod polyphenols (CPPs) on suppressing increases in adipose tissue weight and adipocyte hypertrophy in high fat diet-induced obesity model mice, and the mechanism by which CPPs inhibit the differentiation of 3T3-L1 preadipocytes into adipocytes in vitro. In an in vivo experimental system, we revealed that CPPs significantly suppressed the increase in adipose tissue weight and adipocyte hypertrophy. Moreover, in an in vitro experimental system, CPPs acted at the early stage of differentiation of 3T3-L1 preadipocytes and suppressed cell proliferation because of differentiation induction. They also suppressed the expression of transcription factors involved in adipocyte differentiation, thereby reducing triacylglycerol synthesis ability and triglycerol (TG) accumulation. Notably, CPPs regulated CCAAT/enhancer binding protein (C/EBP)ß, which is expressed at the early stage of differentiation, at the posttranscriptional level. These results demonstrate that CPPs suppress the differentiation of adipocytes through the posttranscriptional regulation of C/EBPß and may serve as an effective anti-obesity compound.

Sesaminol prevents Parkinson's disease by activating the Nrf2-ARE signaling pathway.

Parkinson's disease (PD) is a neurodegenerative disease caused by the degeneration of substantia nigra neurons due to oxidative stress. Sesaminol has strong antioxidant and anti-cancer effects. We investigated the preventive effect on PD as a new physiological action of sesaminol produced from sesaminol glycoside using in vitro and in vivo PD models. To prepare an in vitro PD model, 6-hydroxydopamine (6-OHDA) was added to human neuroblastoma (SH-SY5Y cells). The viability of SH-SY5Y cells decreased dose-dependently following 6-OHDA treatment, but the addition of sesaminol restored viability to the control level. 6-OHDA increased intracellular reactive oxygen species production, and the addition of sesaminol significantly suppressed this increase. No Nrf2 expression in the nucleus was observed in the control group, but a slight increase was observed in the 6-OHDA group. The sesaminol group showed strong expression of Nrf2 in the cytoplasm and nucleus. NAD(P)H: quinone oxidoreductase (NQO1) activity was enhanced in the 6-OHDA group and further enhanced in the sesaminol group. Furthermore, the neurotoxine rotenone was orally administrated to mice to prepare an in vivo PD model. The motor function of rotenone-treated mice was shorter than that of the control group, but a small amount of sesaminol restored it to the control level. The intestinal motility in the rotenone group was significantly lower than that in the control group, but it remained at the control level in the sesaminol group. The expression of α-synuclein in the substantia nigra increased in the rotenone group but decreased in the sesaminol group. The rotenone group exhibited shortening and damage to the colonic mucosa, but these abnormalities of the colonic mucosa were scarcely observed in the sesaminol group. These results suggest that sesaminol has a preventative effect on PD.

Mallotus furetianus extract protects against ethanol-induced liver injury via the activation of the cAMP-PKA pathway.

The protective effects of Mallotus furetianus extract (MF) on liver fibrosis induced with ethanol were examined using in vivo and in vitro model. MF treatment suppressed plasma alanine aminotransferase and aspartate aminotransferase activities in ethanol plus carbon tetrachloride (CCl4)-induced cirrhosis rat model. MF also suppressed the increase in type l collagen and α-smooth muscle actin expression in the livers of ethanol plus CCl4-induced rat by the maintenance of intracellular glutathione levels. Furthermore, we evaluated the effect of MF on the alcohol-induced activation of hepatic stellate cells (HSCs), which are responsible for the increased production and deposition of the extracellular matrix in liver injury. Here, we observed the enhancement of the intracellular reactive oxygen species (ROS) levels and the increase in type I collagen and a-SMA expression in HSCs activated with ethanol. However, the enhanced ROS levels were suppressed with the treatments of MF or diphenyleneiodonium (DPI). Furthermore, the treatment of MF or DPI suppressed the increase in type I collagen and a-SMA expression activated with ethanol. We also observed that the treatment of MF or LY194002 suppressed the increase in type I collagen expression in HSCs activated with ethanol, suggesting that ethanol induced type I collagen expression via the PI3K-Akt signaling pathway. On the other hand, the suppression of the synthesis of type I collagen in ethanol and MF-treated HSCs was inhibited by H-89. From these results, MF may suppress the increase in the activity of NADPH oxidase in HSCs activated with ethanol through the cAMP-PKA pathway.