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Abstract: Objective: We investigated the effects of long-term miso soup drinking on salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. Methods: Dahl S rats were divided into four groups that consumed 1) water, 2) a 0.9% NaCl solution, 3) a 1.3% sodium NaCl solution, or 4) miso soup containing 1.3% NaCl. They were followed for 8 wk. Systolic blood pressure and hypertensive organ damage were determined. Results: Systolic blood pressure increased in an age- and dose-dependent manner in Dahl S rats drinking salt solutions. The systolic blood pressure increase was significantly less in the Dahl S rats that drank miso soup, although the ultimate cumulative salt loading was greater than that in the Dahl S rats given the 1.3% NaCl solution. This blood pressure decrease was associated with a morphologic attenuation of glomerular sclerosis in the kidney and collagen infiltration in the heart. Urinary protein excretions were less in the miso group than in the rats given the 1.3% NaCl solution. The fractional excretion of sodium was increased and that of potassium was decreased in Dahl S rats given the 1.3% NaCl solution, and these effects were reversed in rats given miso soup toward the values of the control. Conclusion: We found that long-term miso soup drinking attenuates the blood pressure increase in salt-induced hypertension with organ damage. This may be caused by a possible retardation of sodium absorption in the gastrointestinal tract or by the direct effects of nutrients in the miso soup from soybeans. The decrease was associated with decreases in cardiovascular and renal damage. [Copyright &y& Elsevier]

In this work related to Carbon Capture and Storage (CCS), the CO 2 sorption capacities of a new family of elastomer poly(ionic liquid)s (PILs) with imidazolium cations having different alkyl chains were studied. These PILs were synthesized by chemical modification of polyepichlorohydrin (polyECH) obtained by living anionic polymerization. PolyECH was quaternized with different 1-alkylimidazoles (alkyl = methyl, n -butyl, and n -hexyl) and followed by anion exchange to obtain three PILs: PIL-Me, PIL-nBu, and PIL-nHex. They were analyzed by NMR (1H, 13C, 2D 1H/13C HSQC, APT 13C) and characterized by SEC, DSC, calorimetry, rheology, and XRD SAXS/WAXS. The influence of the alkyl chain on the PIL CO 2 sorption was studied with a magnetic suspension balance (MSB) at 35 °C and CO 2 pressures varying from 1 to 10 bar. The best results were obtained with PIL having methyl chains (9.60 mg CO 2 /g PIL at 1.1 bar and 159.28 mg CO 2 /g PIL at 10.0 bar at 35 °C). Finally, the CO 2 sorption properties of these PILs were modeled with the PC-SAFT equation of state (EoS). The pure-component parameters were obtained from model regression of the PILs densities calculated by the Bondi's and Van Krevelen's methods. The binary interaction parameters of the systems CO 2 /PIL were optimized with average absolute deviations (AAD) lower than 6.3 % for the three PILs. The PC-SAFT modelling of their sorption properties opens interesting prospects for modelling the CO 2 sorption process for CCS facilities. [Display omitted] • New imidazolium-based PILs with different alkyl chains were obtained from polyECH. • Strong ionic repulsions and low screening effect improved CO 2 sorption. • The best CO 2 sorption was obtained with the methyl chain. • PC-SAFT EoS was used for the first time for modelling CO 2 sorption in PILs. [ABSTRACT FROM AUTHOR]

The muscles morphology of the peroneus longus (PL) and peroneus brevis (PB) has differently changed after lateral ankle sprain respectively (Arima et al., 2022). Resistance training (RT) are needed to restore the changed form, and selective RT of PL and PB has been suggested (Arima et al., 2022). However, it takes a long time to obtain the effect of muscle hypertrophy, so it would be useful to have a simpler index to confirm the effect of RT. Previous studies have shown positive correlation between muscle hypertrophy after long-term RT and changes in muscle swelling immediately after a short-term RT in the quadriceps muscle (Hirono et al., 2022). Therefore, similar results may be obtained for PL and PB. Is acute muscle swelling of the PL and PB after short-term RT associated with muscle hypertrophy after long-term RT? 19 participants were divided into PL (n=10) and PB (n=9) group. Each group performed different RT based on the previous study (Arima et al., 2022). The number of intervention movements at one time was two sets of 100 times. Their RT was performed 3 times a week for 8 weeks as long-term intervention. Cross sectional area (CSA) was measured at the points of proximal 25% (indicating PL) and 75% (indicating PB) between fibular head and lateral malleolus by using an ultrasound system before the intervention and after 8 weeks of intervention. Also, to see the temporal changes after RT over time on a separate day, same measurements were conducted before (pre), immediately after (post), 10, 20, and 30 minutes after the intervention. A one-way repeated ANOVA with post hoc Bonferroni test was performed to see acute changes in CSA. Pearson's correlation analysis was performed to see the correlation between the amount of change over time at each time point after the acute intervention and the amount of change in CSA after the long-term intervention. There was a significant main effect of acute changes in each CSA. Post hoc test revealed CSA at post were significantly greater compared with other (respectively p<0.05). Each CSA showed a significant positive correlation between the amount of change in muscle swelling immediately after the acute intervention and the amount of change in muscle hypertrophy after the 8-week intervention (PL: r=0.682, p<0.05; PB: r=0.680, p<0.05). Acute muscle swelling was greatest immediately after training and returned to its preform over time (Hirono et al., 2022). We thought muscle morphology immediately after training is most reflective of muscle hypertrophy, and only post probably be correlated with muscle hypertrophy in this study. This study suggested the possibility of acute muscle swelling in the PL and PB immediately after RT is associated with muscle hypertrophy after long-term RT. [ABSTRACT FROM AUTHOR]

Abstract In the direct cell membrane penetration, arginine-rich cell-penetrating peptides are thought to penetrate into cells across the hydrophobic lipid membranes. To investigate the effect of the amphipathic property of arginine-rich peptide on the cell-penetrating ability, we designed a novel amphipathic cell-penetrating peptide, A2-17, and its derivative, A2-17KR, in which all lysine residues are substituted with arginine residues, based on the glycosaminoglycan binding region in the N-terminal α-helix bundle of human apolipoprotein E. Isothermal titration calorimetry showed that A2-17 variants have a strong ability to bind to heparin with high affinity. Circular dichroism and tryptophan fluorescence measurements demonstrated that A2-17 variants bind to lipid vesicles with a structural change from random coil to amphipathic α-helix, being inserted into the hydrophobic membrane interiors. Flow cytometric analysis and confocal laser scanning microscopy demonstrated the great cell penetration efficiency of A2-17 variants into CHO-K1 cells when incubated at low peptide concentrations (2 μM or less), suggesting that the increased amphipathicity with α-helix formation enhances the cell membrane penetration ability of arginine-rich peptides. Interestingly, A2-17KR exhibited lower efficiency of cell membrane penetration compared to A2-17 despite of their similar binding affinity to lipid membranes. Since high peptide concentrations (typically >10 μM) are usually prerequisite for efficient cell penetration of arginine-rich peptides, A2-17 is a unique amphipathic cell-penetrating peptide that exhibits an efficient cell penetration ability even at low peptide concentrations. Graphical abstract Unlabelled Image Highlights • An amphipathic cell-penetrating peptide, A2-17, is newly designed. • A2-17 binds to both heparin and lipid membranes with high affinity. • A2-17 forms amphipathic α-helix upon binding to heparin and lipid membranes. • A2-17 efficiently penetrates cell membranes even at low peptide concentrations. [ABSTRACT FROM AUTHOR]

Monocarboxylate transporter 2 (MCT2) is an important component of the lactate transport system in neurons of the adult brain. Purkinje cells in the cerebellum have been shown to have high levels of MCT2, suggesting that this protein has a key function in energy metabolism and neuronal activities in these cells. However, it is not known whether inhibition of lactate transport via MCT2 in the cerebellum affects motor performance. To address this question, we examined motor performance in mice following the inhibition of lactate transport via MCT2 in the cerebellum using α-cyano-4-hydroxycinnamate (4-CIN). 4-CIN or saline was injected into the subarachnoidal space of the cerebellum of mice and motor performance was analyzed by a rotarod test both before and after injection. 4-CIN injection reduced retention time in the rotarod test by approximately 80% at 1 h post-injection compared with pre-injection. No effect was observed at 2 h post-injection or in mice treated with the vehicle control. Because we observed that MCT2 plays an important role in motor performance, we next investigated the effects of acute exercise on MCT2 transcription and protein levels in mice sampled pre-exercise and at 0 and 5 h after 2 h of treadmill running. We found a significant increase in MCT2 mRNA levels, but not of protein levels, in the cerebellum at 5 h after exercise. Our results indicate that lactate transport via MCT2 in the cerebellum may play an important role in motor performance and that exercise can increase MCT2 expression at the transcriptional level. [ABSTRACT FROM AUTHOR]

R2683 --> 605.10 --> Neutral sphingomyelinase activation associated factor (Nsmaf) modulate ceramide production by activating neutral sphingomyelinase enzymes. Nsmaf also regulates tumor necrosis factor‐α (TNF‐α)‐induced signaling pathway. Since both ceramide metabolisms and TNF‐α signaling are key events during inflammation, Nsmaf might play a nodal role in inflammation‐induced events, such as muscle wasting. In the present study, we examined whether Nsmaf gene knock‐down effects on myogenesis in murine C2C12 myoblasts. C2C12 myoblasts were used in this study. In the growth phase, cells were maintained in DMEM and 10% FBS (growth medium: GM). For cell differentiation, the culture medium was switched to DMEM containing 1% HS (differentiation medium: DM). Small interfering RNA (siRNA) was used to induce Nsmaf gene Knock‐down (NsmafKD, n = 6). siRNA with a scrambled sequence was used as negative controls (Scr, n = 6). Gene knockdown was performed both in myoblasts and myotubes. After two‐day siRNA treatment, Western blotting was performed to examine protein expression levels. Laser scanning microscopy was used to investigate cell morphology. Even in the GM condition, differentiation markers, such as myogenin and myosin heavy chain (slow) were upregulated in the NsmafKD cells. In transfected myotubes, myotube diameter of the NsmafKD was about 50% smaller than that of the Scr. Both in myoblasts and myotubes, contents of a cell fusion mediator, myomixer, in the NsmafKD was significantly lower than that in the Scr. These data indicate that Nsmaf is a novel regulator of myogenesis. [ABSTRACT FROM AUTHOR]

Background and Aim: Sarcopenia and osteoporosis adversely impact the clinical outcomes of patients with chronic liver disease (CLD). The Japan Society of Hepatology (JSH) sarcopenia criteria utilize bioelectrical impedance analysis (BIA) for assessing muscle mass rather than dual-energy X-ray absorptiometry (DXA), which can simultaneously diagnose these comorbidities. We investigated the correlations and interchangeability between the appendicular skeletal muscle mass index (ASMI) values determined using BIA and DXA and evaluated the diagnostic ability of DXA for sarcopenia and osteosarcopenia in patients with CLD., Methods: This cross-sectional study included 173 patients with CLD. Sarcopenia was defined as low ASMI BIA according to the JSH and Asian Working Group for Sarcopenia (AWGS) criteria (ASMI BIA cutoff ) or low ASMI DXA according to the AWGS criteria (ASMI DXA cutoff ) and low handgrip strength. For women, a provisional cutoff value was set for ASMI DXA using the ASMI BIA cutoff (ASMI DXA-altered cutoff )., Results: We found that ASMI BIA and ASMI DXA were significantly correlated (r = 0.921; P < 0.001). The Bland-Altman plots demonstrated substantial agreement between ASMI BIA and ASMI DXA , with a mean difference of 0.0116 kg/m 2 . The prevalence rates of sarcopenia and osteosarcopenia diagnosed using the ASMI BIA cutoff were 26.0% and 17.3%, respectively. The kappa coefficients for the prevalence of sarcopenia and osteosarcopenia were 0.759 and 0.775 between ASMI BIA cutoff and ASMI DXA cutoff and 0.780 and 0.806 between ASMI BIA cutoff and ASMI DXA-altered cutoff , respectively., Conclusions: The utilization of DXA can facilitate the comprehensive assessment and management of musculoskeletal comorbidities in patients with CLD., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Atopic dermatitis is common in children and often treated with topical corticosteroids (TCs). A boy in his late teens who had been using TCs for atopic dermatitis was diagnosed with liver damage during a health checkup. A medical examination revealed severe steatotic liver disease and elevated liver enzyme levels despite the absence of typical symptoms such as central obesity. After discontinuation of TCs, an improvement in liver enzyme levels was observed, leading to the diagnosis of drug-induced steatohepatitis. This case underscores the potential liver risks associated with prolonged TC use in children, highlighting the need for parental education.

Ribosome biogenesis is an important regulator of skeletal muscle hypertrophy induced by repeated bouts of resistance exercise (RE). Hot-water immersion (HWI), a widely used post-exercise recovery strategy, activates the mechanistic target of rapamycin (mTOR) signaling, a key regulator of ribosome biogenesis in skeletal muscle. However, the effect of HWI on skeletal muscle ribosome biogenesis is not well understood. Here, we aimed to investigate the effects of HWI and post-exercise HWI on ribosome biogenesis using a rat RE model. Male Sprague-Dawley rats were randomly assigned to HWI and non-HWI groups. In both groups, the right leg was isometrically exercised using transcutaneous electrical stimulation, while the left leg was used as an internal non-RE control. Following RE, both limbs were immersed in hot water (41.2 ± 0.03°C) for 20 min under isoflurane anesthesia in the HWI group and the gastrocnemius muscles were sampled at 3- and 24-h post-exercise. HWI significantly increased mTOR signaling and c-Myc mRNA expression, whereas post-exercise HWI significantly increased transcription initiation factor-IA mRNA expression. However, neither HWI nor post-exercise HWI enhanced 45S pre-rRNA expression, ribosomal RNA, or ribosomal protein content. In addition, HWI tended to decrease 28S rRNA and 18S rRNA content, widely used markers of ribosome content. These results suggest that HWI as a post-exercise recovery is not effective in activating ribosome biogenesis. NEW & NOTEWORTHY Ribosome biogenesis is crucial in resistance exercise (RE)-induced skeletal muscle hypertrophy. This study examined the effects of hot-water immersion (HWI) on ribosome biogenesis after RE. HWI and post-exercise HWI increased c- Myc and transcription initiation factor-IA mRNA but did not alter ribosomal RNA transcription or ribosomal protein content. HWI tended to decrease 28S and 18S ribosomal RNA. These findings suggest that HWI, as a recovery strategy, does not effectively promote ribosome biogenesis or muscle protein synthesis.

White adipose tissue (WAT) in mice undergoes browning in response to cold exposure. Brown and beige adipocytes contain multilocular lipid droplets and abundant iron-containing mitochondria expressing uncoupling protein 1 (UCP-1). Cold exposure-induced browning WAT is accompanied by increased density of blood vessels and sympathetic nerve fibres. A previous study reported a more than threefold increase in sympathetic nerve dendritic tone in inguinal white adipose tissue (iWAT) after cold exposure. Therefore, we hypothesized that water molecule diffusion would be more restricted in brown and beige adipocytes compared to white adipocytes. The characteristics of T2* values and anisotropy parameters by diffusion tensor imaging (DTI) in browning WAT are unclear. The aim of the present study was to investigate the effect of cold exposure on T2* values and anisotropy parameters (fractional anisotropy [FA], apparent diffusion coefficient [ADC], radial diffusivity [RD] and eigenvalues λ1, λ2, λ3) in brown adipose tissue (BAT), iWAT and epididymal white adipose tissue (epiWAT). Furthermore, these parameters were investigated in vivo through additional validation experiments in three control mice. Mice in the cold exposure (CE) group were exposed to a cold environment at 4 °C for 10 days, while these in the control (C) group were maintained at 22 °C throughout the experiment. T2* values, FA, ADC, RD and eigenvalues (λ1, λ2, λ3) were measured in BAT, iWAT and epiWAT using a 9.4T magnetic resonance scanner (Bruker Biospin AG). T2* values of epiWAT in the C group were significantly higher than these of BAT in the C group and iWAT in the CE group. No significant differences were observed between groups for FA, ADC, RD, λ1 and λ2 of iWAT and epiWAT. However, the λ3 values of iWAT and epiWAT in the CE group were significantly higher than these of iWAT, epiWAT and BAT in the C group. Compared to ex vivo measurements, in vivo measurements in control mice showed higher T2* values with reduced intertissue variability while maintaining tissue-specific patterns. These results suggest that T2* values and anisotropy parameters might serve as potential markers for the assessment of adipose tissue plasticity. Further studies are required to investigate their utility as non-invasive indicators of browning WAT., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study aimed to translate a web-based hamstring outcome score (HaOS) questionnaire to the Japanese context. First, the validity and reliability of the translated questionnaires were examined among Japanese athletes. Second, the association between the previous history of hamstring strain and HaOS was examined. The translation was performed according to internationally recognized methodologies. A total of 233 athletes were asked to complete the HaOS questionnaire, and four questions were added to examine the content validity of the questionnaire. Intraclass correlation coefficient (ICC) was calculated to evaluate the test-retest reliability. Internal consistency was determined by calculating Cronbach's alpha values. The translated questionnaires had high acceptance and compliance rates, with a response rate of 84.4%. The ICC for each scale ranged from 0.80 to 0.93, and Cronbach's α from 0.72 to 0.96, confirming good reliability and high internal consistency. HaOS of the previous injury group (93.4 [78.9, 100]) was significantly lower than that of the healthy group (86.2 [68.1, 100]) (p < 0.05). The translated HaOS questionnaires were valid, reliable, and acceptable for monitoring hamstring conditions in Japanese athletes., (© 2024. The Author(s).)

Cancer cachexia is the result of complex interorgan interactions initiated by cancer cells and changes in patient behavior such as decreased physical activity and energy intake. Therefore, it is crucial to distinguish between the direct and indirect effects of cancer cells on muscle mass regulation and bioenergetics to identify novel therapeutic targets. In this study, we investigated the direct effects of Colon-26 cancer cells on the molecular regulating machinery of muscle mass and its bioenergetics using a coculture system with C2C12 myotubes. Our results demonstrated that coculture with Colon-26 cells induced myotube atrophy and reduced skeletal muscle protein synthesis and its regulating mechanistic target of rapamycin complex 1 signal transduction. However, we did not observe any activating effects on protein degradation pathways including ubiquitin-proteasome and autophagy-lysosome systems. From a bioenergetic perspective, coculture with Colon-26 cells decreased the complex I-driven, but not complex II-driven, mitochondrial ATP production capacity, while increasing glycolytic enzyme activity and glycolytic metabolites, suggesting a shift in energy metabolism toward glycolysis dominance. Gene expression profiling by RNA sequencing showed that the increased activity of glycolytic enzymes was consistent with changes in gene expression. However, the decreased ATP production capacity of mitochondria was not in line with the gene expression. The potential direct interaction between cancer cells and skeletal muscle cells revealed in this study may contribute to a better fundamental understanding of the complex pathophysiology of cancer cachexia. NEW & NOTEWORTHY We explored the potential direct interplay between colon cancer cells (Colon-26) and skeletal muscle cells (C2C12 myotubes) employing a noncontact coculture experimental model. Our findings reveal that coculturing with Colon-26 cells substantially impairs the protein synthesis rate, concurrently instigating a metabolic shift toward glycolytic dominance in C2C12 myotubes. This research unveils critical insights into the intricate cellular cross talk underpinning the complex pathophysiology of cancer cachexia.

Objective: In Tokyo 2020 Paralympic Games, there were the rule and goal size changes at the blind football competition. This study aimed to compare the scoring and head impact characteristics during blind football competition between the Rio 2016 and Tokyo 2020 Paralympic Games using the official videos., Design: Video-based observational study., Participants: In total, 36 blind football (men's football 5-a-side) game videos were obtained from the official International Paralympic Committee., Primary and Secondary Outcome Measures: Head impact was defined as the sudden contact of any object with the head. Videos were analysed to assess the number of scores and head impacts along with their corresponding details (ie, round, playing phase, scoring situation, impact situation, occurrence area, impact object, head impact site, fall and foul)., Results: The total number of goals scored at the Tokyo 2020 Paralympic Games was nearly double that at the Rio 2016 Paralympic Games. Regarding head impacts, a total of 2036 cases (Rio 2016, n=1105; Tokyo 2020, n=931) were evaluated. Significant differences were observed in head impact characteristics between the Rio 2016 and Tokyo 2020 Paralympic Games among seven outcomes (round, scoring situation, impact situation, occurrence area, impact object, site of head impact and fall)., Conclusions: Compared with the Rio 2016 Paralympic Games, the Tokyo 2020 Paralympic Games showed an increase in the number of points scored and different head impact characteristics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High-intensity exercise stimulates glycolysis, subsequently leading to elevated lactate production within skeletal muscle. While lactate produced within the muscle is predominantly released into the circulation via the monocarboxylate transporter 4 (MCT4), recent research underscores lactate's function as an intercellular and intertissue signalling molecule. However, its specific intracellular roles within muscle cells remains less defined. In this study, our objective was to elucidate the effects of increased intramuscular lactate accumulation on skeletal muscle adaptation to training. To achieve this, we developed MCT4 knockout mice and confirmed that a lack of MCT4 indeed results in pronounced lactate accumulation in skeletal muscle during high-intensity exercise. A key finding was the significant enhancement in endurance exercise capacity at high intensities when MCT4 deficiency was paired with high-intensity interval training (HIIT). Furthermore, metabolic adaptations supportive of this enhanced exercise capacity were evident with the combination of MCT4 deficiency and HIIT. Specifically, we observed a substantial uptick in the activity of glycolytic enzymes, notably hexokinase, glycogen phosphorylase and pyruvate kinase. The mitochondria also exhibited heightened pyruvate oxidation capabilities, as evidenced by an increase in oxygen consumption when pyruvate served as the substrate. This mitochondrial adaptation was further substantiated by elevated pyruvate dehydrogenase activity, increased activity of isocitrate dehydrogenase - the rate-limiting enzyme in the TCA cycle - and enhanced function of cytochrome c oxidase, pivotal to the electron transport chain. Our findings provide new insights into the physiological consequences of lactate accumulation in skeletal muscle during high-intensity exercises, deepening our grasp of the molecular intricacies underpinning exercise adaptation. KEY POINTS: We pioneered a unique line of monocarboxylate transporter 4 (MCT4) knockout mice specifically tailored to the ICR strain, an optimal background for high-intensity exercise studies. A deficiency in MCT4 exacerbates the accumulation of lactate in skeletal muscle during high-intensity exercise. Pairing MCT4 deficiency with high-intensity interval training (HIIT) results in a synergistic boost in high-intensity exercise capacity, observable both at the organismal level (via a treadmill running test) and at the muscle tissue level (through an ex vivo muscle contractile function test). Coordinating MCT4 deficiency with HIIT enhances both the glycolytic enzyme activities and mitochondrial capacity to oxidize pyruvate., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

This study aimed to investigate the 8-week selective training effect of the peroneus longus (PL) and the peroneus brevis (PB) on muscle morphology, echogenicity, and ankle strength and to examine post-intervention detraining effects. Twenty healthy participants without orthopedic disease in the lower extremities were assigned to either the PL intervention group (training consisted of pushing the Thera-Band® out from the ball of the foot to emphasize ankle eversion) or the PB intervention group (training consisted of pulling the Thera-Band® from the base of the fifth metatarsal to enhance ankle valgus and external rotation). Each intervention was performed three times per week for 8 weeks. The cross-sectional area (CSA), thickness, echogenicity, and ankle strength of the PL and the PB were measured before week 1 and after each training session. Detraining effects were evaluated after the 8-week intervention. The results revealed a significant interaction between within-group (week) and between-group (type of intervention) variables on CSA and ankle strength of both the PL and the PB. Over the 8-week training period, the CSA and ankle strength of the PL significantly increased in the PL intervention group, as did the CSA and ankle strength of the PB in the PB intervention group (p < 0.05). The residual effect of muscle hypertrophy was observed during the detraining period. In conclusion, 8-week selective PL and PB training interventions can increase the CSA and ankle strength of these muscles over time. Long-term selective intervention is required to improve peroneus muscle morphology and function, with separate assessments of the CSA and ankle strength of the PL and the PB., Competing Interests: The authors declare no conflict of interest., (Copyright: © Academy of Physical Education in Katowice.)

Background: In response to the serious lack of physical activity among young adults, recent attempts have been made to encourage young people to exercise through exercise video distribution. However, merely distributing videos does not lead to improved physical activity levels. Metaverse space, which enables web-based interaction through avatars, allows users to watch exercise videos in the same space as other avatars., Objective: This study explored whether exercise video distribution using metaverse space is effective in improving physical activity levels, along with mental health and locomotive function, among young people., Methods: In this parallel-group randomized controlled trial participants were recruited using printed poster displays. A total of 48 young adults aged between 18 and 30 years were assigned to 3 groups of 16 each: the metaverse, YouTube, and control group. To encourage exercise, the metaverse group was given an exercise video each week with a load of around 4-8 metabolic equivalents of tasks (METs) for 8 videos delivered in the metaverse space. The YouTube group was sent a URL on YouTube every week to view exercise videos with the same content as the metaverse group. The control group was given no special instructions. The intervention period was 8 weeks. Pre- and postintervention physical activity, well-being, locomotive syndrome risk tests, and social capital were measured. Although this study was not blinded to the participants, the measurers did not know to which group the participants belonged. Mixed model repeated-measures analyses and a post hoc Wilcoxon signed rank sum test were performed to detect the effects of the intervention in all groups., Results: The results of the mixed model repeated-measures analyses showed a significant interaction between groups and before and after the intervention for total physical activity (metaverse group: pre 737.1, SD 609.5 METs/week, post 1575.4, SD 1071.8 METs/week; YouTube group: pre 661.7, SD 710.7 METs/week, post 911.9, SD 1103.3 METs/week; and control group: pre 930.6, SD 665.1 METs/week, post 844.7, SD 701.8 METs/week; P=.04) but none for the indicators of well-being (P=.40), locomotive function scale (P=.17), and social capital (P=.23). A post hoc test showed a significant increase in physical activity in the metaverse group before and after the intervention (P=.006)., Conclusions: This study is the first to show that delivering exercise videos through metaverse space can increase physical activity in young adults by providing a gathering space for individuals similarly motivated for exercise practice. This way, the sense of isolation during exercise is reduced compared with merely distributing videos on YouTube. The use of metaverse space in health promotion is likely to spread, and this study provides a useful reference for its exploration., Trial Registration: ClinicalTrials.gov NCT06019156; https://ichgcp.net/clinical-trials-registry/NCT06019156., (©Rami Mizuta, Noriaki Maeda, Tsubasa Tashiro, Yuta Suzuki, Sayo Kuroda, Ayano Ishida, Sakura Oda, Tomoya Watanabe, Yuki Tamura, Makoto Komiya, Yukio Urabe. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 16.01.2024.)

The severe acute respiratory syndrome coronavirus 2 vaccine has contributed to infection control and the prevention of complications due to coronavirus disease 2019 (COVID-19). Conversely, the COVID-19 vaccine has been associated with adverse effects due to liver injury caused by autoimmunity or drugs. To date, Japanese journals have only published five reports of autoimmune liver damage associated with the COVID-19 vaccination. Although the pathogenic mechanism has not yet been fully elucidated, corticosteroids or azathioprine have shown effectiveness in certain patients. However, there have been cases of liver injury resulting in deaths. Here, we encountered three patients who developed autoimmune hepatitis (AIH) within 10 days following vaccination. All three patients were treated with prednisolone (PSL) and achieved remission. However, the serum alanine aminotransferase levels in all cases were observed to either increase or cease to improve during the therapeutic course before PSL administration. It is therefore imperative to closely monitor liver injury after the COVID-19 vaccination. In cases where AIH is suspected and a recurrence of liver dysfunction occurs, PSL may be administered. Future considerations should not only encompass the underlying mechanism by which autoimmunity contributes to the development of liver injury following COVID-19 vaccination but also the optimal treatment period for PSL and the long-term prognosis of AIH after COVID-19 vaccination.

Previous studies have demonstrated the beneficial effects of apple polyphenol (AP) intake on muscle endurance. Since mitochondria are critical for muscle endurance, we investigated mitochondrial enzyme activity, biogenesis, degradation and protein quality control. Twenty-four Wistar rats were randomly fed a 5% AP diet (5% AP group, n = 8), a 0.5% AP diet (0.5% AP group, n = 8), or a control diet (control group, n = 8). After a 4-week feeding period, the expression level of peroxisome proliferator-activated receptor γ coactivator-1α, a mitochondrial biosynthetic factor, did not increase, whereas that of transcription factor EB, another regulator of mitochondrial synthesis, significantly increased. Moreover, the mitochondrial count did not differ significantly between the groups. In contrast, mitophagy-related protein levels were significantly increased. The enzymatic activities of mitochondrial respiratory chain complexes II, III and IV were significantly higher in the AP intake group than in the control group. We conclude that AP feeding increases the activity of respiratory chain complex enzymes in rat skeletal muscles. Moreover, mitochondrial biosynthesis and degradation may have increased in AP-treated rats. NEW FINDINGS: What is the central question of this study? Does the administration of apple polyphenols (AP) affect mitochondrial respiratory chain complex enzyme activity, biogenesis, degradation and protein quality control in rat skeletal muscles? What is the main finding and its importance? AP feeding increases respiratory chain complex enzyme activity in rat skeletal muscle. Moreover, AP administration increases transcription factor EB activation, and mitophagy may be enhanced to promote degradation of dysfunctional mitochondria, but mitochondrial protein quality control was not affected., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The peroneus muscles are muscles that mainly act in ankle eversion and can be divided into PL and PB, which have different but important roles in foot and ankle functions. Therefore, PL and PB dysfunction can lead to foot and ankle issues, making. selective strength exercise necessary. This study aimed to identify the effect of two different exercise techniques on PL and PB morphologies. Two interventions were performed on separate days: the PL intervention, in which a Thera-Band ® was placed on the ball of the foot and pushed out from the contact point, and the PB intervention, in which the Thera-Band ® was pulled from the base of the fifth metatarsal. Cross-sectional area (CSA) and thickness of the peroneus muscles at 25% (showing the PL morphology) and 75% (showing the PB morphology) proximal to the line connecting the fibular head and lateral malleolus, as well as ankle strength was measured before and immediately after the interventions and at 10, 20, and 30 min later. A repeated-measures two-way analysis of variance was conducted to identify differences in the effects of the interventions on the PL and PB. Main and interaction effects on CSA, thickness, and ankle strength, with a significant increase in CSA and thickness in the proximal 25% in the PL intervention and the distal 75% in the PB intervention immediately after implementation, were observed (p < 0.05). The transient increase in muscle volume due to edema immediately after exercise indicates the acute effect of exercise. The CSA and thickness of the proximal 25% in the PL intervention and the distal 75% in the PB intervention increased immediately after the intervention, indicating that these interventions can be used to selectively exercise the PL and PB., (© Journal of Sports Science and Medicine.)

Exercise training enhances oxidative capacity whereas detraining reduces mitochondrial content in skeletal muscle. The strategy to suppress the detraining-induced reduction of mitochondrial content has not been fully elucidated. As previous studies reported that branched-chain amino acid (BCAA) ingestion increased mitochondrial content in skeletal muscle, we evaluated whether BCAA supplementation could suppress the detraining-induced reduction of mitochondrial content. Six-week-old male Institute of Cancer Research (ICR) mice were randomly divided into four groups as follows: control (Con), endurance training (Tr), detraining (DeTr), and detraining with BCAA supplementation (DeTr + BCAA). Mice in Tr, DeTr, and DeTr + BCAA performed treadmill running exercises [20-30 m/min, 60 min, 5 times/week, 4 weeks]. Then, mice in DeTr and DeTr + BCAA were administered with water or BCAA [0.6 mg/g of body weight, twice daily] for 2 weeks of detraining. In whole skeletal muscle, mitochondrial enzyme activities and protein content were decreased after 2 weeks of detraining, but the reduction was suppressed by BCAA supplementation. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, a master regulator of mitochondrial biogenesis, was decreased by detraining irrespective of BCAA ingestion. Regarding mitochondrial degradation, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a mitophagy-related protein, was significantly higher in the Tr group than in the DeTr + BCAA group, but not different from in the DeTr group. With respect to mitochondrial quality, BCAA ingestion did not affect oxygen consumption rate (OCR) and reactive oxygen species (ROS) production in isolated mitochondria. Our findings suggest that BCAA ingestion suppresses the detraining-induced reduction of mitochondrial content partly through inhibiting mitophagy., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Skeletal muscle unloading leads to muscle atrophy. Ribosome synthesis has been implicated as an important skeletal muscle mass regulator owing to its translational capacity. Muscle unloading induces a reduction in ribosome synthesis and content, with muscle atrophy. Percutaneous electrical muscle stimulation (pEMS)-induced muscle contraction is widely used in clinics to improve muscle mass. However, its efficacy in rescuing the reduction in ribosomal synthesis has not been addressed thus far. We examined the effects of daily pEMS treatment on ribosome synthesis and content during mouse hindlimb unloading. Male C57BL/6J mice were randomly assigned to sedentary (SED) and hindlimb unloading by pelvic suspension (HU) groups. Muscle contraction was triggered by pEMS treatment of the right gastrocnemius muscle of a subset of the HU group (HU + pEMS). Hindlimb unloading for 6 days significantly lowered 28S rRNA, rpL10, and rpS3 expression, which was rescued by daily pEMS treatment. The protein expression of phospho-p70S6K and UBF was significantly higher in the HU + pEMS than in the HU group. The mRNA expression of ribophagy receptor Nufip1 increased in both the HU and HU + pEMS groups. Protein light chain 3 (LC3)-II expression and the LC3-II/LC3-I ratio were increased by HU, but pEMS attenuated this increase. Our findings indicate that during HU, daily pEMS treatment prevents the reduction in the levels of some proteins associated with ribosome synthesis. In addition, the HU-induced activation of ribosome degradation may be attenuated. These data provide insights into ribosome content regulation and the mechanism of attenuation of muscle atrophy by pEMS treatment during muscle disuse. NEW & NOTEWORTHY Muscle inactivity reduces ribosome synthesis and content during atrophy. Whether percutaneous electrical muscle stimulation (pEMS)-induced muscle contraction rescues the ribosome synthesis and content during muscle unloading is unclear. Using a mouse hindlimb-unloading model with pelvic suspension, we provide evidence that daily pEMS-induced muscle contraction during hindlimb unloading rescues the reduction in the expression of some ribosome synthesis-related proteins and ribosome content in the gastrocnemius muscle.

Aldehyde dehydrogenase (ALDH) is an enzyme that detoxifies aldehydes and is primarily involved in alcohol metabolism. Recently, we have shown that ALDH also plays an important role in skeletal muscle homeostasis. To better understand the role of ALDH in skeletal muscle, it is necessary to clarify the adaptability of ALDH. In this study, we examined the effects of endurance training, compensatory hypertrophy by synergist ablation (SA), and denervation-induced atrophy on gene expression and protein levels of selected ALDH isoforms in skeletal muscle. Ten-week-old C57BL/6J mice were subjected to each intervention, and the plantaris muscle was collected. Gene expression levels of Aldh1a1 were decreased by SA and denervation, but ALDH1A1 protein levels were not affected. Protein levels of ALDH1B1 increased after chronic endurance training, SA, and denervation interventions. However, the increase in Aldh1b1 gene expression was observed only after SA. The gene expression of Aldh2 was decreased after SA, but ALDH2 protein levels remained unchanged. Denervation increased both the Aldh2 gene and ALDH2 protein levels. Taken together, each isoform of ALDH undergoes unique quantitative adaptations in skeletal muscle under different conditions.

Recent evidence has shown that mitochondrial respiratory function contributes to exercise performance and metabolic health. Given that lactate is considered a potential signaling molecule that induces mitochondrial adaptations, we tested the hypothesis that lactate would change mitochondrial respiratory function in skeletal muscle. Male ICR mice (8 weeks old) received intraperitoneal injection of PBS or sodium lactate (1 g/kg BW) 5 days a week for 4 weeks. Mitochondria were isolated from freshly excised gastrocnemius muscle using differential centrifugation and were used for all analyses. Lactate administration significantly enhanced pyruvate + malate- and glutamate + malate-induced (complex I-driven) state 3 (maximal/ATP synthesis-coupled) respiration, but not state 2 (basal/proton conductance) respiration. In contrast, lactate administration significantly decreased succinate + rotenone-induced (complex II-driven) state 3 and 2 respiration. No significant differences were observed in malate + octanoyl-l-carnitine-induced state 3 or 2 respiration. The enzymatic activity of complex I was tended to increase and those of complexes I + III and IV were significantly increased after lactate administration. No differences were observed in the activities of complexes II or II + III. Moreover, lactate administration increased the protein content of NDUFS4, a subunit of complex I, but not those of the other components. The present findings suggest that lactate alters mitochondrial respiratory function in skeletal muscle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takahashi, Tamura, Kitaoka, Matsunaga and Hatta.)

Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde produced from ethanol. A missense single nucleotide polymorphism (SNP) rs671 in ALDH2 exhibits a dominant-negative form of the ALDH2 protein. Nearly 40% of people in East Asia carry an inactive ALDH2*2 mutation. Previous studies reported that ALDH2*2 is associated with increased risk of several diseases. In this study, we examined the effect of ALDH2 deficiency on age-related muscle atrophy and its underlying mechanisms. We found that ALDH2 deficiency promotes age-related loss of muscle fiber cross-sectional areas, especially in oxidative fibers. Furthermore, ALDH2 deficiency exacerbated age-related accumulation of 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress in the gastrocnemius muscle. Similarly, mitochondrial reactive oxygen species (ROS) production increased in aged ALDH2-knockout mice, indicating that ALDH2 deficiency induced mitochondrial dysfunction. In summary, ALDH2 deficiency promotes age-related muscle loss, especially in oxidative fibers, which may be associated with an increased accumulation of oxidative stress via mitochondrial dysfunction.

We report two cases of rapid progression of esophageal varices after atezolizumab-bevacizumab treatment for hepatocellular carcinoma (HCC). Case 1: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral. He was diagnosed with HCC 8 years previously. He had undergone surgical resection 4 times, radio-frequency ablation (RFA) several times, and transcatheter arterial chemoembolization (TACE). However, HCC progressed and could not be controlled by locoregional treatment. Systemic chemotherapy was, therefore, selected. Atezolizumab-bevacizumab was administered after lenvatinib and sorafenib failure. Before starting treatment, his liver function was preserved (Child-Pugh score 5 and class A). His alpha fetoprotein and des-gamma-carboxyprothrombin levels were 3.6 ng/mL and 443 mAU/mL, respectively. Esophagogastroduodenoscopy showed no remarkable esophageal varices before atezolizumab-bevacizumab treatment. Nine months after the initiation of atezolizumab-bevacizumab, the patient was admitted for hematemesis from esophageal varices. The disease control of HCC was classified as stable disease (SD) for the liver and lung metastases, and partial response for the lymph node metastases. Neither AST nor ALT was markedly elevated in the clinical course. Endoscopic variceal ligation (EVL) for the spurting point of large esophageal varices with red wale signs was able to successfully achieve hemostasis. Atezolizumab-bevacizumab was stopped and additional EVL eradicated the esophageal varices. However, the post-banding ulcer was prolonged in comparison to usual cases. Case 2: a man in his 60s with hepatitis C-related liver cirrhosis after viral eradication by direct acting antiviral therapy. He was diagnosed with HCC 6 years previously. He had received RFA 2 times and TACE 7 times. Atezolizumab-bevacizumab was administered after lenvatinib failure. The disease control of HCC was classified as SD; however, the esophageal varices ruptured after 15 courses of atezolizumab-bevacizumab. Neither AST nor ALT were markedly elevated in the clinical course. The esophageal varices of these patients did not require treatment before atezolizumab-bevacizumab; however, they rapidly worsened and ruptured during atezolizumab-bevacizumab treatment. Although rare, similar cases with rapid progression of portal hypertension after atezolizumab-bevacizumab have been reported. We should pay attention to the worsening of esophageal varices during atezolizumab-bevacizumab treatment and poor wound healing after EVL., (© 2022. Japanese Society of Gastroenterology.)

Aldehyde dehydrogenase 2 (ALDH2) catalyses aldehyde species, including alcohol metabolites, mainly in the liver. We recently observed that ALDH2 is also expressed in skeletal muscle mitochondria; thus, we hypothesize that rs671 polymorphism-promoted functional loss of ALDH2 may induce deleterious effects in human skeletal muscle. We aimed to clarify the association of the ALDH2 rs671 polymorphism with muscle phenotypes and athletic capacity in a large Japanese cohort. A total of 3,055 subjects, comprising 1,714 athletes and 1,341 healthy control subjects (non-athletes), participated in this study. Non-athletes completed a questionnaire regarding their exercise habits, and were subjected to grip strength, 30-s chair stand, and 8-ft walking tests to assess muscle function. The ALDH2 GG, GA, and AA genotypes were detected at a frequency of 56%, 37%, and 7% among athletes, and of 54%, 37%, and 9% among non-athletes, respectively. The minor allele frequency was 25% in athletes and 28% in controls. Notably, ALDH2 genotype frequencies differed significantly between athletes and non-athletes (genotype: p = 0.048, allele: p = 0.021), with the AA genotype occurring at a significantly lower frequency among mixed-event athletes compared to non-athletes (p = 0.010). Furthermore, non-athletes who harboured GG and GA genotypes exhibited better muscle strength than those who carried the AA genotype (after adjustments for age, sex, body mass index, and exercise habits). The AA genotype and A allele of the ALDH2 rs671 polymorphism were associated with a reduced athletic capacity and poorer muscle phenotypes in the analysed Japanese cohort; thus, impaired ALDH2 activity may attenuate muscle function., Competing Interests: The authors have no conflict of interest to declare., (Copyright © Biology of Sport 2021.)

We herein report a successfully treated case of huge ruptured hepatocellular carcinoma (HCC) by conversion hepatectomy after transarterial embolization (TAE) and lenvatinib therapy. A 33-year-old male patient with right hypochondralgia and liver tumor was referred to our hospital. He had a history of surgery for heart malformation. The tumor at the right lobe was 15 cm in diameter with bloody ascites. Right atrial thrombus 4.5 cm in diameter and marked cardiac dilatation were observed. TAE with ethanol suspended in lipiodol and gelatin sponge achieved hemostasis of the ruptured HCC. Although viable HCC remained after TAE, surgical treatment was abandoned because of abdominal wall invasion and his heart function. Lenvatinib and rivaroxaban were then initiated for HCC and atrial thrombus, respectively. Lenvatinib treatment resulted in a reduction in tumor marker levels and the tumor size. First, we planned conversion hepatectomy after 5 months of lenvatinib. However, recurrence of atrial thrombus prompted us to put off the surgery, and lenvatinib was re-administered. After improvement of atrial thrombus, we finally performed conversion hepatectomy 10 months after starting lenvatinib administration. The tumor was completely removed by combined resection of the diaphragm, and the patient has been doing well without any signs of recurrence., (© 2021. Japanese Society of Gastroenterology.)

High-intensity muscle contractions (HiMCs) are known to increase c-Myc expression that is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, although c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this connection has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 wk increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-sequencing (RNA-seq) analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC. NEW & NOTEWORTHY Resistance exercise is known to increase c-Myc expression, which is known to stimulate ribosome biogenesis and protein synthesis in a variety of cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. We found that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is threatening people's lives and impacting their health. It is still unclear whether people engaged in physical activity are at an increased risk of SARS-CoV-2 infection and severe forms of COVID-19. In order to provide data to help answer this question, we, therefore, investigated the effects of endurance training on the levels of host proteins involved in SARS-CoV-2 infection in mice. Eight-week-old C57BL/6J mice were subjected to treadmill running (17-25 m/min, 60-90 min, 5 sessions/week, 8 weeks). After the intervention, the levels of angiotensin-converting enzyme 2 (ACE2; host receptor for SARS-CoV-2), transmembrane protease serine 2 (TMPRSS2; host protease priming fusion of SARS-CoV-2 to host cell membranes), FURIN (host protease that promotes binding of SARS-CoV-2 to host receptors), and Neuropilin-1 (host coreceptor for SARS-CoV-2) were measured in 10 organs that SARS-CoV-2 can infect (larynx, trachea, lung, heart, jejunum, ileum, colon, liver, kidney, and testis). Six organs (heart, lung, jejunum, liver, trachea, and ileum) showed changes in the levels of at least one of the proteins. Endurance training increased ACE2 levels in heart (+66.4%), lung (+37.1%), jejunum (+24.7%) and liver (+27.4%), and FURIN in liver (+17.9%) tissue. In contrast, endurance training decreased Neuropilin-1 levels in liver (-39.7%), trachea (-41.2%), and ileum (-39.7%), and TMPRSS2 in lung (-11.3%). Taken together, endurance training altered the levels of host proteins involved in SARS-CoV-2 cell entry in an organ-dependent manner., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Glycoconjugates are an important class of biomolecules that regulate numerous biological events in cells. However, these complex, medium-size molecules are metabolically unstable, which hampers detailed investigations of their functions as well as their potential application as pharmaceuticals. Here we report sialidase-resistant analogues of ganglioside GM3 containing a monofluoromethylene linkage instead of the native O -sialoside linkage. Stereoselective synthesis of CHF -linked disaccharides and kinetically controlled Au(I)-catalyzed glycosylation efficiently furnished both stereoisomers of CHF -linked as well as CF 2 - and CH 2 -linked GM3 analogues. Like native GM3, the C -linked GM3 analogues inhibited the autophosphorylation of epidermal growth factor (EGF) receptor induced by EGF in vitro . Assay of the proliferation-enhancing activity toward Had-1 cells together with NMR-based conformational analysis showed that the ( S )- CHF -linked GM3 analogue with exo -gauche conformation is the most potent of the synthesized compounds. Our findings suggest that exo -anomeric conformation is important for the biological functions of GM3., Competing Interests: The authors declare no competing financial interest., (© 2020 The Authors. Published by American Chemical Society.)

The contraction of myotubes using electrical pulse stimulation is a research tool used to mimic muscle contractile activity and exercise in rodents and humans. Most protocols employed in previous work used low-frequency twitch contractions. However, high-frequency tetanus contractions that are more physiologically relevant to muscle contractions in vivo are poorly characterized. In this report, the similarities and differences in acute responses and chronic adaptations with different contractile modes using twitches (2 Hz, continuous, 3 h) and tetanus (66 Hz, on: 5 s/off: 5 s, 3 h) were investigated. RNA sequencing-based transcriptome analysis and subsequent bioinformatics analysis suggest that tetanus may promote bioenergetic remodeling rather than twitch. Based on in silico analyses, metabolic remodeling after three contractile sessions of twitch and tetanus were investigated. Although twitch and tetanus had no significant effect on glycolysis, both types of contraction upregulated glucose oxidation capacity. Both twitch and tetanus qualitatively caused mitochondrial adaptations (increased content, respiratory chain enzyme activity, and respiratory function). The magnitude of adaptation was much greater under tetanus conditions. Our findings indicate that the contraction of myotubes by tetanus may be a useful experimental model, especially in the study of metabolic adaptations in C 2 C 12 myotubes.

Acetaldehyde dehydrogenase 2 (ALDH2) is an enzyme involved in redox homeostasis as well as the detoxification process in alcohol metabolism. Nearly 8% of the world's population have an inactivating mutation in the ALDH2 gene. However, the expression patterns and specific functions of ALDH2 in skeletal muscles are still unclear. Herein, we report that ALDH2 is expressed in skeletal muscle and is localized to the mitochondrial fraction. Oxidative muscles had a higher amount of ALDH2 protein than glycolytic muscles. We next comprehensively investigated whether ALDH2 knockout in mice induces mitochondrial adaptations in gastrocnemius muscle (for example, content, enzymatic activity, respiratory function, supercomplex formation, and functional networking). We found that ALDH2 deficiency resulted in partial mitochondrial dysfunction in gastrocnemius muscle because it increased mitochondrial reactive oxygen species (ROS) emission (2',7'-dichlorofluorescein and MitoSOX oxidation rate during respiration) and the frequency of regional mitochondrial depolarization. Moreover, we determined whether ALDH2 deficiency and the related mitochondrial dysfunction trigger mitochondrial stress and quality control responses in gastrocnemius muscle (for example, mitophagy markers, dynamics, and the unfolded protein response). We found that ALDH2 deficiency upregulated the mitochondrial serine protease Omi/HtrA2 (a marker of the activation of a branch of the mitochondrial unfolded protein response). In summary, ALDH2 deficiency leads to greater mitochondrial ROS production, but homeostasis can be maintained via an appropriate stress response.

Purpose: Histopathological imaging is widely used for the analysis and diagnosis of multiple diseases. Several methods have been proposed for the 3D reconstruction of pathological images, captured from thin sections of a given specimen, which get nonlinearly deformed due to the preparation process. The majority of the available methods for registering such images use the degree of matching of adjacent images as the criteria for registration, which can result in unnatural deformations of the anatomical structures. Moreover, most methods assume that the same staining is used for all images, when in fact multiple staining is usually applied in order to enhance different structures in the images., Methods: This paper proposes a non-rigid 3D reconstruction method based on the assumption that internal structures on the original tissue must be smooth and continuous. Landmarks are detected along anatomical structures using template matching based on normalized cross-correlation (NCC), forming jagged shape trajectories that traverse several slices. The registration process smooths out these trajectories and deforms the images accordingly. Artifacts are automatically handled by using the confidence of the NCC in order to reject unreliable landmarks., Results: The proposed method was applied to a large series of histological sections from the pancreas of a KPC mouse. Some portions were dyed primarily with HE stain, while others were dyed alternately with HE, CK19, MT and Ki67 stains. A new evaluation method is proposed to quantitatively evaluate the smoothness and isotropy of the obtained reconstructions, both for single and multiple staining., Conclusions: The experimental results show that the proposed method produces smooth and nearly isotropic 3D reconstructions of pathological images with either single or multiple stains. From these reconstructions, microanatomical structures enhanced by different stains can be simultaneously observed.

Mechanical unloading impairs cytosolic calcium (Ca 2+ ) homeostasis in skeletal muscles. In this study, we investigated whether sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) itself or one of the regulators of the Ca 2+ SERCA pump, sarcolipin (SLN), is altered to deregulate Ca 2+ homeostasis in cast immobilized, atrophied muscles. Hindlimb muscles of 8-wk-old male C57BL/6J mice were subjected to bilateral cast immobilization for 2 wk. Two-week-cast immobilization induced both body weight and skeletal muscle loss. Highly phosphorylated Ca 2+ /calmodulin-dependent protein kinase II in the atrophied muscles suggested that cytosolic Ca 2+ concentration was elevated. Extremely high expression levels of SLN mRNA and protein were observed in the atrophied muscles. Upregulation of SLN at the transcriptional level was supported by low RCAN1 expression, which is a negative regulator of SLN. We treated C 2 C 12 cells with dexamethasone to mimic muscle atrophy in vitro and showed a direct relationship between high SLN mRNA expression and low Ca 2+ uptake by sarcoplasmic reticulum. Since SLN reportedly plays a role in nonshivering thermogenesis, we performed a cold tolerance test of the whole body. As a result, we found that mice with cast immobilization showed high cold tolerance, suggesting that cast immobilization promoted whole body thermogenesis. Although the activity level was decreased during cast immobilization without change in food intake, adipose tissue weights also decreased significantly after cast immobilization. Concomitantly, we conclude that cast immobilization of hindlimb increased thermogenesis in C57Bl/6J mice, probably via high expression of SLN.

Purpose: In the past decade, augmented reality systems have been expected to support surgical operations by making it possible to view invisible objects that are inside or occluded by the skull, hands, or organs. However, the properties of biological tissues that are non-rigid and featureless require a large number of distributed features to track the movement of tissues in detail., Methods: With the goal of increasing the number of feature points in organ tracking, we propose a feature detection using multi-band and narrow-band imaging and a new band selection method. The depth of light penetration into an object depends on the wavelength of light based on optical characteristics. We applied typical feature detectors to detect feature points using three selected bands in a human hand. To consider surgical situations, we applied our method to a chicken liver with a variety of light conditions., Results: Our experimental results revealed that the image of each band exhibited a different distribution of feature points. In addition, the total number of feature points determined by the proposed method exceeded that of the R, G, and B images obtained using a normal camera. The results using a chicken liver with various light sources and intensities also show different distributions with each selected band., Conclusions: We have proposed a feature detection method using multi-band and narrow-band imaging and a band selection method. The results of our experiments confirmed that the proposed method increased the number of distributed feature points. The proposed method was also effective for different light conditions.

Salicylates are used as fragrance and flavor ingredients for foods, as UV absorbers and as medicines. Here, we examined the hydrolytic metabolism of phenyl and benzyl salicylates by various tissue microsomes and plasma of rats, and by human liver and small-intestinal microsomes. Both salicylates were readily hydrolyzed by tissue microsomes, predominantly in small intestine, followed by liver, although phenyl salicylate was much more rapidly hydrolyzed than benzyl salicylate. The liver and small-intestinal microsomal hydrolase activities were completely inhibited by bis(4-nitrophenyl)phosphate, and could be extracted with Triton X-100. Phenyl salicylate-hydrolyzing activity was co-eluted with carboxylesterase activity by anion exchange column chromatography of the Triton X-100 extracts of liver and small-intestinal microsomes. Expression of rat liver and small-intestinal isoforms of carboxylesterase, Ces1e and Ces2c (AB010632), in COS cells resulted in significant phenyl salicylate-hydrolyzing activities with the same specific activities as those of liver and small-intestinal microsomes, respectively. Human small-intestinal microsomes also exhibited higher hydrolyzing activity than liver microsomes towards these salicylates. Human CES1 and CES2 isozymes expressed in COS cells both readily hydrolyzed phenyl salicylate, but the activity of CES2 was higher than that of CES1. These results indicate that significant amounts of salicylic acid might be formed by microsomal hydrolysis of phenyl and benzyl salicylates in vivo. The possible pharmacological and toxicological effects of salicylic acid released from salicylates present in commercial products should be considered., (Copyright © 2015. Published by Elsevier Ltd.)

Background/aim: Oral intake of lipopolysaccharide (LPS) has been demonstrated to be effective in the prevention of various diseases. We have found that the subaleurone layer of rice contains a large amount of LPS. The aim of this study was to evaluate the role of this layer in innate immunity., Materials and Methods: Using the Saika-style rice polishing process, a sbaleurone layer and the rice retaining a subaleurone layer and polished white rice were prepared from brown rice. Using hot-water extracts from rice, LPS content was measured by the Limulus reaction and the effect of activation of macrophages was evaluated on the basis of their phagocytic activity and nitric monoxide (NO) and tumor necrosis factor (TNF) production levels. Toll-like receptor (TLR)-2-, TLR-4- and TLR-9-transfected human embryonic kidney (HEK) cells were used to identify the activation pathway. An allergy mouse model was used to evaluate the prevention of pollen allergy., Results: When compared to polished white rice, rice retaining a subaleurone layer had a 6-fold increase in LPS and an increased macrophage activation when phagocytic activity and NO and TNF production were used as indices. TRL4 was the major pathway for such activation. Anti-allergy test by oral intake of subaleurone showed a significant preventive effect for pollen allergy., Conclusion: Compared to polished white rice, rice retaining a subaleurone layer contained a high level of LPS with higher macrophage activation. Furthermore, oral administration of the rice demonstrated a preventive effect for pollen allergy, thus indicating its utility as a functional food that has a regulatory effect on innate immunity., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Key Points: Traumatic nerve injury or nerve disease leads to denervation and severe muscle atrophy. Recent evidence shows that mitochondrial loss could be a key mediator of skeletal muscle atrophy. Here, we show that daily heat stress treatment rescues denervation-induced loss of mitochondria and concomitant muscle atrophy. We also found that denervation-activated autophagy-dependent mitochondrial clearance (mitophagy) was suppressed by daily heat stress treatment. The molecular basis of this observation is explained by our results showing that heat stress treatment attenuates the increase of key proteins that regulate the tagging step for mitochondrial clearance and the intermediate step of autophagosome formation in denervated muscle. These findings contribute to the better understanding of mitochondrial quality control in denervated muscle from a translational perspective and provide a mechanism behind the attenuation of muscle wasting by heat stress., Abstract: Traumatic nerve injury or motor neuron disease leads to denervation and severe muscle atrophy. Recent evidence indicates that loss of mitochondria and the related reduction in oxidative capacity could be key mediators of skeletal muscle atrophy. As our previous study showed that heat stress increased the numbers of mitochondria in skeletal muscle, we evaluated whether heat stress treatment could have a beneficial impact on denervation-induced loss of mitochondria and subsequent muscle atrophy. Here, we report that daily heat stress treatment (mice placed in a chamber with a hot environment; 40°C, 30 min day(-1) , for 7 days) rescues the following parameters: (i) muscle atrophy (decreased gastrocnemius muscle mass); (ii) loss of mitochondrial content (decreased levels of ubiquinol-cytochrome c reductase core protein II, cytochrome c oxidase subunits I and IV and voltage-dependent anion channel protein); and (iii) reduction in oxidative capacity (reduced maximal activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase) in denervated muscle (produced by unilateral sciatic nerve transection). In order to gain a better understanding of the above mitochondrial adaptations, we also examined the effects of heat stress on autophagy-dependent mitochondrial clearance (mitophagy). Daily heat stress normalized denervation-activated induction of mitophagy (increased mitochondrial microtubule-associated protein 1A/1B-light chain3-II (LC3-II) with and without blocker of autophagosome clearance). The molecular basis of this observation was explained by the results that heat stress attenuated the denervation-induced increase in key proteins that regulate the following steps: (i) the tagging step of mitochondrial clearance (increased mitochondrial Parkin, ubiquitin-conjugated, P62/sequestosome 1 (P62/SQSTM1)); and (ii) the elongation step of autophagosome formation (increased Atg5-Atg12 conjugate and Atg16L). Overall, our results contribute to the better understanding of mitochondrial quality control and the mechanisms behind the attenuation of muscle wasting by heat stress in denervated skeletal muscle., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

A recent study demonstrated that heat stress induces mitochondrial biogenesis in C2C12 myotubes, thereby implying that heat stress may be an effective treatment to enhance endurance training-induced mitochondrial adaptations in skeletal muscle. However, whether heat stress actually induces mitochondrial adaptations in skeletal muscle in vivo is unclear. In the present study, we report the novel findings that 1) whole body heat stress produced by exposure of ICR mice to a hot environment (40°C, 30 min/day, 5 days/wk, 3 wk) induced mitochondrial adaptations such as increased mitochondrial enzyme activity (citrate synthase and 3-hydroxyacyl CoA dehydrogenase) and respiratory chain protein content (complexes I-V) in skeletal muscle in vivo and 2) postexercise whole body heat stress additively enhanced endurance training-induced mitochondrial adaptations (treadmill running, 25 m/min, 30 min/day, 5 days/wk, 3 wk). Moreover, to determine the candidate mechanisms underlying mitochondrial adaptations, we investigated the acute effects of postexercise whole body heat stress on the phosphorylation status of cellular signaling cascades that subsequently induce mitochondrial gene transcription. We found that whole body heat stress boosted the endurance exercise-induced phosphorylation of p38 MAPK, increased the phosphorylation status of p70S6K, a biomarker of mammalian target of rapamycin complex 1 activity, and unexpectedly dephosphorylated AMP-activated protein kinase and its downstream target acetyl-CoA carboxylase in skeletal muscle. Our present observations suggest that heat stress can act as an effective postexercise treatment. Heat stress treatment appeared to be clinically beneficial for people who have difficulty participating in sufficient exercise training, such as the elderly, injured athletes, and patients., (Copyright © 2014 the American Physiological Society.)

We report here that the delivery of both alpha-galactosylceramide (alphaGalCer), a representative ligand for invariant natural killer T (iNKT) cells, and an antigenic polypeptide to marginal zone B cells induces the differentiation of regulatory cells in vivo, and suppresses the secondary antibody responses in mice. Splenic CD21+ CD23- B cells of mice treated with alphaGalCer-liposomes produce IL-10 when co-cultured with iNKT cells, whereas the cells treated with aqueous alphaGalCer fail to do so. Adoptive transfer of the B cells into syngenic mice leads to the expansion of splenic CD11c(low) CD45RB(high) cells, which convert naive CD4+ T cells from RAG2-deficient DO11.10 mice to CD4+ CD25(high) Foxp3+ T cells in the presence of OVA323-339 peptide. Administration of alphaGalCer-OVA-liposomes into OVA-primed mice causes the development of CD4+ CD25(high) Foxp3+ T cells that produce both IL-10 and IFN-gamma, and induced the antigen-specific suppression of the secondary antibody responses when boosted with OVA alone. These results indicate that antigen-containing alphaGalCer-liposomes can facilitate the development of tolerogenic antigen-presenting cells and inducible regulatory T cells that are involved in the suppression of immune responses to antigens.

Motivation: Although a huge amount of mammalian genomic data does become publicly available, there are still hurdles for biologists to overcome before such data can be fully exploited. One of the challenges for gaining biological insight from genomic data has been the inability to cross-reference transcriptomic and proteomic data using a single informational platform. To address this, we constructed an open-access database that enabled us to cross-reference transcriptomic and proteomic data obtained from immune cells., Results: The database, named RefDIC (Reference genomics Database of Immune Cells), currently contains: (i) quantitative mRNA profiles for human and mouse immune cells/tissues obtained using Affymetrix GeneChip technology; (ii) quantitative protein profiles for mouse immune cells obtained using two-dimensional gel electrophoresis (2-DE) followed by image analysis and mass spectrometry and (iii) various visualization tools to cross-reference the mRNA and protein profiles of immune cells. RefDIC is the first open-access database for immunogenomics and serves as an important information-sharing platform, enabling a focused genomic approach in immunology., Availability: All raw data and information can be accessed from http://refdic.rcai.riken.jp/. The microarray data is also available at http://cibex.nig.ac.jp/ under CIBEX accession no. CBX19, and http://www.ebi.ac.uk/pride/ under PRIDE accession numbers 2354-2378 and 2414.