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Abstract Background Reducing socioeconomic inequalities in obesity is a public health priority. Limited research exists on the role of neighbourhood environmental attributes in mitigating these inequalities. However, it has been shown that neighbourhoods with more greenery tend to have lower levels of socioeconomic inequalities in non-obesity health outcomes. We examined whether neighbourhood greenery moderates the association of area-level socioeconomic status (SES) with waist circumference. Methods Data from 3,261 middle-aged and older adults who participated in a national cohort study conducted in Australia (2011–12) were used. The outcome was objectively measured waist circumference. For area-level SES, a composite index of disadvantage based on census data was used. We used two measures of neighbourhood greenery: mean greenness and geographic size of greenspace. They were assessed using the Normalized Difference Vegetation Index (NDVI) within 0.5, 1, and 2 km radius buffers around participants’ homes. The mean NDVI value within each buffer area was used for the former, and the geographic size of the area with NDVI ≥ 0.6 (dense greenery) was used for the latter. Results There was a significant negative association between area-level SES and waist circumference: one standard deviation higher score in the area-level SES indicator (less disadvantage) was associated with 1.76 cm (95% CI: -2.68, -0.83) lower waist circumference. Analyses stratified by greenery levels found similar significant associations in the areas with low and high levels of greenery but not in the areas with medium levels of greenery for both greenery measures within 1 km and 2 km buffers. Conclusions Consistent with previous studies, our study found that participants living in disadvantaged suburbs were likely to have a larger waist circumference than those living in advantaged suburbs. However, we also found that such socioeconomic inequalities in obesity were mitigated in the areas with medium levels of greenery for this sample of Australian adults. Our findings suggest that there may be an optimum level of greenery where inequalities in obesity are alleviated. Further research is needed to understand the mechanisms underlying these findings.

Abstract Individual-level analyses have consistently shown associations of travel behaviours with obesity-related measures. However, transport planning policies often target areas rather than individuals. To better inform transport-related policies and initiatives for obesity prevention, area-level relationships need to be investigated. This study linked data from two travel surveys with data from the Australian National Health Survey at the level of Population Health Areas (PHAs) and examined to what extent area-level travel behaviours metrics (prevalence of active travel, mixed travel and sedentary travel, diversity of travel modes) were associated with the rate of high waist circumference. Data from 51,987 travel survey participants were aggregated into 327 PHAs. Bayesian conditional autoregressive models were used to account for spatial autocorrelation. It was found that statistically replacing participants who relied on cars for travel (without walking/cycling) with those engaging in 30+ min/d of walking/cycling (without car use) was associated with a lower rate of high waist circumference. Areas with greater diversity of travel modes (mix of walking/cycling, car use, public transport use) also had lower prevalence of high waist circumference. This data-linkage study suggests that area-level transport planning strategies addressing car dependency, shifting car use to walking/cycling over 30 min/d, may help to reduce obesity.

Abstract Texture has enormous effects on food preferences. The materials used to study texture discrimination also have tastes that experimental animal can detect; therefore, such studies must be designed to exclude taste differences. In this study, to minimize the effects of material tastes, we utilized high- and low-viscosity forms of carboxymethyl cellulose (CMC-H and CMC-L, respectively) at the same concentrations (0.1–3%) for viscosity discrimination tests in rats. In two-bottle preference tests of water and CMC, rats avoided CMC-H solutions above 1% (63 mPa·s) but did not avoid less viscous CMC-L solutions with equivalent taste magnitudes, suggesting that rats spontaneously avoided high viscosity. To evaluate low-viscosity discrimination, we performed conditioned aversion tests to 0.1% CMC, which initially showed a comparable preference ratio to water in the two-bottle preference tests. Conditioning with 0.1% CMC-L (1.5 mPa·s) did not induce aversion to 0.1% CMC-L or CMC-H. However, rats acquired a conditioned aversion to 0.1% CMC-H (3.6 mPa·s) even after latent inhibition to CMC taste by pre-exposure to 0.1% CMC-L. These results suggest that rats can discriminate considerably low viscosity independent of CMC taste. This novel approach for viscosity discrimination can be used to investigate the mechanisms of texture perception in mammals.

Abstract Workplace settings—both internal and external—can influence how workers are physically active or sedentary. Although research has identified some indoor environmental attributes associated with sitting at work, few studies have examined associations of workplace neighbourhood built-environment attributes with workplace sitting time. We examined the cross-sectional associations of perceived and objective workplace neighbourhood built-environment attributes with sitting time at work and for transport among desk-based workers in Japan. Data were collected from a nationwide online survey. The Abbreviated Neighborhood Environment Walkability Scale (n = 2137) and Walk Score® (for a subsample of participants; n = 1163) were used to assess perceived and objective built-environment attributes of workplace neighbourhoods. Self-reported daily average sitting time at work, in cars and in public transport was measured using a Japanese validated questionnaire. Linear regression models estimated the associations of workplace neighbourhood built-environment attributes with sitting time. All perceived workplace neighbourhood built-environment attributes were positively correlated with Walk Score®. However, statistically significant associations with Walk Score® were found for sitting for transport but not for sitting at work. Workers who perceived their workplace neighbourhoods to be more walkable reported a longer time sitting at work and in public transport but a shorter sitting time in cars. Our findings suggest that walkable workplace neighbourhoods may discourage longer car use but have workplaces where workers spend a long time sitting at work. The latter finding further suggests that there may be missed opportunities for desk-based workers to reduce sitting time. Future workplace interventions to reduce sitting time may be developed, taking advantage of the opportunities to take time away from work in workplace neighbourhoods.

Severe intraoral pain induces difficulty in eating and speaking, leading to a decline in the quality of life. However, the molecular mechanisms underlying intraoral pain remain unclear. Here, we investigated gene modulation in the trigeminal ganglion and intraoral pain-related behavior in a rat model of acetic acid-induced oral ulcerative mucositis. Oral ulceration was observed on day 2 after acetic acid treatment to the oral mucosa of male Wistar rats, causing spontaneous pain and mechanical allodynia. Deoxyribonucleic acid microarray analysis of trigeminal ganglion tissue indicated that Hamp (a hepcidin gene that regulates cellular iron transport) was the most upregulated gene. In the oral ulcerative mucositis model, the upregulation of Hamp was also induced in the ulcer region but not in the liver, with no increase in hepcidin levels in the plasma and saliva, indicating that hepcidin was produced locally in the ulcer region in the model. Systemic antibiotic pretreatment did not increase the mRNA levels of Hamp in the trigeminal ganglion and ulcer regions. Hepcidin injection into the oral mucosa enhanced neuronal excitability in response to noxious mechanical stimulation of the oral mucosa in trigeminal spinal subnucleus interpolaris/caudalis neurons. These results imply that oral ulcerative mucositis induces oral mucosal pain because of infectious inflammation of the ulcerative area and potentiates Hamp, which represents anti-bacterial and anti-peptidase gene expression in the ulcer region and trigeminal ganglion. The regulation of cellular iron transport by hepcidin is likely involved in oral ulcerative mucositis-induced pain.

Abstract: Aim: Stomach contractions show two types of specific patterns in many species, that is migrating motor contraction (MMC) and postprandial contractions (PPCs), in the fasting and fed states respectively. We found gastric PPCs terminated with migrating strong contractions in humans, dogs and suncus. In this study, we reveal the detailed characteristics and physiological implications of these strong contractions of PPC. Methods: Human, suncus and canine gastric contractions were recorded with a motility‐monitoring ingestible capsule and a strain‐gauge force transducer. The response of motilin and ghrelin and its receptor antagonist on the contractions were studied by using free‐moving suncus. Results: Strong gastric contractions were observed at the end of a PPC in human, dog and suncus models, and we tentatively designated this contraction to be a postprandial giant contraction (PPGC). In the suncus, the PPGC showed the same property as those of a phase III contraction of MMC (PIII‐MMC) in the duration, motility index and response to motilin or ghrelin antagonist administration. Ghrelin antagonist administration in the latter half of the PPC (LH‐PPC) attenuated gastric contraction prolonged the duration of occurrence of PPGC, as found in PII‐MMC. Conclusion: It is thought that the first half of the PPC changed to PII‐MMC and then terminated with PIII‐MMC, suggesting that PPC consists of a digestive phase (the first half of the PPC) and a discharge phase (LH‐PPC) and that LH‐PPC is coincident with MMC. In this study, we propose a new approach for the understanding of postprandial contractions. [ABSTRACT FROM AUTHOR]

Abstract Research has identified built environmental attributes associated with children’s physical activity (PA); however, less is known for environmental correlates of refugee children’s PA. This narrative review summarised the current evidence of associations between built environment attributes and refugee children’s PA. Six databases were searched with three sets of terms related to exposure (built environment); outcome (PA); and target population (refugee children aged 6–12 years). Eight studies (one quantitative; seven qualitative) met the inclusion criteria. Key PA barriers were limited play space and lack of neighbourhood safety. Design of refugee facilities and surrounding environments should provide better access to formal, informal and safe spaces for children’s play.

Desk-based workers are highly sedentary; this has been identified as an emerging work health and safety issue. To reduce workplace sitting time and promote physical activity it is important to understand what factors are already present within workplaces to inform future interventions. This cross-sectional study examined the prevalence of supportive environmental factors, prior to workplaces taking part in a ‘sit less, move more’ initiative (BeUpstanding). Participants were 291 Australian-based workplace champions (representing 230 organisations) who unlocked the BeUpstanding program’s online toolkit between September 2017 and mid-November 2020, and who completed surveys relating to champion characteristics, organisation and workplace characteristics, and the availability of environmental factors to support sitting less and moving more. Factors were characterized using descriptive statistics and compared across key sectors and factor categories (spatial; resources/initiatives; policy/cultural) using mixed logistic regression models. Of the 42 factors measured, only 11 were present in > 50% of workplaces. Spatial design factors were more likely to be present than resources/initiatives or policy/cultural factors. Centralised printers were the most commonly reported attribute (94%), while prompts to encourage stair use were the least common (4%). Most workplace factors with

Contralateral ureteral metastasis after renal cell carcinoma (RCC) nephrectomy is uncommon. In such cases, a mass in the contralateral ureter needs to be differentiated from the primary ureteral tumor. If high grade primary ureteral tumor is found and total nephroureterectomy is performed, dialysis is introduced. In cases of metastasis of RCC, the kidney may be preserved by local treatment by partial ureterectomy. We report a case of contralateral ureteral metastasis after nephrectomy for right RCC. We underwent an originative method of pure laparoscopic partial ureterectomy and ureteral end-to-end anastomosis.

Abstract Background Living in walkable neighborhoods may provide long-term cardio-metabolic health benefits to residents. Little empirical research has examined the behavioral mechanisms in this relationship. In this longitudinal study, we examined the potential mediating role of physical activity (baseline and 12-year change) in the relationships of neighborhood walkability with 12-year changes in cardio-metabolic risk markers. Methods The Australian Diabetes, Obesity and Lifestyle study collected data from adults, initially aged 25+ years, in 1999–2000, 2004–05, and 2011–12. We used 12-year follow-up data from 2023 participants who did not change their address during the study period. Outcomes were 12-year changes in waist circumference, weight, systolic and diastolic blood pressure, fasting and 2-h postload plasma glucose, high-density lipoprotein cholesterol, and triglycerides. A walkability index was calculated, using dwelling density, intersection density, and destination density, within 1 km street-network buffers around participants’ homes. Spatial data for calculating these measures were sourced around the second follow-up period. Physical activity was assessed by self-reported time spent in moderate-to-vigorous physical activity (including walking). Multilevel models, adjusting for potential confounders, were used to examine the total and indirect relationships. The joint-significance test was used to assess mediation. Results There was evidence for relationships of higher walkability with smaller increases in weight (P = 0.020), systolic blood pressure (P

Background: Prolonged periods of sitting time can be adversely associated with older adults’ well-being and functional capacities. Understanding patterns and contexts of sedentary behaviors (SB) can inform approaches to prevention. This study examined Japanese older adults’ objectively-assessed patterns and reported domains of SB and their interrelationships. Methods: Participants (n = 297; aged 65–84 years) of this cross-sectional study wore an accelerometer for 7 days and completed a survey. Five measures related to SB patterns were identified from the accelerometer data. SB from six domains, socio-demographics, and chronic conditions were identified from the survey data. Relative contributions of six domains to objectively-measured prolonged sedentary time (≥30 minutes) and the number of breaks were examined in a series of multivariate linear regressions. Covariates were socio-demographics, chronic conditions, and accelerometer wear time. Results: On average, participants spent 8.8 hours a day sedentary (58% of accelerometer wear time), with 7.6 breaks per sedentary hour, and 3.7 hours a day through prolonged sedentary bouts (4.4 time/day). The proportions of time in the SB domains were 9.4% for car, 4.0% for public transport, 6.1% for work, 45.5% for television (TV) viewing, 9.8% for computer use, and 25.1% for other leisure. Domains of SB that contributed significantly to longer sedentary time through prolonged bouts were TV viewing and computer use. TV viewing was also associated with a lesser number of breaks. Conclusions: For Japanese older adults, initiatives to address SB could focus on breaking-up prolonged periods of SB by encouraging more frequent breaks, especially during TV viewing.

Abstract Background Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that typically arises from the pleura. Although it may appear in other organs, it rarely develops in the pancreas. We report herein a rare case of metastatic SFT of the pancreas originating from an intracranial tumor and subsequently identified as a cystic neoplasm of the pancreas. Case presentation A 58-year-old woman with a past medical history of brain tumor visited the hospital for further investigation of a cystic tumor in the pancreas tail. Abdominal imaging showed a heterogeneously enhancing mass that was initially suspected as a neuroendocrine neoplasm, solid pseudopapillary neoplasm, or mucinous cystic neoplasm of the pancreas. Distal pancreatectomy was performed without any intraoperative and postoperative complications. Pathological findings confirmed a diagnosis of malignant SFT of the pancreas with hyperproliferative potential. A histopathological review of her brain tumor revealed that the pancreatic tumor was derived from her brain lesion. The patient developed recurrent brain disease 4 years after the pancreatectomy, but no recurrence has been observed in the abdominal cavity. Conclusions SFT should be considered in the differential diagnosis of untypical hypervascular pancreatic mass, particularly in patients with a history of an intrathoracic or intracranial mesenchymal tumor. Immunohistochemical analysis is crucial in detecting this tumor entity. Hyperproliferative status indicates a malignant disease and requires careful postoperative observation.

Abstract Background Considering that building a sports facility is a major investment to promote population health, it is important to understand whether it is effective in increasing the level of physical activity (PA) in the community. This study examined the impact of building a new multipurpose exercise facility on community-level PA in Japan. Methods This non-randomised panel study compared two sites: an intervention site where a new exercise facility was built (opened after baseline data collection) and a control site where there was no such additional exercise facility. From each site, 3200 adult residents (aged 30–74 years) were randomly selected at baseline (2013) and at follow-up (2015). The number of participants retained for analysis was 845 at baseline and 924 at follow-up for the intervention site, and 821 at baseline and 1018 at follow-up for the control site. The outcomes were participants’ self-reported PA, perceived availability of PA facilities, awareness of others being active, and willingness to engage in PA. We examined the interaction terms between the sites and time of measurement in regression analyses to examine whether the magnitude of change from baseline to follow-up differed between the two sites. Results The changes in the proportion of participants meeting the PA guideline and those engaging in moderate-to-vigorous intensity PA were not significantly different between the intervention and control sites. The intervention site had a greater increase in the proportion of participants who were aware of PA facilities from baseline to follow-up than in the control site. The odds ratio for awareness of others being active approached significance, suggesting that there was a tendency at the intervention site towards a greater increase in the proportion of participants who noticed physically active people. Conclusions This study did not find community-level increases in PA after the construction of the exercise facility. However, a significant improvement in the awareness of PA facilities was observed in the intervention site. A sustained community-level effort to promote PA, possibly including social components, and a further tracking of residents’ PA are needed to take a full advantage of the new exercise facility and to assess its long-term impact. Trial registration UMIN-CTR UMIN000034116 (retrospectively registered: 13 September 2018).

ObjectivesCross-sectional studies have found some built environmental attributes to be associated with residents' lower levels of mobility (functional capacity to walk outside the home). However, less is known about what environmental attributes are related to mobility decline. This longitudinal study examined area-level associations of specific environmental attributes with mid-to-older aged adults' changes in walking mobility.MethodsData collected from 4,088 adults (aged 46-71 years at baseline) who participated in a cohort study in Brisbane, Australia were used. The outcome was the change in self-reported mobility score (SF-36) from 2013 to 2016, which were aggregated at the neighborhood (N = 156) and suburb (N = 99) levels, due to the known lack of sensitivity in SF-36 subscales to individual changes. Linear regression analysis examined associations of mobility change with seven environmental attributes measured at baseline (residential density, intersection density, land use mix, density of walking/bike paths, park density, bus stop density, density of social incivilities), adjusting for confounding variables.ResultsParticipants on average reported 4% of mobility decline during the 3-year study period. It was found that greater land use diversity was consistently associated with less decline in walking mobility, while greater density of social incivilities was associated with more decline in walking mobility. The latter finding was significant only at the neighborhood level. No consistent associations were observed for residential density, intersection density, density of walking/bike paths, park density, and bus stop density.DiscussionOur findings suggest that mid-to-older aged adults who live in areas with lower land use diversity and more social incivilities may be at risk of developing mobility limitations. Recommended policies to slow residents' mobility decline and to achieve aging in place include improving these environmental attributes where needed and advising older adults to relocate to safer, mixed-use neighborhoods.

Background There are spatial disparities in cardiovascular disease (CVD) mortality related to area‐level socioeconomic status (SES) disadvantage, but little is known about the spatial distribution of CVD mortality according to built environment factors. We examined joint associations of neighborhood walkability attributes and SES with CVD mortality rates through linkage of Japanese national data sets. Methods and Results National data were used from the 1824 municipalities (of the 1880 potentially eligible municipalities) across Japan. The outcome was mortality from CVD for a 5‐year period (2008–2012) for each municipality. A national index of neighborhood deprivation was used as an indicator of municipality‐level SES. A national walkability index (based on population density, road density, and access to commercial areas) was calculated. Compared with higher SES municipalities, relative rates for CVD mortality were significantly higher in medium SES municipalities (relative rate, 1.05; 95% CI, 1.02–1.07) and in lower SES municipalities (relative rate, 1.09; 95% CI, 1.07–1.12). There were walkability‐related gradients in CVD mortality within the high and medium SES areas, in which lower walkability was associated with higher rates of mortality; however, walkability‐related CVD mortality gradients were not apparent in lower SES municipalities. Conclusions CVD mortality rates varied not only by area‐level SES but also by walkability. Those living in areas of lower walkability were at higher risk of CVD mortality, even if the areas have a higher SES. Our findings provide a novel element of the evidence base needed to inform better allocation of services and resources for CVD prevention.

Background: The RESIDential Environments (RESIDE) project is a unique longitudinal natural experiment designed to evaluate the health impacts of the “Liveable Neighbourhoods” planning policy, which was introduced by the Western Australian government to create more walkable suburbs. Objectives: To summarize the RESIDE evidence of the impact of the planning policy on a range of health-supportive behaviours and wellbeing outcomes and to assess the consistency and direction of the estimates of associations. Methods: An audit of 26 RESIDE research papers (from 2003 to 2012) identified the number of positive associations (statistically significant and consistent with policy expectations), negative associations (statistically significant and inconsistent with policy expectations), and null findings from multiple-exposure models between objective and perceived measures of 20 policy design requirements and 13 health-supportive behaviors and wellbeing outcomes. Results: In total 332 eligible estimates of associations (n = 257 objective measures and n = 75 perceived measures) were identified. Positively significant findings were detected for: 57% of walking estimates with objectively measured policy design features (negative = 3%; null = 40%) (n = 115) and 54% perceived measures (negative = 0%; null = 33%) (n = 27); 42% of sense of community estimates with objectively measured of policy design features (negative = 8%; null = 50%) (n = 12) and 61% perceived measures (negative = 8%; null = 31%) (n = 13); 39% of safety or crime-related estimates with objectively measured of policy design features (negative = 22%; null = 39%) (n = 28) and 100% perceived measures (n = 7). All (n = 4) estimates for mental health outcomes with objectively measured policy-related design features were positively significant. Conclusions: The synthesis of findings suggests that new suburban communities built in accordance with the “Liveable Neighbourhoods” policy have the potential to encourage health supportive behaviors and wellbeing outcomes including transport and recreation walking, and to create neighborhoods with a stronger sense of community where residents may feel safer.

Introduction Numerous studies have found associations between characteristics of urban environments and risk factors for dementia and cognitive decline, such as physical inactivity and obesity. However, the contribution of urban environments to brain and cognitive health has been seldom examined directly. This cohort study investigates the extent to which and how a wide range of characteristics of urban environments influence brain and cognitive health via lifestyle behaviours in mid-aged and older adults in three cities across three continents.Methods and analysis Participants aged 50–79 years and living in preselected areas stratified by walkability, air pollution and socioeconomic status are being recruited in Melbourne (Australia), Barcelona (Spain) and Hong Kong (China) (n=1800 total; 600 per site). Two assessments taken 24 months apart will capture changes in brain and cognitive health. Cognitive function is gauged with a battery of eight standardised tests. Brain health is assessed using MRI scans in a subset of participants. Information on participants’ visited locations is collected via an interactive web-based mapping application and smartphone geolocation data. Environmental characteristics of visited locations, including the built and natural environments and their by-products (e.g., air pollution), are assessed using geographical information systems, online environmental audits and self-reports. Data on travel and lifestyle behaviours (e.g., physical and social activities) and participants’ characteristics (e.g., sociodemographics) are collected using objective and/or self-report measures.Ethics and dissemination The study has been approved by the Human Research Ethics Committee of the Australian Catholic University, the Institutional Review Board of the University of Hong Kong and the Parc de Salut Mar Clinical Research Ethics Committee of the Government of Catalonia. Results will be communicated through standard scientific channels. Methods will be made freely available via a study-dedicated website.Trial registration number ACTRN12619000817145.

Abstract Background The isotemporal substitution (IS) approach can be used to assess the effect of replacing one activity with the equal duration of another activity on relevant outcomes. This study examined the associations of objectively assessed sedentary behavior (SB) and physical activity (PA) with health-related quality of life (HRQOL) in older Japanese adults, using the IS approach. Methods Participants were 287 older Japanese adults (aged 65–84 years) who wore accelerometers for at least 7 days. We calculated the average daily time spent in SB (≤1.5 METs); light-intensity PA (LPA: > 1.5 to

Abstract Background Inconsistent associations of neighbourhood walkability with adults’ body weight have been reported. Most studies examining the relationships of walkability and adiposity are cross-sectional in design. We examined the longitudinal relationships of two walkability indices – conventional walkability and space syntax walkability, and their individual components, with weight change among adults over four years. Methods Data were from the Physical Activity in Localities and Community study in Adelaide, Australia. In 2003–2004, 2650 adults living in 154 Census Collection Districts (CCDs) returned baseline questionnaires; in 2007–2008, the follow-up survey was completed by 1098. Participants reported their weight at baseline and at follow-up. Neighbourhood walkability indices were calculated using geographic information systems and space syntax software. Linear marginal models using generalized estimating equations with robust standard errors were fitted to examine associations of the two walkability indices and their individual components with the weight at follow-up, adjusting for baseline weight, socio-demographic variables, and spatial clustering at the level of CCD. Results The overall mean weight gain over four years was 1.5 kg. The two walkability indices were closely correlated (r = 0.76, p

Objective measures of environmental attributes have been used to understand how neighborhood environments relate to physical activity. However, this method relies on detailed spatial data, which are often not easily available. Walk Score® is a free, publicly available web-based tool that shows how walkable a given location is based on objectively-derived proximity to several types of local destinations and street connectivity. To date, several studies have tested the concurrent validity of Walk Score as a measure of neighborhood walkability in the USA and Canada. However, it is unknown whether Walk Score is a valid measure in other regions. The current study examined how Walk Score is correlated with objectively-derived attributes of neighborhood walkability, for residential addresses in Japan.Walk Scores were obtained for 1072 residential addresses in urban and rural areas in Japan. Five environmental attributes (residential density, intersection density, number of local destinations, sidewalk availability, and access to public transportation) were calculated using geographic information systems for each address. Pearson's correlation coefficients between Walk Score and these environmental attributes were calculated (conducted in May 2017).Significant positive correlations were observed between Walk Score and environmental attributes relevant to walking. Walk Score was most closely associated with intersection density (r = 0.82) and with the number of local destinations (r = 0.77).Walk Score appears to be a valid measure of neighborhood walkability in Japan. Walk Score will allow urban designers and public health practitioners to identify walkability of local areas without relying on detailed geographic data. Keywords: Urban design, Walking, Tool, Built environment, Active design, Geographic information systems

Background: Good quality measures of Japanese adults’ sedentary behaviors are needed to accurately assess correlates of specific sedentary behaviors. The present study assessed criterion validity of total sedentary behavior and test-retest reliability of six domain-specific sedentary behaviors. Methods: We administered a questionnaire, based on previous studies, that measured domain-specific sedentary behaviors. To examine validity, agreement between self-reported time spent in sedentary behaviors from the questionnaire and objectively-measured sedentary time using accelerometers was compared among 392 adults (aged 40–64 years) in two Japanese cities. For reliability, a 2-week interval test-retest was administered to a convenience sample of 34 participants. Results: The correlation between total self-reported and objectively measured sedentary time was significant (all P < 0.001) and fair-to-good for workdays (ρ = 0.57) and whole week (ρ = 0.49), but was low for non-workdays (ρ = 0.23). The difference between the two measures was significant for whole week (z = −2.25, P = 0.03) and non-workdays (z = −5.50, P < 0.001), but was not significant for workdays (z = −0.60, P = 0.55). There was a significant positive association between the difference in the two measures and the average of these two measures (workdays: r = 0.53; non-workdays: r = 0.45; and whole week: r = 0.54, all P < 0.001). There was fair-to-good test-retest reliability of total sedentary time for each domain (workdays: interclass correlation coefficient [ICC] = 0.77, non-workdays: ICC = 0.53, and whole week: ICC = 0.7; all P < 0.01). Conclusions: The scale of domain-specific sedentary behaviors is reliable for estimating where and for what purpose Japanese adults spend their sedentary time, and total sedentary time is valid for workdays and the whole week.

Abstract Backgrounds The purpose of this study was to examine, in a sample of Japanese older adults, the associations of objectively-assessed sedentary behavior (SB) and physical activity (PA) with performance-based physical function. The isotemporal substitution (IS) approach was used to model simultaneously the effects of the specific activity being performed and the activity being displaced, in an equal time-exchange manner. Methods Among 287 older adults (65–84 years), we used accelerometers to identify the daily average time spent on SB (≤1.5 METs); light-intensity PA (LIPA) (>1.5 to

Abstract Primary human hepatocytes are necessary to evaluate cytotoxicity, drug metabolism, and drug–drug interactions for candidate compounds in early-phase drug discovery and development. However, these analyses are often hampered by limited resources and functional or genetic variation among lots. HepaRG human hepatocellular carcinoma cells can differentiate into mature hepatocyte-like cells (HepLCs) that possess similar metabolic activity to human hepatocytes. We previously established transgenic HepaRG cells carrying a dual reporter that express red fluorescent protein (RFP) under the transcriptional regulation of CYP3A7 in the hepatoblast-like cell state and enhanced green fluorescent protein (EGFP) under the transcriptional regulation of CYP3A4 following HepLC differentiation. In this study, we successfully isolated a subclone of transgenic CYP3A4G/7R HepaRG cells with an improved HepLC differentiation potency. Midazolam metabolism by CYP3A4 in these HepLCs was comparable to that in wild-type HepLCs. The EGFP fluorescence intensity was greatly induced by rifampicin (RIF) treatment. There was a strong correlation between fluorometric and metabolic analyses. The fold change in EGFP-positive cells was comparable to those in the CYP3A4 mRNA level and luminescence of proluciferin metabolites. RIF treatment and cell proliferation increased the RFP-positive cell number. Thus, CYP3A4G/7R HepLCs provide a real-time, multiwell-based system to co-evaluate CYP3A4 induction and hepatic regeneration.

Background Population densities of many cities are increasing rapidly, with the potential for impacts on cardiovascular health. This longitudinal study examined the potential impact of population‐density increases in urban areas (urban densification) on cardiovascular risk markers among Australian adults. Methods and Results Data were from the Australian Diabetes, Obesity and Lifestyle Study, in which adult participants’ cardiovascular risk markers were collected in 3 waves (in 1999–2000, 2004–2005, and 2011–2012). We included 2354 participants with a mean age of 51 years at baseline who did not change their residence during the study period. Outcomes were 12‐year changes in waist circumference, weight, systolic and diastolic blood pressure, fasting and 2‐hour postload plasma glucose, high‐density lipoprotein cholesterol, and triglycerides. The exposure was neighborhood population densification, defined as 12‐year change in population density within a 1‐km radius buffer around the participant’s home. Multilevel linear growth models, adjusting for potential confounders, were used to examine the relationships. Each 1% annual increase in population density was related with smaller increases in waist circumference (b=−0.043 cm/y; 95% CI, −0.065 to −0.021 [P

This study aims to compare the outputs of the waist-worn Active style Pro HJA-350IT (ASP; used in studies with Asian populations), the waist-worn ActiGragh™GT3X+ using the normal filter (GT3X+) and the thigh-worn activPAL3 (AP) in assessing adults' sedentary behaviour (total sedentary time, number of breaks) under free-living conditions. Fifty healthy workers wore the three monitors simultaneously during their waking hours on two days, including a work day and a non-work day. Valid data were at least 10 hours of wearing time, and the differences between monitors on the sedentary outputs using the AP as criterion measurement were analyzed by ANOVA. The number of participants who had complete valid data for work day and non-work day was 47 and 44, respectively. Total sedentary time and breaks estimated by the AP were respectively 466.5 ± 146.8 min and 64.3 ± 24.9 times on the work day and 497.7 ± 138.3 min and 44.6 ± 15.4 times on the non-work day. In total sedentary time, the ASP estimated 29.7 min (95%CI = 7.9 to 51.5) significantly shorter than the AP on the work day but showed no significant difference against the AP on the non-work day. The GT3X+ estimated 80.1 min (54.6 to 105.6) and 52.3 (26.4 to 78.2) significantly longer than the AP on the work day and the non-work day, respectively. For the number of breaks from sedentary time, on both days, the ASP and the GT3X+ estimated significantly more than the AP: 14.1 to 15.8 times (6.3 to 22.5) for the ASP and 27.7 to 28.8 times (21.8 to 34.8) for the GT3X+. Compared to the AP as the criterion, the ASP can underestimate total sedentary time and the GT3X+ can overestimate it, and more so at the lower levels of sedentary time. For breaks from sedentary time, compared to the AP, both the GT3X+ the ASP can overestimate.

A growing number of studies focus on the role of environments in promoting active lifestyles.1 Being physically active in daily life, which is known to have significant health benefits,2 is easier to do in some environments than it is in others. Despite mounting evidence on the relationships between environmental characteristics, activity patterns, and health,3 most decisions on environmental planning and design appear to be made without considering their implications for residents’ activity and their health. In order to promote physically-active lifestyles through environmental design, it is desirable that environmental decision-making processes explicitly incorporate people’s activity patterns as a key criterion. However, those who are involved in environmental planning and design are not necessarily aware that their decisions could ultimately affect people’s health by influencing their behaviors. Although the importance of collaboration between planning, transportation and public health has been advocated for many years,1 there remains significant work to be done to realize such cooperation. This commentary discusses the possibility of making use of existing planning and design initiatives to promote active lifestyles. More specifically, I argue that environmental planning principles aiming for sustainability in urban or suburban areas, such as compact city and smart growth, could not only make environments conducive to physical activity, but also help reduce time in sedentary behavior— newly identified and significant health risk. Human health and environmental sustainability are both top-priority issues in today’s society. The planning and design of environments that can improve human and environmental health simultaneously are more likely to receive strong support from a wide range of stakeholders, thus have a better chance of being implemented.

Live imaging visualizes the structure, dynamics, and function of cells and tissues to reveal the molecular mechanisms, and has contributed to the advancement of life science. In live imaging, it has been well known that there is a trade-off between higher-resolution analysis and cell damage caused by light illumination, i.e., phototoxicity. However, despite the risk of unknowingly distorting experimental results, phototoxicity is an unresolved issue in live imaging because overall consequences occurring inside cells due to phototoxicity remains unknown. Here, we determined the molecular process of phototoxicity-induced cell damage systematically under low- and high-dose light illumination conditions by analyzing differential gene expression using RNA-sequencing in a three-dimensional organoid of small intestinal epithelial cells, enteroid. The low-dose light illumination already induced various abnormalities in functional molecules involved in the response to reactive oxygen species generated by the excitation of fluorescent dyes, intracellular metabolism, mitosis, immune responses, etc., at mRNA expression level. Together with the behavior toward apoptosis caused by high-dose light illumination, the light dose-dependent progression of intracellular damage was revealed. About visible impairment of intestinal epithelial function, failures in both the structure-forming ability of enteroids and Paneth cell granule secretion were observed under high-dose light illumination, while the drug efflux was not disturbed despite abnormal drug efflux transporter mRNA expression. Based on the gene expression profiles, we comprehensively clarified phenomena in the cells at mRNA level that cannot be recognized both morphologically and functionally during live imaging, further providing a new insight into the risk of phototoxicity. This study warns from the aspect of mRNA expression that awareness of phototoxic artifacts is needed when analyzing cellular function and the mechanism in live imaging., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yokoi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In a fasting gastrointestinal tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occur that comprises of three phases: I, II, and III. Among these, phase III contractions propagate from the stomach to the lower intestine in mammals, including humans, dogs, and Suncus murinus (suncus). Apart from the phase III of MMC propagating from the stomach, during the gastric phase II, small intestine-originated strong contractions propagate to the lower small intestine; however, the mechanism of contractions originating in the small intestine has not been clarified. In this study, we aimed to elucidate the role of cholecystokinin (CCK) in small intestinal motility. Administration of sulfated CCK-8 in phase I induced phase II-like contractions in the small intestine, which lasted for approximately 10-20 min and then returned to the baseline, while no change was observed in the stomach. Contractions of small intestine induced by CCK-8 were abolished by lorglumide, a CCK1 receptor antagonist. Gastrin, a ligand for the CCK2 receptor, evoked strong contractions in the stomach, but did not induce contractions in the small intestine. To examine the effect of endogenous CCK on contractions of small intestinal origin, lorglumide was administered during phase II. However, there was no change in the duodenal motility pattern, and strong contractions of small intestinal origin were not abolished by treatment with lorglumide. These results suggest that exogenous CCK stimulates contractions of small intestine via CCK1 receptors, whereas endogenous CCK is not involved in the strong contractions of small intestinal origin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ghrelin is a gut-derived peptide with several physiological functions, including feeding, gastrointestinal motility, and hormonal secretion. Recently, a host defense peptide, liver-expressed antimicrobial peptide-2 (LEAP2), was reported as an endogenous antagonist of growth hormone secretagogue receptor (GHS-R). The physiological relevance of the molecular LEAP2-GHS-R interaction in mammals has been explored; however, studies on non-mammals are limited. Here, we report the identification and functional characterization of ghrelin and its related molecules in Western clawed frog (Xenopus tropicalis), a known model organism. We first identified cDNA encoding X. tropicalis ghrelin and GHS-R. RT-qPCR revealed that ghrelin mRNA expression was most abundant in the stomach. GHS-R mRNA was widely distributed in the brain and peripheral tissues, and a relatively strong signal was observed in the stomach and intestine. In addition, LEAP2 was mainly expressed in intestinal tissues at higher levels than in the liver. In functional analysis, X. tropicalis ghrelin and human ghrelin induced intracellular Ca 2+ mobilization with EC 50 values in the low nanomolar range in CHO-K1 cells expressing X. tropicalis GHS-R. Furthermore, ghrelin-induced GHS-R activation was antagonized with IC 50 values in the nanomolar range by heterologous human LEAP2. We also validated the expression of ghrelin and feeding-related factors under fasting conditions. After 2 days of fasting, no changes in ghrelin mRNA levels were observed in the stomach, but GHS-R mRNA levels were significantly increased, associated with significant downregulation of nucb2. In addition, LEAP2 upregulation was observed in the duodenum. These results provide the first evidence that LEAP2 functions as an antagonist of GHS-R in the anuran amphibian X. tropicalis. It has also been suggested that the ghrelin/GHS-R/LEAP2 system may be involved in energy homeostasis in X. tropicalis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cell-coupled field-effect transistor (FET) biosensors have attracted considerable attention because of their high sensitivity to biomolecules. The use of insect cells (Sf21) as a core sensor element is advantageous due to their stable adhesion to sensors at room temperature. Although visualization of the insect cell-substrate interface leads to logical amplification of signals, the spatiotemporal processes at the interfaces have not yet been elucidated. We quantitatively monitored the adhesion dynamics of Sf21 using interference reflection microscopy (IRM). Specific adhesion signatures with ring-like patches along the cellular periphery were detected. A combination of zeta potential measurements and lectin staining identified specific glycoconjugates with low electrostatic potentials. The ring-like structures were disrupted after cholesterol depletion, suggesting a raft domain along the cell periphery. Our results indicate dynamic and asymmetric cell adhesion is due to low electrostatic repulsion with fluidic sugar rafts. We envision the logical design of cell-sensor interfaces with an electrical model that accounts for actual adhesion interfaces.

Cholecystokinin (CCK) is a peptide hormone mainly secreted by small intestinal endocrine I-cells and functions as a regulator of gallbladder contraction, gastric emptying, gastrointestinal (GI) motility, and satiety. The cellular effects of CCK in these peripheral tissues are predominantly mediated via CCK-A receptors which are found in smooth muscles, enteric neurons, and vagal afferent neurons in humans and animal models. Although various functions of CCK have been reported to be neurally mediated, it can also stimulate contraction via the CCK receptor on the smooth muscle. However, the entire underlying neural and cellular mechanisms involved in CCK-induced GI contractions are not clearly understood. Here, we first determined the cDNA and amino acid sequences of CCK and CCK-A receptor along with the distributions of cck mRNA and CCK-producing cells in house musk shrew (Suncus murinus, the laboratory strain named as suncus) and examined the mechanism of CCK-induced contraction in the GI tract. Mature suncus CCK-8 was identical to other mammalian species tested here, and suncus CCK-A receptor presented high nucleotide and amino acid homology with that of human, dog, mouse, and rat, respectively. Suncus CCK mRNA and CCK-producing cells were found mainly in small intestine and colon. In the organ bath study, CCK-8 induced dose-dependent contractions in the suncus stomach, duodenum, and jejunum, and these contractions were inhibited by atropine and CCK-A receptor antagonist. These results suggest that CCK-8-induced contraction is mediated in the myenteric cholinergic neural network and that CCK-A receptor is partly responsible for CCK-8-induced contractions. This study indicates that suncus is a useful animal model to study the functions of CCK involved in GI motility., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Motilin, a peptide hormone consisting of 22 amino acid residues, was identified in the duodenum of pigs in the 1970s. It is known to induce gastrointestinal contractions during the interdigestive state in mammals. Although the motilin gene has been identified in various animal species, it has not been studied in amphibians. Here, we identified the motilin gene in the Japanese fire bellied newt (Cynops pyrrhogaster), and conducted an analysis of tissue distribution, morphological observations, and physiological experiments. The deduced mature newt motilin comprises 22 amino acid residues, like in mammals and birds. The C-terminus of the newt motilin showed high homology with motilin from other species compared to the N-terminus region, which is considered the bioactive site. Motilin mRNA expression in newts was abundant in the upper small intestine, with notably high motilin mRNA expression found in the pancreas. Motilin-producing cells were found in the mucosal layer of the upper small intestine and existed as two cell types: open-and closed-type cells. Motilin-producing cells in the pancreas were also found to produce insulin but not glucagon. Newt motilin stimulated gastric contractions but not in other parts of the intestines in vitro, and motilin-induced gastric contraction was significantly inhibited by treatment with atropine, a muscarinic acetylcholine receptor antagonist. These results indicate that motilin is also present in amphibians, and that its gastrointestinal contractile effects are conserved in mammals, birds, and amphibians. Additionally, we demonstrated for the first time the existence of pancreatic motilin, suggesting that newt motilin has an additional unknown physiological role., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to investigate the fundamental mechanisms of colonic motility in the house musk suncus (Suncus murinus) as an established animal model of gut motility., Methods: To measure gut motility in free-moving conscious suncus, strain gauge force transducers were implanted on the serosa of the colon and gastric body., Key Results: We recorded diurnal changes in colonic motility and observed the relationship between feeding and colonic motility. Giant migrating contractions (GMCs) of the colon were invariably detected during defecation and tended to increase during the dark period, thereby indicating that colonic motility has a circadian rhythm. Given that GMCs in the suncus were observed immediately after feeding during the dark period, we assume the occurrence of a gastrocolic reflex in suncus, similar to that observed in humans and dogs. We also examined the factors that regulate suncus GMCs. Intravenous administration of 5-HT (100 µg/kg), substance P (10 and 100 µg/kg), calcitonin gene-related peptide (10 µg/kg), and α2 adrenergic receptor antagonist yohimbine (0.5, 1, and 3 mg/kg) induced GMC-like contractions, as did intragastric and intracolonic administration of the transient receptor potential vanilloid 1 agonist, capsaicin (1 mg/kg)., Conclusions & Inferences: These results indicate that the fundamental mechanisms of colonic motility in suncus are similar to those in humans and dogs, and we thus propose that suncus could serve as a novel small animal model for studying colonic motility., (© 2021 John Wiley & Sons Ltd.)

Nesfatin-1 is an anorectic peptide expressed in both peripheral tissues and brain areas involved in the regulation of feeding, emotion and emesis. The aim of the present study is to characterize the distribution of NUCB2/nesfatin-1 in Suncus murinus and to investigate the actions of nesfatin-1 to affect gastrointestinal contractility, emesis, food and water intake, and locomotor activity. The deduced amino acid sequence of S. murinus nesfatin-1 using in silico cloning showed high homology with humans and rodents. NUCB2 mRNA was detected throughout the entire brain and in the gastrointestinal tract, including the stomach and gut. Western blot analysis and immunohistochemistry confirmed the expression of nesfatin-1 protein in these regions. The NUCB2 mRNA levels in the hypothalamus, hippocampus and brainstem were significantly decreased, whereas that in the striatum were increased after 24 h starvation compared to ad libitum -fed animals ( p < 0.05). In in vitro studies, nesfatin-1 (0.3-1,000 pM) failed to contract or relax the isolated gastric antrum and intestinal segments. In conscious, freely moving animals, intracerebroventricular administration of nesfatin-1 (1-50 pmol) induced emesis ( p < 0.05) and suppressed 6-h cumulative food intake ( p < 0.05), without affecting the latency to feeding. Nesfatin-1 (25 pmol, i.c.v.) decreased 24-h cumulative food and water intake by 28.3 and 35.4%, respectively ( p < 0.01). No significant differences in locomotor activity were observed. In conclusion, NUCB2/nesfatin-1 might be a potent regulator of feeding and emesis in S. murinus . Further studies are required to elucidate the mechanism of actions of this peptide as a mediator linking the brainstem NUCB2/nesfatin-1 to forebrain system., 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 Lu, Cui, Liu, Jiang, Ngan, Sakata, Takemi, Sakai, Lin, Chan and Rudd.)

Ghrelin is a multifunctional gut peptide with a unique structure, which is modified by a medium chain fatty acid at the third serine by ghrelin O-acyl transferase (GOAT). It is well known that the major source of plasma ghrelin is the stomach, but the transcriptional regulation of gastric ghrelin and GOAT is incompletely understood. Here, we studied the involvement of the nuclear receptors REV-ERBα and REV-ERBβ on ghrelin and GOAT gene expression in vivo and in vitro. Reverse-transcriptase polymerase chain reaction analysis showed that REV-ERBα and REV-ERBβ mRNAs were expressed in the stomach and a stomach-derived ghrelin cell line (SG-1 cells). In vivo experiments with mice revealed the circadian rhythm of ghrelin, GOAT, and REV-ERBs. The peak expression of ghrelin and GOAT mRNAs occurred at Zeitgeber time (ZT) 4, whereas that of REV-ERBα and REV-ERBβ was observed at ZT8 and ZT12, respectively. Treatment of SG-1 cells with SR9009, a REV-ERB agonist, led to a significant reduction in ghrelin and GOAT mRNA levels. Overexpression of REV-ERBα and REV-ERBβ decreased ghrelin and GOAT mRNA levels in SG-1 cells. In contrast, small-interfering RNA (siRNA)-mediated double-knockdown of REV-ERBα and REV-ERBβ in SG-1 cells led to the upregulation in the expression of ghrelin and GOAT mRNAs. These results suggest that REV-ERBs suppress ghrelin and GOAT mRNA expression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion., Methods: We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice., Results: LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2-119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O 2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet., Conclusions: LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed a high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake. Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell-selective insulin receptor-KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell-expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell-expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice - not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell-expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin's actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin's full potential to protect against insulin-induced hypoglycemia.

Pyridoxine (PN), one of the vitamers of vitamin B6, plays an important role in the maintenance of epidermal function and is used to treat acne and rough skin. Clinical studies have revealed that PN deficiency causes skin problems such as seborrheic dermatitis and stomatitis. However, the detailed effects of PN and its mechanism of action in epidermal function are poorly understood. In this study, we examined the effects of PN on epidermal function in normal human epidermal keratinocytes and found that PN specifically causes an increase in the expression of profilaggrin mRNA, among marker genes of terminal epidermal differentiation. In addition, PN treatment caused an increase in the production of filaggrin protein in a concentration-dependent manner. Treatment with P 2x purinoceptor antagonists, namely, pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium salt hydrate and TNP-ATP hydrate, induced an increase in the filaggrin protein levels. Moreover, we showed that elevated filaggrin production induced upon PN treatment was suppressed by ATP (known as P 2x purinoceptor agonist). This study is the first to report that PN causes an increase in filaggrin transcription and production, and these results suggest that PN-induced filaggrin production may be a useful target as a daily care component in atopic dermatitis, wherein filaggrin levels are specifically reduced., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose of Review: Ghrelin was discovered in 1999; extensive research and clinical studies on ghrelin have been published in the last 20 years. Physiological research on ghrelin ranges from its appetite-stimulating effects to its association with energy homeostasis. The physiological effects of ghrelin in the gastrointestinal tract and its relevance in the pathological conditions of the gastrointestinal tract have gradually become clearer. The purpose of the review is to provide current information on ghrelin cell biology and physiology, particularly in the gastrointestinal tract., Recent Findings: Ghrelin-producing cells in the stomach are characterized as X/A-like cells, but immunohistochemical analyses have revealed co-expression of several secreted proteins and hormones in ghrelin-producing cells such as nesfatin-1, somatostatin, and pancreastatin. Furthermore, the local physiological roles and/or mechanisms of ghrelin in gastrointestinal functions such as gastric motility and inflammation are discussed., Summary: Ghrelin is a brain-gut hormone with a wide range of physiological actions; hence, it is important to understand its effects on the physiological functions of the gastrointestinal tract to elucidate the biological significance of ghrelin., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Under severe calorie restriction (CR), the ghrelin-growth hormone axis in mice is involved in the maintenance of plasma glucose levels. Ghrelin, a stomach-derived acylated peptide, is up-regulated by the sympathetic nerve in the negative energy status. Central corticotrophin-releasing factor receptor (CRF-R) signalling stimulates the sympathetic tone. The present study aimed to examine the effect of central CRF-R signalling on the maintenance of plasma glucose concentrations in severe calorie-restricted mice with the involvement of ghrelin. Intracerebroventricular injections of urocorin-1 and urocorin-2, which are natural ligands for CRF-R1 and CRF-R2, elevated plasma ghrelin concentrations and ghrelin elevation with an i.c.v. injection of urocorin-1 was cancelled by atenolol (β1 adrenergic receptor antagonist) administration. We then established a mice model of 60% CR and found that the administration of [d-Lys3]-GHRP-6 (a ghrelin receptor antagonist) in mice under 60% CR reduced the plasma glucose concentration more compared to the vehicle mice. Similarly, the atenolol injection in mice under 60% CR significantly reduced the plasma glucose concentration, which was rescued by the co-administration of ghrelin. An i.c.v. injection of the alpha helical CRH, a non-selective corticotrophin-releasing factor receptor antagonist, in mice under 60% CR significantly reduced the plasma glucose concentration, although the co-administration of α-helical CRH with ghrelin maintained plasma glucose levels. These results suggest that central CRF-R signalling is involved in the maintenance of plasma glucose levels in mice under severe CR via the sympathetic-ghrelin pathway., (© 2021 British Society for Neuroendocrinology.)

Gastric contractions show two specific patterns in many species, migrating motor contractions (MMC) and postprandial contractions (PPCs), that occur in the fasted and fed states, respectively. In this study, we examined the role of somatostatin (SST) in gastric motility both in vivo and in vitro using the Asian house shrew (Suncus murinus). We performed in vivo recordings of gastric motility and in vitro organ bath experiments using S. murinus, which was recently established as a small laboratory animal for use in tests of gastrointestinal motility. SST (1.65 µg kg -1  min -1 ) was intravenously administered during phase II of MMC and PPCs. Next, the effect of SST on motilin-induced gastric contractions at phase I of MMC was measured. Cyclosomatostatin (CSST), an SST receptor antagonist, was administered at the peak of phase III of MMC. In addition, the effect of SST (10 -11 -10 -9  M) on motilin-induced gastric contractions was evaluated using an organ bath experiment in vitro. In conscious, free-moving S. murinus, the administration of SST decreased the occurrence of the spontaneous phase II of MMC and PPCs. Pretreatment with SST and octreotide suppressed the induction of motilin-induced gastric contractions both in vivo and in vitro. Administration of CSST before the peak of spontaneous phase III contractions had no effect on gastric contractions. Endogenous SST is not involved in the regulation of gastric MMC and PPCs, but exogenous SST suppresses spontaneous gastric contractions. Thus, SST would be good for treating abnormal gastrointestinal motility disorders.

Motilin, a 22-amino-acid peptide produced in the upper small intestine, induces strong gastric contraction in fasted state. In many rodents, motilin and its cognate receptors exist as pseudogenes, which has delayed motilin research in the past decades. Recently, the house musk shrew (Suncus murinus) was developed as a useful model for studying motilin and gastrointestinal motility. However, due to a lack of motilin-producing cell lines and difficulties in culturing small intestinal cells, the regulatory mechanisms of motilin secretion and its messenger RNA (mRNA) transcription have remained largely unclear. In this study, we generated small intestinal organoids from S. murinus for the first time. Using methods similar to mouse organoid generation, we found crypt-like budding structures 3 days after isolating intestinal tissues. The organoids grew gradually with time. In addition, the generated organoids were able to be passaged and maintained for 6 months or longer. Motilin messenger RNA (mRNA) and immunopositive cells were observed in both S. murinus intestinal organoids and primary tissues. This is the first report of intestinal organoids in S. murinus, and our results suggest that S. murinus intestinal organoids could be useful for analyzing motilin secretion and transcription., (© 2019 International Federation for Cell Biology.)

Motilin and ghrelin were identified in the pheasant by molecular cloning, and the actions of both peptides on the contractility of gastrointestinal (GI) strips were examined in vitro. Molecular cloning indicated that the deduced amino acid sequences of the pheasant motilin and ghrelin were a 22-amino acid peptide, FVPFFTQSDIQKMQEKERIKGQ, and a 26-amino acid peptide, GSSFLSPAYKNIQQQKDTRKPTGRLH, respectively. In in vitro studies using pheasant GI strips, chicken motilin caused contraction of the proventriculus and small intestine, whereas the crop and colon were insensitive. Human motilin, but not erythromycin, caused contraction of small intestine. Chicken motilin-induced contractions in the proventriculus and ileum were not inhibited by a mammalian motilin receptor antagonist, GM109. Neither atropine (a cholinergic receptor antagonist) nor tetrodotoxin (a neuron blocker) inhibited the responses of chicken motilin in the ileum but both drugs decreased the responses to motilin in the proventriculus, suggesting that the contractile mechanisms of motilin in the proventriculus was neurogenic, different from that of the small intestine (myogenic). On the other hand, chicken and quail ghrelin did not cause contraction in any regions of pheasant GI tract. Since interaction of ghrelin and motilin has been reported in the house musk shrew, interaction of two peptides was examined. The chicken motilin-induced contractions were not modified by ghrelin, and ghrelin also did not cause any contraction under the presence of motilin, suggesting the absence of interaction in both peptides. In conclusion, both the motilin system and ghrelin system are present in the pheasant. Regulation of GI motility by motilin might be common in avian species. However, absence of ghrelin actions in any GI regions suggests the avian species-related difference in regulation of GI contractility by ghrelin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The intestinal epithelial monolayer forms a mucosal barrier between the gut microbes and the host tissue. The mucosal barrier is composed of mucins and antimicrobial peptides and proteins (AMPs). Several animal studies have reported that Paneth cells, which occupy the base of intestinal crypts, play an important role in the intestinal innate immunity by producing AMPs, such as lysozyme, Reg3 lectins, α-defensins, and group IIA secretory phospholipase A2 (GIIA sPLA2). The house musk shrew (Suncus murinus) has only a few intestinal commensal bacteria and is reported to lack Paneth cells in the intestine. Although the expression of lysozyme was reported in the suncus intestine, the expression of other AMPs has not yet been reported. Therefore, the current study was focused on GIIA sPLA2 expression in Suncus murinus. GIIA sPLA2 mRNA was found to be most abundant in the spleen and also highly expressed in the intestine. Cells expressing GIIA sPLA2 mRNA were distributed not only in the crypt, but also in the villi. In addition, intragastric injection of lipopolysaccharide increased GIIA sPLA2 expression in the small intestine of suncus. These results suggest that suncus may host unique AMP-secreting cells in the intestine., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Molecular hydrogen (H 2 ) showed protection against various kinds of oxidative-stress-related diseases. First, it was reported that the mechanism of therapeutic effects of H 2 was antioxidative effect due to inhibition of the most cytotoxic reactive oxygen species, hydroxy radical (•OH). However, after chronic administration of H 2 in drinking water, oxidative-stress-induced nerve injury is significantly attenuated even in the absence of H 2 . It suggests indirect signaling of H 2 and gastrointestinal tract is involved. Indirect effects of H 2 could be tested by giving H 2 water only before nerve injury, as preconditioning. For example, preconditioning of H 2 for certain a period (∼7 days) in Parkinson's disease model mice shows significant neuroprotection. As the mechanism of indirect effect, H 2 in drinking water induces ghrelin production and release from the stomach via β1-adrenergic receptor stimulation. Released ghrelin circulates in the body, being transported across the blood-brain barrier, activates its receptor, growth-hormone secretagogue receptor. H 2 -induced upregulation of ghrelin mRNA is also shown in ghrelin-producing cell line, SG-1. These observations help with understanding the chronic effects of H 2 and raise intriguing preventive and therapeutic options using H 2 .