Dysbiosis is associated with various diseases. The composition and diversity of gut microbiota affect host physiology through the production of bioactive metabolites. Short-chain fatty acids are the ...main metabolites produced by microbial fermentation of dietary fiber. They play a crucial role in maintaining metabolic, nervous, and immune system. Short-chain fatty acids not only serve as an energy source for the host but also act as for G-protein-coupled receptor signaling molecules and histone deacetylase inhibitors. In particular, the discovery and deorphanization of free fatty acid receptors 2 and 3 (GPR43/41) have shed light on the molecular mechanisms underlying the regulation of physiological processes by short-chain fatty acids. The short-chain fatty acid receptors sense the nutrient status and transduce signals to maintain cellular homeostasis. Dysbiosis affects short-chain fatty acid production and impairs the signaling, leading to cellular dysfunction. We review the current understanding of short-chain fatty acid-mediated regulation of physiological processes and discuss the molecular pharmacology of short-chain fatty acid and the receptor. We also discuss recent advances in the use of prebiotics and probiotics in the treatment of disease.
Intermittent fasting (IF) is a dietary restriction regimen that extends the lifespans of Caenorhabditis elegans and mammals by inducing changes in gene expression. However, how IF induces these ...changes and promotes longevity remains unclear. One proposed mechanism involves gene regulation by microRNAs (miRNAs), small non-coding RNAs (∼22 nucleotides) that repress gene expression and whose expression can be altered by fasting. To test this proposition, we examined the role of the miRNA machinery in fasting-induced transcriptional changes and longevity in C. elegans. We revealed that fasting up-regulated the expression of the miRNA-induced silencing complex (miRISC) components, including Argonaute and GW182, and the miRNA-processing enzyme DRSH-1 (the ortholog of the Drosophila Drosha enzyme). Our lifespan measurements demonstrated that IF-induced longevity was suppressed by knock-out or knockdown of miRISC components and was completely inhibited by drsh-1 ablation. Remarkably, drsh-1 ablation inhibited the fasting-induced changes in the expression of the target genes of DAF-16, the insulin/IGF-1 signaling effector in C. elegans. Fasting-induced transcriptome alterations were substantially and modestly suppressed in the drsh-1 null mutant and the null mutant of ain-1, a gene encoding GW182, respectively. Moreover, miRNA array analyses revealed that the expression levels of numerous miRNAs changed after 2 days of fasting. These results indicate that components of the miRNA machinery, especially the miRNA-processing enzyme DRSH-1, play an important role in mediating IF-induced longevity via the regulation of fasting-induced changes in gene expression.
Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein-coupled 84 (GPR84) acts as a receptor for ...MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake-induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.
Deworming wild foxes by baiting with the anthelmintic praziquantel is being established as a preventive technique against environmental contamination with Echinococcus multilocularis eggs. ...Improvement of the cost-benefit performance of baiting treatment is required urgently to raise and maintain the efficacy of deworming. We established a spatial model of den site selection by urban red foxes, the definitive host, to specify the optimal micro-habitats for delivering baits in a new modeling approach modified for urban fox populations.
The model was established for two cities (Obihiro and Sapporo) in Hokkaido, Japan, in which a sylvatic cycle of E. multilocularis is maintained. The two cities have different degrees of urbanization. The modeling process was designed to detect the best combination of key environmental factors and spatial scale that foxes pay attention to most (here named 'heeding range') when they select den sites. All possible models were generated using logistic regression analysis, with "presence" or "absence" of fox den as the objective variable, and nine landscape categories customized for urban environments as predictor variables to detect the best subset of predictors. This procedure was conducted for each of ten sizes of concentric circles from dens and control points to detect the best circle size. Out of all models generated, the most parsimonious model was selected using Akaike's Information Criterion (AIC) inspection.
Our models suggest that fox dens in Obihiro are located at the center of a circle with 500 m radius including low percentages of wide roads, narrow roads, and occupied buildings, but high percentages of green covered areas; the dens in Sapporo within 300 m radius with low percentages of wide roads, occupied buildings, but high percentages of riverbeds and green covered areas. The variation of the models suggests the necessity of accumulating models for various types of cities in order to reveal the patterns of the model.
Our denning models indicating suitable sites for delivering baits will improve the cost-benefit performance of the campaign. Our modeling protocol is suitable for the urban landscapes, and for extracting the heeding range when they select the den sites.
Aim: Atherosclerotic lesions are reported to be hypoxic. Since hypoxia is known to induce the production of growth factors, such as vascular endothelial growth factor (VEGF), we examined the ...implication of hypoxia-induced VEGF in the proliferation of human coronary artery smooth muscle cells (CASMCs). Methods: Cells were cultured under hypoxic conditions (1% O2, 5% CO2) and several responses were measured. Results: Under hypoxic conditions, the mRNA and protein levels of VEGF, and the mRNA level of VEGF receptor-1 (VEGFR-1) increased with an increase in hypoxia-inducible factor-1α (HIF-1α) protein, and considerable amounts of VEGF were secreted. Hypoxia enhanced the incorporation of 3H-thymidine by CASMCs, which was completely inhibited by a neutralizing antibody against VEGF. A neutralizing antibody against NADPH-cytochrome P-450 reductase (NPR), which contributes to the stabilization of HIF-1α, also attenuated hypoxia-stimulated proliferation. In NPR-knockdown cells, the expression of VEGF, proliferation, and transcriptional activity were attenuated, whereas in NPR-overexpressing cells, they were enhanced. Conclusion: Hypoxia-induced proliferation of CASMCs is mediated through the expressions of VEGF and VEGFR-1 in an autocrine mechanism. Their expressions are dependent on the stabilization of HIF-1α, which is regulated by NPR. We suggest that hypoxia and hypoxia-induced VEGF expression are involved in the pathogenesis of progressive atherosclerosis.
Background. Tyrosine phosphorylation of proteins has been a focus of extensive studies since it plays crucial roles in regulation of diverse biological reactions. To understand the involvement of ...tyrosine phosphorylation in kidney functions, a comprehensive proteomic study for tyrosine-phosphorylated proteins was performed in the normal rat kidney. Methods. Two-dimensional gel electrophoresis and immunoprecipitation using anti-phosphotyrosine antibodies were employed to detect tyrosine-phosphorylated proteins. The proteins were analysed by mass spectrometry and validated by immunological analyses using specific antibodies. Results. Most of tyrosine-phosphorylated proteins were confined to the glomerulus and predominantly localized along the glomerular capillary wall, especially in the foot processes of podocytes. Our systematic proteomic analysis identified nephrin, SHPS-1 (tyrosine-protein phosphatase non-receptor-type substrate 1), FAK1 and paxillin as major tyrosine-phosphorylated proteins and Neph1, talin and vinculin as minor tyrosine-phosphorylated proteins. In the present study, SHPS-1 was identified as a novel tyrosine-phosphorylated protein in the glomerulus and was also predominantly localized at the foot processes. Mass spectrometric analysis identified in vivo phosphorylation sites of SHPS-1 on Y460, Y477 and Y501. Conclusion. This study identified tyrosine-phosphorylated proteins in normal rat kidney, which were prominently rich in the glomerulus and localized at the podocyte foot processes. These proteins were categorized as cell-to-cell or cell-to-matrix adhesion complex-related molecules, suggesting their pivotal roles in the glomerular ultrafiltration.
The well‐known link between longevity and the Sir2 histone deacetylase family suggests that histone deacetylation, a modification associated with repressed chromatin, is beneficial to longevity. ...However, the molecular links between histone acetylation and longevity remain unclear. Here, we report an unexpected finding that the MYST family histone acetyltransferase complex (MYS‐1/TRR‐1 complex) promotes rather than inhibits stress resistance and longevity in Caenorhabditis elegans. Our results show that these beneficial effects are largely mediated through transcriptional up‐regulation of the FOXO transcription factor DAF‐16. MYS‐1 and TRR‐1 are recruited to the promoter regions of the daf‐16 gene, where they play a role in histone acetylation, including H4K16 acetylation. Remarkably, we also find that the human MYST family Tip60/TRRAP complex promotes oxidative stress resistance by up‐regulating the expression of FOXO transcription factors in human cells. Tip60 is recruited to the promoter regions of the foxo1 gene, where it increases H4K16 acetylation levels. Our results thus identify the evolutionarily conserved role of the MYST family acetyltransferase as a key epigenetic regulator of DAF‐16/FOXO transcription factors.
Synopsis
FOXO transcription factors regulate stress resistance and longevity in diverse organisms. Here, the MYST family HAT complex is shown to increase FOXO transcription and thus promote longevity and stress resistance in C. elegans and human cells.
The MYS‐1/TRR‐1 HAT complex regulates oxidative stress resistance and longevity by up‐regulating the expression of daf‐16 genes in C. elegans.
The Tip60/TRRAP HAT complex regulates cellular defense against oxidative stress by up‐regulating the expression of foxo1 gene in human cells.
The Tip60/TRRAP HAT is an evolutionarily conserved epigenetic regulator of FOXO transcription factors.
FOXO transcription factors regulate stress resistance and longevity in diverse organisms. Here, the MYST family HAT complex is shown to increase FOXO transcription and thus promote longevity and stress resistance in C. elegans and human cells.
It is well known that the disruption of the mitochondrial respiratory components prolongs lifespan in many species. The mitochondrial stress response can lead to an increased survival rate through ...the restoration of the cellular homeostasis. Therefore, developing pharmacological interventions that induce mitochondrial stress response may be desirable to delay the onset of age-related diseases and promote a healthy life. In this study, we present chemical compounds, revealed by systematic screening of chemical libraries, which inhibit mitochondrial ATP synthesis in mammalian cells. Our study demonstrates that these compounds alter the body length and promote the oxidative stress response which leads to an increased longevity in Caenorhabditis elegans. Thus, our study identifies chemical compounds that may have potential therapeutic applications through affecting the mitochondrial function.
•Our screen identifies inhibitors of mitochondrial ATP synthesis in HeLa cells.•Key respiratory components inhibited by chemical compounds are identified.•Chemical compounds affect ATP levels, stress resistance and lifespan in C. elegans.
Background and objectives: School lunches are required to give consideration to actively ingest calcium, which is particularly needed during the growth period. However, the method of evaluating food ...education activities at present educational site has not been established. In this research, we aimed to develop and evaluate a food education program on calcium for junior high school students incorporating PDCA cycle. Methods: Survey was conducted in July and December 2016, targeting all 251 students enrolled in F junior high school. Actual condition survey on food, questionnaire survey on dietary habits, mental health survey, and BDHQ 15y (Simple self-registered diet history questionnaire: brief-type self-administered diet history questionnaire) for junior high school students were examined. The effect of grade level on each item and the impact assessment by comparing before and after educational activities were examined using X2 test (effective response rate 94.8%). The intake of normal milk, low fat milk, yoghurt and cheese was divided into quartiles and a one-way analysis of variance was conducted on the mental health score and micronutrient deficiency score (effective response rate 88.4%). Results: The micronutrient deficiency score and the mental health score both gained higher scores than adults. Significant correlation was found between mental health score and micronutrient deficiency score in yoghurt ingestion and dairy product intake, and in the group with low yoghurt intake, the score of mental health and micronutrient deficiency tends to be high in all students. In the group with low dairy intake, mental health scores in female students and mental health and micronutrient deficiency scores in all students tended to be higher. Students who can correctly select 5 kinds of calcium-rich foods which are particularly necessary for junior high school students was 39.1% before food education, but significantly increased after food education. Conclusions: Development of nutritional education program on calcium accompanied with evaluation based on the concept of health promotion using the PDCA cycle is effective for improving the school's dietary education activity and motivation for student's calcium intake and increasing student calcium intake can be expected.
Background/Aims: In Japan, admiration among young women for thin figures has led to them dieting, having an unbalanced diet, skipping meals, and acquiring other inappropriate dietary habits. ...According to the National Health and Nutrition Survey conducted in Japan in the year 2017 (Ministry of Health, Labor and Welfare,2017), 21.7% of women in their twenties are underweight. Methods: The subjects included 45 female university students in Tokyo. Physical stature (height and weight), physical strength (muscle strength, flexibility, instantaneous power, agility, and endurance), and nutritional intake were measured. Results: The mean age of the subjects was 19 years, height was 157 cm, weight was 49 kg, and BMI was 20 kg/m2. Their mean daily caloric intake was 1845 kcal. Our investigation of physical strength indicated that the muscle strength of the participants was less. Conclusions: We believe the fact that there were no obese students in this cohort and none of the students regularly exercised and still exhibited only average physiques can be attributed to their dietary habits, which resulted in a decreased physical strength. The decrease in physical strength, in particular, contributes to the issue of whether or not a person regularly exercise. We would also like to see improved dietary habits as part of these efforts.
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