Physiological genomics最新文献

Objective: This research explored the effect of high-fiber diet based on gut microbiota on chronic heart failure (HF) patients. Methods: Chronic HF patients, who had undergone a dietary survey indicating a daily dietary fiber intake of less than 15g/d were divided into the control and study groups (n = 50). In addition to conventional heart failure treatment, the study group received dietary guidance, while the control group did not receive any dietary guidance and maintained their usual low-fiber dietary habits. After one year intervention, the daily dietary fiber intake, abundance of gut microbiota, plasma trimethylamine N-oxide (TMAO), albumin (ALB), prealbumin (PA), transferrin (TF), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), left ventricular ejection fraction (LVEF), left ventricular end-diastolic index (LVEDVI), and left ventricular end-systolic volume index (LVESVI), Barthel index (BI), and 6 min walking distance (6 MWD) were compared. Results: After intervention, in both groups, the daily dietary fiber intake increased, abundance of Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria decreased and that of Bacteroides increased; the plasma TMAO decreased; serum ALB, PA, and TF levels increased; serum CRP, TNF-α, IL-6, and IL-8 levels decreased, and the change was greater in the study group; LVEF elevated, LVEDVI and LVESVI reduced, and the differences between both groups were not significant; BI and 6 MWD elevated, and the study group was higher than the control group. Conclusion: High-fiber diet positively regulates the composition of gut microbiota, nutritional status and microinflammatory level in chronic HF patients, thereby improving patients' quality of life.

Background: Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though inter-individual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA)were used to profile genomic and cellular ASA responses. Methods: Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3mM ASA or vehicle control for 24h. Gene expression was assessed by RNA-seq, and differentially responsive genes analyzed by condition, population and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Proliferation, apoptosis and necrosis assays were performed, and apoptosis gene expression measured in organoids. Results: Overall, 8343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and PPAR signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with identification of significant differential responses of apoptotic genes to ASA. Conclusions: Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.

Purpose: The study aimed to verify the physiological and metabolic parameters associated with the time to task failure (TTF) during cycling exercise performed within the severe-intensity domain. Methods: Forty-five healthy and physically active males participated in two independent experiments. In experiment 1, after a graded exercise test, participants underwent constant work rate cycling efforts (CWR) at 115% of peak power output to assess neuromuscular function (Potentiated twitch) pre- and post-exercise. Experiment 2 was similarl to experiment 1, but with physiological (respiratory parameters, energetic pathway contribution) and metabolic parameters in the blood (gasometry and blood lactate responses) and vastus lateralis muscle tissue (target metabolomic analysis, glycogen content, muscle pH and buffering capacity in vitro) measured instead of neuromuscular function. Results: Experiment 1 evidenced a significant decrease in muscle force with instauration of peripheral fatigability indices and no change in central fatigue indices. Severe-intensity domain exercise in Experiment 2 was accompanied by changes in physiological and metabolic parameters and in blood and muscle parameters. However, the TTF was associated with oxidative contribution (r=0.811, p<0.001), as well as anaerobic capacity (r=0.554, p=0.027), muscle buffering capacity (r=0.792, p=0.035), phosphagen energy contribution (r=0.583, p=0.017), and carnitine changes (r=0.855, p=0.016), but no correlated with electromyographic response, blood acid-base balance, and muscular glycogen content and pH. Conclusion: TTF during CWR exercise within the severe-intensity domain is likely explained by a combination of interacting mechanisms, with oxidative and phosphagen contributions, and muscle buffering capacity suggested as the main peripherals limiting factors to exercise within this exercise intensity domain.

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy with an incidence rate of up to 8% worldwide. However, the complete pathogenesis is still unknown. Obesity increases the risk of developing PE three-fold. To better understand the relationship of maternal risk factors, the BPH/5 mouse was described as a model of superimposed PE. Previous research demonstrated that adult BPH/5 female mice have an adverse cardiometabolic phenotype characterized by hypertension, obesity with increased white adipose tissue and dyslipidemia, exaggerated by pregnancy. We hypothesize that BPH/5 mice have gut dysbiosis characterized by changes in alpha and beta diversity of bacterial community structure as well as perturbed short chain fatty acids (SCFA) compared to controls in pregnancy. Fecal samples were used for Illumina sequencing of 16S v4 rRNA amplicons. Microbial community composition of the pregnant BPH/5 compared to C57 controls was different using PERMANOVA with Bray-Curtis dissimilarity. Alpha diversity was increased in pregnant BPH/5 dams compared to controls. Alistipes and Helicobacter were increased while Bacteroides, Lactobacillus, Parasulterrella, and Parabacteroides were decreased compared to controls. Fecal SCFAs were not different between groups, but BPH/5 serum acetic and butyric acid were decreased while isobutyric and isovaleric acid were increased specifically in pregnancy. BPH/5 pregnant colons had decreased expression of free fatty acid receptor, GPR41. In conclusion, the BPH/5 maternal fecal microbiome demonstrates microbial dysbiosis characterized by community structure and diversity changes before and after the onset of pregnancy. Gut dysbiosis may be a key mechanism linking SCFA signaling and obesity to the BPH/5 PE-like phenotype.

The elusive function of myosin light chain 9 (MYL9) in cancer is an area ripe for further investigation. Bioinformatics was used to compare the expression levels of MYL9 in non-small-cell lung cancer (NSCLC) and normal tissues. Gene set enrichment analysis was used to investigate the pathways associated with MYL9. The BioGRID database was used to screen for potential targets of MYL9. The expression of MYL9 and myosin 19 (MYO19) mRNA was quantified using quantitative reverse transcriptase PCR. Cell migration was assessed using a scratch wound healing assay. The protein levels of MYL9, MYO19, and epithelial-mesenchymal transition (EMT) biomarkers were examined using Western blot (WB). Epithelial cell adhesion molecule (EpCAM) expression in different cell groups was profiled using flow cytometry analysis. Coimmunoprecipitation assays were performed to determine the binding affinity between MYL9 and MYO19. In addition, the direct protein interaction between MYL9 and MYO19 was explored using a glutathione-S-transferase (GST) pull-down assay. In NSCLC patients, MYL9 was significantly downregulated both in vivo and in cell cultures and had a high enrichment score in the EMT pathway. Scratch assays pointed to its inhibitory effect on cancer cell migration. WB showed that MYL9 could suppress EMT marker protein expression in NSCLC cells. Flow cytometry found that MYL9 greatly reduced the distribution of EpCAM on the cell surface. MYO19 was pinpointed as a potential target of MYL9, as confirmed by coimmunoprecipitation and GST pull-down assays. Rescue experiments confirmed that MYO19 could enhance cell migration, promote the expression of EMT markers, and increase EpCAM levels on the cell surface, but these effects were reserved by MYL9 overexpression. MYL9 impedes the migration and EMT in NSCLC cells by binding to MYO19.NEW & NOTEWORTHY Myosin light chain 9 (MYL9) is downregulated in non-small-cell lung cancer (NSCLC). MYL9 suppresses epithelial-mesenchymal transition (EMT) in NSCLC cells. MYL9 binds to myosin 19 (MYO19). MYL9/MYO19 signaling inhibits EMT in NSCLC.

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion, resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a nonviral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the subplacenta/decidua that provide insight into the underlying mechanism driving placental insufficiency and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at midpregnancy, and subplacenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR subplacenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 subplacenta/decidua when compared with sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis, indicative of homeostasis. Overall, this study identified changes to the subplacenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on to restore or maintain appropriate placenta function.NEW & NOTEWORTHY Placental insufficiency at midpregnancy, established through moderate maternal nutrient restriction, is characterized with fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. Treatment of placenta insufficiency with a hIGF1 nanoparticle results in marked changes to transporter activity and increases our mechanistic understanding of how therapies designed to improve fetal growth may impact the placenta.

The purpose of this study was to elucidate the skeletal muscle transcriptomic response unique to rest duration during high-intensity interval exercise. Thoroughbred horses performed three 1-min bouts of exercise at their maximal oxygen uptake (10.7-12.5 m/s), separated by 15 min (long) or 2 min (short) walking at 1.7 m/s. Gluteus medius muscle was collected before and at 4 h after the exercise and used for RNA sequencing. We identified 1,756 and 1,421 differentially expressed genes in response to the long and short protocols, respectively, using DEseq2 analysis [false discovery rate (FDR) cutoff = 0.05, minimal fold change = 1.5]. The overall transcriptional response was partially aligned, with 43% (n = 949) of genes altered in both protocols, whereas no discordant directional changes were observed. K-means clustering and gene set enrichment analyses based on Gene Ontology biological process terms showed that genes associated with muscle adaptation and development were upregulated regardless of exercise conditions; genes related to immune and cytokine responses were more upregulated following the long protocol, and protein folding and temperature response were highly expressed after the short protocol. We found that 11 genes were upregulated to a greater extent by the short protocol and one was by the long protocol, with GNA13, SPART, PHAF1, and PTX3 identified as potential candidates for skeletal muscle remodeling. Our results suggest that altered metabolic fluctuations dependent on the intermittent pattern of interval exercise modulate skeletal muscle gene expression, and therefore, rest interval length could be an important consideration in optimizing skeletal muscle adaptation.NEW & NOTEWORTHY This is the first study to address the comparison of transcriptional responses to high-intensity interval exercise with two different rest periods in skeletal muscle. The expression of genes related to metabolic adaptations altered in both conditions, while genes associated with immune and cytokine responses and protein folding and temperature response were varied with the length of the rest period. These results provide evidence for rest duration-specific transcriptional response to high-intensity interval training.

Low carbohydrate availability during recovery from aerobic exercise alters skeletal muscle microRNA (miRNA) profiles, which may mechanistically regulate exercise recovery. However, its impact on circulating miRNA (c-miRNA) profiles remains unclear. Purpose: This study aimed to determine the effects of low versus adequate carbohydrate availability on c-miRNA profiles during recovery from aerobic exercise. Methods: Nine males (22±4yrs, 1.81±0.09m, 83.9±11.9kg, 25.7±2.3kg/m², mean±SD) completed this randomized, crossover study consisting of two glycogen depletion trials, followed by 24 hours of isocaloric refeeding to induce low (LOW; 1.5 g/kg carbohydrate, 3.0 g/kg fat) or adequate (AD; 6.0 g/kg carbohydrate, 1.0 g/kg fat) carbohydrate availability. Total c-miRNA were extracted from serum 24 hours following glycogen depletion exercise. Data were log transformed and analyzed as fold change relative to AD. Bioinformatics were conducted on significant c-miRNA and associated pathways (miRTarBase/KEGG). Follow-up transfection of miR-375-3p mimic or inhibitor into C2C12 cells assessed metabolic, inflammatory, and catabolic pathways at the gene and protein levels. Results: Of the 84 miRNA assessed, miR-335-5p (-0.49±0.60; P=0.04) and miR-375-3p (-1.57±1.25; P=0.01) were significantly lower, and miR-214-3p (1.76±1.85; P=0.02) was significantly higher in AD versus LOW. In vitro experiments indicated that miR-375-3p regulates catabolic pathways at the gene and protein level. Conclusion: Low carbohydrate availability alters c-miRNA profiles, particularly miR-375-3p, which targets proteostasis and metabolism 24 hours into recovery from aerobic exercise. These findings identify unique c-miRNA targets as potential biomarkers for the mechanistic effects of low carbohydrate availability on exercise recovery.

Glioblastoma multiforme (GBM) is one of the most common and aggressive type of malignant glioma with an average survival time of 12-18 mo. Despite the utilization of extensive surgical resections using cutting-edge neuroimaging, and advanced chemotherapy and radiotherapy, the prognosis remains unfavorable. The heterogeneity of GBM and the presence of the blood-brain barrier further complicate the therapeutic process. It is crucial to adopt a multifaceted approach in GBM research to understand its biology and advance toward effective treatments. In particular, omics research, which primarily includes genomics, transcriptomics, proteomics, and epigenomics, helps us understand how GBM develops, finds biomarkers, and discovers new therapeutic targets. The availability of large-scale multiomics data requires the development of computational models to infer valuable biological insights for the implementation of precision medicine. Artificial intelligence (AI) refers to a host of computational algorithms that is becoming a major tool capable of integrating large omics databases. Although the application of AI tools in GBM-omics is currently in its early stages, a thorough exploration of AI utilization to uncover different aspects of GBM (subtype classification, prognosis, and survival) would have a significant impact on both researchers and clinicians. Here, we aim to review and provide database resources of different AI-based techniques that have been used to study GBM pathogenesis using multiomics data over the past decade. We summarize different types of GBM-related omics resources that can be used to develop AI models. Furthermore, we explore various AI tools that have been developed using either individual or integrated multiomics data, highlighting their applications and limitations in the context of advancing GBM research and treatment.