Physiological genomics最新文献

This research explored the effect of a high-fiber diet based on gut microbiota on patients with chronic heart failure (HF). Patients with chronic HF, who had undergone a dietary survey indicating a daily dietary fiber intake of less than 15 g/day, 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 1 yr 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. After the intervention, in both groups, the daily dietary fiber intake increased and the abundance of Firmicutes, Proteobacteria, Actinobacteria, and 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. High-fiber diet positively regulates the composition of gut microbiota, nutritional status, and microinflammatory level in patients with chronic HF, thereby improving patients' quality of life.NEW & NOTEWORTHY Traditional heart failure (HF) treatment primarily focuses on medications and surgery, whereas this study explores the improvement effects of a diet high in dietary fiber on patients with chronic HF from the perspective of gut microbiota, providing a new perspective for HF treatment.

This study aimed to examine the protective effect of celastrol on testicular dysfunction in diabetic rats and the potential underlying mechanisms. All rats included in the study were divided into four groups: a control group treated with sodium citrate buffer and vehicle), a celastrol-treated control group, a streptozotocin (STZ)-induced diabetic group following insulin resistance, and a celastrol-treated diabetic group. Serum glucose, triglyceride, total cholesterol, high-density lipoprotein cholesterol, interleukin (IL)-1β, tumor necrosis factor-α, and testosterone levels were measured. In addition, the levels of testicular homogenate superoxide dismutase and malondialdehyde were assessed. Furthermore, testicular tissue relative toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and myeloid differentiation factor 88 (MYD88) expressions were quantitatively measured using polymerase chain reaction. Histopathological and immunohistochemical studies were also conducted. The results revealed that treatment with celastrol significantly reduced TLR4, MyD88, and NF-κB expressions, and the levels of inflammatory mediators such as tumor necrosis factor-α and IL-1β in the testicular tissue of treated rats. These findings suggest that celastrol has the potential to be effective in the treatment of diabetes-induced testicular injury by inhibiting testicular inflammation, apoptosis, and oxidative stress.NEW & NOTEWORTHY Celastrol inhibits the production of proinflammatory cytokines in the testicular tissue by specifically targeting the TLR4/MyD88/NF-κB signaling cascade pathways. This indicates that celastrol may serve as a promising new therapeutic target for treating diabetic reproductive dysfunction.

Gut microbiota impacts host homeostasis and diseases. Chronic plus binge ethanol consumption has been linked to increased injuries than chronic or binge ethanol intake alone. We hypothesized that distinct shapes in gut microbiota composition are induced by chronic, binge, and the association of these treatments, thereby affecting host functions and contributing to sex-based differences in alcohol use disorders. Male and female C57BL/6J mice were submitted to chronic, binge, or chronic plus binge ethanol feeding. DNA was extracted from fecal microbiota, followed by analysis of the V3-V4 region of the 16S rRNA gene and sequencing on an Illumina platform. Gut microbiome analysis was performed using QIIME v2022.2.0. Functional profiling of the gut microbiome was performed using PICRUSt2. Ethanol differentially affected the gut microbiota of female and male mice. Decreased α diversity was observed in male and female mice from the chronic plus binge and chronic groups, respectively. The genera Faecalibaculum, Lachnospiraceae, and Alistipes were identified as major potential biomarkers for gut dysbiosis induced by ethanol consumption. In addition, ethanol-induced gut dysbiosis altered several metabolic pathways. Ethanol consumption modifies the mouse gut microbiome in a drinking pattern- and sex-dependent manner, potentially leading to different susceptibility to ethanol-related diseases. Chronic plus binge ethanol intake induces a more pronounced gut dysbiosis in male mice. Conversely, chronic ethanol is linked to a greater degree of gut dysbiosis in female mice. The changed gut microbiome may be potentially targeted to prevent, mitigate, or treat alcohol use disorders.NEW & NOTEWORTHY Ethanol alters the mouse gut microbiome in a drinking pattern- and sex-dependent manner. Chronic plus binge ethanol intake induces a more severe gut dysbiosis in male mice, whereas chronic ethanol consumption appears to be a more potent inductor of gut dysbiosis in female mice. Ethanol-induced gut dysbiosis alters several pathways linked to metabolism, genetic and environmental information processing, cellular processes, organism systems, and neurological human diseases.

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 threefold. 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 (SCFAs) compared with controls in pregnancy. Fecal samples were used for Illumina sequencing of 16S v4 rRNA amplicons. Microbial community composition of the pregnant BPH/5 mice compared with C57 controls was different using permutational multivariate analysis of variance (PERMANOVA) with Bray-Curtis dissimilarity. Alpha diversity was increased in pregnant BPH/5 dams compared with controls. Alistipes and Helicobacter were increased, whereas Bacteroides, Lactobacillus, Parasutterella, and Parabacteroides were decreased compared with controls. Fecal SCFAs were not different between groups, but BPH/5 serum acetic and butyric acids were decreased, whereas isobutyric and isovaleric acids 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.NEW & NOTEWORTHY This is the first time the pregnant fecal microbiome has been identified in the BPH/5 spontaneous mouse model of superimposed PE. Community composition changed with the onset of pregnancy in this model. BPH/5 showed an altered colonic signaling with decreased GPR41 expression, suggesting that gut dysbiosis may link SCFA signaling to the PE phenotype. This data highlights the importance of the maternal obesogenic gut microbiome in pregnancy.

Pyruvate carboxylase (PC) catalyzes the formation of oxaloacetate, a TCA cycle intermediate and gluconeogenic substrate. Altering saturated to unsaturated fatty acid ratio alters PC expression, suggesting a central role in mediating carbon flow through metabolic pathways. Herein, we describe changes in metabolic flux of TCA cycle intermediates and proteome in Madin-Darby bovine kidney (MDBK) cells with PC expression knocked-down (PC-KD), overexpressed (PC-OE), unaltered using a Scramble control, or cells pretreated for 21 h with vehicle control bovine serum albumin (BSA) or different ratios of palmitic acid (P) and α-linolenic acid (L) ranging from 1 mM P:0 mM L (1P:0L) to 0P:1L. All cells were collected for proteome analysis and to measure [U-¹³C] pyruvate flux or oxidation of [1-¹⁴C] palmitic acid and [U-¹⁴C] lactate. Compared with Scramble, ¹³C enrichment of all TCA cycle intermediates was greater in PC-OE, but all were reduced in PC-KD except succinate. Proteins greater in abundance in both cell lines included solute transporters, propionyl CoA carboxylase, and fatty acid binding protein 3. Relative to BSA, 1P:0L increased cell death and increased ¹³C flux to citrate but decreased enrichment of succinate. Abundance of citrate synthase, aconitase, glutamine aminotransferases, and succinyl CoA synthetases was greater in 1P:0L, but not different in other pretreatments. Results indicate preferential utilization of pyruvate and amino acids by 1P:0L cells whereas 0P:1L treated cells show preference for α-linolenic acid metabolism. PC regulates metabolic flux, C18:3n - 3 cis prevents lipotoxicity, and both alterations in PC and the addition of C18:3n - 3 cis promote oxidation of fatty acids.NEW & NOTEWORTHY PC overexpression increases the capacity for fatty acid oxidation, whereas PC knockdown requires extracellular amino acids to support TCA cycle intermediates. Cells incubated in palmitic acid demonstrated dependency of pyruvate and amino acids as substrates for the TCA cycle. Exposure to α-linolenic acid reduces the dependency of pyruvate as a substrate likely because carbon from α-linolenic acid can be used to supply TCA cycle intermediates whereas palmitic acid carbon is not used.

Guillain-Barré syndrome (GBS) and cardiovascular diseases (CVDs) have been observed to have a potential association, with GBS potentially leading to cardiovascular complications. However, these observational studies may be influenced by confounding factors. This study aimed to assess the causal relationship between GBS and CVDs, including heart failure (HF), atrial fibrillation (AF), and coronary artery disease (CAD), using a two-sample bidirectional Mendelian randomization (MR) analysis. We analyzed four datasets from the UK Biobank, selecting only datasets of European origin according to predetermined criteria to avoid population stratification bias. Datasets for GBS and CVDs were retrieved from the UK Biobank and analyzed using selected instrumental variables (IVs) related to genetic variations. Sensitivity tests, including heterogeneity and horizontal pleiotropy tests, were conducted to ensure the reliability of the selected IVs. The analysis results were then visualized to illustrate the causal relationships. The study identified genetic variants as IVs for both GBS and CVDs. MR analysis revealed a significant causal effect of GBS on the increased risk of HF [inverse-variance weighted (IVW), P < 0.05], but no significant causal relationship was found between GBS and AF or CAD. Similarly, no causal effect of CVDs on the occurrence of GBS was observed. Sensitivity analyses indicated no significant heterogeneity or horizontal pleiotropy, supporting the robustness of the results. These findings underscore the importance of considering cardiovascular complications, particularly HF, in the clinical management of patients with GBS in European populations.NEW & NOTEWORTHY This study utilizes bidirectional Mendelian randomization to analyze the causal relationships between Guillain-Barré syndrome (GBS) and cardiovascular diseases (CVDs). It uniquely demonstrates a significant causal link from GBS to an increased risk of heart failure (HF), without similar effects on atrial fibrillation (AF) or coronary artery disease (CAD). No reverse causality from CVDs to GBS was found, highlighting the need for targeted cardiovascular management in patients with GBS.

This study investigates the molecular responses to heatstroke in young and old patients by comparing whole-genome transcriptomes between age groups. We analyzed transcriptomic profiles from patients categorized into two age-defined cohorts: young (mean age = 44.9 ± 6 yr) and old (mean age = 66.1 ± 4 yr). Control subjects, exposed to similar environmental heat conditions but without developing heatstroke, were also included in the analysis to provide a baseline for comparison. Despite uniform heatstroke severity at admission, as indicated by core body temperature, consciousness level, and organ damage markers, notable gene expression differences emerged. Old patients showed 37% fewer differentially expressed genes compared with young patients at admission, with a shift toward gene upregulation, deviating from the usual downregulation seen in heat stress responses. Both age groups exhibited increased heat shock protein gene expression, activated the heat stress, and unfolded protein responses indicating comparable proteotoxic stress. Nonetheless, age-specific differences were evident in critical regulatory pathways like Sirtuin, mTOR, and p53 signaling, along with key pathways related to proteostasis, energy metabolism, oxidative stress, and immune responses. Following cooling, older adults exhibited a decline in the heat stress response and a cessation of the unfolded protein response, in contrast to the sustained responses seen in younger individuals. This pattern suggests an age-related adaptability or a diminished protective response capacity with aging. These findings provide insights into the biological mechanisms that may contribute to age-specific vulnerabilities to heat.NEW & NOTEWORTHY Our study reveals distinct molecular responses to heatstroke across age groups, with older adults showing fewer differentially expressed genes and an atypical pattern of gene upregulation, contrasting with the downregulation in usual heat stress responses. It also uncovers a reduced heat stress response and an abbreviated unfolded protein response in older adults, likely impairing their cellular repair mechanisms. This contributes to increased vulnerability during severe heat waves, underscoring the urgent need for age-specific interventions.

The regulation of oxygen homeostasis is critical in physiology and disease pathogenesis. High-altitude environment or hypoxia (lack of oxygen) can lead to adverse health conditions such as high-altitude pulmonary edema (HAPE) despite initial adaptive physiological responses. Studying genetic, hematological and biochemical, and the physiological outcomes of hypoxia together could yield a comprehensive understanding and potentially uncover valuable biomarkers for predicting responses. To this end, healthy individuals (n = 51) were recruited and exposed to graded normobaric hypoxia. Physiological parameters such as heart rate (HR), heart rate variability (HRV), oxygen saturation (Spo₂), and blood pressure (BP) were constantly monitored, and a blood sample was collected before and after the hypoxia exposure for the hematological and gene-expression profiles. HR was elevated, and Spo₂ and HRV were significantly reduced in a fraction of inspired oxygen ([Formula: see text])-dependent manner. After exposure to hypoxia, there was a minimal decrease in HCT, red blood cell distribution width (RDW)-coefficient of variation (CV), mean platelet volume (MPV), platelet distribution width, plateletcrit, eosinophils, lymphocytes, and HDL cholesterol. Additionally, there was a marginal increase observed in neutrophils. The effect of hypoxia was further assessed at the genome-wide expression level in a subset of individuals. Eighty-two genes significantly differed after hypoxia exposure, with 46 upregulated genes and 36 downregulated genes (P ≤ 0.05 and log₂-fold change greater than ±0.5). We also conducted an integrative analysis of global gene expression profiles linked with physiological parameters, and we uncovered numerous reliable gene signatures associated with BP, Spo₂, HR, and HRV in response to graded normobaric hypoxia.NEW & NOTEWORTHY Our study delves into the multifaceted response to hypoxia, integrating gene expression and hematological, biochemical, and physiological assessments. Hypoxia, crucial in both physiology and pathology, prompts varied responses, necessitating a thorough systemic understanding. Examining healthy subjects exposed to graded normobaric hypoxia, we observed significant shifts in heart rate, oxygen saturation, and heart rate variability. Moreover, genomic analysis unveiled distinct gene signatures associated with physiological parameters, offering insights into molecular perturbations and adaptations to oxygen deprivation.

We examined the effects of a 20-wk exercise intervention on whole blood genome-wide DNA methylation signature and its association with the exercise-induced changes in gene expression profiles in boys and girls with overweight/obesity (OW/OB). Twenty-three children (10.05 ± 1.39 yr, 56% girls) with OW/OB were randomized to either a 20-wk exercise intervention [exercise group (EG); n = 10; 4 boys/6 girls] or to usual lifestyle [control group (CG); n = 13; 6 boys/7 girls]. Whole blood genome-wide methylome (CpG sites) analysis using Infinium Methylation EPIC array and transcriptome analysis using RNA-seq (STRT2 protocol) were performed. Exercise-induced modifications in DNA methylation at 485 and 386 CpGs sites in boys and girls, respectively. These CpG sites are mapped to loci enriched in distinct gene pathways related to metabolic diseases, fatty acid metabolism, and immune function. In boys, changes in the DNA methylation of 87 CpG sites (18% of the 485 CpGs sites altered by exercise) were associated with changes in the gene expression levels of 51 genes also regulated by exercise. Among girls, changes in DNA methylation at 46 CpG sites (12% of the initial 386 significant CpGs) were associated with changes in the expression levels of 30 exercise-affected genes. Genes affected by exercise that were associated with DNA methylation are related to obesity, metabolic syndrome, and inflammation. Multiomics analysis of whole blood samples from children with OW/OB suggests that gene expression response to exercise may be modulated by DNA methylation and involve gene pathways related to metabolism and immune functions.NEW & NOTEWORTHY This study pioneers the exploration into the effects of exercise on whole blood genome-wide DNA methylation patterns and its association with changes in transcriptome profiles in children with overweight/obesity. Exercise potentially impacts molecular pathways involved in metabolism and immune functions in children with overweight/obesity (sex-specific responses) through the modification of epigenetic and transcriptomic profiles. Our preliminary results provide initial steps to understand better the molecular mechanisms underlying cardiometabolic benefits of exercise in children with overweight/obesity.

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.