Physiological genomics最新文献

Ischemia reperfusion (I/R) injury is an important initiating cause of chronic kidney disease and renal failure. Changes in proximal tubule (PT) morphology, including brush border loss, occur rapidly in response to ischemic stress and I/R injury. Vacuole membrane protein 1 (VMP1) is a compelling target for ischemia-associated renal damage, because it is a necessary regulator of autophagy and the genomic location of hypoxia-responsive microRNA miR-21 lies within an intronic region of the Vmp1 gene. Autophagy is reported to have protective and pathological effects on I/R injury. In this study we find that VMP1 is rapidly upregulated in renal cortex tissue in response to 15 and 30-minutes of ischemia. Intravenous delivery of Vmp1-targeting GapmeR or a scrambled GapmeR was performed on adult male Sprague Dawley rats for two days prior to either 30-minutes of renal ischemia, 30-minutes of ischemia followed by 24-hours of reperfusion (I/R), or corresponding control procedures. Autophagy markers and PT morphology were assessed in the renal cortex. Suppression of ischemia-induced upregulation of VMP1 attenuated PT brush border loss following 30-minutes of ischemia and 24-hours post-I/R. Our study reveals a novel and mechanistically important dissociation between VMP1 expression, miR-21-5p expression, autophagy markers, and I/R tubular injury in the renal cortex.

Preeclampsia is a pregnancy specific hypertensive disorder and is associated with an increased postpartum risk of cardiovascular morbidity for both women and their offspring. Previous studies have indicated that cord blood endothelial colony forming cells (ECFCs) are dysfunctional in preeclampsia. The specific mechanisms are not yet fully understood but dysregulation of alternative splicing has been proposed as one of the pathogenic pathways. In order to identify specific targets of alternative splicing in fetal ECFCs, we performed transcriptome-wide differential splicing analyses between cord blood ECFCs from preeclamptic (n=16) and normal pregnancies (n=13). Selected splicing events were validated using fragment length analysis and Sanger sequencing. In silico transcriptome-wide differential splicing analysis identified a significantly increased abundance of the CADM1 isoform ENST00000542447 in the preeclamptic cohort (p=0.002), which was confirmed by wet-lab validation. The deleted exon 8 harbours glycosylation sites known to mediate cell-cell adhesion. To investigate the functional impact of alternative splice variants, we induced an in vitro splice switch using antisense morpholino treatment and followed cellular effects using migration and angiogenesis assays in ECFCs from six normal pregnancies. The CADM1 exon 8 skipping converted the normal ECFCs to a preeclampsia-like state characterised by a decreased migration ability (panova=0.005) and decreased tubule length (panova=0.02). We propose aberrant splicing of CADM1 and the resulting changes in the adherence properties of ECFCs as a potential contributor to cardiovascular sequelae in the offspring of preeclamptic pregnancies.

Background: 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. Methods: 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. Results: Ethanol differentially affected the gut microbiota of female and male mice. Decreased alpha 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. Conclusion: 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.

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 to 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 addition of C18:3n-3 cis promote oxidation of fatty acids.

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.

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.

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.

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.

Decades of artificial selection have markedly enhanced egg production efficiency, yet the epigenetic underpinnings, notably DNA methylation dynamics in the gut, remain largely unexplored. Here, we investigate how breeds and developmental stages influence DNA methylation profiles in laying hens, and their potential relationship to laying performance and gut health. We compared two highly selected laying hen strains, Lohmann Brown-Classic (LB) and Lohmann LSL-Classic (LSL), which exhibited similar egg production but divergent physiological, metabolic, and immunological characteristics. Our sampling encompassed key developmental stages: the pullet stage (10 and 16 weeks old), peak production (24 and 30 weeks old), and later stage (60 weeks old) (n=99; 10 per group), allowing us to elucidate the temporal dynamics of epigenetic regulation. Our findings highlight a crucial window of epigenetic modulation during the pre-laying period, characterized by stage-specific methylation alterations and the involvement of predicted transcription factor motifs within methylated regions. This observation was consistent with the expression patterns of DNA methyltransferases (DNMTs), including DNMT1, DNMT3a, and DNMT3b. In addition, a higher methylation level was observed in specific loci or regions in the LSL compared to the LB strain. Notably, we uncover strain-specific differences in methylation levels, particularly pronounced in genomic regions associated with intestinal integrity, inflammation, and energy homeostasis. Our research contributes to the multidisciplinary framework of epigenetics and egg laying performance, offering valuable implications for poultry production and welfare.

Background: "Jiedutongluo Tiaoying Formula" (JDTLTYF) TCM prescriptions can effectively treat hyperthyroidism and effectively improve the condition of patients. Methods: The main active ingredients of JDTLTYF were collected from the TCMSP database and the target was predicted. Genes related to hyperthyroidism were identified using DisGeNET, GeneCards and OMIM databases. Protein-protein interaction (PPI) network and interaction network of "formula-herb-active ingredient-target genes" was constructed. Mass spectrometry was used to identify the components. The binding of key components to the target was verified by molecular docking and molecular dynamics (MD) simulations. A hyperthyroidism mouse model was established using levothyroxine sodium tablets, and the hormone and expression levels of inflammatory factorswere examined by ELISA and western blot. Results: The key genes of JDTLTYF in the treatment of hyperthyroidism were TNF and AKT1. The results of mass spectrometry also showed that quercetin was one of the main components. The results of molecular docking and MD simulation showed that the binding free energy between AKT1 and quercetin was the lowest and the binding was stable. In vivo experimental results showed that gastric lavage with JDTLTYF could target AKT1 and TNF-α, effectively alleviate the pathological features of hyperthyroidism in mice and reduce inflammation response. Conclusion: This study elucidated the key small molecule compounds and their action targets of JDTLTYF in the treatment of hyperthyroidism. It provides a direction for the development of new drugs for clinical hyperthyroidism.