Physiological genomics最新文献

Extracellular vesicles (EVs) are small, membrane-bound vesicles that transfer biological content through the extracellular environment. The role of EVs in energy metabolism has primarily focused on EV proteins and microRNAs, with less attention on the metabolic content of EVs. This exploratory study assessed changes in the EV metabolome in response to an arduous, 16-day military training exercise. Forty male soldiers (21 ± 2 yr, 24.8 ± 2.7 kg/m²) provided blood from which circulating EVs were isolated and completed assessments of body composition and lower body power on days 1 (PRE) and 16 (POST) of a mountain training exercise (MTX). Total daily energy expenditure during the MTX was 4,187 ± 519 kcal·day^-1. Fat mass (POST-PRE [95% confidence interval]: -0.9 [-1.3, -0.6] kg), lean body mass (-1.6 [-2.0, -1.2] kg), body fat percentage (-0.7 [-1.1, -0.3]%), and lower body power (-133 [-204, -63] W) decreased from PRE to POST (P < 0.05). Global metabolite profiling identified 81 metabolites from lipid (81%), energy (5%), cofactor and vitamin (5%), xenobiotic (4%), carbohydrate (2%), amino acid (1%), and nucleotide (1%) pathways in serum-derived EVs. After adjusting for EV concentration, 11 metabolites were different from PRE to POST (P < 0.05, Q < 0.20), with the largest increases in the oxidative stress-associated metabolites 5-oxoproline and benzoate. Changes in lean body mass were positively associated with changes in the energy metabolites citrate (ρ = 0.361, P = 0.022) and phosphate (ρ = 0.369, P = 0.019). Findings suggest that EV metabolites change in response to physiological stress and reflect increased oxidative stress, energy metabolism, and fatty acid metabolism, which may provide early indicators of stress adaptations relevant for optimizing training and sustaining military performance.NEW & NOTEWORTHY EV metabolites change in response to periods of increased metabolic demand, reflecting increased oxidative stress, energy metabolism, and fatty acid metabolism, and may be associated with changes in lean body mass. This exploratory study adds to the limited existing literature by highlighting the potential of EV-derived metabolites to provide insight into metabolic responses and their contribution to stress-induced metabolic adaptations.

The human microbiome is emerging as a key regulator of cancer biology, modulating tumor development, immune dynamics, and therapeutic responses across diverse malignancies. In this review, recent insights are synthesized regarding how microbial communities (bacterial, fungal, and viral) shape oncogenic signaling, immune checkpoint blockade (ICB) efficacy, and metabolic reprogramming in lung, pancreatic, colorectal, breast, cervical, melanoma, and gastric cancers. Mechanistic links between microbial metabolites, intratumoral colonization, and host immune phenotypes are highlighted proposing that the microbiome constitutes a programmable axis within the tumor immune-metabolic ecosystem. Drawing on multiomics integration and translational studies, a shift from associative profiling toward causal, spatially resolved, and intervention-ready frameworks is proposed. This perspective positions the microbiome not as a passive bystander, but as a coevolving participant in tumor progression and treatment response, with the potential to reshape diagnostics, prognostics, and therapeutic strategies in precision oncology.

We describe global microRNA (miRNA) changes in the central autonomic control circuits during the development of neurogenic hypertension. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY), we analyzed the dynamic miRNA expression changes in three brainstem regions-the nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla-as a time series beginning at 8 wk of age before hypertension onset through to extended chronic hypertension. Our analysis yielded nine miRNAs that were significantly differentially regulated in all three regions between SHR and WKY over time. We collated computationally predicted gene targets of these nine miRNAs in pathways related to neuronal plasticity and autonomic regulation to construct a putative miRNA-target gene network involved in the development of neurogenic hypertension. We analyzed the dynamic correlations between the miRNAs and their putative targets to identify the regulatory interactions shifting between WKY and SHR. Comparing the results with previously published data in male SHR and WKY identified miRNA network dynamics specific to female SHR during hypertension development. Collectively, our results point to distinct rewiring of the miRNA regulatory networks governing angiotensin signaling and homeostasis, neuronal plasticity, and inflammatory processes contributing to the development of hypertension in female SHR.NEW & NOTEWORTHY Hypertension is the primary risk factor for cardiovascular complications and stroke. The microRNA expression changes in the central nervous system circuits driving hypertension development are understudied. Here, we show that microRNA-mediated regulatory networks are dynamically rewired during the development of high blood pressure phenotype by targeting key signaling pathways, neuronal plasticity, and inflammatory processes in a female rat model of human essential hypertension.

Excess glucocorticoids induce skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, yet the transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to define the glucocorticoid-responsive transcriptome in young and aged muscle following both acute and more prolonged glucocorticoid treatment. Young (4-mo-old) or aged (24-mo-old) male mice were administered either an acute injection of dexamethasone (DEX) or vehicle or daily DEX or vehicle injections for 7 days. Muscles were harvested 6.5 h after the final or only injection. The tibialis anterior (TA) was selected for RNA sequencing analysis as DEX treatment lowered TA mass specifically in aged males. In silico analyses identified enriched pathways and transcription factors predicted to regulate DEX-sensitive genes. Acute DEX altered similar numbers of genes in young (950) versus aged males (913), although aged males had greater magnitudes of fold change. After 7 days of DEX treatment, aged muscle exhibited more DEGs compared with acute exposure (1,196 vs. 913), whereas young muscle exhibited fewer DEGs than after acute exposure (599 vs. 950). In aged males, glucocorticoid-sensitive genes were consistently enriched for growth regulatory processes across both time points, a pattern that was not evident in young males. Despite those age-associated transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding into how aging modifies the transcriptional response to excess glucocorticoids in skeletal muscle.NEW & NOTEWORTHY Glucocorticoids promote mass loss in certain muscles with advanced age but not at younger ages. In a muscle whose mass is lost in response to elevated glucocorticoids only in advanced age in males, we show that glucocorticoids initiate a unique and exaggerated transcriptional profile after both acute exposure to the hormone and after prolonged treatment that is consistent with muscle atrophy. These findings expand our understanding of the effect primary aging has on glucocorticoid-induced atrophy in males.

In a randomized, dose-response trial, we used molecular and phenomic profiling to compare responses with traditional moderate-intensity endurance and resistance training (TRAD) versus high-intensity tactical training (HITT) that encompassed explosive whole-body interval training and high-intensity resistance training. Ninety-four participants (18-27 yr) completed 12 wk of TRAD or HITT followed by 4 wk of detraining. Although similar performance and body composition improvements were observed in response to HITT and TRAD, some dose-dependent differences were observed for: 1) ex vivo muscle tissue changes in myofiber size, capillarization, satellite cell frequency, and mitochondrial function and 2) differential gene expression (DGE) of muscle and serum exosomal miRNAs (miRs). However, these dose-dependent ex vivo muscle adaptations were overshadowed by wide-ranging interindividual response heterogeneity (IRH). We therefore explored response heterogeneity by first establishing minimum clinically important difference (MCID) scores to classify each participant based on MCIDs for functional muscle quality (fMQ) and cardiorespiratory fitness (CRF) and then modeling all data based on MCID classification. Using higher-order singular value decomposition (HOSVD), we established multidimensional biocircuitry linked to interindividual response heterogeneity that identified the most influential features across lifestyle, body composition, performance, ex vivo muscle tissue, and miRNA mapping domains. Via cross-comparison of MCID-linked miRs identified via DGE and HOSVD, nine miRs emerged as robust features of training adaptability, providing new insights into the integrated biocircuitry driving IRH.NEW & NOTEWORTHY We examined in vivo and ex vivo adaptations to traditional moderate-intensity endurance and resistance training (TRAD) versus high-intensity tactical training (HITT; explosive whole-body interval training and high-intensity resistance training). TRAD and HITT improved physiological performance and body composition, and induced ex vivo muscle adaptations, with remarkable interindividual response heterogeneity (IRH) in improvements. We leveraged multidimensional modeling to identify interindividual response heterogeneity biocircuitry that integrates deep phenotyping and miR transcriptomics (serum exosomes and skeletal muscle).

The homocysteine-methionine cycle is involved in the critical human cellular functions, such as proliferation and epigenetic regulation. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolites are synthesized in this metabolic cycle, and their levels are finely regulated to ensure proper functioning of key enzymes controlling the cellular growth and differentiation. SAM and SAH levels were found altered in the plasma of subjects with trisomy 21 (T21), but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. SAM and SAH quantifications were performed in urine samples of 58 subjects with T21 and 48 controls (N) through liquid chromatography with tandem mass spectrometry. SAH resulted slightly more excreted in urine of subjects with T21 (T21/N mean ratio = 1.16, P value = 0.021), although no difference was found in SAM levels. Metabolite urine levels were compared with those previously observed in plasma, in which higher amounts of SAM and SAH were found. In addition, we examined if an association between the levels of SAM and SAH in T21 and the expression levels of genes involved in their production/utilization exists using the transcriptome map of blood samples of T21 and N subjects. The analysis showed overexpression of 44 methyltransferase genes responsible for the conversion of SAM to SAH, of two genes involved in SAH utilization, adenosylhomocysteinase-like 1, adenosylhomocysteinase-like 2, and of one gene involved in SAM utilization, adenosylmethionine decarboxylase 1. These data support the hypothesis that T21 genetic imbalance is responsible for SAM and SAH excess, which may be involved in the T21 phenotypic features.NEW & NOTEWORTHY S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are critical metabolites for the fundamental cellular functions, such as proliferation and epigenetic regulation. For the first time, their levels were quantified in the urine of subjects with trisomy 21 (T21) and compared with euploid controls (N). These dosages were compared with their plasma levels, and the expression of genes involved in SAM and SAH production/utilization was further investigated in the differential blood transcriptome map of T21 versus N samples.

Immunotherapy is often thwarted by the innate ability of cancer to evade immune detection. Lysine-specific demethylase 1A (KDM1A/LSD1) has been implicated in the development of various cancers, yet its specific influence on immune evasion in lung cancer and the mechanisms at play are not well defined in the current scientific discourse. Through bioinformatics, we probed the expression patterns of KDM1A and fibrinogen-like protein 1 (FGL1) in lung cancer continues with cellular validation. Lactate dehydrogenase (LDH) and enzyme-linked immunosorbent assay were used for the assessment of CD8⁺ T-cell responses to tumor cells. To uncover the molecular underpinnings, we use a suite of techniques including bioinformatics, luciferase reporter assays, chromatin immunoprecipitation, and qRT-PCR. Bioinformatics pointed to a positive relationship between KDM1A and FGL1, with both markers highly expressed in lung cancer. KDM1A was found to dampen the cytotoxicity of CD8⁺ T cells toward lung cancer cells through its transcriptional activation of FGL1. Our work reveals the role of KDM1A in lung cancer immune evasion by transcriptionally activating FGL1, which could inform the design of new immunotherapies.NEW & NOTEWORTHY KDM1A and FGL1 exhibit high expression in lung cancer. KDM1A expression is associated with immune evasion in tumors. KDM1A regulates FGL1, thereby influencing the antitumor activity of CD8⁺ T cells in lung cancer.