Energy metabolism in health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 18, 2025

Language: Английский

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Worm Perturb-Seq: massively parallel whole-animal RNAi and RNA-seq

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

The transcriptome provides a highly informative molecular phenotype to connect genotype and is most frequently measured by RNA-sequencing (RNA-seq). Therefore, an ultimate goal perturb every gene measure changes in the transcriptome. However, this remains challenging, especially intact organisms due different experimental computational challenges. Here, we present ‘Worm Perturb-Seq (WPS)’, which high-resolution RNA-seq profiles for hundreds of replicate perturbations at time living animal. WPS introduces multiple advances that combine strengths bulk single cell RNA-seq, further analytical framework, EmpirDE, leverages unique power large datasets. EmpirDE identifies differentially expressed genes (DEGs) using gene-specific empirical null distributions, rather than control conditions alone, thereby systematically removing technical biases improving statistical rigor. We applied 103 Caenhorhabditis elegans nuclear hormone receptors (NHRs) delineate Gene Regulatory Network (GRN) found GRN presents striking ‘pairwise modularity’ where pairs NHRs regulate shared target genes. envision should be useful not only C. , but will broadly applicable other models, including human cells.

Language: Английский

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Preclinical models of prostate cancer — modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo

Nature Reviews Urology, Journal Year: 2023, Volume and Issue: 20(8), P. 480 - 493

Published: Feb. 14, 2023

Language: Английский

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Mitotic bookmarking redundancy by nuclear receptors in pluripotent cells

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(3), P. 513 - 522

Published: Jan. 9, 2024

Mitotic bookmarking transcription factors (TFs) are thought to mediate rapid and accurate reactivation after mitotic gene silencing. However, the loss of individual TFs often leads deregulation only a small proportion their targets, raising doubts on biological significance importance function. Here we used targeted proteomics TF ESRRB, an orphan nuclear receptor, discover large redundancy in binding among members protein super-family receptors. Focusing receptor NR5A2, which together with ESRRB is essential maintaining pluripotency mouse embryonic stem cells, demonstrate conjoint activity both promoters enhancers fraction active genes, particularly those most efficiently reactivated G1. Upon fast simultaneous degradation during exit, hundreds targets ESRRB/NR5A2, including key players network, display attenuated transcriptional reactivation. We propose that TFs, especially receptors, confers robustness reestablishment regulatory networks mitosis.

Language: Английский

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The effect of exercise and physical activity on skeletal muscle epigenetics and metabolic adaptations

European Journal of Applied Physiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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Systems-level design principles of metabolic rewiring in an animal

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Language: Английский

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NR4A1 Acts as a Novel Regulator of Platelet Activation and Thrombus Formation

Circulation Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

BACKGROUND: Mounting evidence indicates that nuclear receptors play a critical regulatory role in platelet pathophysiology and thrombotic disorders. Although NR4A (the receptor subfamily 4 group A) plays an important cardiovascular pathophysiology, the expression profile biological function of member 1 (NR4A1) platelets have never been reported. METHODS: We evaluated functions underlying mechanisms NR4A1 activation thrombus formation using platelet-specific NR4A1-deficient mice NR4A1-specific agonists. Using hyperlipidemic mouse model from patients with hypercholesterolemia, we explored influence hypercholesterolemia on effects agonists hyperreactivity induced by hypercholesterolemia. RESULTS: was expressed both human platelets. Platelet-specific deletion accelerated FeCl 3 -induced carotid arterial occlusive formation, enhanced collagen/epinephrine-induced pulmonary thromboembolism, exacerbated microvascular microthrombi obstruction infarct expansion acute myocardial infarction model. exhibited agonist-induced aggregation responses, integrin α IIb β activation, dense granule release, α-granule spreading, clot retraction. Consistently, pharmacological specific decreased Mechanistically, CAP1 (adenylyl cyclase-associated protein 1) identified as direct downstream interacting NR4A1. cAMP levels phosphorylation VASP (vasodilator-stimulated phosphoprotein), while increased Importantly, upregulated setting which derived its upregulation megakaryocytes reactive oxygen species-dependent manner. Platelets hypercholesterolemic hyperreactivity. However, significantly inhibited to healthy control CONCLUSIONS: provide first negatively regulates formation. may serve novel therapeutic target for managing thrombosis-based diseases, especially

Language: Английский

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A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR)

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 154, P. 113577 - 113577

Published: Aug. 19, 2022

Nonalcoholic fatty liver disease (NAFLD) is primarily caused by abnormal lipid metabolism and the accumulation of triglycerides in liver. NAFLD also associated with hepatic steatosis nutritional energy imbalances a chronic number factors. Nuclear receptors play key role balancing nutrient metabolism, peroxisome proliferator-activated receptor alpha (PPARα) farnesoid X (FXR) regulate genes, controlling hepatocyte utilization regulating bile acid (BA) synthesis transport. They an important BA homeostasis. At present, PPARα FXR are most promising targets for treatment among nuclear receptors. This review focuses on crosstalk mechanisms transcriptional regulation pathogenesis summarizes drugs clinical trials, laying theoretical foundation targeted development novel therapeutic strategies.

Language: Английский

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Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Journal of Endocrinology, Journal Year: 2023, Volume and Issue: 257(1)

Published: Jan. 23, 2023

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target group insulin sensitizers called thiazolidinediones (TZDs) which regulate expression genes involved in glucose and metabolism well adipokines metabolic function other tissues. Non-alcoholic fatty liver disease (NAFLD) has high prevalence worldwide even higher patients with obesity resistance. TZD-mediated activation good treatment for NAFLD because TZDs have shown anti-fibrogenic anti-inflammatory effects vitro increase sensitivity peripheral tissues improves pathology. However, mechanistic studies mouse models suggest hepatocytes might reduce or limit therapeutic potential TZD against NAFLD. In this review, we briefly describe short history PPAR isoforms, relevance their different tissues, pathogenesis therapeutics We also discuss some evidence derived from be useful endocrinologists assess tissue-specific roles PPARs, complement reverse endocrinology approaches, understand direct role non-parenchymal cells.

Language: Английский

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Modulating glucocorticoid receptor actions in physiology and pathology: Insights from coregulators

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 251, P. 108531 - 108531

Published: Sept. 16, 2023

Glucocorticoids (GCs) are a class of steroid hormones that regulate key physiological processes such as metabolism, immune function, and stress responses. The effects GCs mediated by the glucocorticoid receptor (GR), ligand-dependent transcription factor activates or represses expression hundreds to thousands genes in tissue- state-specific manner. activity GR is modulated numerous coregulator proteins interact with response different stimuli assembling into multitude DNA-protein complexes facilitate integration these signals, helping communicate basal transcriptional machinery chromatin. Here, we provide brief overview molecular functions GR, discuss roles coregulators system, metabolic tissues central nervous system. We also present an analysis interactome cells tissues, which suggests tissue-specific utilization coregulators, despite widespread shared some them.

Language: Английский

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