Bioinformation and deep-learning based model reveals norepinephrine inhibiting PRDX1 aggravates atherosclerosis
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ABSTRACT:
PROVIDER: PRJNA1186652 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31363300_1.fastq.gz | Fastqsanger.gz | |||
| SRR31363300_2.fastq.gz | Fastqsanger.gz | |||
| SRR31363301_1.fastq.gz | Fastqsanger.gz | |||
| SRR31363301_2.fastq.gz | Fastqsanger.gz | |||
| SRR31363302_1.fastq.gz | Fastqsanger.gz |
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Project description:The regulation of metabolites comprises the fundamental biological processes of human. More new phenotypes of classic metabolites were revealed, while the devolution of functional targets and mechanisms of them still have many gaps due to diversity in structures and functions. Here, we report a bioinformation and attention mechanism based deep learning model leveraging abundant bioinformation of metabolites for functional target prediction of specific phenotypes. Taking advantage of this model, the potential target database of 3,382 common human metabolites were resourced publicly. Norepinephrine was identified as a selective peroxidase inhibitor of peroxiredoxin 1 (PRDX1) for atherosclerosis aggravation in model validation experiments. Salvianolic acid A (SAA) was screened out as PRDX1 exogenous stabilization compound for rescuing norepinephrine’s aggravation effects in vivo. Besides, bulk RNA-Sequencing analysis indicated norepinephrine aggravates atherosclerosis through activating transcriptional activity of SREBP2 in a ROS dependent manner. Overall, our research provides a new computational regime for metabolites target identification besides experimental chemical proteomics and PRDX1 stabilization was validated a potential druggable target for cardiovascular diseases intervention.
2025-05-07 | GSE282003 | GEO
Project description:Peroxiredoxin 1 (PRDX1), traditionally known as an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (SAA3) and aconitate decarboxylase 1 (ACOD1), known inhibitors of osteoclast differentiation. Mechanistically, PRDX1-TLR4 signaling activates p65, promoting SAA3 and ACOD1 expression while inhibiting NFATc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from NFATc1 to SAA3/ACOD1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that monomeric variants of PRDX1 with enhanced TLR4 binding exhibit potent inhibition of osteoclast differentiation. Our findings elucidate the inhibitory role of PRDX1-TLR4 axis in osteoclastogenesis, providing insights into therapeutic strategies for bone-related disorders.
2024-11-12 | GSE267039 | GEO
Project description:Macrophages respond to environmental cues in a plastic manner and play a crucial role in host defense, inflammation, and tissue homeostasis. Macrophage activation undergoes metabolic and transcriptomic reprogramming to adapt and tailor an appropriate response, regulating inflammation. Reactive oxygen species (ROS) have been shown to play a pivotal role in macrophage activation. Nevertheless, the detailed molecular mechanism of how initial redox signals direct macrophage activation is not fully elucidated. Here, we uncover an unconventional role for histone acetyltransferase MOF (also known as KAT8) in regulating LPS-induced macrophage activation via modulating the acetylation of peroxiredoxin 1 (PRDX1), an H2O2 scavenger. We demonstrate that PRDX1 is a novel substrate of MOF and identify the major MOF-mediated acetylation site at lysine 197. K197 acetylation of PRDX1 (K197ac PRDX1) is dynamic and reversely regulated by HDAC6 or SIRT2. We observe that this acetylation is readily diminished in the immediate response to LPS. We demonstrate that K197ac PRDX1 fine-tunes its peroxidase activity, leading to the modulation of intracellular ROS levels in early response to LPS stimulation. Moreover, K197ac PRDX1 specifically regulates ERK1/2 phosphorylation, thereby modulating glycolytic metabolism in inflammatory macrophages. Consequently, K197ac PRDX1 tunes the expression and production of the proinflammatory cytokine, IL-6. Taken together, our findings describe a novel signaling module, MOF-PRDX1-ERK, which regulates LPS-induced macrophage activation at the metabolic and transcriptional levels.
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Project description:We overexpressed Prdx1 in HeLa cells to study Prdx1-regulated genes using RNA-seq technology, followed by bioinformatic analysis of target genes of Prdx1-regulated.
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Project description:Objective: Peroxiredoxin 1 (PRDX1) is a peroxidase and guards against oxidative stress by scavenging intracellular peroxides, whereas it also has been shown to stimulate inflammatory response by functioning as a chaperone protein. The potential in vivo link between PRDX1’s peroxidase activity and its pro-inflammatory activity remains elusive. Methods: We generated peroxidase-dead PRDX1 variant mice by mutating its peroxidatic cysteine at 52 (Cys52) to serine, here referred to as PRDX1Cys52Ser. Trx-TrxR-NADPH coupled activity assay was applied to evaluate the peroxidase activity of global PRDX in PRDX1Cys52Ser variant mice. PRDX1Cys52Ser mice and their wild-type littermates were subjected to western diet or methionine and choline deficient diet feeding. NASH phenotypes were assessed through different analyses including physiological measurements, immunohistochemical staining, and quantitative PCR (qPCR). RNA sequencing, qPCR and western blotting were used to reveal and validate any changes in the signaling pathways responsible for the altered NASH phenotypes observed between WT and PRDX1Cys52Ser variant mice. Results: PRDX1Cys52Ser variant mice showed impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, PRDX1 Cys52Ser variant suppressed NF-κB signaling and STAT1 signaling pathways that are known to promote inflammation and NASH. Conclusion: The peroxidatic Cys52 of PRDX1 is required for its pro-inflammatory activity in vivo. This study further suggests that PRDX1 plays dual but opposing roles in NASH
2023-08-11 | GSE240198 | GEO
Project description:Macrophage activation undergoes signal-transduced changes in protein modifications, enabling the coordinated control of transcription and cellular metabolism. However, the role of protein acetylation in signal transduction during macrophage activation remains obscure. Here, we demonstrate that peroxiredoxin 1 (PRDX1), a key regulator of redox signaling, is a novel substrate of the MOF lysine acetyltransferase. Employing a gel based in vitro HAT assay followed by LC-MS, we mapped PRDX1 lysine acetylation sites. PRDX1 K197ac was identified as the most prominent MOF acetylation site. We show that MOF-dependent acetylation of lysine 197 of PRDX1 (PRDX1 K197ac) enhances its peroxidase activity. We find that PRDX1 K197ac is an inflammatory signal-regulated modification, which decreases in mouse macrophages stimulated with bacterial lipopolysaccharides (LPS) but not with IL-4 or IL-10. LPS-induced decrease of PRDX1 K197ac elevates cellular ROS accumulation and augments phosphorylation of ERK1/2 but not p38 or AKT phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Collectively, our findings uncover a regulatory role for redox protein acetylation during inflammatory macrophage activation through modulating signal transduction and coordinating metabolic and transcriptional programs.
2024-10-25 | PXD046284 | Pride
Project description:We overexpressed Prdx1 in HeLa cells to study Prdx1-regulated genes using RNA-seq technology, followed by bioinformatic analysis of target genes of Prdx1-regulated.In order to find the precise regulatory mechanisms,we performed iRIP-seq experiment in HeLa cell.
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Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.
2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress
Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.
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