Targeting c-Jun orchestrates heat stroke induced myocardial injury and reveals its biomarker potential
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PROVIDER: PRJNA1294902 | ENA |
REPOSITORIES: ENA
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Project description:These experiments aim to detect changes in the transcript (mRNA) of cardiac tissue when animals are exposed to high temperatures and heat stroke occurs due to the increase in environmental temperature. The research objectives include: 1) detecting changes in transcripts (mRNA) of heart tissue during heat stroke caused by elevated environmental temperatures; 2) Detecting transcripts that can serve as biomarkers for heat stroke induced myocardial injury.
2025-07-26 | GSE303366 | GEO
Project description:Sterile tissue injury after stroke causes lymphocyte contraction in lymphoid tissues and may decrease circulating IgA-levels. Intestinal Peyer’s patches (PP) harbor large numbers of IgA+ B cell precursors and plasma cells. Whether and how tissue injury triggers PP-B cell death, thereby mediating IgA-loss, is unknown. We found decreased circulating IgA levels in stroke and myocardial infarction patients. Experimental stroke and myocardial infarction in mice phenocopied the human situation. Decreased plasma and fecal IgA were accompanied by rapid and macroscopic shrinkage of PP caused by substantial losses of PP-resident IgA+ precursors and plasma cells in mice. Tissue injury induced neutrophil activation endowed with the release of toxic neutrophil extracellular traps (NETs). Antibody-mediated or genetically- induced neutrophil loss, digestion of NETs, or inhibition of their release by the Gasdermin D blockade completely prevented lymphocyte loss and PP shrinkage. We also identified NETs in the plasma of stroke and myocardial infarction patients. Hence, tissue injury induces systemic NET-release, which might be targeted to maintain immune homeostasis at mucosal barriers.
2024-02-28 | PXD044644 | Pride
Project description:Post-injury dysfunction of humoral immunity accounts for infections and poor outcome in cardiovascular diseases. Immunoglobulin A (IgA), the most abundant mucosal antibody is produced by plasma B cells in intestinal Peyer’s patches (PP) and lamina propria. Here, we show that stroke and myocardial ischemia (MI) patients had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid and macroscopic shrinkage of PP caused by substantial B cell loss. Stroke/MI triggered neutrophils to release neutrophil extracellular traps (NETs). Depletion of neutrophils, NET-degradation, or blockade of NET-release inhibited PP shrinkage and loss of B cells and IgA in stroke mice. Also, stroke and MI patients had higher amounts of circulating NETs, correlating with reduced IgA levels. Strikingly, stroke patients treated with DNase-I had reduced circulating NETs and stable IgA levels. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological IgA secretion and how this can be inhibited in patients.
2024-03-17 | GSE254410 | GEO
Project description:CircRNA as Predictive Biomarker of Penumbra in Acute Ischemic Stroke
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Project description:Despite recent advancement in sequencing technologies and large-scale drug screenings with hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient to guide cancer therapy. Therefore, novel types of diagnostic methods with alternative biomarkers are highly appreciated. To develop the novel methods, we hypothesized that sensitivity-specific changes in phosphorylations of signaling molecules could be useful as predictive biomarkers. Here, we aimed to develop predictive methods for cisplatin with a combination of such type of biomarker(s) and patient-derived tumor organoids (PDOs). We found that cisplatin sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h in response to cisplatin treatment. We also compared responses to cisplatin in 6 PDOs with therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Thus, our data implicates the feasibility of enhanced p-c-Jun by cisplatin treatment as a predictive biomarker for the efficacy.
2023-06-01 | GSE186142 | GEO
Project description:Neuroinflammation is a hallmark of ischemic stroke, which is a leading cause of death and longterm disability. Understanding the exact cellular signaling pathways that initiate and propagate neuroinflammation after stroke will be critical for developing immunomodulatory stroke therapies. In particular, the precise mechanisms of inflammatory signaling in the clinically relevant hyperacute period, hours after stroke, have not been elucidated. We used the RiboTag technique to obtain Astrocyte IP and microglia-derived mRNA transcripts in a hyperacute (4 hours) and acute (3 days) period after stroke, as these two cell types are key modulators of acute neuroinflammation. Microglia initiated a rapid response to stroke at 4 hours by adopting an inflammatory profile associated with the recruitment of immune cells. The hyperacute Astrocyte IP profile was marked by stress response genes and transcription factors, such as Fos and Jun, involved in pro-inflammatory pathways such as TNF-α. By 3 days, microglia shift to a proliferative state and Astrocyte IPs strengthen their inflammatory response. The Astrocyte IP pro-inflammatory response at 3 days is partially driven by the upregulation of the transcription factors C/EBPβ, Spi1, and Rel, which comprise 25% of upregulated transcription factor-target interactions. Surprisingly, few sex differences across all groups were observed. Expression and log2 fold data for all sequenced genes are available on a user-friendly website for researchers to examine gene changes and generate hypotheses for stroke targets. Taken together our data comprehensively describe the Astrocyte IP and microglia-specific translatome response in the hyperacute and acute period after stroke and identify pathways critical for initiating neuroinflammation.
2023-02-14 | GSE225110 | GEO
Project description:Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity. Four biological replicas of each of the four conditions: NO = not transduced with virus; NT = transduced with control lentiviruses containing a non-targeting shRNA sequence; KD = transduced with lentiviruses expressing PRR7-specific shRNAs; OE= transduced with lentiviruses to overexpress PRR7.
2014-10-25 | E-GEOD-62686 | biostudies-arrayexpress
Project description:To further dissect whether and how activated JUN reconfigures the chromatin landscape, we performed Chromatin Immunoprecipitation (ChIP)-seq analyses for H3K4me1 and H3K27ac. Based on the significant increase of H3K27ac levels at H3K4me1+ sites, we identified 3,017 JUN-activated enhancers in JUN WT cells. In contrast, JUN AA fails to significantly induce H3K27ac accumulation at these regions. Their enrichment levels at JUN-activated enhancers were significantly decreased after JNKi treatment. Besides, these enhancers are directly driven by JUN, especially phosphorylated JUN.
2022-12-09 | GSE196345 | GEO
Project description:Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults such as stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, little is known about the molecular mechanisms that regulate c-Jun abundance in neurons. Here we show that PRR7, a component of synaptic junctions, can upregulate c-Jun levels by inhibiting its ubiquitination in neurons. PRR7 interacts with the GLUN1 subunit of NMDARs and is upregulated in the nucleus following NMDAR activation. We show that PRR7 interacts with the E3 ligase SCFFBW7 (FBW7) and blocks the FBW7-mediated ubiquitination of c-Jun. PRR7 overexpression increases c-Jun-dependent transcriptional activity and promotes neuronal death. Microarray assays indicate that both Prr7 knockdown or overexpression alter the abundance of c-Jun-regulated transcripts associated with cellular viability as well as synaptic function. Moreover, Prr7 knockdown attenuates NMDA-mediated excitotoxicity in primary neuronal cultures. Our results show that PRR7 links NMDAR activity to c-Jun function and provide insight into the processes that underlie NMDA-dependent excitotoxicity.
2014-10-25 | GSE62686 | GEO
Project description:To examine the effects of phosphorylated JUN-mediated enhancers activation on gene expression, we conducted RNA-seq analysis in JUN wildtype (WT) or JUN inactive mutant (JUN AA) overexpressed MRC5 cells. The expression levels of genes associated with JUN-activated enhancers are significantly upregulated in JUN WT cells rather than in JUN AA cells. To quantify the effects of JUN inactivation on gene expression, we also performed RNA-seq analysis in JNKi-treated induced CAFs (iCAFs). We observed that JNKi significantly reduced expression levels of JUN-activated enhancers-associated genes.
2022-12-09 | GSE196351 | GEO