Transcription Factor STAT3 Research Articles

The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

In triple-negative breast cancer (TNBC), stromal restriction of CD8+ Tcells associates with poor clinical outcomes and lack of responsiveness to immune-checkpoint blockade (ICB). To identify mediators of Tcell stromal restriction, we profiled murine breast tumors lacking the transcription factor Stat3, which is commonly hyperactive in breast cancers and promotes an immunosuppressive tumor microenvironment. Expression of the cytokine Chi3l1 was decreased in Stat3-/- tumors. CHI3L1 expression was elevated in human TNBCs and other solid tumors exhibiting Tcell stromal restriction. Chi3l1 ablation in the polyoma virus middle T (PyMT) breast cancer model generated an anti-tumor immune response and delayed mammary tumor onset. These effects were associated with increased Tcell tumor infiltration and improved response to ICB. Mechanistically, Chi3l1 promoted neutrophil recruitment and neutrophil extracellular trap formation, which blocked Tcell infiltration. Our findings provide insight into the mechanism underlying stromal restriction of CD8+ Tcells and suggest that targeting Chi3l1 may promote anti-tumor immunity in various tumor types.

Methyltransferase Set7/9 controls PARP1 expression and regulates cisplatin response of breast cancer cells

The protein-specific methyltransferase Set7/9 is known for its ability to add methyl groups to lysine residues on many targets, including as histones H1.4, H2A, H2B, H3, and non-histone proteins such as p53, NFκB, E2F1, pRb, Hif1α, β-catenin, STAT3, and YY1 transcription factors. Set7/9 affects both the landscape of histone modifications and the functionality of the aforementioned TFs, and acts as an essential mediator of vital cellular functions, regulating tumor growth and the neoplastic transformation of normal cells.The number of studies demonstrating the determining role of Set7/9 in cancer is growing. Importantly, the effect of Set7/9 on tumor progression is ambivalent and cancer-type dependent. In this study we analyzed the potential participation of Set7/9 in the essential cellular processes in breast cancer cells and revealed that Set7/9 may be involved in DNA damage signaling and DNA repair processes. We further demonstrated that Set7/9 expression is downregulated in cancerous breast tissues and inversely correlated to PARP1 expression level.Using breast cancer cell lines of HER2-positive and triple negative subtypes we have shown that the attenuation of Set7/9 led to the stabilization of PARP1 on both mRNA and protein levels that in turn resulted in cisplatin resistance acquiring.Finally, we demonstrated that the combination of cisplatin with FDA approved PARP1 inhibitor niraparib (Zejula) has a synergistic effect with cisplatin and thereby allows to overcome cisplatin resistance of Set7/9 deficient breast cancer cells.

The Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors

Background and Hypothesis: B-cell precursor leukaemia (B-ALL) subtypes can be distinguished by their initiating genetic lesions. Likewise, each subtype exhibits a unique transcriptional program that drives the malignancy and defines the subtype. This often relates to the initiating genetic alteration that affects genes encoding transcription factors (TFs). However, for B-ALLs not driven by TF alterations it is less clear how the transcriptional program is established. Ph+B-ALL is a historically poor prognosis B-ALL driven by the BCR::ABL1 oncogene, a constitutive tyrosine kinase that activates its targets via phosphorylation. We hypothesised that BCR::ABL1 initiates the transcriptional signature of Ph+B-ALL cells by a two-step mechanism involving phosphorylation-activatable TFs, which then induce the expression of additional TFs that consecutively establish the Ph+B-ALL-defining transcriptome. As gene expression is often modulated by cis-regulatory elements such as enhancers, we further speculated that BCR::ABL1 reprograms the enhancer landscape to promote the transcriptional changes that define Ph+B-ALL. Results: Using an in vitro model of BCR::ABL1-induced transformation of murine B-cell precursors, we show that transcriptional deregulation by BCR::ABL1 is a continuous process evolving until full transformation is established. Only a minority of induced transcriptional changes occur immediately upon BCR::ABL1 expression (3 days), while most affected genes require an extended period of BCR::ABL1 to become deregulated. Furthermore, less than half of deregulated genes in murine Ph+B-ALL and less than 10% of human Ph+B-ALL-defining genes were sensitive to 24h BCR::ABL1 inhibition, suggesting an involvement of phosphorylation-dependent and phosphorylation-independent TFs. TF motif enrichment analysis of active chromatin in human and mouse Ph+B-ALL cells indicated the phosphorylation-dependent TF STAT5 and the phosphorylation-independent TF ETV5 as main mediators. Degron-induced rapid degradation of each TF in Ph+B-ALL cells confirmed their unique and overlapping roles and coordinated action. In parallel to gene expression changes, Ph+B-ALL cells further acquire changes in their enhancer signatures defined by H3K27ac+ at non-promoter regions, and these enhancer signatures can be efficiently used to distinguish Ph+B-ALL from other B-ALL subtypes. Analysis of chromatin interactions of these active enhancers with respective active promoters by Promoter-Capture Hi-C (PCHI-C) in combination with H3K27ac-ChIP-Seq showed that most active genes in Ph+B-ALL cells physically interact with an enhancer, including many genes described to be essential for Ph+B-ALL cells, such as CCND2, BCL2, BCL2L1, and ETV5. Using PCHI-C and H3K27ac-HiChIP we further show that, like gene expression and enhancer signatures, physical contacts of promoters and enhancers can be efficiently used to identify Ph+B-ALL cells and distinguish them from other B-ALLs such as KMT2A-rearranged B-ALL. Subtype-specific chromatin interactions that allow this differentiation directly relate to the transcriptional programs that define the respective B-ALL subtype. Conclusion: We describe here the molecular details of how signals from an oncogenic tyrosine kinase become converted into changes in gene expression that define the B-lineage leukaemia subtype Ph+B-ALL. Our work highlights the complexity of these changes by acknowledging the role of gene regulatory elements/enhancers in this process and further describe for the first time that B-ALL subtypes can be distinguished by their enhancer usage and promoter-enhancer interactions. Uncovering the precise enhancer regions for the genes deregulated in Ph+B-ALL and the TFs recruited to them may open new windows for therapeutic intervention.

Endothelial cells adopt a pro-reparative immune responsive signature during cardiac injury.

Modulation of the heart's immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have immune regulatory functions; however, interactions between ECs and the immune environment in the heart after MI remain poorly understood. We identified an EC-specific IFN responsive and immune regulatory gene signature in adult and pediatric heart failure (HF) tissues. Single-cell transcriptomic analysis of murine hearts subjected to MI uncovered an EC population (IFN-ECs) with immunologic gene signatures similar to those in human HF. IFN-ECs were enriched in regenerative-stage mouse hearts and expressed genes encoding immune responsive transcription factors (Irf7, Batf2, and Stat1). Single-cell chromatin accessibility studies revealed an enrichment of these TF motifs at IFN-EC signature genes. Expression of immune regulatory ligand genes by IFN-ECs suggests bidirectional signaling between IFN-ECs and macrophages in regenerative-stage hearts. Our data suggest that ECs may adopt immune regulatory signatures after cardiac injury to accompany the reparative response. The presence of these signatures in human HF and murine MI models suggests a potential role for EC-mediated immune regulation in responding to stress induced by acute injury in MI and chronic adverse remodeling in HF.

Mapping individual cardiac cell types and their contribution in the development of heart failure in a multiple comorbidity porcine model

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired left ventricular (LV) relaxation and filling due to increased myocardial stiffness and hypertrophy. The development of HFpEF is associated with multiple, interrelated risk factors including obesity, chronic kidney disease (CKD), diabetes mellitus (DM), hypertension. Mechanistic studies have implied that comorbidity-driven chronic inflammation, oxidative stress, and endothelial dysfunction act as contributors to the onset and development of HFpEF. Multiple studies that support this HFpEF paradigm highlight the complexity of the disease with different pathways active in and across different cell types. A recently developed multiple comorbidity swine (MCS) model with DM, CKD hypercholesterolemia, demonstrate inflammation, microvascular endothelial dysfunction and LV diastolic dysfunction. This model mimics the slow progression of disease in patients and is therefore ideal to study the earliest mechanisms underlying HFpEF. Purpose Here we hypothesize that single nuclei RNA (snRNA) sequencing aid in mapping the contribution of each individual cardiac cell cluster to disease development, to improve our mechanistic understanding of HFpEF. Methods We performed snRNA sequencing to analyze the transcriptional landscape of the cardiac environment in the well validated MCS model. Frozen left ventricle myocardial samples of MCS (n=4) and healthy control (n=3) swine were used. Results The analysis included ∼100.000 individual nuclei and offers new insights in cell type specific mechanisms during HFpEF onset and development against the background of common comorbidities. We identified 34 different cell clusters, which together represent 6 major cell types. Besides cardiomyocytes (CMs), endothelial cells (ECs) and fibroblasts, a large population of immune cells and smaller populations of mural cells and neurons were present in both MCS and control swine. IPA pathway analysis predicts transcriptomic changes within the cell clusters in response to comorbidities including activation of semaphoring and estrogen signaling in the largest CM cluster (CM2) and activation of EIF2 signaling in ECs (Fig. 1). Gene set enrichment analysis confirmed the activation of HFpEF paradigm pathways in the MCS dataset. Overlap of human HFpEF heart bulk RNA sequencing data and the MCS dataset showed overlapping disease processes including interferon gamma (IFNG) signaling. Moreover, IFNG signaling and IFNG associated transcription factor STAT1 were activated in most of the CM and EC clusters. Conclusion These findings suggest an essential role of multiple pathways during the onset and development of HFpEF. Further improvement of our understanding of underlying molecular mechanisms and crosstalk between cell populations, could pinpoint drug targets and aid the development of new treatments for HFpEF.Top 5 IPA predicted canonical pathways

JAK3 Inhibition Regulates Stemness and Thereby Controls Glioblastoma Pathogenesis.

Glioblastoma multiforme (GBM) is the most deadly brain tumor, effective treatment options for which still remain elusive. The current treatment procedure of maximal resection followed by chemotherapy has proved to be grossly insufficient to prevent disease progression and death. Despite best efforts, the maximum survival post-diagnosis is a mere 1.5 years. Therefore, there is a huge unmet clinical need to find effective therapeutic procedures to prevent the pathogenesis and relapse of GBM. Small-molecule inhibitors of signaling pathways are an attractive option to prevent various types of tumors. However, no effective small-molecule inhibitors have been successful against GBM in clinical trials. Various signaling pathways are altered and an array of signaling molecules, transcription factors (TFs), and epigenetic modifying factors have been implicated in the pathogenesis of GBM. JAK-STAT pathway alteration is an important contributor to GBM pathogenesis and relapse. Many small-molecule inhibitors of JAKs, or STAT TFs, especially JAK2 and STAT3, have been assessed for their anti-tumor activity in GBM. However, no definitive success so far has been achieved. Herein, by using two small-molecule inhibitors of JAK3, we show that they are quite effective in inhibiting GBM cell proliferation and neurosphere formation, downregulating their stemness character, and inducing differentiation into neuronal origin cells. The effect of a single treatment with the drugs, both in a serum-containing differentiation medium and in a proliferation medium containing EGF and FGF, was really strong in limiting GBM cell growth, suggesting a potential therapeutic application for these JAK inhibitors in GBM therapy.

Transcription factor STAT enhanced antimicrobial activities in Bombyx mori

STAT, a transcription factor in the JAK/STAT signaling pathway, regulates immune response to pathogens. In the silkworm (Bombyx mori), STAT exists as two split-forms, STAT-S and STAT-L. However, the role of STAT in silkworm immunity remains unclear. Our purpose was to investigate the effect of STAT on the expression of antimicrobial peptide (AMP) genes and resistance against pathogens. The expression levels of STAT-S and STAT-L were significantly up-regulated after induction by pathogenic microorganisms. In BmE cells, lipopolysaccharide (LPS), peptidoglycan (PGN) and β-glucan stimulated STAT-S and STAT-L to transfer from the cytoplasm to the nucleus. We found that overexpression of STAT-S and STAT-L in cells could promote the expression of AMPs. We generated transgenic silkworm lines overexpressing STAT-L or STAT-S (OE-STAT-S; OE-STAT-L) or interfering with STAT (A4-dsSTAT). Overexpression of STAT-S and STAT-L upregulated the expression of AMP genes in the OE-STAT-S and OE-STAT-L, increased the survival rates of the OE-STAT-S silkworms and lowered the mortality of OE-STAT-L silkworms infected with S. aureus or Beauveria bassiana. By contrast, the death rate of A4-dsSTAT silkworms was higher after infection with these pathogenic microorganisms. These findings may provide insights into the role of STAT in the antimicrobial immune response of silkworms.

STAT6-induced production of mucus and resistin-like molecules in lung Club cells does not protect against helminth or influenza A virus infection.

Airway epithelial cells contribute to a variety of lung diseases including allergic asthma, where IL-4 and IL-13 promote activation of the transcription factor STAT6. This leads to goblet cell hyperplasia and the secretion of effector molecules by epithelial cells. However, the specific effect of activated STAT6 in lung epithelial cells is only partially understood. Here, we created a mouse strain to selectively investigate the role of constitutively active STAT6 in Club cells, a subpopulation of airway epithelial cells. CCSP-Cre_STAT6vt mice and bronchiolar organoids derived from these show an enhanced expression of the chitinase-like protein Chil4 (Ym2) and resistin-like molecules (Relm-α, -β, -γ). In addition, goblet cells of these mice spontaneously secrete mucus into the bronchi. However, the activated epithelium resulted neither in impaired lung function nor conferred a protective effect against the migrating helminth Nippostrongylus brasiliensis. Moreover, CCSP-Cre_STAT6vt mice showed similar allergic airway inflammation induced by live conidia of the fungus Aspergillus fumigatus and similar recovery after influenza A virus infection compared to control mice. Together these results highlight that STAT6 signaling in Club cells induces the secretion of Relm proteins and mucus without impairing lung function, but this is not sufficient to confer protection against helminth or viral infections.

STAT4-Mediated Klotho Up-Regulation Contributes to the Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning via Inhibiting Neuronal Pyroptosis.

Our previous study has proved that the Klotho up-regulation participated in cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance. However, the exact neuroprotective mechanism of Klotho in CIP remains unclear. We explored the hypothesis that STAT4-mediated Klotho up-regulation contributes to the CIP-induced brain ischemic tolerance via inhibiting neuronal pyroptosis. Firstly, the expressions of pyroptosis-associated proteins (i.e., NLRP3, GSDMD, pro-caspase-1, and cleaved caspase-1) in hippocampal CA1 region were determined during the process of brain ischemic tolerance. We found the expression of pyroptosis-associated proteins was significantly up-regulated in the ischemic insult (II) group, and showed no significant changes in the CIP group. The expression level of each pyroptosis-associated proteins was lower in the CIP + II group than that in the II group. Inhibition of Klotho expression increased the expression of pyroptosis-associated proteins in the CIP + II group and blocked the CIP-induced brain ischemic tolerance. Injection of Klotho protein decreased the expression of pyroptosis-associated proteins in the II group, and protected neurons from ischemic injury. Secondly, the transcription factor STAT4 of Klotho was identified by bioinformatic analysis. Double luciferase reporter gene assay and chromatin immunoprecipitation assay showed STAT4 can bind to the site between nt - 881 and - 868 on the Klotho promoter region and positively regulates Klotho expression. Moreover, we found CIP significantly enhanced the expression of STAT4. Knockdown STAT4 suppressed Klotho up-regulation after CIP and blocked the CIP-induced brain ischemic tolerance. Collectively, it can be concluded that STAT4-mediated the up-regulation of Klotho contributed to the brain ischemic tolerance induced by CIP via inhibiting pyroptosis.

Identification the immune related marker genes and transcription-factor network in ruptured cerebral aneurysms using bioinformatics analysis and machine-learning strategies

BackgroundAs a high level of mortality and morbidity disease, ruptured cerebral aneurysms (RCA) is the most common cause of intracranial hemorrhage. MethodsThe expression profiles of GSE13353, GSE26969 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between RCA and unruptured cerebral aneurysms (URCA). The Least Absolute Shrinkage Selection Operator (LASSO) and the SVM-RFE (SVM-RFE) analysis were used to screen the potential diagnostic genes for RCA, which were further tested in the validation cohort (GSE54083). The TRRUST database was used to predict transcription factors (TF) and the JASPAR database was used to validate the marker genes and STAT1 binding sites. Finally, the CMAP database was used to predict RCA-associated drugs for clinical transformation. ResultsA total of 120 DEGs were identified. The functional enrichment analysis revealed that NF-kappa B signaling pathway, tuberculosis, rheumatoid arthritis were enriched in the RCA group. NANS, NTRK3, OLFML2A were identified as diagnostic biomarkers of RCA. Transcription of all three marker genes is regulated by the predicted transcription factor STAT1, the CMAP database was eventually used to screen 10 most promising drugs for the treatment of RCA. ConclusionNANS, NTRK3, OLFML2A may become new candidate biomarkers of RCA, moreover, STAT1 plays an important role in the development of RCA. The mentioned immune cells may play a key role in the development and progression of RCA. MEK and MAP kinase inhibitors are the most likely drug mechanisms for RCA therapy.

AXL transcriptionally up-regulates TMEM14A expression to mediate cell proliferation in non-small-cell lung cancer cells

In non-small cell lung cancer (NSCLC), the receptor tyrosine kinase AXL has been identified as a potent activator of tumor progression and resistance to therapies. However, the molecular mechanisms behind AXL-mediated oncogenesis remain elusive. Current study thus aimed to uncover potential downstream genes regulated by AXL in NSCLC. Through transcriptomic RNA sequencing of AXL-silenced NSCLC cells, TMEM14A was identified as a significantly up-regulated gene. Clinical evaluations using GEPIA2 revealed that TMEM14A mRNA expression was notably higher in lung adenocarcinoma (LUAD) tumor tissues compared to normal tissues. Further, significantly increased TMEM14A levels were associated with poorer overall survival in LUAD patients. Experimentally, silencing TMEM14A in NSCLC cells led to reduced cellular proliferation and ATP levels, highlighting a key role of TMEM14A in NSCLC progression. Moreover, our promoter analysis demonstrated that AXL-mediated regulation of TMEM14A transcription could involve binding of transcription factors STAT and NF-κB to 5′-promoter of TMEM14A. Collectively, current study unveils TMEM14A as a novel downstream target of AXL, suggesting its potential as a therapeutic target to counteract resistance in future NSCLC patients undergoing AXL-targeted therapies.

FRI294 The Dopamine Agonist Cabergoline Targets Multiple Pathways To Inhibit PRL Secretion And Increases Stromal Fibrosis Via The Serotonin Receptor 5HTR1F

Abstract Disclosure: D. Zhang: None. W. Hugo: None. M. Bergsneider: None. M.B. Wang: None. W. Kim: None. H.V. Vinters: None. A.P. Heaney: None. Prolactinomas (PRLomas) are comparatively common and make up ∼50% of all pituitary adenomas. Occurring in both genders, they can cause galactorrhea, amenorrhea and sub-fertility in females, and loss of libido and sexual dysfunction in males. Dopamine agonist (DA) therapy is an effective first line medical treatment in most PRLomas, and ∼1/3 of patients can stop therapy after 2 years and thereafter maintain normal prolactin (PRL) levels. However, 1/3 of patients require long-term DA therapy to maintain normal PRL levels and a further 1/3 of patients are either refractory to DA therapy or intolerant of their side effects including severe depression and/or anxiety. To begin to unravel potential mechanism(s) of on- and off-target effects of DA therapy, we used single cell RNA sequencing (scRNA-seq) to compare cellular composition and the transcriptional landscape in 3 surgically resected but previously cabergoline (CBG) treated and 3 surgically resected but dopamine agonist treatment naive PRLomas. We identified 6 major cell populations that included tumor (90.2%), immune (4.6%), stromal (4.3%), progenitor cells (0.5%), proliferating cells (0.25%), and erythrocytes (0.1%). In the tumor cell population, genes involved in hormone secretion regulation, such as SCG2, VGF, TIMP1, NNAT, and CALD1 were reduced in CBG-treated samples, consistent with the inhibitory effects of CBG on PRL hormone processing and secretion. Interestingly, we also observed a reduction in MHC-I complex HLA-A and B2M expression concomitant with an increase of CD8+ T cells in the CBG-treated PRL-oma samples. This group of cytotoxic CD8+ T cells expressed killing granule components, such as perforin (PRF1) and granzymes GZMA/H/K/M as well as the inflammatory cytokines CCL4/5. Further analysis to elucidate the upstream regulators of this pathway highlighted activation of IL2, and involvement of the inflammatory transcription factors NFκB and STATs in response to CBG treatment. We also noted previously unreported increased PRLoma expression of several genes implicated in psychological disorders such as PTN, PCLO, THSD7A, and TXNIP. Additionally, and confirming prior reports, we noted a higher stromal cell population in CBG-treated compared to non CBG-treated samples, with high fibroblast expression of the serotonin receptor HTR1F, potentially implicating HTR1F as a mediator of CBG-induced stromal fibrosis. In summary, our scRNAseq studies revealed key differences in the transcriptomic features of CBG-treated and -untreated prolactinomas, and suggest previously unknown activation of CD8+ T cells may play a role in the tumoricidal actions of CBG therapy. Furthermore, our observed induction of several genes implicated in psychological disorders may provide insight into the not infrequent side effects of mood alteration following DA therapy. Presentation: Friday, June 16, 2023

Myeloid cell deficiency of the inflammatory transcription factor Stat4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet

Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), and consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4fl/flLdlr−/− mice fed a HFD-C diabetogenic diet, we show that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4ΔLysMLdlr−/− mice compared to Stat4fl/flLdlr−/− controls. Stat4ΔLysMLdlr−/− mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr−/− mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr−/− mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4ΔLysMLdlr−/− mice. These data suggest that suppression of Stat4 activation may protect against effects of Western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer’s disease and other neurodegenerative disorders associated with neuroinflammation.

A bacterial effector protein promotes nuclear translocation of Stat3 to induce IL-10

The multifunctional Yersinia effector YopM inhibits effector triggered immunity and increases production of the anti-inflammatory cytokine Interleukin-10 (IL-10) to suppress the host immune response. Previously it was shown that YopM induces IL-10 gene expression by elevating phosphorylation of the serine-threonine kinase RSK1 in the nucleus of human macrophages. Using transcriptomics, we found that YopM strongly affects expression of genes belonging to the JAK-STAT signaling pathway. Further analysis revealed that YopM mediates nuclear translocation of the transcription factor Stat3 in Y. enterocolitica infected macrophages and that knockdown of Stat3 inhibited YopM-induced IL-10 gene expression. YopM-induced Stat3 translocation did not depend on autocrine IL-10, activation of RSK1 or tyrosine phosphorylation of Stat3. Thus, besides activation of RSK1, stimulation of nuclear translocation of Stat3 is another mechanism by which YopM increases IL-10 gene expression in macrophages.

Złocień maruna – starożytny lek na współczesne choroby

The Feverfew – an ancient remedy for modern diseases The feverfew (Tanacetum parthenium L.), also known as the Chrysanthemum parthenium, is a perennial plant belonging to the Asteraceae family, growing mainly in gardens and open spaces, can be found growing in the regions of Southern Europe and Asia Minor. The healing effects of feverfew were known in antiquity. In folk medicine, this plant has been used to treat fever, migraine headaches, as well as rheumatoid arthritis, stomach and toothache, and insect bites. The active compounds contained in the feverfew include sesquiterpene lactones, and the most important of them – is parthenolide, which is considered to be the main ingredient determining the biological activity of extracts from this perennial. Feverfew preparations, containing parthenolide, reduce the production of prostaglandins, inhibit the release of serotonin and histamine, and antagonize the 5-HT2A receptors, thus showing the anti-migraine effects. Moreover, feverfew extract has anti-infl ammatory properties and reduces allergy symptoms by inhibiting the secretion of histamine from mast cells. Currently, studies are being conducted on the use of parthenolide in the treatment of neuropathic pain. This type of chronic pain is caused by damage to the somatosensory nervous system, which is observed in the development of diabetes, stroke, cancer, or after mechanical injuries (e.g. as postoperative complications or after traffic accidents). In in vivo studies parthenolide showed a strong analgesic effect, moreover, its use allowed for the reduction of morphine doses in neuropathic animals. This important clinical implication raises great hopes for designing a multimodal therapy for neuropathic pain. In addition to its anti-infl ammatory and analgesic properties, parthenolide exhibits antitumor activity by inhibiting the NF-κB and STAT transcription factors and inducing the permanent activation of JNK kinase and p53 protein, thereby sensitizing neoplastic cells to radio- and chemotherapy. Interestingly, parthenolide induces apoptosis of cancer cells but has no toxic effects on normal cells. Currently, preparations from the feverfew are used in the phytotherapy of migraine headaches, however, the results of the preclinical research open up new perspectives for the use of this perennial, in particular parthenolide, in modern therapy.

Cross-talk between PARN and EGFR-STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells.

A positive feedback loop comprising PARN and EGFR-STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Shock drives a STAT3 and JunB-mediated coordinated transcriptional and DNA methylation response in the endothelium.

Endothelial dysfunction is a crucial factor in promoting organ failure during septic shock. However, the underlying mechanisms are unknown. Here, we show that kidney injury after lipopolysaccharide (LPS) insult leads to strong endothelial transcriptional and epigenetic responses. Furthermore, SOCS3 loss leads to an aggravation of the responses, demonstrating a causal role for the STAT3-SOCS3 signaling axis in the acute endothelial response to LPS. Experiments in cultured endothelial cells demonstrate that IL-6 mediates this response. Furthermore, bioinformatics analysis of in vivo and in vitro transcriptomics and epigenetics suggests a role for STAT, AP1 and interferon regulatory family (IRF) transcription factors. Knockdown of STAT3 or the AP1 member JunB partially prevents the changes in gene expression, demonstrating a role for these transcription factors. In conclusion, endothelial cells respond with a coordinated response that depends on overactivated IL-6 signaling via STAT3, JunB and possibly other transcription factors. Our findings provide evidence for a critical role of IL-6 signaling in regulating shock-induced epigenetic changes and sustained endothelial activation, offering a new therapeutic target to limit vascular dysfunction.

Role of Long Non-coding RNA HSD17B3-AS1 in Trauma for COVID-19.

COVID-19, an acute respiratory syndrome caused by the SARS-CoV-2 virus, was first reported in late 2019 in Wuhan, China, and rapidly escalated into a global pandemic. The condition can lead to organ dysfunction and ultimately death through its onset of acute respiratory distress syndrome (ARDS). Disease severity has been linked to proinflammatory cytokines which activate the NF-κB and STAT transcription factors in infected cells. It has been proven that lncRNAs play a very important role in reducing or increasing inflammatory factors. This makes them potentially valuable in recognizing pathogenesis pathways and therapeutic targets in COVID-19. Nanocurcumin is known as an antioxidant, tumor suppressor and anti-inflammatory substance, and it can be effective to reduce inflammation caused by the disease of COVID-19. This study analyzed Sequence Read Archive data from COVID-19 patients with acute versus milder symptoms, identifying dysregulated genes and non-coding RNAs. To verify this correlation, the expression of the candidate gene was evaluated with quantitative polymerase chain reaction (qPCR) in mouse models, while immunoglobulin (Ig) G titer was measured using enzyme-linked immunosorbent assay (ELISA) in mouse serum samples. Here we introduced a novel lncRNA called HSD17B3-AS1, suggested as a therapeutic target in COVID-19 patients with acute symptoms. Furthermore, we revealed nanocurcumin is reducing the expression of HSD17B3-AS1 which leads to reduced inflammation in mice. These results suggest that HSD17B3-AS1 plays a significant regulatory role in managing COVID-19, and the downregulation of HSD17B3-AS1 by Nanocurcumin presents a promising treatment option for minimizing complications in COVID-19 patients.

Programmed Cell Death Protein 2-like Promotes Inflammation and Oxidative Stress in Vascular Endothelial Cells.

Programmed cell death protein 2-like (PDCD2L) is a shuttle protein of the nucleus and cytoplasm and is related to the ribosome biogenesis. However, there are few reports on the relationship between PDCD2L and inflammation, and the exact relationship between PDCD2L and inflammation has not been determined in vascular endothelial cells yet. Accordingly, we focus on exploring the relationship between PDCD2L and inflammation and its potential mechanisms. Our research findings suggested that PDCD2L is a proinflammatory target. The result showed that, by interfering with the expression of PDCD2L, LPS-induced inflammation of vascular endothelial cells can be reduced, such as IL-6 and IL-1β, as well as the adhesion factor ICAM1. Meanwhile, overexpression of PDCD2L can further increase LPS-induced inflammation levels, ICAM1, and ROS production, reduce CAT, GSH/GSSG levels, and increase SOD levels. Therefore, we determined that PDCD2L has a regulatory effect on inflammation and oxidative stress of vascular endothelial cells, and its regulatory mechanism may be related to inflammatory transcription factors STAT1, NF-κB regulation, transport of inflammatory messenger mRNA, and ribosome biogenesis. Then, we screened that andrographolide (Andro) can bind to PDCD2L, thus inhibiting inflammation and endothelial cell adhesion caused by the overexpression of PDCD2L. This study reveals that PDCD2L is a potential anti-inflammatory therapeutic target, providing new exploration for the development of anti-inflammatory drugs.