Signal Transducer And Activator Of Transcription Research Articles

Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons.

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aβ25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aβ25-35 and Aβ1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aβ exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aβ25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aβs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis.

Identification and validation of diagnostic genes associated with neutrophil extracellular traps of type 2 diabetes mellitus.

Neutrophil extracellular traps (NETs) cause delayed wound closed up in type 2 diabetes mellitus (T2DM), but the specific regulatory mechanism of NETs-related genes (NETs-RGs) in T2DM is unclear. We acquired GSE21321 and GSE15932 datasets from gene expression omnibus (GEO) database. First, differentially expressed genes (DEGs) between T2DM and control samples of GSE21321 dataset were sifted out by differential expression analysis. NETs scores were calculated for all samples in GSE21321 dataset, and key module genes associated with NETs scores were screened by constructing co-expression network. Then, DEGs and key module genes were intersected to yield intersection genes, and candidate genes were identified by constructing a protein protein interaction (PPI) network. Least absolute shrinkage and selection operator (LASSO) regression analysis was implemented on candidate genes to screen out diagnostic genes, and they were subjected to single sample gene set enrichment analysis (ssGSEA). Finally, immune characteristic analysis was carried out, and we constructed the gene-drug and transcription factor (TF)-miRNA-mRNA networks. Besides, we validated the expression of diagnostic genes by quantitative real-time polymerase chain reaction (qRT-PCR). In total, 23 candidate genes were gained by PPI analysis. The 5 diagnostic genes, namely, inter-trypsin inhibitor heavy chain 3 (ITIH3), fibroblast growth factor 1 (FGF1), neuron cell adhesion molecule (NRCAM), advanced glycosylation end-product-specific receptor (AGER), and calcium voltage-gated channel subunit alpha1 C (CACNA1C), were identified via LASSO analysis, and they were involved in carboxylic acid transport, axonogenesis, etc. M2 Macrophage, Monocyte, Natural killer (NK) cell, and Myeloid dendritic cells (DC) were remarkably different between T2DM and control samples. Diagnostic genes had the strongest and the most significant positive correlation with B cells. The gene-drug network included CACNA1C-Isradipine, CACNA1C-Benidipine and other relationship pairs. Totally 76 nodes and 44 edges constituted the TF-miRNA-mRNA network, including signal transducer and activator of transcription 1(STAT1) -hsa-miR-3170-AGER, CCCTC-binding factor (CTCF)-hsa-miR-455-5p-CACNA1C, etc. Moreover, qRT-PCR suggested that the expression trends of FGF1 and AGER were in keeping with the results of bioinformatic analysis. FGF1 and AGER were markedly regulated downwards in the T2DM group. Through bioinformatic analysis, we identified NETs-related diagnostic genes (ITIH3, FGF1, NRCAM, AGER, CACNA1C) in T2DM, and explored their mechanism of action from different aspects, providing new ideas for the studies related to diagnosis and treatment of T2DM.

Graph Attention Network-Based Prediction of Drug-Gene Interactions of Signal Transducer and Activator of Transcription (STAT) Receptor in Periodontal Regeneration.

Introduction The signal transducer and activator of transcription-1 (STAT-1) are tightly controlled signaling pathways, with induced genes acting as positive and negative regulators. Persistent activation of the signal transducer and activator of transcription (STATs), particularly signal transducer and activator of transcription-3 (STAT-3) and signal transducer and activator of transcription-5 (STAT-5), is common in human tumors and cell lines. STAT molecules act as transcription factors, regulated by ligands like interferon-α (IFN-α), interferon-γ (IFN-γ), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), interleukin-6 (IL-6)and interleukin-27 (IL-27). STAT-1 mutations can cause infections like periodontitis, a chronic inflammatory disease affecting gum tissue and bone. STAT-1 drug-gene interactions are being studied for therapeutic applications. Our study aims to predict drug-gene interactions of STAT-1 receptors in periodontal inflammation using graph attention networks (GATs). Methodology The study used a dataset of 215 drug-gene interactions to train and test a GATmodel. The data was cleaned and normalized before being subjected to GATs using the Python library. Cytoscape and cytoHubba were used to visualize and analyze biological networks, including drug-gene interactome networks. The GAT model consisted of two graph attention layers, with the first layer producing eight features and the second layer aggregating outputs for binary classification. The model was trained using the Adam optimizer and CrossEntropyLoss function. Results The drug-gene interactome network, analyzed using Cytoscape, had 657 nodes, 1591 edges, and 4.755 neighbors. The predictive GAT model had low accuracy due to data availability and complexity. Conclusion The GAT model for drug-gene interactions in periodontal inflammation had low accuracy due to data limitations, complexity, and inability to capture all relevant features.

Cas-CLOVER-mediated knockout of STAT1: A novel approach to engineer packaging HEK-293 cell lines used for rAAV production.

In addressing the limitations of CRISPR-Cas9, including off-target effects and high licensing fees for commercial use, Cas-CLOVER, a dimeric gene editing tool activated by two guide RNAs, was recently developed. This study focused on implementing and evaluating Cas-CLOVER in HEK-293 cells used for recombinant adeno-associated virus (rAAV) production by targeting the signal transducer and activator of transcription 1 (STAT1) locus, which is crucial for cell growth regulation and might influence rAAV production yields. Cas-CLOVER demonstrated impressive efficiency in gene editing, achieving over 90% knockout (KO) success. Thirteen selected HEK-293 STAT1 KO sub-clones were subjected to extensive analytical characterization to assess their genomic stability, crucial for maintaining cell integrity and functionality. Additionally, rAAV9 productivity, Rep protein pattern profile, and potency, among others, were assessed. Clones showed significant variation in capsid and vector genome titers, with capsid titer reductions ranging from 15% to 98% and vector genome titers from 16% to 55%. Interestingly, the Cas-CLOVER-mediated STAT1 KO bulk cell population showed a better ratio of full to empty capsids. Our study also established a comprehensive analytical workflow to detect and evaluate the gene KOs generated by this innovative tool, providing a solid groundwork for future research in precise gene editing technologies.

A Comprehensive Network Map of Interleukin-26 Signaling Pathway.

Interleukin-26 (IL-26) is a cytokine that belongs to the IL-20 subfamily and is primarily expressed in T helper 1 cells and Th17 memory CD4+ cells. Its receptor complex, consisting of IL-20R1 and IL-10R2, activates a signaling pathway involving several proteins such as Janus kinase 1 and tyrosine-protein kinase, signal transducer and activator of transcription (STAT) 1, and STAT3. This leads to the initiation of downstream signaling cascades that play a crucial role in various biological processes, including inflammation, immune response regulation, atopic dermatitis, macrophage differentiation, osteoclastogenesis, antibacterial host defense, anti-apoptosis, and tumor growth. In this study, we curated literature data pertaining to IL-26 signaling. The curated map includes a total of seven activation/inhibition events, 16 catalysis events, 33 gene regulation events, 25 protein expression types, two transport events, and three molecular associations.

Genetic causes of primary immunodeficiency in the Jordanian population.

Ιnborn errors of immunity (IEI) represents a heterogenous collection of >480 immune system anomalies, leading to severe infections, autoimmune disorders and malignancies. While these conditions are rare globally, their prevalence is notably higher in the Jordanian population, attributed to elevated rates of consanguinity. The intricate nature of IEI has driven the adoption of genomic technologies for the identification of associated genetic defects. In the present study, whole-exome sequencing was performed on nine Jordanian IEI patient samples, confirming germline single-nucleotide variations (SNVs) in 14 genes through Sanger sequencing. Of note, signal transducer and activator of transcription 1 (STAT1), elastase, neutrophil expressed (ELANE) and interferon induced with helicase c domain 1 (IFIH1) harbored mutations that were previously unreported in the Jordanian IEI population. In addition, mutations in capping protein regulator and myosin 1 linker 2 (c.3683C>T), TNFα-induced protein 3-interacting protein 1 (TNIP1) (c.460C>G) and STAT1 (c.1061T>C) were confirmed, marking their association with Jordanian IEI. For robustness, the genomic databases Ensemble, Genome AD and ClinVar were used to confirm the SNVs' associations with IEI. Kyoto Encyclopedia of Genes and Genomes pathway analysis also showed involvement of the IL-17 signaling pathway (including IL-17 receptor A), T-helper type 17 cell differentiation (including STAT1), the JAK-STAT signaling pathway (including STAT2 and tyrosine kinase 2), neutrophil extracellular trap formation (including ELANE), cocaine addiction [G protein signaling modulator 1 (GPSM1)] and cytokine-cytokine receptor interaction (IL-17 receptor C). In summary, exome sequencing identified a likely causative genetic defect in ELANE (PID-28), STAT1 (PID-30) and IFIH1 (PID-33). The present findings reveal the association of novel STAT1, ELANE mutations with the clinical phenotype of the patients, as well as known mutations in NLRP12, GPSM1 and TNIP1, in addition to novel ELANE, STAT1 and IFIH1 mutations associated in the context of Jordanian IEI.

Janus kinase inhibitors for skin disorders

Immune factors such as interferon‑ɣ and interleukin4 belong to the group of cytokines that are dependent on typeI/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via asignaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK1, JAK2, JAK3, and tyrosine kinase2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into apharmacological target for the treatment of inflammatory diseases in which cytokines using typeI/II receptors play apathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of aJAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with abroader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent avaluable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology.

Increased serum interferon activity in sarcoidosis compared to that in tuberculosis: Implication for diagnosis?

ObjectivesIn this study, we measured serum interferon (IFN) levels and activity in patients with sarcoidosis and tuberculosis (TB) with and without uveitis. We aimed to understand the role of IFN in the pathophysiology of both conditions and explore its potential as a discriminating marker for these clinically similar diseases. MethodsSera from an Indonesian TB and a Dutch sarcoidosis cohort were used in the analysis. IFNα2 and IFNγ concentrations were measured using Simoa® and Luminex assays, respectively. Serum IFN activity was assessed by incubating THP-1 cells with patient serum and measuring IFN-stimulated gene transcription using qPCR. Anti-IFNα2 and IFNγ autoantibodies were detected via Luminex assay and tested for neutralizing capacity using a flow cytometry-based signal transducer and activator of transcription (STAT) 1 phosphorylation inhibition assay. ResultsIFNα2 was detected in 74 % and 64 % of patients with sarcoidosis and pulmonary TB, respectively, while IFNγ was found in 78 % and 23 % of patients with sarcoidosis and TB, respectively. For uveitis cases specifically, IFNα2 was detected in 85 % of sarcoid uveitis (SU) and 33 % of tubercular uveitis (TBU) cases. Similarly, IFNγ was detected in 69 % of SU and 17 % of TBU cases. IFNγ serum concentrations were higher in sarcoidosis than that in TB patients (p < 0.0001). Focusing on patients with uveitis, SU showed increased IFNα2 (p = 0.004) and IFNγ (p < 0.002) serum concentrations compared to that in TBU. Notably, TBU displayed significantly reduced IFNα2 concentrations compared to that in healthy controls (p = 0.006). These results align with the increased interferon stimulated gene (ISG) transcriptional upregulation observed in THP-1 cells stimulated with serum from patients with sarcoidosis. Elevated levels of non-neutralizing anti-IFN autoantibodies were observed in patients with TB; however, these levels were similar to those observed in geographically matched healthy Indonesian controls. ConclusionOur results suggest decreased serum levels and activity of type I and II IFN in TB compared to those in sarcoidosis. This is indicative of distinct pathophysiological processes in these highly clinically similar diseases. We propose that the assessment of serum IFN levels and IFN activity has the potential to distinguish between sarcoidosis/SU and TB/TBU.

APOL6 predicts immunotherapy efficacy of bladder cancer by ferroptosis

BackgroundImmune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure.MethodsOur analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated.ResultsThe results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1).ConclusionsTo conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.

Small Molecule Therapy for Inflammatory Bowel Disease: JAK Inhibitors and S1PR Modulators

Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

Aloperine Attenuates Hepatic Ischemia/Reperfusion-Induced Liver Injury via STAT-3 Signaling in a Murine Model.

Hepatic ischemia/reperfusion (I/R) damage is one of the most common side effects of liver surgery. This pathophysiological process may lead to excessive hepatic damage. Aloperine is an active ingredient isolated from Sophora alopecuroides Linn and has a variety of therapeutic effects, including organ protection. However, the hepatoprotective effect of aloperine against hepatic I/R damage has not yet been determined. C57BL/6 mice were allocated to the sham-operated (sham), hepatic ischemia/reperfusion (I/R), and aloperine groups. The mice were exposed to 30 min of hepatic hilum occlusion. Then a 3-h reperfusion was performed. Mice in the sham group underwent sham surgery. Hepatic injury was evaluated by plasma aspartate aminotransferase (AST) and transaminase alanine aminotransferase (ALT) levels, histological evaluation, cell apoptosis, the number of activated inflammatory cells, and the expression levels of inflammatory cytokines, including tumor necrosis factor-α and interleukin-6. The protein phosphorylation status of the reperfusion-associated survival pathways was evaluated. Mice with hepatic I/R injury presented increased plasma ALT and AST levels, increased hepatic apoptosis, abnormal histological structure, and elevated inflammatory responses. However, aloperine ameliorated hepatic I/R-induced injury. Moreover, aloperine enhanced the level of signal transducer and activator of transcription (STAT)-3 phosphorylation after I/R. Ag490, an agent that inhibits STAT-3 activity, abolished aloperine-induced STAT-3 phosphorylation and liver protection. Aloperine ameliorates hepatic I/R-induced liver injury via a STAT-3-mediated protective mechanism. Patients with hepatic I/R injury may benefit from aloperine treatment. SIGNIFICANCE STATEMENT: Hepatic I/R can cause excessive liver damage. This study revealed that aloperine, an active component isolated from Sophora alopecuroides Linn, ameliorates hepatic I/R injury and related liver damage in vivo. The underlying protective mechanism may involve the STAT-3 signaling pathway. These findings may lead to the development of a novel approach for treating hepatic I/R damage in clinical practice.

From traditional to targeted: the changing trajectory of therapies in dermatomyositis.

New breakthroughs in our understanding of dermatomyositis (DM) have spawned the recent development of novel agents that specifically target key drivers in DM immunopathogenesis. This review aims to provide a comprehensive overview of new and forthcoming therapies for DM and to highlight their mechanisms of action, best evidence to date, and potential impact on disease management. Strategies that either counteract dysregulated interferon signaling [via the inhibition of interferon β, the type I interferon receptor subunit 1 (IFNAR1), or janus kinase (JAK)-signal transducer and activator of transcription (STAT) transduction] or induce durable autoreactive B cell depletion through chimeric antigen receptor (CAR) T-cell therapy appear to hold the most promise for sustained remission in DM. The trajectory of DM treatments is rapidly evolving, fueled by the unparalleled insights provided by multiomic studies and big data analysis pipelines. Targeted therapies that maximize both efficacy and safety have the potential to complement or replace traditional immunosuppressives and revolutionize the approach to the management of DM.

The PRMT6/STAT1/ACSL1 axis promotes ferroptosis in diabetic nephropathy.

Hyperglycaemia-induced ferroptosis is a significant contributor to kidney dysfunction in diabetic nephropathy (DN) patients. In addition, targeting ferroptosis has clinical implications for the treatment of DN. However, effective therapeutic targets for ferroptosis have not been identified. In this study, we aimed to explore the precise role of protein arginine methyltransferase 6 (PRMT6) in regulating ferroptosis in DN. In the present study, we utilized a mouse DN model consisting of both wild-type and PRMT6-knockout (PRMT6-/-) mice. Transcriptomic and lipidomic analyses, along with various molecular biological methodologies, were used to determine the potential mechanism by which PRMT6 regulates ferroptosis in DN. Our results indicate that PRMT6 downregulation participates in kidney dysfunction and renal cell death via the modulation of ferroptosis in DN. Moreover, PRMT6 reduction induced lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 1 (ACSL1) expression, ultimately contributing to ferroptosis. Furthermore, we investigated the molecular mechanism by which PRMT6 interacts with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ACSL1 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. Furthermore, we observed that PRMT6 and STAT1 synergistically regulate ACSL1 transcription to mediate ferroptosis in hyperglycaemic cells. Our study demonstrated that PRMT6 and STAT1 comodulate ACSL1 transcription to induce the production of phospholipid-polyunsaturated fatty acids (PL-PUFAs), thus participating in ferroptosis in DN. These findings suggest that the PRMT6/STAT1/ACSL1 axis is a new therapeutic target for the prevention and treatment of DN.

The JAK1/JAK2 inhibitor ruxolitinib inhibits mediator release from human basophils and mast cells.

The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils. In this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs). Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C4) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance P-activated HSMCs. These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders.

The intersection of endocrine signaling and neuroimmune communication regulates neonatal nociception.

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates. We found that local GH treatment inhibited neonatal inflammatory myalgia but appeared to do so through a unique signal transducer and activator of transcription (STAT) dependent pathway within sensory neurons. The STAT1 transcription factor appeared to regulate peripheral inflammation itself by modulation of monocyte chemoattractant protein 1 (MCP1) release from sensory neurons. Data suggests that STAT1 upregulation, downstream of GH signaling, contributes to neonatal nociception during muscle inflammation through a novel neuroimmune loop involving cytokine release from primary afferents. Results could uncover new ways to treat muscle pain and inflammation in neonates.

Integrated network toxicology, transcriptomics and gut microbiomics reveals hepatotoxicity mechanism induced by benzo[a]pyrene exposure in mice

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant posing various toxicity effects on organisms. Previous studies demonstrated that BaP could induce hepatotoxicity, while the underlying mechanism remains incompletely elucidated. In this study, a comprehensive strategy including network toxicology, transcriptomics and gut microbiomics was applied to investigate the hepatotoxicity and the associated mechanism of BaP exposure in mice. The results showed that BaP induced liver damage, liver oxidative stress and hepatic lipid metabolism disorder. Mechanistically, BaP may disrupt hepatic lipid metabolism through increasing the uptake of free fatty acid (FFA), promoting the synthesis of FA and triglyceride (TG) in the liver and suppressing lipid synthesis in white adipose tissue. Moreover, integrated network toxicology and hepatic transcriptomics revealed that BaP induced hepatotoxicity by acting on several core targets, such as signal transducer and activator of transcription 1 (STAT1), C-X-C motif chemokine ligand 10 (CXCL10) and toll-like receptor 2 (TLR2). Further analysis suggested that BaP inhibited JAK2-STAT3 signaling pathway, as supported by molecular docking and western blot. The 16S rRNA sequencing showed that BaP changed the composition of gut microbiota which may link to the hepatotoxicity based on the correlation analysis. Taken together, this study demonstrated that BaP caused liver injury, hepatic lipid metabolism disorder and gut microbiota dysbiosis, providing novel insights into the hepatotoxic mechanism induced by BaP exposure.

RNF149 Destabilizes IFNGR1 in Macrophages to Favor Postinfarction Cardiac Repair.

Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (ring finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 (signal transducer and activator of transcription 1) activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.

Selective Tyrosine Kinase 2 (TYK2) Inhibition in Plaque Psoriasis.

Members of the Janus kinase (JAK) superfamily, comprising tyrosine kinase 2 (TYK2) and JAK1, JAK2, and JAK3, mediate signaling by cytokines (eg, interleukin [IL]-23) involved in psoriasis pathogenesis. Binding of IL-23 to its receptor activates TYK2 and JAK2, which trigger signal transducer and activator of transcription (STAT) translocation to the nucleus to regulate target gene transcription, including genes of proinflammatory mediators such as IL-17. Physiologically, TYK2 solely mediates immune function, whereas JAK1,2,3 mediate broad systemic and immune functions. Inhibition of individual JAK family members is being evaluated in many dermatologic indications, including psoriasis. Selective TYK2 inhibition is therefore expected to be associated with few adverse effects in patients with psoriasis. People with genetic mutations leading to loss of function of TYK2 are protected from the development of psoriasis without an increased risk of infections or malignancies. In contrast, treatments with JAK1,2,3 inhibitors are associated with various systemic effects. We review the unique allosteric mechanism of action of the selective TYK2 inhibitor, deucravacitinib, which binds to the TYK2 regulatory (pseudokinase) domain, and the mechanisms of action of JAK1,2,3 inhibitors, which bind to the adenosine 5'-triphosphate-binding active (catalytic) site in the kinase domains of JAK1,2,3. Deucravacitinib, which is approved for the treatment of moderate to severe plaque psoriasis in adults in the United States and several other countries, represents a novel, targeted systemic treatment approach with a favorable safety profile. J Drugs Dermatol. 2024;23(8):645-652.&nbsp; doi:10.36849/JDD.8293.

Gamma-delta T-cell large granular lymphocytic leukemia in the setting of rheumatologic diseases.

T-cell leukemia originating from large granular lymphocytes (T-LGL leukemia) is a rare lymphoid neoplasia characterized by clonal proliferation of large granular T lymphocytes expressing αβ or γδ T-cell receptor (TCR) on the cell membrane. γδT-LGL leukemia, accounting for approximately 17% of all T-LGL leukemia cases, is associated with autoimmune diseases. However, the features of γδT-LGL leukemia in patients with rheumatologic diseases are still insufficiently characterized. In this retrospective study, 15 patients with rheumatologic disease-associated γδT-LGL leukemia were included. The patients were obtained from a single center from 2008 to 2023. Data related to clinical characteristics and rheumatologic diagnoses were collected. Immunophenotype evaluations as well as T-lymphocyte clonality (based on TCR-γ, TCR-β, and TCR-δ gene rearrangements), and signal transducer and activator of transcription (STAT) three and STAT5B mutation analyses (by next-generation sequencing) were performed on blood, bone marrow, and spleen samples. All but one patient had rheumatoid arthritis (RA). In 36% of patients, manifestations of γδT-LGL leukemia were present before or concurrently with clinical manifestations of RA. Splenomegaly was observed in 60% of patients and neutropenia (<1.5 × 109/L) was detected in 93% of cases. CD4-/CD8- and CD4-/CD8+ subtypes were detected in seven cases each. Mutations in STAT3 were detected in 80% of patients; however, STAT5B mutations were not detected. Evaluations of T-cell clonality and variant allele frequencies at STAT3 in the blood, bone marrow, and spleen tissue revealed an unusual variant of CD4-/CD8- γδT-LGL leukemia with predominant involvement of the spleen, involvement of the bone marrow to a less extent, and no tumor cells in peripheral blood. The mechanism by which γδT-LGL leukemia may induce the development of RA in some patients requires further investigation. Cases of RA-associated γδT-LGL leukemia with neutropenia and splenomegaly but no detectable tumor-associated lymphocytes in peripheral blood (the so-called splenic variant of T-LGL leukemia) are difficult to diagnose and may be misdiagnosed as Felty syndrome or hepatosplenic T-cell lymphoma.

African Swine Fever Virus Immunosuppression and Virulence-Related Gene.

African swine fever virus (ASFV), a highly contagious pathogen characterized by a complex structure and a variety of immunosuppression proteins, causes hemorrhagic, acute, and aggressive infectious disease that severely injures the pork products and industry. However, there is no effective vaccine or treatment. The main reasons are not only the complex mechanisms that lead to immunosuppression but also the unknown functions of various proteins. This review summarizes the interaction between ASFV and the host immune system, along with the involvement of virulence-related genes and proteins, as well as the corresponding molecular mechanism of immunosuppression of ASFV, encompassing pathways such as cGAS-STING, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus Kinase (JAK) and JAK Signal Transducers and Activators of Transcription (STAT), apoptosis, and other modulation. The aim is to summarize the dynamic process during ASFV infection and entry into the host cell, provide a rational insight into development of a vaccine, and provide a better clear knowledge of how ASFV impacts the host.