RÉSUMÉ
Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health. Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases. These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.
Sujet(s)
Exercice physique , Interleukine-15 , Muscles squelettiques , Interleukine-15/métabolisme , Muscles squelettiques/métabolisme , Humains , Animaux , Exercice physique/physiologie , Locomotion , Souris , p38 Mitogen-Activated Protein Kinases/métabolisme , Transduction du signal , Mâle , Système de signalisation des MAP kinases , Obésité/métabolismeRÉSUMÉ
Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR-induced toxicity and improved the survival of iPSC-derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72.
Sujet(s)
Sclérose latérale amyotrophique , Protéine C9orf72 , Expansion de séquence répétée de l'ADN , Démence frontotemporale , Cellules souches pluripotentes induites , Neurones , Protéine C9orf72/génétique , Protéine C9orf72/métabolisme , Sclérose latérale amyotrophique/génétique , Sclérose latérale amyotrophique/métabolisme , Sclérose latérale amyotrophique/anatomopathologie , Humains , Démence frontotemporale/génétique , Démence frontotemporale/métabolisme , Démence frontotemporale/anatomopathologie , Neurones/métabolisme , Neurones/anatomopathologie , Cellules souches pluripotentes induites/métabolisme , Expansion de séquence répétée de l'ADN/génétique , Élongation de la traduction , p38 Mitogen-Activated Protein Kinases/métabolisme , p38 Mitogen-Activated Protein Kinases/génétique , Stress physiologique/génétique , Ribosomes/métabolisme , Ribosomes/génétiqueRÉSUMÉ
Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood-brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher ß-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction.
Sujet(s)
Barrière hémato-encéphalique , Vieillissement de la cellule , Cellules endothéliales , Peroxyde d'hydrogène , Facteur de transcription NF-kappa B , Stress oxydatif , Sénothérapie , p38 Mitogen-Activated Protein Kinases , Stress oxydatif/effets des médicaments et des substances chimiques , Humains , Vieillissement de la cellule/effets des médicaments et des substances chimiques , Cellules endothéliales/métabolisme , Cellules endothéliales/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolisme , Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Barrière hémato-encéphalique/métabolisme , Barrière hémato-encéphalique/anatomopathologie , Sénothérapie/pharmacologie , Peroxyde d'hydrogène/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Protéine-1 de la zonula occludens/métabolismeRÉSUMÉ
To explore the effect of Hei Xiaoyaosan on autophagy levels in Alzheimer's disease(AD). A total of 100 4-month-old Wistar male rats were randomly selected as a blank group, and 10 rats were taken as a sham operation group and injected with 1 µL of normal saline on both sides of the hippocampus. The other rats were injected with Aß_(1-42) solution in the hippocampus to replicate the AD model. Fifty successfully modeled rats were selected and randomly divided into the model group, Aricatio group(0.5 mg·kg~(-1)), and high, medium, and low dose groups of Hei Xiaoyaosan(15.30, 7.65, and 3.82 g·kg~(-1)), with 10 rats in each group. The rats were administered by continuous gavage for 42 days. Morris water maze was used to detect the learning and memory ability of rats, and Hoechst staining was used to observe the pathological changes of nerve cells in the hippocampal CA1 region. The mRNA expression of p38MAPK, Beclin-1, and Bcl-2 was detected by RT-qPCR.Western blot was used to detect the expressions of p38MAPK, Beclin-1, Bcl-2, APP, and related proteins. The level of Aß_(1-42) in the hippocampus was detected by ELISA, and the expression level of LC3â ¡ in the hippocampus was detected by immunohistochemistry. The experimental results showed that compared with the blank group, the learning and memory ability of rats in the model group decreased(P<0.01). The nuclei in the CA1 region of the hippocampus showed blue bright spots and were closely arranged. The mRNA expression of p38MAPK was up-regulated, and the mRNA expressions of Beclin-1 and Bcl-2 were down-regulated(P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were increased, while those of Beclin-1, Bcl-2, and p-Bcl-2 were decreased(P<0.01). The expression of Aß_(1-42) was increased(P<0.01). The relative expression of LC3â ¡ decreased(P<0.01). Compared with the model group, the learning and memory ability of rats in each administration group was improved(P<0.05 or P<0.01). The nuclei in the CA1 region of the hippocampus gradually became clear, showing light blue. The mRNA expression of p38MAPK was down-regulated(P<0.01), and that of Beclin-1 and Bcl-2 was increased(P<0.05 or P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were down-regulated, while those of Beclin-1, Bcl-2, and p-Bcl-2 were up-regulated(P<0.05 or P<0.01). The expression of Aß_(1-42) was decreased(P<0.01). The relative expression of LC3â ¡ was increased(P<0.01). It can be concluded that Hei Xiaoyaosan can improve the cognitive ability of AD model rats, and its potential mechanism may be related to regulating the p38MAPK/Beclin-1/Bcl-2 signaling pathway, increasing the level of autophagy, and reducing the accumulation of Aß_(1-42).
Sujet(s)
Maladie d'Alzheimer , Autophagie , Bécline-1 , Modèles animaux de maladie humaine , Médicaments issus de plantes chinoises , Protéines proto-oncogènes c-bcl-2 , Rat Wistar , p38 Mitogen-Activated Protein Kinases , Animaux , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/génétique , Mâle , Rats , Médicaments issus de plantes chinoises/administration et posologie , Médicaments issus de plantes chinoises/pharmacologie , Autophagie/effets des médicaments et des substances chimiques , p38 Mitogen-Activated Protein Kinases/métabolisme , p38 Mitogen-Activated Protein Kinases/génétique , Bécline-1/métabolisme , Bécline-1/génétique , Protéines proto-oncogènes c-bcl-2/métabolisme , Protéines proto-oncogènes c-bcl-2/génétique , Humains , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Objective: This study aims to systematically evaluate the protective role of quercetin (QCT), a naturally occurring flavonoid, against oxidative damage in human endometrial stromal cells (HESCs) induced by hydrogen peroxide (H2O2). Oxidative stress, such as that induced by H2O2, is known to contribute significantly to cellular damage and has been implicated in various reproductive health issues. The study is focused on investigating how QCT interacts with specific molecular pathways to mitigate this damage. Special attention was given to the p38 MAPK/NOX4 signaling pathway, which is crucial to the regulation of oxidative stress responses in cellular systems. By elucidating these mechanisms, the study seeks to confirm the potential of QCT not only as a protective agent against oxidative stress but also as a therapeutic agent that could be integrated in treatments of conditions characterized by heightened oxidative stress in endometrial cells. Methods: I n vitro cultures of HESCs were treated with QCT at different concentrations (0, 10, 20, and 40 µmol/L) for 24 h to verify the non-toxic effects of QCT on normal endometrial cells. Subsequently, 250 µmol/L H2O2 was used to incubate the cells for 12 h to establish an H2O2-induced HESCs injury model. HESCs were pretreated with QCT for 24 h, which was followed by stimulation with H2O2. Then, CCK-8 assay was performed to examine the cell viability and to screen for the effective intervention concentration. HESCs were divided into 3 groups, the control group, the H2O2 model group, and the H2O2+QCT group. Intracellular levels of reactive oxygen species (ROS) were precisely quantified using the DCFH-DA fluorescence assay, a method known for its accuracy in detecting and quantifying oxidative changes within the cell. The mitochondrial membrane potential was determined by JC-1 staining. Annexin â ¤/PI double staining and flow cytometry were performed to determine the effect of QCT on H2O2-induced apoptosis of HESCs. Furthermore, to delve deeper into the cellular mechanisms underlying the observed effects, Western blot analysis was conducted to measure the expression levels of the critical proteins involved in oxidative stress response, including NADPH oxidase 4 (NOX4), p38 mitogen-activated protein kinase (p38 MAPK), and phosphorylated p38 MAPK (p-p38 MAPK). This analysis helps increase understanding of the specific intracellular signaling pathways affected by QCT treatment, giving special attention to its potential for modulation of the p38 MAPK/NOX4 pathway, which plays a significant role in cellular defense mechanisms against oxidative stress. Results: In this study, we started off by assessing the toxicity of QCT on normal endometrial cells. Our findings revealed that QCT at various concentrations (0, 10, 20, and 40 µmol/L) did not exhibit any cytotoxic effects, which laid the foundation for further investigation into its protective roles. In the H2O2-induced HESCs injury model, a significant reduction in cell viability was observed, which was linked to the generation of ROS and the resultant oxidative damage. However, pretreatment with QCT (10 µmol/L and 20 µmol/L) significantly enhanced cell viability after 24 h (P<0.05), with the 20 µmol/L concentration showing the most substantial effect. This suggests that QCT can effectively reverse the cellular damage caused by H2O2. Furthermore, the apoptosis assays demonstrated a significant increase in the apoptosis rates in the H2O2 model group compared to those in the control group (P<0.01). However, co-treatment with QCT significantly reversed this trend (P<0.05), indicating QCT's potential protective role in mitigating cell apoptosis. ROS assays showed that, compared to that in the control group, the average fluorescence intensity of ROS in the H2O2 model group significantly increased (P<0.01). QCT treatment significantly reduced the ROS fluorescence intensity in the H2O2+QCT group compared to the that in the H2O2 model group, suggesting an effective alleviation of oxidative damage (P<0.05). JC-1 staining for mitochondrial membrane potential changes revealed that compared to that in the control, the proportion of cells with decreased mitochondrial membrane potential significantly increased in the H2O2 model group (P<0.01). However, this proportion was significantly reduced in the QCT-treated group compared to that of the H2O2 model group (P<0.05). Finally, Western blot analysis indicated that the expression levels of NOX4 and p-p38 MAPK proteins were elevated in the H2O2 model group compared to those of the control group (P<0.05). Following QCT treatment, these protein levels significantly decreased compared to those of the H2O2 model group (P<0.05). These results suggest that QCT may exert its protective effects against oxidative stress by modulating the p38 MAPK/NOX4 signaling pathway. Conclusion: QCT has demonstrated significant protective effects against H2O2-induced oxidative damage in HESCs. This protection is primarily achieved through the effective reduction of ROS accumulation and the inhibition of critical signaling pathways involved in the oxidative stress response, notably the p38 MAPK/NOX4 pathway. The results of this study reveal that QCT's ability to modulate these pathways plays a key role in alleviating cellular damage associated with oxidative stress conditions. This indicates not only its potential as a protective agent against cellular oxidative stress, but also highlights its potential for therapeutic applications in treating conditions characterized by increased oxidative stress in the endometrium, thereby offering the prospect of enhancing reproductive health. Future studies should explore the long-term effects of QCT and its clinical efficacy in vivo, thereby providing a clear path toward its integration into therapeutic protocols.
Sujet(s)
Endomètre , Peroxyde d'hydrogène , Stress oxydatif , Quercétine , Transduction du signal , Cellules stromales , Femelle , Humains , Apoptose/effets des médicaments et des substances chimiques , Cellules cultivées , Endomètre/cytologie , Endomètre/effets des médicaments et des substances chimiques , Endomètre/métabolisme , Peroxyde d'hydrogène/toxicité , NADPH Oxidase 4/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , p38 Mitogen-Activated Protein Kinases/métabolisme , Quercétine/pharmacologie , Espèces réactives de l'oxygène/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Cellules stromales/effets des médicaments et des substances chimiques , Cellules stromales/métabolismeRÉSUMÉ
2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.
Sujet(s)
Acinetobacter baumannii , Caenorhabditis elegans , Lipopolysaccharides , Macrophages , Choc septique , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Souris , Acinetobacter baumannii/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Choc septique/traitement médicamenteux , Choc septique/induit chimiquement , Choc septique/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Peptides antimicrobiens/pharmacologie , Peptides antimicrobiens/composition chimique , Humains , p38 Mitogen-Activated Protein Kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Inflammation/traitement médicamenteux , Inflammation/métabolisme , Antibactériens/pharmacologie , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/composition chimique , Stress oxydatif/effets des médicaments et des substances chimiques , Mitogen-Activated Protein Kinases , Protéines de Caenorhabditis elegansRÉSUMÉ
This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor ß-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-ß1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-ß1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-ß1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk.
Sujet(s)
Protéines adaptatrices de la transduction du signal , Maladies cardiovasculaires , Vieillissement de la cellule , Progéniteurs endothéliaux , Agranulocytes , microARN , p38 Mitogen-Activated Protein Kinases , microARN/génétique , microARN/métabolisme , Humains , Progéniteurs endothéliaux/métabolisme , Vieillissement de la cellule/génétique , Agranulocytes/métabolisme , Adulte d'âge moyen , Protéines adaptatrices de la transduction du signal/génétique , Protéines adaptatrices de la transduction du signal/métabolisme , Mâle , Maladies cardiovasculaires/génétique , Maladies cardiovasculaires/métabolisme , Maladies cardiovasculaires/anatomopathologie , p38 Mitogen-Activated Protein Kinases/métabolisme , p38 Mitogen-Activated Protein Kinases/génétique , Femelle , Sujet âgé , Néovascularisation physiologique/génétique , Facteur de croissance transformant bêta-1/métabolisme , Facteur de croissance transformant bêta-1/génétique , Adulte , Facteurs de risqueRÉSUMÉ
We aimed to study the reparative effects of orientin against spinal cord injury (SCI) in rats and explore its potential mechanisms. Sprague-Dawley rats were divided into Sham, SCI, Orientin, and SB203580 [an inhibitor of p38 mitogen-activated protein kinase (p38MAPK)] groups. In the SCI group, rats underwent Allen's beat. SCI animals in Orientin and SB203580 groups were respectively treated with 40â mgâ kg-1 orientin and 3â mgâ kg-1 SB203580 once daily. Functional recovery was evaluated based on Basso, Beattie, and Bresnahan scoring. Histopathological analysis was performed using hematoxylin-eosin and Nissl staining. Cell apoptosis was examined by TUNEL staining. The relative quantity of apoptosis-related proteins, glial fibrillary acidic protein (GFAP), neurofilament 200 (NF200), and brain derived neurotrophic factor (BDNF) was detected via western blotting. The indices related to inflammation and oxidation were measured using agent kits. The p38MAPK/inducible nitric oxide synthase (iNOS) signaling activity was detected using real-time quantitative PCR, western blotting, and immunohistochemical staining. Orientin was revealed to effectively mitigate cell apoptosis, neuroinflammation, and oxidative stress in impaired tissues. Meanwhile, orientin exerted great neuroprotective effects by abating GFAP expression, and up-regulating the expression of NF200 and BDNF, and significantly suppressed the p38MAPK/iNOS signaling. Orientin application could promote the repair of secondary SCI through attenuating oxidative stress and inflammatory response, reducing cell apoptosis and suppressing p38MAPK/iNOS signaling.
Sujet(s)
Apoptose , Flavonoïdes , Glucosides , Neuroprotecteurs , Rat Sprague-Dawley , Traumatismes de la moelle épinière , Animaux , Traumatismes de la moelle épinière/métabolisme , Traumatismes de la moelle épinière/traitement médicamenteux , Traumatismes de la moelle épinière/anatomopathologie , Neuroprotecteurs/pharmacologie , Flavonoïdes/pharmacologie , Rats , Apoptose/effets des médicaments et des substances chimiques , Glucosides/pharmacologie , Glucosides/usage thérapeutique , Mâle , p38 Mitogen-Activated Protein Kinases/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Récupération fonctionnelle/effets des médicaments et des substances chimiques , Récupération fonctionnelle/physiologie , Imidazoles/pharmacologie , PyridinesRÉSUMÉ
This study aimed to investigate a synergistic anti-inflammatory effect of a citrus flavonoid nobiletin and docosahexaenoic acid (DHA), one of n-3 long-chain polyunsaturated fatty acids, in combination. Simultaneous treatment with nobiletin and DHA synergistically inhibited nitric oxide production (combination index < 0.9) by mouse macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS) without cytotoxicity. On the other hand, the inhibitory effect of nobiletin and DHA in combination on proinflammatory cytokine production was not synergistic. Neither nobiletin nor DHA affected the phagocytotic activity of RAW 264.7 cells stimulated with LPS. Immunoblot analysis revealed that the inhibition potency of DHA on the phosphorylation of ERK and p38 and nuclear translocation of NF-κB is markedly enhanced by simultaneously treating with nobiletin, which may lead to the synergistic anti-inflammatory effect. Overall, our findings show the potential of the synergistic anti-inflammatory effect of nobiletin and DHA in combination.
Sujet(s)
Anti-inflammatoires , Acide docosahexaénoïque , Synergie des médicaments , Flavones , Lipopolysaccharides , Macrophages , Monoxyde d'azote , Animaux , Souris , Flavones/pharmacologie , Lipopolysaccharides/pharmacologie , Cellules RAW 264.7 , Anti-inflammatoires/pharmacologie , Acide docosahexaénoïque/pharmacologie , Monoxyde d'azote/métabolisme , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Phosphorylation/effets des médicaments et des substances chimiques , Phagocytose/effets des médicaments et des substances chimiques , Cytokines/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolismeRÉSUMÉ
Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-ß (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-ß inhibitor, IC50 114.3 µM), losmapimod (p38 inhibitor, IC50 17.6 µM) and SP600125 (c-Jun inhibitor, IC50 3.9 µM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.
Sujet(s)
Cardiomyopathie associée à la maladie de Chagas , Fibrose , Souris de lignée C57BL , Pyridones , Animaux , Pyridones/pharmacologie , Pyridones/usage thérapeutique , Cardiomyopathie associée à la maladie de Chagas/traitement médicamenteux , Cardiomyopathie associée à la maladie de Chagas/parasitologie , Cardiomyopathie associée à la maladie de Chagas/métabolisme , Cardiomyopathie associée à la maladie de Chagas/anatomopathologie , Souris , Fibroblastes/effets des médicaments et des substances chimiques , Fibroblastes/métabolisme , Fibroblastes/parasitologie , Myocarde/anatomopathologie , Myocarde/métabolisme , Collagène/métabolisme , Trypanosoma cruzi/effets des médicaments et des substances chimiques , Humains , Maladie chronique , Facteur de croissance transformant bêta/métabolisme , Modèles animaux de maladie humaine , p38 Mitogen-Activated Protein Kinases/métabolisme , Mâle , AnthracènesRÉSUMÉ
Drug repositioning is a method for exploring new effects of existing drugs, the safety and pharmacokinetics of which have been confirmed in humans. Here, we demonstrate the potential drug repositioning of midazolam (MDZ), which is used for intravenous sedation, as an inhibitor of inflammatory bone resorption. We cultured a mouse macrophage-like cell line with or without MDZ and evaluated its effects on the induction of differentiation of these cells into osteoclasts. For in vivo investigations, we administered lipopolysaccharide (LPS) together with MDZ (LPS+MDZ) to the parietal region of mice and evaluated the results based on the percentage of bone resorption and calvaria volume. Furthermore, we examined the effects of MDZ on the production of reactive oxygen species (ROS) in cells and on its signaling pathway. MDZ inhibited osteoclast differentiation and bone resorption activity. In animal studies, the LPS+MDZ group showed a decreasing trend associated with the rate of bone resorption. In addition, the bone matrix volume in the LPS+MDZ group was slightly higher than in the LPS only group. MDZ inhibited osteoclast differentiation by decreasing ROS production and thereby negatively regulating the p38 mitogen-activated protein kinase pathway. Thus, we propose that MDZ could potentially be used for treating inflammatory bone resorption, for example, in periodontal disease.
Sujet(s)
Résorption osseuse , Différenciation cellulaire , Repositionnement des médicaments , Lipopolysaccharides , Midazolam , Ostéoclastes , Espèces réactives de l'oxygène , Animaux , Résorption osseuse/traitement médicamenteux , Souris , Repositionnement des médicaments/méthodes , Midazolam/pharmacologie , Espèces réactives de l'oxygène/métabolisme , Ostéoclastes/effets des médicaments et des substances chimiques , Ostéoclastes/métabolisme , Différenciation cellulaire/effets des médicaments et des substances chimiques , Lipopolysaccharides/pharmacologie , p38 Mitogen-Activated Protein Kinases/métabolisme , Mâle , Inflammation/traitement médicamenteux , Inflammation/anatomopathologie , Cellules RAW 264.7 , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolismeRÉSUMÉ
Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.
Sujet(s)
Apoptose , Autophagie , Prolifération cellulaire , Tumeurs de l'ovaire , Triterpènes , Protéine p53 suppresseur de tumeur , p38 Mitogen-Activated Protein Kinases , Humains , Apoptose/effets des médicaments et des substances chimiques , Femelle , Autophagie/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/anatomopathologie , Tumeurs de l'ovaire/métabolisme , Protéine p53 suppresseur de tumeur/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolisme , Triterpènes/pharmacologie , Triterpènes/composition chimique , Relation structure-activité , Tests de criblage d'agents antitumoraux , Relation dose-effet des médicaments , Lignée cellulaire tumorale , Structure moléculaire , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Antinéoplasiques d'origine végétale/pharmacologie , Antinéoplasiques d'origine végétale/composition chimiqueRÉSUMÉ
Background: Gingivitis is an inflammation of the gums that is the initial cause of the development of periodontal disease by the activity of Nuclear Factor-kappa B (NF-κB), Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), p38, and Tumor Necrosis Factor-α (TNF-α). Unaddressed chronic inflammation can lead to persistent disturbances in other parts of the body. Brazilin is a naturally occurring plant chemical that may have antibacterial and anti-inflammatory effects. Treatment based on the natural plant compound, brazilin, is developed in the form of a topical cream for easy application. Objective: The aim is to develop the natural compound brazilin in the form of a topical cream as an anti-inflammatory agent to reduce NF-κB expression through Imunohistochemistry (IHC) methods, and the expression of pro-inflammatory genes IL-1ß, IL-6, p38, and TNF-α. Methods: Male Sprague-Dawley rats were induced with gingivitis using P. gingivalis bacteria. The observed groups included rats treated with a single application of brazilin cream and rats treated with two applications of brazilin cream. The treatment was administered for 15 days. On days 3, 6, 9, 12, and 15, anatomical wound observations and wound histology using hematoxylin-eosin and Masson's Trichrome staining were performed. NF-κB protein expression was analyzed using the IHC method. Gingival inflammation gene expression of NF-κB, IL-1ß, IL-6, p38, and TNF-α was measured using q-RTPCR. Results: Single and double applications of brazilin cream increased angiogenesis and decreased NF-κB protein expression, in addition to the IL-1ß, IL-6, p38, and TNF-α gene expressions. Conclusion: In a rat gingivitis model, Brazilin cream may function as an anti-inflammatory agent in the gingival tissue.
Sujet(s)
Benzopyranes , Caesalpinia , Gingivite , Facteur de transcription NF-kappa B , Rat Sprague-Dawley , Animaux , Caesalpinia/composition chimique , Mâle , Rats , Benzopyranes/pharmacologie , Benzopyranes/administration et posologie , Benzopyranes/usage thérapeutique , Facteur de transcription NF-kappa B/métabolisme , Gingivite/traitement médicamenteux , Gingivite/anatomopathologie , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/administration et posologie , Anti-inflammatoires/usage thérapeutique , Maladies parodontales/traitement médicamenteux , Interleukine-1 bêta/métabolisme , Interleukine-1 bêta/génétique , Modèles animaux de maladie humaine , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/génétique , Interleukine-6/métabolisme , Interleukine-6/génétique , p38 Mitogen-Activated Protein Kinases/métabolismeRÉSUMÉ
Previous studies have indicated that heterocyclic substituted dihydropyrazole derivatives, particularly MW-19, potentially exert anticancer activity in vitro; however, the underlying mechanism remains unknown. The present study was designed to investigate the mechanisms underlying MW-19 activity in triple-negative breast cancer cells. A sulforhodamine B assay was performed to evaluate cell proliferation inhibition rates, and the antitumor effect of MW-19 was evaluated in mice with HCC-1806 xenografts. Apoptosis was analyzed by Hoechst 33342 and annexin V/propidium iodide staining. Expression of pro- and antiapoptotic proteins and mRNA were analyzed by western blotting and reverse transcription-quantitative (RT-q) PCR, respectively. We found that MW-19 significantly inhibited HCC-1806 cell proliferation in a dose- and time-dependent manner, and significantly inhibited MDA-MB-231 cell migration. Importantly, oral administration of MW-19 significantly inhibited HCC-1806 tumor growth in BALB/c-nu/nu mice. Moreover, MW-19 treatment induced marked apoptosis and G2/M arrest in the sensitive cell line, HCC-1806. RT-qPCR analysis showed that levels of proapoptotic genes (Bax, caspase-3, caspase-7, and Fas) were considerably increased in the MW-19 group relative to the control group, while those of antiapoptotic factors (Bcl-2, C-MYC) were dramatically decreased. Consistently, Bax, caspase-3, and caspase-7 were significantly induced after MW-19 treatment, while levels of phosphorylated (p-)AKT, p-PI3K, p-ERK, and the antiapoptotic protein, Bcl-2, were clearly diminished, and the P38 MAPK signaling pathway was activated. Furthermore, P38 pharmacological inhibitors abrogated MW-19-induced apoptosis. Together, our findings indicate that MW-19 exerts antitumor effects by targeting PI3K/AKT and ERK/P38 signaling pathways.
Sujet(s)
Antinéoplasiques , Apoptose , Prolifération cellulaire , Souris de lignée BALB C , Pyrazoles , Tumeurs du sein triple-négatives , Apoptose/effets des médicaments et des substances chimiques , Humains , Animaux , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/métabolisme , Femelle , Lignée cellulaire tumorale , Pyrazoles/composition chimique , Pyrazoles/pharmacologie , Pyrazoles/synthèse chimique , Souris , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Protéines proto-oncogènes c-akt/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Souris nude , Mouvement cellulaire/effets des médicaments et des substances chimiques , p38 Mitogen-Activated Protein Kinases/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe , Phosphatidylinositol 3-kinases/métabolismeRÉSUMÉ
CDK5RAP3 is a recognized tumor suppressor that inhibits Chk1 and Chk2 and activates p53, all of which are involved with mediating toxin-induced apoptosis of cancer cells. CDK5RAP3 also inhibits p38MAPK phosphorylation and activity via mediating a p38 interaction with wild-type p53-induced phosphatase 1. This study aimed to investigate the antiangiogenic activity of CDK5RAP3 and its molecular mechanisms in human umbilical vein endothelial cells (HUVECs) under conditions of hypoxic conditions. Angiogenesis was induced in HUVECs mainly by vascular endothelial growth factor (VEGF). The CDK5RAP3 levels of HUVECs were reduced in a time-dependent manner in response to hypoxic treatment at 2% O2. The reduction of CDK5RAP3 was accompanied with increased p38MAPK phosphorylation and activation. Moderate hypoxia was found to significantly increase secreted VEGF concentrations, and the hypoxic conditioned medium (HCM) markedly enhanced proliferation, migration, and tube formation. Our findings indicate that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3. CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.
Sujet(s)
Protéines du cycle cellulaire , Cellules endothéliales de la veine ombilicale humaine , Néovascularisation physiologique , p38 Mitogen-Activated Protein Kinases , Humains , p38 Mitogen-Activated Protein Kinases/métabolisme , Protéines du cycle cellulaire/métabolisme , Néovascularisation physiologique/physiologie , Protéines de tissu nerveux/métabolisme , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Mouvement cellulaire , Prolifération cellulaire , Cellules cultivées , Hypoxie cellulaire/physiologie , Phosphorylation , , Protéines suppresseurs de tumeursRÉSUMÉ
Sodium tanshinone IIA sulfonate (STS), which is extracted from a Chinese medicinal herb, possesses many pharmacologic functions, such as coronary dilation, anti-inflammatory properties, and antiapoptotic and antioxidant effects. It remains unknown whether STS can protect cardiomyocytes injured after radiation therapy. An in vitro Sprague-Dawley (SD) rat neonatal cardiomyocyte system was established. Primary cardiomyocytes (PCMs) from neonatal SD rats were isolated under sterile conditions. PCM cells were divided into a control group (0 Gy/hour) and 5 experimental radiation therapy groups (0.25 Gy/hour, 0.5 Gy/hour, 1 Gy/hour, 2 Gy/hour, and 4 Gy/hour). Cell viability, the content of malondialdehyde (MDA), the lactate dehydrogenase (LDH) leakage rate, and superoxide dismutase (SOD) and glutathione (GSH) activities were recorded separately in each group after 7 days of culture. Western blot was used to detect the levels of p38, caspase-3 protein, and X protein (BAX) associated with B-cell lymphoma 2 (Bcl-2) in PCMs. X-rays inhibited cell growth, decreased cell viability, and induced an oxidative stress response in PCMs. STS and SB203580 (the inhibitor of P38 mitogen-activated protein kinase pathway) alleviated X-ray-induced damage to PCMs. An enzyme-linked immunosorbent assay showed that X-rays increased the cTnT level. STS and SB203580 ameliorated the X-ray-induced increase in cTnT leakage. X-rays enhanced the expression of p38/p-p38 and caspase-3 while reducing the expression of Bcl-2/BAX in PCMs, as demonstrated by western blotting. STS and SB203580 mitigated the changes in protein expression triggered by X-ray radiation. In conclusions, STS was shown to exert significant cardioprotective, anti-inflammatory, and antioxidant effects in PCMs by inhibiting the p38 mitogen-activated protein kinase pathway.
Sujet(s)
Myocytes cardiaques , Phénanthrènes , Rat Sprague-Dawley , p38 Mitogen-Activated Protein Kinases , Animaux , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Myocytes cardiaques/effets des radiations , Rats , Phénanthrènes/pharmacologie , p38 Mitogen-Activated Protein Kinases/métabolisme , Cellules cultivées , Animaux nouveau-nés , Survie cellulaire/effets des médicaments et des substances chimiques , Stress oxydatif/effets des médicaments et des substances chimiques , Apoptose/effets des médicaments et des substances chimiques , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Antioxydants/pharmacologieRÉSUMÉ
Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1ß levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1ß. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.
Sujet(s)
Encéphalopathie ischémique , Aescine , Inflammasomes , Pyroptose , Récepteurs aux glucocorticoïdes , Transduction du signal , Animaux , Humains , Mâle , Rats , Encéphalopathie ischémique/traitement médicamenteux , Encéphalopathie ischémique/métabolisme , Cellules Caco-2 , Modèles animaux de maladie humaine , Aescine/pharmacologie , Aescine/usage thérapeutique , Infarctus du territoire de l'artère cérébrale moyenne/traitement médicamenteux , Infarctus du territoire de l'artère cérébrale moyenne/anatomopathologie , Infarctus du territoire de l'artère cérébrale moyenne/immunologie , Inflammasomes/métabolisme , Interleukine-1 bêta/métabolisme , Intestins/anatomopathologie , Intestins/effets des médicaments et des substances chimiques , Intestins/immunologie , Lipopolysaccharides , Facteur de transcription NF-kappa B/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolisme , Pyroptose/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Récepteurs aux glucocorticoïdes/métabolisme , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Autoimmune hepatitis (AIH) is a chronic liver disease characterized by immune dysregulation and hepatocyte damage. FKBP38, a member of the immunophilin family, has been implicated in immune regulation and the modulation of intracellular signaling pathways; however, its role in AIH pathogenesis remains poorly understood. In this study, we aimed to investigate the effects of hepatic FKBP38 deletion on AIH using a hepatic FKBP38 knockout (LKO) mouse model created via cre-loxP technology. We compared the survival rates, incidence, and severity of AIH in LKO mice with those in control mice. Our findings revealed that hepatic FKBP38 deletion resulted in an unfavorable prognosis in LKO mice with AIH. Specifically, LKO mice exhibited heightened liver inflammation and extensive hepatocyte damage compared to control mice, with a significant decrease in anti-apoptotic proteins and a marked increase in pro-apoptotic proteins. Additionally, transcriptional and translational levels of pro-inflammatory cytokines and chemokines were significantly increased in LKO mice compared to control mice. Immunoblot analysis showed that MCP-1 expression was significantly elevated in LKO mice. Furthermore, the phosphorylation of p38 was increased in LKO mice with AIH, indicating that FKBP38 deletion promotes liver injury in AIH by upregulating p38 phosphorylation and increasing MCP-1 expression. Immune cell profiling demonstrated elevated populations of T, NK, and B cells, suggesting a dysregulated immune response in LKO mice with AIH. Overall, our findings suggest that FKBP38 disruption exacerbates AIH severity by augmenting the immune response by activating the MCP-1/p38 signaling pathway.
Sujet(s)
Chimiokine CCL2 , Hépatite auto-immune , Protéines de liaison au tacrolimus , p38 Mitogen-Activated Protein Kinases , Animaux , Mâle , Souris , Chimiokine CCL2/métabolisme , Chimiokine CCL2/génétique , Concanavaline A , Modèles animaux de maladie humaine , Hépatite auto-immune/immunologie , Foie/anatomopathologie , Foie/immunologie , Foie/métabolisme , Souris de lignée C57BL , Souris knockout , p38 Mitogen-Activated Protein Kinases/métabolisme , Transduction du signal , Protéines de liaison au tacrolimus/génétique , Protéines de liaison au tacrolimus/métabolismeRÉSUMÉ
The aim of this study was to investigate the signaling pathways involved in the proliferation and differentiation of pig Sertoli cells (SCs) mediated by thyroid hormone (T3) to provide a theoretical and practical basis for enhancing pig semen production. The effects of different concentrations of T3 on the proliferation of pig SCs were evaluated using the CCK8 assay. The impact of T3 on the proliferation and differentiation of pig SCs was further examined using RNA-seq, qPCR, and Western Blotting techniques. Additionally, the involvement of the p38 MAPK and NFκB pathways in mediating the effects of T3 on SCs proliferation and differentiation was investigated. Our findings revealed a strong correlation between the dosage of T3 and the inhibition of pig SCs proliferation and promotion of maturation. T3 regulated the activation state of the NFκB signaling pathway by upregulating IKKα, downregulating IKKß, and promoting IκB phosphorylation. Furthermore, T3 facilitated SCs maturation by upregulating AR and FSHR expression while downregulating KRT-18. In conclusion, T3 inhibits pig SCs proliferation and promote pig SCs maturation through the IKK/NFκB and p38 MAPK pathways. These findings provide valuable insights into the mechanisms by which T3 influences the proliferation and maturation of pig SCs.
Sujet(s)
Prolifération cellulaire , Facteur de transcription NF-kappa B , Cellules de Sertoli , Transduction du signal , Thyroxine , p38 Mitogen-Activated Protein Kinases , Animaux , Mâle , Suidae , Cellules de Sertoli/effets des médicaments et des substances chimiques , Cellules de Sertoli/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , p38 Mitogen-Activated Protein Kinases/métabolisme , p38 Mitogen-Activated Protein Kinases/génétique , Facteur de transcription NF-kappa B/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Thyroxine/pharmacologie , Lignée cellulaire , I-kappa B Kinase/métabolisme , I-kappa B Kinase/génétique , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Différenciation cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
The Type-I interferon (IFN-I) response is the major outcome of stimulator of interferon genes (STING) activation in innate cells. STING is more abundantly expressed in adaptive T cells; nevertheless, its intrinsic function in T cells remains unclear. Intriguingly, we previously demonstrated that STING activation in T cells activates widespread IFN-independent activities, which stands in contrast to the well-known STING-mediated IFN response. Here, we have identified that STING activation induces regulatory T cells (Tregs) differentiation independently of IRF3 and IFN. Specifically, the translocation of STING from the endoplasmic reticulum to the Golgi activates mitogen-activated protein kinase (MAPK) activity, which subsequently triggers transcription factor cAMP response element-binding protein (CREB) activation. The activation of the STING-MAPK-CREB signaling pathway induces the expression of many cytokine genes, including interleukin-2 (IL-2) and transforming growth factor-beta 2 (TGF-ß2), to promote the Treg differentiation. Genetic knockdown of MAPK p38 or pharmacological inhibition of MAPK p38 or CREB markedly inhibits STING-mediated Treg differentiation. Administration of the STING agonist also promotes Treg differentiation in mice. In the Trex1-/- autoimmune disease mouse model, we demonstrate that intrinsic STING activation in CD4+ T cells can drive Treg differentiation, potentially counterbalancing the autoimmunity associated with Trex1 deficiency. Thus, STING-MAPK-CREB represents an IFN-independent signaling axis of STING that may have profound effects on T cell effector function and adaptive immunity.