关键词： Premature ovarian failure   miR-22-3p   hUCMSCs   Granulosa cells   KLF6   EPITHELIAL-CELLS  

摘要： Background: Human umbilical cord mesenchymal stem cells (hUCMSCs)-derived exosomes carrying microRNAs (miRNAs) have promising therapeutic potential in various disorders, including premature ovarian failure (POF). Previous evidence has revealed the low plasma level of miR-22-3p in POF patients. Nevertheless, exosomal miR-22-3p specific functions underlying POF progression are unclarified. Methods: A cisplatin induced POF mouse model and in vitro murine ovarian granulosa cell (mOGC) model were established. Exosomes derived from miR-22-3p-overexpressed hUCMSCs (Exos-miR-22-3p) were isolated. CCK-8 assay and flow cytometry were utilized for measuring mOGC cell viability and apoptosis. RT-qPCR and western blotting were utilized for determining RNA and protein levels. The binding ability between exosomal miR-22-3p and Kruppel-like factor 6 (KLF6) was verified using luciferase reporter assay. Hematoxylin-eosin staining, ELISA, and TUNEL staining were performed for examining the alteration of ovarian function in POF mice. Results: Exos-miR-22-3p enhanced mOGC viability and attenuated mOGC apoptosis under cisplatin treatment. miR-22-3p targeted KLF6 in mOGCs. Overexpressing KLF6 reversed the above effects of Exos-miR-22-3p. Exos-miR-22-3p ameliorated cisplatin-triggered ovarian injury in POF mice. Exos-miR-22-3p repressed ATF4-ATF3-CHOP pathway in POF mice and cisplatin-treated mOGCs. Conclusion: Exosomal miR-22-3p from hUCMSCs alleviates OGC apoptosis and improves ovarian function in POF mouse models by targeting KLF6 and ATF4-ATF3-CHOP pathway.

摘要： This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://***/about/policies/article-withdrawal.

关键词： GENE-EXPRESSION   CHIP-SEQ   R/BIOCONDUCTOR PACKAGE   QUALITY-CONTROL   TRANSCRIPTOME   EPIGENETICS   HALLMARKS   SNAP-25   CELL  

摘要： Epigenetic remodeling is emerging as a critical process for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Genetics alone fails to explain the etiology of ALS, the investigation of the epigenome might therefore provide novel insights into the molecular mechanisms of the disease. In this study, we interrogated the epigenetic landscape in peripheral blood mononuclear cells (PBMCs) of familial ALS (fALS) patients with either chromosome 9 open reading frame 72 (C9orf72) or superoxide dismutase 1 (SOD1) mutation and aimed to identify key epigenetic footprints of the disease. To this end, we used an integrative approach that combines chromatin immunoprecipitation targeting H3K27me3 (ChIP-Seq) with the matching gene expression data to gain new insights into the likely impact of blood-specific chromatin remodeling on ALS-related molecular mechanisms. We demonstrated that one of the hub molecules that modulates changes in PBMC transcriptome in SOD1-mutant ALS patients is ATF3, which has been previously reported in an SOD1(G93A) mouse model. We also identified potential suppression of SNAP25, with impaired ATF3 signaling in SOD1-mutant ALS blood. Together, our study shed light on the mechanistic underpinnings of SOD1 mutations in ALS.

关键词： IRG1   Inflammation   Myocardial injury   Doxorubicin   NRF2   ATF3   OXIDATIVE STRESS   MACROPHAGE   INNATE   EXPRESSION   ITACONATE   GENE-1   DOXORUBICIN   MODULATION   ACTIVATION   METABOLITE  

摘要： Acute myocardial infarction (MI) and chemotherapeutic drug administration can induce myocardial damage and cardiomyocyte cell death, and trigger the release of damage-associated molecular patterns (DAMPs) that initiate the aseptic inflammatory response. The moderate inflammatory response is beneficial for repairing damaged myocardium, while an excessive inflammatory response exacerbates myocardial injury, promotes scar formation, and results in a poor prognosis of cardiac diseases. Immune responsive gene 1 (IRG1) is specifically highly expressed in activated macrophages and mediates the production of tricarboxylic acid (TCA) cycle metabolite itaconate. However, the role of IRG1 in the inflammation and myocardial injury of cardiac stress-related diseases remains unknown. Here, we found that IRG1 knockout mice exhibited increased cardiac tissue inflammation and infarct size, aggravated myocardial fibrosis, and impaired cardiac function after MI and in vivo doxorubicin (Dox) administration. Mechanically, IRG1 deficiency enhanced the production of IL-6 and IL-1 beta by suppressing the nuclear factor red lineage 2-related factor 2 (NRF2) and activating transcription factor 3 (ATF3) pathway in cardiac macrophages. Importantly, 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, reversed the inhibited expression of NRF2 and ATF3 caused by IRG1 deficiency. Moreover, in vivo 4-OI administration inhibited the cardiac inflammation and fibrosis, and prevented adverse ventricle remodeling in IRG1 knockout mice with MI or Dox-induced myocardial injury. Our study uncovers the critical protective role of IRG1 in suppressing inflammation and preventing cardiac dysfunction under ischemic or toxic injury conditions, providing a potential target for the treatment of myocardial injury.

关键词： Acsl4   Astragaloside IV   Atf3   ferroptosis   Fto   ACTIVATING TRANSCRIPTION FACTOR-3   BRAIN-INJURY   ACSL4   MECHANISMS  

摘要： Ischemic stroke (IS) is a detrimental neurological disease with limited treatment options. Astragaloside IV (As-IV) was a promising bioactive constituent in the treatment of IS. However, the functional mechanism remains unclear. Here, IS cell and mouse models were established by oxygen glucose deprivation/re-oxygenation (OGD/R) and middle cerebral artery occlusion (MCAO). Quantitative reverse transcription PCR (RT-qPCR), Western blotting, or Immunofluorescence staining measured related gene and protein expression of cells or mice brain tissues, and the results revealed altered expression of acyl-CoA synthetase long-chain family member 4 (Acsl4), fat mass and obesity-associated (Fto), and activation transcription factor 3 (Atf3) after treatment with As-IV. Then, increased N-6-methyladenosine (m(6)A) levels caused OGD/R or MCAO were reduced by As-IV according to the data from methylated RNA immunoprecipitation (MeRIP)-qPCR and dot blot assays. Moreover, through a series of functional experiments such as observing mitochondrial changes under transmission electron microscopy (TEM), evaluating cell viability by cell counting kit-8 (CCK-8), analyzing infract area of brain tissues by 2,3,5-triphenyltetrazolium chloride (TTC) staining, measuring levels of malondialdehyde (MDA), lactate dehydrogenase (LDH), Fe2+, solute carrier family 7 member 11 (Slc7a11) and glutathione peroxidase 4 (Gpx4) and concentration of glutathione (GSH), we found that Fto knockdown, Acsl4 overexpression or Atf3 knockdown promoted the viability of OGD/R cells, inhibited cell ferroptosis, reduced infract size, while As-IV treatment or Fto overexpression reversed these changes. In mechanism, the interplays of YTH N-6-methyladenosine RNA-binding protein 3 (Ythdf3)/Acsl4 and Atf3/Fto were analyzed by RNA-pull down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay. Fto regulated the m(6)A levels of Acsl4. Ythdf3 bound to Acsl4, and modulated its level

关键词： Idiopathic pulmonary fibrosis   Endoplasmic reticulum stress   Inflammation   Mitophagy   Apoptosis   Naringin   Activating transcription factor 3   PTEN-induced kinase 1   ACUTE LUNG INJURY   MITOCHONDRIAL DYSFUNCTION   PROTEIN-SYNTHESIS   OXIDATIVE STRESS   INFLAMMASOME   INHIBITION  

摘要： Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that is characterized by abnormal proliferation of fibroblasts and extracellular matrix remodeling, ultimately leading to respiratory insufficiency or even death. Naringin (Nar), a natural compound derived from grapefruit and citrus fruits, has several pharmacological activities that are associated with therapeutic benefits for IPF. However, the specific molecular mechanisms underlying its pulmonary tissue-protective effects remain largely unknown. This study aimed to investigate the effects of Nar on endoplasmic reticulum stress (ERS) and mitophagy. A bleomycin (BLM)-induced mouse model of IPF was established for treatment with different doses of Nar. Histopathological changes in the lung were examined by hematoxylin and eosin (HE) staining and Masson staining. The extent of fibrosis was determined by measuring hydroxyproline and collagen expression levels. The levels of inflammatory cytokines and oxidative stress indicators were determined by Enzyme linked immunosorbent assay (ELISA) and biochemical kits. Western blot and immunofluorescence were used to evaluate the expression levels of the mitophagy-related markers. Cell apoptosis was estimated by western blot and TUNEL staining. Nar reduced the levels of inflammatory response, oxidative stress and decreased the proportion of apoptosis. Nar also inhibited the expression of the ERS and mitophagy-related genes and ERS-downstream proteins, thereby activating transcription factor (ATF) 3 and inhibiting the transcription of PTEN-induced kinase 1 (PINK1). Taken together, Nar is a promising therapeutic agent for treating IPF via inhibiting ERS, reducing apoptosis, and maintaining mitochondrial homeostasis, all of which may be associated with the regulation of the ATF3/PINK1 signaling axis.

关键词： Immunoglobulin a nephropathy   Machine learning algorithm   ATF3   CXLC6   FOSB   B-CELL   PATHOGENESIS   DIAGNOSIS   ATF3   INFLAMMATION   EXPRESSION   NETWORK   BAFF  

摘要： Introduction: The pathogenesis and progression mechanism of Immunoglobulin A nephropathy (IgAN) is not fully understood. There is a lack of panoramic analysis of IgAN immune cell infiltration and algorithms that are more efficient and accurate for screening key pathogenic genes. Methods: RNA sequencing (RNA-seq) data sets on IgAN were downloaded from the Gene Expression Omnibus (GEO) database, including GSE93798, GSE35489, and GSE115857. The RNA-seq data set of kidney tissue as control samples were downloaded from the Genotype-Tissue Expression (GTEx) database. Three machine learning algorithms-weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO), and support vector machine-were used to identify the key pathogenic gene sets of the IgAN disease. The ssGSEA method was applied to calculate the immune cell infiltration (ICI) of IgAN samples, whereas the Spearman test was used for correlation analysis. The receiver operator characteristic curve (ROC) was used to evaluate the diagnostic efficacy of key genes. The correlation between the key genes and ICI was analyzed using the Spearman test. Results: A total of 177 genes were screened out as differentially expressed genes (DEGs) for IgAN, including 135 up-regulated genes and 42 down-regulated genes. The DEGs were significantly enriched in the inflammatory-or immune-related pathways (gene sets). Activating transcription factor 3 (AFT3), C-X-C Motif Chemokine Ligand 6 (CXCL6), and v-fos FBJ murine osteosarcoma viral oncogene homolog B (FOSB) were identified using WGCNA, support vector machine, and LASSO algorithms. These three genes revealed good diagnostic efficacy in the training and test cohorts. The CXCL6 expression positively correlated with activated B cells and memory B cells. Conclusion: ATF3, FOSB, and CXCL6 genes were identified as potential biomarkers of IgAN. These three genes exhibited good diagnostic efficacy for IgAN. We described the landscape of immun

关键词： Gastric cancer   miR-221-3p   ATF3   Ferroptosis   HRD1   GPX4  

摘要： Background: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221-3p in GC remains largely unknown. Methods: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The relation between miR-221-3p and ATF3 was investigated by dual-luciferase reporter assay. ChIP and dual-luciferase reporter assay were applied to assess the interaction between ATF3 and HRD1 or GPX4. Meanwhile, cell proliferation was investigated by CCK8 and colony formation assay. The content of erastin-induced Fe2+ was investigated by iron assay kit. Erastin-induced lipid ROS level was assessed by C11-BODIPY 581/591. Co-immunoprecipitation was used to detect the interaction between HRD1 and ACSL4. In addition, xenograft mice model was established to detect the effect of miR-221-3p in GC. Results: Depletion of miR-221-3p greatly attenuated GC cell proliferation through promoting ferroptosis. Meanwhile, ATF3 was downregulated in GC, and it was identified to be the downstream mRNA of miR-221-3p. MiR-221-3p downregulation could promoted the ferroptosis in GC cells through upregulation of ATF3. HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. ATF3 upregulation could reduce GC cell proliferation via downregulating the transcription of GPX4 and HRD1. Furthermore, downregulation of miR-221-3p markedly attenuated the growth of GC in ***: HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. MiR-221-3p deple-tion upregulates the ferroptosis in GC cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Our study might provide a novel target for GC treatment.

关键词： chemophototherapy   econazole   immunotherapy   pancreatic ductal adenocarcinoma   PD-L1 blockade   THERAPY   CELLS   ATF3  

摘要： Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8(+)T lymphocytes. The combined FBE NPs and alpha-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

关键词： STROKE   DIFFERENTIATION   EXPRESSION   PROTECTS   MODELS   CTIP2   ATF3  

摘要： The aim of this study was to characterize expression of corticogenesis-related transcription factors BCL11B and SATB2 after brain ischemic lesion in the adult mice, and to analyze their correlation to the subsequent brain recovery. Ischemic brain lesion was induced by transient middle cerebral artery occlusion followed by reperfusion, and the animals with ischemic lesion were compared to the sham controls. Progression of the brain damage and subsequent recovery was longitudinally monitored structurally, by magnetic resonance imaging, and functionally, by neurological deficit assessment. Seven days after the ischemic injury the brains were isolated and analyzed by immunohistochemistry. The results showed higher expression in the brain of both, BCL11B and SATB2 in the animals with ischemic lesion compared to the sham controls. The co-expression of both markers, BCL11B and SATB2, increased in the ischemic brains, as well as the co-expression of BCL11B with the beneficial transcriptional factor ATF3 but not its co-expression with detrimental HDAC2. BCL11B was mainly implicated in the ipsilateral and SATB2 in the contralateral brain hemisphere, and their level in these regions correlated with the functional recovery rate. The results indicate that the reactivation of corticogenesis-related transcription factors BCL11B and SATB2 is beneficial after brain ischemic lesion.