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Enhancing tissue repair and angiogenesis post-Acute myocardial infarction (AMI) is critical to improving cardiac function and preventing heart failure. Recent studies have highlighted the interaction between immune cells and endothelial cells in post-AMI angiogenesis, yet the specific contributions of different immune cell subsets remain poorly understood. Emerging evidence suggests the presence of a subset of regulatory T cells (Tregs) expressing Amphiregulin (AREG) in infarcted myocardial tissue, with AREG acting as a paracrine protein that plays a key role in angiogenesis. However, whether AREG⁺ Tregs mediate post-AMI angiogenesis and the underlying molecular mechanisms remain unclear. In this study, we demonstrate that Treg activation promotes tissue repair and improves cardiac function after AMI, although it does not significantly impact angiogenesis or endothelial cell behaviors. Notably, overexpression of AREG⁺ Tregs stimulates robust neovascularization post-AMI, reduces myocardial fibrosis, and further enhances cardiac function. Our in vitro data reveal that AREG⁺ Tregs secrete not only AREG but also angiogenic factors such as VEGF and FGF, which promote endothelial cell proliferation, migration, and tube formation. RNA sequencing analysis identifies FoxM1 as a key regulator of this angiogenic process in cardiac microvascular endothelial cells (CMECs). Importantly, inhibition of AREG in Tregs abolishes the FoxM1-dependent angiogenic response.In summary, we identified AREG⁺ Tregs as a distinct cell population driving neovascularization post-AMI, with FoxM1-mediated angiogenesis in CMECs. This may provide a foundation for harnessing specific Treg subsets for cardioprotection following AMI.

Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family and is expressed in a plethora of cancers. The biological roles of AREG in the regulation of the epithelial-mesenchymal transition (EMT) in pancreatic cancer remain unclear. To investigate the expression of epidermal growth factor receptor (EGFR) and AREG in pancreatic cancer cell lines, RT-qPCR, western blot analysis, and ELISA were performed. RNAi and exogenous AREG treatment were used to alter AREG expression. Wound-healing and Transwell assays were performed to evaluate cell migration and invasion abilities. Western blot analysis and immunofluorescence staining were utilized to detect the expression of EMT markers. The protein expression of potential key factors involved in EMT, as well as those of the ERK, AKT, STAT3 and NF-κB pathways, were analysed by western blotting. The role of AREG in tumour growth in vivo was further determined using an orthotopic model of pancreatic cancer. Knockdown of AREG inhibited AsPC-1 cell migration and invasion. AREG knockdown upregulated E-cadherin but downregulated vimentin, Snail and Slug expression in AsPC-1 cells. In addition, AREG stimulation increased cell migration, invasion and EMT in PANC-1 cells, and an NF-κB inhibitor decreased AREG-induced cell migration, invasion and EMT in PANC-1 cells. AREG stimulation increased the nuclear accumulation of NF-κB through the EGFR/ERK signalling pathway to induce EMT. Tumour growth and metastasis were decreased by AREG silencing in an orthotopic model of pancreatic cancer. AREG may play a critical role in cell migration, invasion, and EMT by activating the EGFR/ERK/NF-κB signalling pathway in pancreatic cancer cells.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer. Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication in women undergoing induction of ovulation with human chorionic gonadotropin (hCG) for assisted reproductive techniques. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) ligand expressed in human granulosa cells and follicular fluid and can be upregulated by luteinizing hormone (LH)/hCG. However, whether the expression levels of AREG, EGFR, and HER2 change in the granulosa cells of OHSS patients remains unknown. If it does, whether these molecules are involved in the development of OHSS requires investigation. In the present study, we showed that AREG, EGFR, and HER2 transcripts in granulosa cells as well as follicular fluid AREG proteins were elevated in OHSS patients. Increased AREG levels were associated with transcript levels and follicular content of vascular endothelial growth factor (VEGF), the marker for OHSS pathology. Treatment of cultured granulosa cells with AREG stimulated VEGF expression and secretion, with granulosa cells from OHSS patients showing more rapid and pronounced increases than the non-OHSS group. In addition, siRNA-mediated knockdown of EGFR and AREG attenuated the hCG-induced upregulation of VEGF. This study demonstrated that granulosa cell-secreted AREG plays an important role in the development of OHSS, suggesting that the EGFR/HER2-mediated signaling could be a novel drug target for the prevention and treatment of OHSS. Summary Sentence AREG-EGFR/HER2 partially mediates hCG-induced VEGF expression in human granulosa cells. Upregulation of AREG and EGFR/HER2 can enhance the hCG-induced VEGF expression which contributes to the development of OHSS.

High grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy in which chemoresistant recurrence rates remain high. Furthermore, HGSOC patients have demonstrated overall low response rates to clinically available immunotherapies. Amphiregulin (AREG), a low affinity epidermal growth factor receptor ligand is known to be significantly upregulated in HGSOC patient tumors following neoadjuvant chemotherapy exposure. While much is known about AREG’s role in oncogenesis and classical immunity, it is function in tumor immunology has been comparatively understudied. Therefore, the objective of this present study was to elucidate how increased AREG exposure impacts the ovarian tumor immune microenvironment (OTIME). Using NanoString IO 360 and protein analysis, it was revealed that treatment with recombinant AREG led to prominent upregulation of genes associated with ovarian pathogenesis and immune evasion ( CXCL8 , CXCL1 , CXCL2 ) along with increased STAT3 activation in HGSOC cells. In vitro co-culture assays consisting of HGSOC cells and peripheral blood mononuclear cells (PBMCs) stimulated with recombinant AREG (rAREG) led to significantly enhanced tumor cell viability. Moreover, PBMCs stimulated with rAREG exhibited significantly lower levels of IFNy and IL-2 . In vivo rAREG treatment promoted significant reductions in circulating levels of IL-2 and IL-5. Intratumoral analysis of rAREG treated mice revealed a significant reduction in CD8 + T cells coupled with an upregulation of PD-L1. Finally, combinatorial treatment with an AREG neutralizing antibody and carboplatin led to a synergistic reduction of cell viability in HGSOC cell lines OVCAR8 and PEA2. Overall, this study demonstrates AREG’s ability to modulate cytotoxic responses within the OTIME and highlights its role as a novel HGSOC immune target.

Bone allografts are widely used as osteoconductive support to guide bone regrowth. Bone allografts are more than a scaffold for the immigrating cells as they maintain some bioactivity of the original bone matrix. Yet, it remains unclear how immigrating cells respond to bone allografts. To this end, we have evaluated the response of mesenchymal cells exposed to acid lysates of bone allografts (ALBA). RNAseq revealed that ALBA has a strong impact on the genetic signature of gingival fibroblasts, indicated by the increased expression of IL11, AREG, C11orf96, STC1, and GK—as confirmed by RT-PCR, and for IL11 and STC1 by immunoassays. Considering that transforming growth factor-β (TGF-β) is stored in the bone matrix and may have caused the expression changes, we performed a proteomics analysis, TGF-β immunoassay, and smad2/3 nuclear translocation. ALBA neither showed detectable TGF-β nor was the lysate able to induce smad2/3 translocation. Nevertheless, the TGF-β receptor type I kinase inhibitor SB431542 significantly decreased the expression of IL11, AREG, and C11orf96, suggesting that other agonists than TGF-β are responsible for the robust cell response. The findings suggest that IL11, AREG, and C11orf96 expression in mesenchymal cells can serve as a bioassay reflecting the bioactivity of the bone allografts.

Eosinophilic esophagitis (EoE) is a chronic allergic disorder characterized by eosinophilia and epithelial thickening, resulting in dysphagia. While emerging evidence implicates increased frequencies of group 2 innate lymphoid cells (ILC2s) and increased interleukin (IL)-33 expression in EoE pathogenesis, the precise mechanisms remain unclear. In this study, we investigated the role of ILC2s in EoE pathogenesis. We observed an abundance of KLRG1 + ILC2s in the esophagi of healthy mice, with their numbers significantly increasing in murine EoE models and humans. Using a murine EoE model, we demonstrated the recapitulation of EoE-associated features, including basal-cell hyperproliferation, epithelial thickening, and eosinophilia. Notably, these characteristics are absent in ILC-deficient mice, whereas mice lacking IL-5 or eosinophils display epithelial defects, highlighting the pivotal role of ILC2s in EoE pathogenesis. Further investigations revealed increased amphiregulin (Areg) production by esophageal ILC2s in mice. The administration of Areg induced epithelial defects similar to those observed in EoE. Mechanistic studies using human esophageal cell lines revealed Areg-induced phosphorylation of epidermal growth factor receptor (EGFR). Significatntly, treatment with anti-Areg agents and EGFR inhibitors effectively attenuated EoE development, highlighting the therapeutic potential of targeting the Areg-EGFR axis.

Background With advanced maternal age, abnormalities during oocyte meiosis increase significantly. Aneuploidy is an important reason for the reduction in the quality of aged oocytes. However, the molecular mechanism of aneuploidy in aged oocytes is far from understood. Histone acetyltransferase 1 (HAT1) has been reported to be essential for mammalian development and genome stability, and involved in multiple organ aging. Whether HAT1 is involved in ovarian aging and the detailed mechanisms remain to be elucidated. Methods The level of HAT1 in aged mice ovaries was detected by immunohistochemical and immunoblotting. To explore the function of HAT1 in the process of mouse oocyte maturation, we used Anacardic Acid (AA) and small interfering RNAs (siRNA) to culture cumulus-oocyte complexes (COCs) from ICR female mice in vitro and gathered statistics of germinal vesicle breakdown (GVBD), the first polar body extrusion (PBE), meiotic defects, aneuploidy, 2-cell embryos formation, and blastocyst formation rate. Moreover, the human granulosa cell (GC)-like line KGN cells were used to investigate the mechanisms of HAT1 in this progress. Results HAT1 was highly expressed in ovarian granulosa cells (GCs) from young mice and the expression of HAT1 was significantly decreased in aged GCs. AA and siRNAs mediated inhibition of HAT1 in GCs decreased the PBE rate, and increased meiotic defects and aneuploidy in oocytes. Further studies showed that HAT1 could acetylate Forkhead box transcription factor O1 (FoxO1), leading to the translocation of FoxO1 into the nucleus. Resultantly, the translocation of acetylated FoxO1 increased the expression of amphiregulin (AREG) in GCs, which plays a significant role in oocyte meiosis. Conclusion The present study suggests that decreased expression of HAT1 in GCs is a potential reason corresponding to oocyte age-related meiotic defects and provides a potential therapeutic target for clinical intervention to reduce aneuploid oocytes.

Changes in innate and adaptive immunity occurring in/around pancreatic islets had been observed in peripheral blood mononuclear cells (PBMC) of Caucasian T1D patients by some, but not all researchers. The aim of our study was to investigate whether gene expression patterns of PBMC of the highly admixed Brazilian population could add knowledge about T1D pathogenic mechanisms. We assessed global gene expression in PBMC from two groups matched for age, sex and BMI: 20 patients with recent-onset T1D (≤ 6 months from diagnosis, in a time when the autoimmune process is still highly active), testing positive for one or more islet autoantibodies and 20 islet autoantibody-negative healthy controls. We identified 474 differentially expressed genes between groups. The most expressed genes in T1D group favored host defense, inflammatory and anti-bacterial/antiviral effects ( ) and cell cycle progression. Several of the downregulated genes in T1D target cellular repair, control of inflammation and immune tolerance. They were related to T helper 2 pathway, induction of FOXP3 expression ( ) and immune tolerance ( ) expression correlated negatively with islet ZnT8 antibody. The expression of , that offers resistance to viral pathogens was decreased and negatively related to ZnT8A and GADA levels. The increased expression of long non coding RNAs MALAT1 and NEAT1, related to inflammatory mediators, autoimmune diseases and innate immune response against viral infections reinforced these data. Our analysis suggested the activation of cell development, anti-infectious and inflammatory pathways, indicating immune activation, whereas immune-regulatory pathways were downregulated in PBMC from recent-onset T1D patients with a differential genetic profile.

Lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 is a crucial molecule of tricellular contacts in the epithelial barrier of normal cells and the malignancy of cancer cells. To investigate whether LSR/angulin-1 affects the epithelial barrier and malignancy in human pancreatic cancer, human pancreatic cancer cell line HPAC was used. Treatment with EGF or TGF-β increased the expression of LSR, but not tricellulin (TRIC), and induced the localization of LSR and TRIC to bicellular tight junctions from tricellular tight junctions. TGF-β receptor type-1 inhibitor EW-7197 prevented changes of the distribution and the barrier function of LSR by TGF-β. Knockdown of LSR increased cell migration, invasion, proliferation and EGF ligand amphiregulin expression and decreased the epithelial barrier. Treatment with amphiregulin induced cell migration and invasion and knockdown of amphiregulin prevented the increases of cell migration, invasion and proliferation caused by knockdown of LSR. Treatment with LSR ligand peptide angubindin-1 decreased the epithelial barrier and the expression of LSR, but not TRIC, and increased cell invasion. Knockdown of TRIC decreased cell migration and the epithelial barrier. In immunohistochemical analysis of human pancreatic cancer tissues, LSR and TRIC were found to be localized at the cell membranes of normal pancreatic ducts and well-differentiated pancreatic ductal adenocarcinomas (PDAC), whereas in poorly differentiated PDAC, LSR was weakly detected in the cytoplasm. Amphiregulin was highly expressed in the cytoplasm of well- and poorly differentiated PDAC. In pancreatic cancer, LSR contributes to the epithelial barrier and malignancy via growth factors and may be a potential targeting molecule in the therapy.