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Control of nutrient homeostasis plays a central role in cell proliferation/survival during embryonic development and tumor growth. Activation of the Notch signaling pathway, a major contributor to cell–cell interactions, is a potential mechanism for cell adaptation to nutrient‐poor conditions. Our previous study also demonstrated that during embryogenesis when nutrients such as glutamine and growth factors are potentially maintained at lower levels, Notch signaling suppresses mRNA expression of hexokinase 2 (hk2), which is a glycolysis‐associated gene, in the central nervous system. However, whether and how the genetic regulation of HK2 via Notch signaling contributes to cellular adaptability to nutrient‐poor environments remains unknown. In this study, we performed gene expression analysis using a U87‐MG human glioma cell line and revealed that under conditions where both glutamine and serum were absent, Notch signaling was activated and HK2 expression was downregulated by Notch signaling. We also found that Notch‐mediated HK2 suppression was triggered in a Notch ligand‐selective manner. Furthermore, HK2 was shown to inhibit cell proliferation of U87‐MG gliomas, which might depend on Notch signaling activity. Together, our findings suggest the involvement of Notch‐mediated HK2 suppression in an adaptive mechanism of U87‐MG glioma cells to nutrient‐poor conditions. [ABSTRACT FROM AUTHOR]

Background: Roburic acid (ROB) is a newly discovered tetracyclic triterpene acid extracted from oak galls, which has anti-inflammatory effects, but the mechanism of its anticancer effect is not clear. Our study focuses on exploring the potential mechanism of action of ROB in the treatment of lung cancer using a combination of network pharmacological prediction, molecular docking technique and experimental validation. Methods: A network pharmacology approach was used to screen the protein targets of ROB and lung cancer, and PPI network analysis and enrichment analysis were performed on the intersecting genes. The tissue and organ distribution of the targets was also evaluated based on the BioGPS database. To ensure the reliability of the network pharmacology prediction results, we proceeded to use molecular docking technique to determine the relationship between drugs and targets. Finally, in vitro experiments with cell lines were performed to further reveal the potential mechanism of ROB for the treatment of lung cancer. Results: A total of 83 potential targets of ROB in lung cancer were collected and further screened by using Cytoscape software, and 7 targets of PTGS2, CYP19A1, PTGS1, AR, CYP17A1, PTGES and SRD5A1 were obtained as hub genes and 7 hub targets had good binding energy with ROB. GO and KEGG analysis showed that ROB treatment of lung cancer mainly involves Arachidonic acid metabolism, Notch signaling pathway, cancer pathway and PPAR signaling pathway. The results of in vitro experiments indicated that ROB may inhibit the proliferation and metastasis of lung cancer cells and activate the PPARg signaling pathway, as well as induce cellular autophagy. Conclusions: The results of this study comprehensively elucidated the potential targets and molecular mechanisms of ROB for the treatment of lung cancer, providing new ideas for further lung cancer therapy. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a progressive interstitial lung disease associated with aging. The pathogenesis of pulmonary fibrosis remains unclear, however, alveolar epithelial cell injury, myofibroblast activation, and extracellular matrix (ECM) accumulation are recognized as key contributors. Moreover, recent studies have implicated cellular senescence, endothelial-mesenchymal transition (EndMT), and epigenetic modifications in the pathogenesis of fibrotic diseases. Various signaling pathways regulate pulmonary fibrosis, including the TGF-β, Notch, Wnt, Hedgehog, and mTOR pathways. Among these, the TGF-β pathway is extensively studied, while the Notch pathway has emerged as a recent research focus. The Notch pathway influences the fibrotic process by modulating immune cell differentiation (e.g., macrophages, lymphocytes), inhibiting autophagy, and promoting interstitial transformation. Consequently, inhibiting Notch signaling represents a promising approach to mitigating pulmonary fibrosis. In this review, we discuss the role of Notch signaling pathway in pulmonary fibrosis, aiming to offer insights for future therapeutic investigations. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophil extracellular traps (NETs) are complex structures released by activated neutrophils that may modulate different steps of the metastatic cascade. The aim of our study was to investigate how NETs can modulate the adhesion properties of cancer cells and whether cell exposure to NETs can activate the epithelial-to-mesenchymal transition (EMT) program thus enhancing the migratory and invasive properties of tumor cells. Materials and methods: Different cancer cell lines were subjected to a solidphase adhesion assay using NET-coated plates with or without the addition of antibodies against α5β1 or CCDC25 receptor. After 1-4 h of incubation, adherent cells were expressed as the percentage of total cell number. To test EMT occurrence, cells were treated with NETs for up to 48 h and then the levels of E-cadherin, vimentin, Snail, Slug, Zeb 1 and Twist 1 along with levels of Notch 1 and cleaved Notch 1 were determined by western blotting. Untreated and NETtreated cells were subjected to migration assays using 24-multiwell plates with transwell and FBS as chemoattractant. Results: Cancer cell adhesion to NET-coated plates varied between 30% and 92.7% and was significantly higher than that obtained in uncoated plates. The addition of antibodies against α5β1 or CCDC25 caused a strong reduction of cell adhesion to NETs. The prolonged exposure of EGFR-driven cancer cell lines to NETs caused the activation of the EMT program through the upregulation and cleavage of Notch 1 and was confirmed by the enhanced expression of EMT markers. The consequent loss of the epithelial phenotype induced a strong reduction of the expression of the oncogene driver. Cell migration was significantly enhanced in NET-treated cells as compared to untreated cells. Discussion: Our findings reveal the dynamic role of NETs that may provide a DNA and fibronectin rich environment for binding of many cancer cells at distant sites where the prolonged exposure to NETs triggers the EMT through the activation of Notch 1 signaling pathway with the subsequent enhancement of migratory and invasive properties of cancer cells. Furthermore, our findings provide an example of how an immune/inflammatory microenvironment may directly modulate the sensitivity of cancer cells to oncogene targeted agents. [ABSTRACT FROM AUTHOR]

Introduction: Extracellular vesicles (EVs) known for their pivotal role in intercellular communication through RNA delivery, hold paramount implications for understanding muscle phenotypic variations in diverse pig breeds. Methods: In this study, we compared the mRNA expression profiles of longissimus dorsi muscles and muscle-derived extracellular vesicles (M-EVs), and also examined the diversity of enriched genes in M-EVs between weaned wild boars and commercial Large White pigs with respect to their numbers and biological functions. Results: The results of the study showed that the variation in the expression profiles of mRNAs between muscles and M-EVs was much greater than the variability between the respective breeds. Meanwhile, the enrichment trend of low-expressed genes (ranked <1,000) was significantly (p-value = 0.05) powerful in M-EVs compared to highly expressed genes in muscles. In addition, M-EVs carried a smaller proportion of coding sequences and a larger proportion of untranslated region sequences compared to muscles. There were 2,110 genes enriched in M-EVs (MEGs) in Large White pigs and 2,322 MEGs in wild boars, with 1,490 MEGs shared interbreeds including cyclin D2 (CCND2), which inhibits myogenic differentiation. Of the 89 KEGG pathways that were significantly enriched (p-value = 0.05) for these MEGs, 13 unique to Large White pigs were mainly related to immunity, 27 unique to wild boars were functionally diverse but included cell fate regulation such as the Notch signaling pathway and the TGF-beta signaling pathway, and 49 were common to both breeds were also functionally complex but partially related to innate immunity, such as the Complement and coagulation cascades and the Fc gamma R-mediated phagocytosis. Discussion: These findings suggest that mRNAs in M-EVs have the potential to serve as indicators of muscle phenotype differences between the two pig breeds, highlighting the need for further exploration into the role of EV-RNAs in pig phenotype formation. [ABSTRACT FROM AUTHOR]

Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch. Recent studies have shown that both Notch and angiogenesis are influenced by extracellular matrix stiffness; however, the underlying mechanisms are poorly understood. Here, we addressed this challenge by combining computational models of Notch signaling and YAP/TAZ, stiffness- and cytoskeleton-regulated mechanotransducers whose activity inhibits both Dll4 (Notch ligand) and LFng (Notch-Dll4 binding modulator). Our simulations successfully mimicked previous experiments, indicating that this YAP/TAZ-Notch crosstalk elucidates the Notch and angiogenesis mechanoresponse to stiffness. Additional simulations also identified possible strategies to control Notch activity and sprouting angiogenesis via cytoskeletal manipulations or spatial patterns of alternating stiffnesses. Our study thus inspires new experimental avenues and provides a promising modeling framework for further investigations into the role of Notch, YAP/TAZ, and mechanics in determining endothelial cell behavior during angiogenesis and similar processes. [ABSTRACT FROM AUTHOR]

The present study is designed to evaluate the nanotherapeutic efficacy of prepared PLGA‐loaded Nedaplatin (PLGA‐NDP) against 7,12‐dimethyl benz(a)anthracene (DMBA)‐induced experimental oral carcinogenesis in hamster buccal pouch (HBP) model. The buccal pouch of golden Syrian hamsters was painted with 0.5% DMBA in liquid paraffin three times a week for 14 weeks, ultimately leading to the development of oral squamous cell carcinoma (OSCC). Oral administration of PLGA‐NDP (preinitiation) and Cisplatin delivery (5 mg/kg b.wt) started 1 week before the carcinogen exposure and continued on alternative days. Post‐administration of PLGA‐NDP (5 mg/kg b.wt) started 2 days after carcinogen (DMBA) induction until the end of the experiment. After the 14th week, we observed that DMBA‐painted hamsters exhibited tumor formation, morphological alterations, and well‐differentiated OSSC in addition to the responsive molecular proteins during oral carcinogenesis. Furthermore, immunoblotting analysis demonstrated that PLGA‐NDP inhibits Notch signaling, as evidenced by downregulation of Bcl‐Xl, Bcl‐2, p21, PGE2, HGF, and CXCL12 proteins, and upregulation of p53 and Bax. This apoptotic response is crucial for PLGA‐NDP to induce apoptosis. In addition, RT‐PCR results showed that PLGA‐NDP nanoparticles play a downregulatory role in the therapeutic action of the notch signaling gene (Notch1, Notch 2, Hes1, Hey1, and Jagged1) at the mRNA transcription level in HBP carcinoma. Taken together, these data indicate that PLGA‐NDP is a potent inhibitor of oral carcinogenesis and the expansion of cells that specifically target the Notch signaling pathway indicates that obstructing Notch signaling could potentially serve as a new and innovative therapeutic approach for oral squamous cell carcinoma (OSCC). Summary: The present investigation assesses the therapeutic efficacy of PLGA‐loaded Nedaplatin (PLGA‐NDP) in treating oral cancer within a hamster model. The research highlights that PLGA‐NDP specifically targets the Notch signaling pathway and initiates apoptosis to impede oral carcinogenesis. To achieve this, we incorporate techniques such as histopathological examination, Western blot analysis, and quantitative mRNA expression analysis to visualize the presence of PLGA‐NDP nanoparticles within specific organs and tissues, evaluate their role in binding and uptake, and assess internalization and clearance. Our findings indicate that obstructing Notch signaling may represent a novel therapeutic strategy for oral squamous cell carcinoma (OSCC). [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited. Methods: We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling. Results: Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons. Conclusion: Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC. [ABSTRACT FROM AUTHOR]

The Notch signaling pathway is an evolutionarily conserved regulatory cascade critical in skin development and homeostasis. Mice deficient of Notch signaling molecules have impaired skin and hair follicle development associated with local tissue inflammation. However, mechanisms underlying skin inflammation and pathology resulting from defective Notch signals are not well understood. To dissect molecular and cellular mechanisms underlying development of skin immunopathology in mice defective of the Notch ligand Jagged-1 (Jag1). We assessed involvement of microbiota and immune cell subsets in skin pathogenic symptoms in Foxn1CreJag1fl/fl mice that were deficient of Jag1 in keratinocytes. We also used RNA-seq and 16S rRNA gene-seq analyses to identify molecular factors and bacterial species contributing to skin pathologic symptoms in Foxn1CreJag1fl/fl mice. Compared to Jag1-sufficient littermate control mice, Foxn1CreJag1fl/fl mice had specific expansion of IL-17a-producing T cells accompanying follicular and epidermal hyperkeratosis and cyst formation while antibody blockage of IL-17a reduced the skin pathology. RNA-sequencing and 16S rRNA gene-sequencing analyses revealed dysregulated immune responses and altered microbiota compositions in the skin of Foxn1CreJag1fl/fl mice. Antibiotic treatment completely prevented over-activation of IL-17a-producing T cells and alleviated skin pathology in Foxn1CreJag1fl/fl mice. Dysbiosis-induced over-activation of IL-17a-producing T cells is critically involved in development of skin pathology in Foxn1CreJag1fl/fl mice, establishing Foxn1CreJag1fl/fl mice as a useful model to study pathogenesis and therapeutic targets in microbiota-IL-17-mediated skin inflammatory diseases such as hidradenitis suppurativa (HS) and psoriasis. • A novel Jag1-knockout (KO) mouse model of epidermal and follicular hyperkeratosis. • Over-activation of IL-17+ T cells is responsible for skin pathology in Jag1-KO mice. • Dysbiosis causes the IL-17+ T cell over-activation in the skin of Jag1-KO mice. [ABSTRACT FROM AUTHOR]

Fibrosis is a major medical challenge, as it leads to irreversible tissue remodeling and organ dysfunction. Its progression contributes significantly to morbidity and mortality worldwide, with limited therapeutic options available. Extensive research on the molecular mechanisms of fibrosis has revealed numerous factors and signaling pathways involved. However, the interactions between these pathways remain unclear. A comprehensive understanding of the entire signaling network that drives fibrosis is still missing. The TGF-β and Notch signaling pathways play a key role in fibrogenesis, and this review focuses on their functional interplay and molecular mechanisms. Studies have shown synergy between TGF-β and Notch cascades in fibrosis, but antagonistic interactions can also occur, especially in cardiac fibrosis. The molecular mechanisms of these interactions vary depending on the cell context. Understanding these complex and context-dependent interactions is crucial for developing effective strategies for treating fibrosis. [ABSTRACT FROM AUTHOR]

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex that affect Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most reported HS cases do not follow a simple genetic pattern. In this article, we performed whole-exome sequencing (WES) on a cohort of 100 individuals with HS, and we provide a comprehensive review of the variants known to be described or associated with HS. 91 variants were associated with the γ-secretase complex, and 78 variants were associated with other genes involved in the Notch pathway, keratinization, or immune response. Through this new genetic analysis, we have added ten new variants to the existing catalogs. All variants are available in a.vcf file and are provided as a resource for future studies. [ABSTRACT FROM AUTHOR]

Background and objectives: Idiopathic pulmonary fibrosis is a chronic, progressive, incurable lung disease, leading to irreversible lung tissue remodeling. The Notch signaling pathway, essential for lung development, has gained attention for its role in pulmonary fibrosis. While Notchl and Notch3 have been extensively studied, the involvement of other Notch receptors, especially Notch4, remains less explored. This study aimed to evaluate the impact of Notch4 on lung fibroblast activation and its potential interaction with the transforming growth factor-beta 1 (TGFpi) signaling. Methods: Primary human lung fibroblasts were transduced with lentivirus containing the intracellular domain of NOTCH4 (N4ICD). Changes in gene expression in transduced cells were assessed using real-time polymerase chain reaction, immunoflu-orescence staining, and Western blotting. Transcriptomic analysis was also performed on N4ICD-transduced lung fibroblasts. Results: N4ICD overexpression significantly upregulated key fibrotic markers such as ACTA2 and COL1A1. It also induced the TGFpi pathway, as evidenced by SMAD2 phosphorylation and elevated TGFfll mRNA level. Transcriptomic analysis revealed that N4ICD-induced cells exhibited characteristics of highly invasive myofibroblasts. Conclusions: This study establishes Notch4 as a novel contributor to pulmonary fibrosis, by demonstrating its ability to induce myofibroblast differentiation and interact with the TGFpi pathway. [ABSTRACT FROM AUTHOR]

A recent study published in Cell by Liu et al. introduced a new dual homologous recombinase‐mediated genetic profiling tracer technique to track lung epithelial cells accurately, shedding light on the regenerative origin and regulatory mechanism of adult alveolar epithelial stem cells. The research highlights the importance of alveolar regeneration for maintaining lung homeostasis and facilitating post‐injury healing, emphasizing the role of club cells and bronchioalveolar stem cells in promoting alveolar regeneration after lung injury. By developing a novel dual homologous recombination tool, the authors were able to identify club cells as the primary source of alveolar stem cell regeneration, offering new insights for lung stem cell therapy and potential treatment approaches for lung damage healing. [Extracted from the article]

Background: The role of Mediator complex subunit 1 (MED1), a pivotal transcriptional coactivator implicated in diverse biological pathways, remains unexplored in the context of oral squamous cell carcinoma (OSCC). This study aims to elucidate the contributory mechanisms and potential impact of MED1 on the progression of OSCC. Methods: The expression and clinical significance of MED1 in OSCC tissues were evaluated through the bioinformatics analyses. The effects of MED1 on the biological behavior of OSCC cancer cells were assessed both in vitro and in vivo. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, bioinformatic analysis, CD8+ T cell isolation experiment, coculture experiment, enzyme-linked immunosorbent assay (ELISA), and flow cytometric analysis were employed to elucidate the underlying mechanism through which MED1 operates in the progression of OSCC. Results: MED1 exhibited upregulation in both OSCC tissues and multiple OSCC cell lines, which correlated with decreased overall survival in patients. In vitro experiments demonstrated that knockdown of MED1 in metastatic OSCC cell lines SCC-9 and UPCI-SCC-154 hindered cell migration and invasion, while overexpression of MED1 promoted these processes. Whereas, MED1 knockdown had no impact on proliferation of cell lines mentioned above. In vivo studies further revealed that downregulation of MED1 effectively suppressed distant metastasis in OSCC. Mechanistically, MED1 enhanced the binding of transcription factors c-Jun and c-Fos to the matrix metalloprotein 9 (MMP9) promoters, resulting in a significant upregulation of MMP9 transcription. This process contributes to the migration and invasion of SCC-9 and UPCI-SCC-154 cells. Furthermore, MED1 modulated the expression of programmed death-ligand 1 (PD-L1) through the Notch signaling pathway, consequently impacting the tumor-killing capacity of CD8+ T cells in the tumor microenvironment. Conclusions: Our findings indicate that MED1 plays a pivotal role in OSCC progression through the activation of MMP9 transcription and suppression of CD8+ T cell antitumor immunity, suggesting that MED1 may serve as a novel prognostic marker and therapeutic target in OSCC. [ABSTRACT FROM AUTHOR]

Background: In recent years, e-cigarettes have been used as alternatives among adult smokers. However, the impact of e-cigarette use on human bronchial epithelial (HBE) cells remains controversial. Methods: We collected primary HBE cells of healthy nonsmokers and chronic obstructive pulmonary disease (COPD) smokers, and analyzed the impact of e- cigarette vapor extract (ECE) or cigarette smoke extract (CSE) on HBE cell differentiation and injury by single-cell RNA sequencing, immunostaining, HE staining, qPCR and ELISA. We obtained serum and sputum from healthy non- smokers, smokers and e-cigarette users, and analyzed cell injury markers and mucin proteins. Results: ECE treatment led to a distinct differentiation program of ciliated cells and unique patterns of their cell–cell communications compared with CSE. ECE treatment caused increased Notch signaling strength in a ciliated cell subpopulation, and HBE cell remodeling and injury including hypoplasia of ciliated cells and club cells, and shorter cilia. ECE-induced hypoplasia of ciliated cells and shorter cilia were ameliorated by the Notch signaling inhibition. Conclusions: This study reveals distinct characteristics in e-cigarette vapor-induced airway epithelial remodeling, pointing to Notch signaling pathway as a potential targeted intervention for e-cigarette vapor-caused ciliated cell differentiation defects and cilia injury. In addition, a decrease in SCGB1A1 proteins is associated with e- cigarette users, indicating a potential lung injury marker for e-cigarette users. [ABSTRACT FROM AUTHOR]

This study investigated the possible mechanisms of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism. β-Thiol ethanol induced Notch1 mRNA expression, microRNA-124a inhibitor reduced the effects of β-thiol ethanol on Notch1 mRNA expression in BMSCs. Baicalin induced Hes1 mRNA expression, and microRNA-124a inhibitor reduced the effects of baicalin on Hes1 mRNA expression in BMSCs. Si-Notch1 suppressed Hes1 mRNA expression in BMSCs. Baicalin increased the effects of Notch1 on Hes1 mRNA expression in BMSCs. Si-Notch1 increased cell growth of BMSCs. Baicalin reduced the effects of si-Notch1 on cell growth and the differentiation of BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons through Notch/Hes1 signal pathway. [ABSTRACT FROM AUTHOR]

The number of neural stemcells reflects the total number of neurons in the mature brain. As neural stem cells arise from neuroepithelial cells, the neuroepithelial cell population must be expanded to secure a sufficient number of neural stem cells. However, molecular mechanisms that regulate timely differentiation from neuroepithelial to neural stem cells are largely unclear. Here, we show that TCF4/Daughterless is a key factor that determines the timing of the differentiation in Drosophila. The neuroepithelial cells initiated but never completed the differentiation in the absence of TCF4/Daughterless. We also found that TCF4/Daughterless binds to the Notch locus, suggesting that Notch is one of its downstream candidate genes. Consistently, Notch expression was ectopically induced in the absence of TCF4/Daughterless. Furthermore, ectopic activation of Notch signaling phenocopied loss of TCF4/Daughterless. Our findings demonstrate that TCF4/Daughterless directly inactivates Notch signaling pathway, resulting in completion of the differentiation from neuroepithelial cells into neural stem cells with optimal timing. Thus, the present results suggest that TCF4/Daughterless is essential for determining whether to move to the next state or stay in the current state in differentiating neuroepithelial cells. [ABSTRACT FROM AUTHOR]

The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an unusual accumulation of mineral substances containing calcium and phosphate. The main component is hydroxyapatite. Many cells are involved in this process, such as smooth muscle cells (SMCs) and endothelial cells. CVC is an osteogenic process initiated by complex mechanisms such as metabolic disorders of calcium and phosphorus minerals, inflammation, extracellular vesicles, autophagy, and micro-RNAs with a variety of signaling pathways like Notch, STAT, and JAK. Although drug therapy and dialysis technology continue to advance, the survival time and quality of life of CVC patients still face challenges. Therefore, early diagnosis and prevention of CKD-related CVC, reducing its mortality rate, and improving patients' quality of life have become urgent issues in the field of public health. In this review, we try to summarize the state-of-the-art understanding of the progression of CVC and hope that it will help in the prevention and treatment of CVC in CKD. [ABSTRACT FROM AUTHOR]

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The Turquoise Killifish is an important vertebrate for the study of aging and age-related diseases due to its short lifespan. Within Nothobranchiidae, species possess annual, semi-annual, or non-annual life-histories. We took a comparative approach and examined gene expression profiles (QuantSeq) from 62 individuals from eleven nothobranchid species that span three life-histories. Our results show significant differences in differentially expressed genes (DEGs) across life-histories with non-annuals and semi-annuals being most similar, and annuals being the most distinct. At finer scales, we recovered significant differences in DEGs for DNA repair genes and show that non-annual and semi-annuals share similar gene expression profiles, while annuals are distinct. Most of the GO terms enriched in annuals are related to metabolic processes. However, GO terms, including translation, protein transport, and DNA replication initiation also are enriched in annuals. Non-annuals are enriched in Notch signaling pathway genes and downregulated in the canonical Wnt signaling pathway compared to annual species, which suggests that non-annuals have stronger regulation in cellular processes. This study provides support for congruency in DEGs involved in these life-histories and provides strong evidence that a particular set of candidate genes may be worthy of study to investigate their role in the aging process. [ABSTRACT FROM AUTHOR]

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level. [ABSTRACT FROM AUTHOR]

Placenta accreta spectrum (PAS) disorders are characterized by abnormal trophoblastic invasion into the myometrium, leading to significant maternal health risks. PAS includes placenta accreta (invasion < 50% of the myometrium), increta (invasion > 50%), and percreta (invasion through the entire myometrium). The condition is most associated with previous cesarean deliveries and increases in chance with the number of prior cesarians. The increasing global cesarean rates heighten the importance of early PAS diagnosis and management. This review explores genetic expression and key regulatory processes, such as apoptosis, cell proliferation, invasion, and inflammation, focusing on signaling pathways, genetic expression, biomarkers, and non-coding RNAs involved in trophoblastic invasion. It compiles the recent scientific literature (2014–2024) from the Scopus, PubMed, Google Scholar, and Web of Science databases. Identifying new biomarkers like AFP, sFlt-1, β-hCG, PlGF, and PAPP-A aids in early detection and management. Understanding genetic expression and non-coding RNAs is crucial for unraveling PAS complexities. In addition, aberrant signaling pathways like Notch, PI3K/Akt, STAT3, and TGF-β offer potential therapeutic targets to modulate trophoblastic invasion. This review underscores the need for interdisciplinary care, early diagnosis, and ongoing research into PAS biomarkers and molecular mechanisms to improve prognosis and quality of life for affected women. [ABSTRACT FROM AUTHOR]

Lenvatinib resistance (LenR) presents a significant challenge in hepatocellular carcinoma (HCC) treatment, leading to high cancer-related mortality rates globally. Unlike traditional chemotherapy resistance mechanisms, LenR in HCC is primarily driven by increased cancer cell stemness. Disulfiram, (DSF), functioning as a Cu ionophore, can coordinate with Cu2+ to overcome LenR in HCC by inhibiting cancer cell stemness and cuproptosis. However, DSF faces challenges due to its poor water solubility, while copper ions present issues related to systemic toxicity during widespread use. To address this, DSF and CuO nanoparticles (NPs) were co-encapsulated to form an oil-in-water Pickering emulsion (DSF@CuO), effectively elevating DSF and copper ion concentrations within the tumor microenvironment (TME). DSF@CuO was then combined with sodium alginate (SA) to form a DSF@CuO-SA solution, which gelatinizes in situ with Ca2+ in the TME to form a DSF@CuO Gel, enhancing Pickering emulsion stability and sustaining DSF and copper ion release. A DSF@CuO Gel exhibits enhanced stability and therapeutic efficacy compared to conventional administration methods. It effectively induces mitochondrial dysfunction and cuproptosis in LenR HCC cells by downregulating DLAT, LIAS, and CDKN2A, while upregulating FDX1. Furthermore, it suppresses cancer stemness pathways through activation of the JNK/p38 MAPK pathway and inhibition of the NF-κB and NOTCH signaling pathways. These findings suggest that DSF@CuO Gels are a promising therapeutic strategy for treating LenR HCC. In vivo and in vitro LenR HCC models demonstrated significant therapeutic efficacy. In conclusion, this novel approach underscores DSF@CuO Gel's potential to overcome LenR in HCC, offering a novel approach to address this clinical challenge. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant tumor of the skin. B7 homolog 4 (B7-H4) and B7-H5 (B7 homolog 5) are associated with a variety of tumors. Investigate the potential role of B7-H4 and B7-H5 in regulating the tumorigenesis and progression of CSCC. B7-H4 and B7-H5 transcriptome data were collected from GEO and TCGA databases and subjected to bioinformatical analysis by protein–protein interaction (PPI) network, functional enrichment analysis, immune analysis, and drug–gene interaction prediction analysis. We characterized the expression of B7-H4 and B7-H5 in carcinoma tissues of CSCC patients by immunohistochemistry. Meanwhile, the clinical correlation of B7-H4 and B7-H5 in CSCC was explored by statistical analysis. B7-H4 and B7-H5 genes were under-expressed in CSCC and correlated with tumor staging. According to GO and KEGG Pathway enrichment analysis, B7-H4, and B7-H5 can regulate the proliferation and activation of T cells, lymphocytes, and monocytes, and the expression of cytokines, such as IL-6 and IL-10, in CSCC. B7-H4 and B7-H5 are also jointly involved in the occurrence and development of CSCC via the JAK-STAT and Notch signaling pathways. We found that B7-H4 and B7-H5 proteins were abnormally highly expressed in CSCC tissue and correlated with tumor size and stage. Our findings offer new insights into the pathogenesis of CSCC and suggest that B7-H4 and B7-H5 are novel tissue biomarkers and promising therapeutic targets for CSCC. [ABSTRACT FROM AUTHOR]

The occurrence of myocardial ischemia/reperfusion injury is commonly observed during cardiac surgery; however, there remains a dearth of effective therapeutic strategies to mitigate this injury. The a disintegrin and metallopeptidase domain 10 (ADAM10) is a transmembrane protein anchored on the cell membrane surface, and its precise mechanism of action in myocardial ischemia/reperfusion injury remains incompletely understood. This study aims to investigate the impact of ADAM10 on cardiomyocyte injury induced by hypoxia/reoxygenation (H/R) and elucidate the underlying mechanisms. The ADAM10 overexpression plasmid was transfected into H9c2 cells, which were subsequently treated with the Notch signaling pathway inhibitor DAPT and cultured under H/R conditions. Cell proliferation activity was assessed using the CCK-8 assay. The levels of LDH, SOD, and MDA were quantified through colorimetric analysis. The levels of ROS and the rate of apoptosis were measured using flow cytometry. The morphological changes in the nucleus of H9c2 cells were observed by employing Hoechst 33258 staining. The mRNA expression levels of ADAM10, Notch1, NICD, and Hes1 in H9c2 cells were determined using qRT-PCR. The expressions of Notch signaling pathway and apoptosis-related proteins were analyzed by Western blot. Overexpression of ADAM10 provided protection to H9c2 cells against injury induced by H/R, leading to an increase in SOD levels and alleviation of oxidative stress caused by the accumulation of ROS and the decrease of SOD activity. Meanwhile, overexpression of ADAM10 inhibited apoptosis in H9c2 cells exposed to H/R by regulating the expression of apoptosis-related proteins, such as Bax, Bcl-2 and Cleaved-caspase-3. Additionally, overexpression of ADAM10 facilitated the activation of the Notch1 signaling pathway in H9c2 cells exposed to H/R by upregulating the protein expression of Notch1, NICD, and Hes1. However, the protective effect of ADAM10 on H/R-induced H9c2 cells was partially reversed by DAPT. Our findings demonstrate that ADAM10 exerts protective effects in H/R-induced H9c2 cells by suppressing oxidative stress and apoptosis via the activation of the Notch signaling pathway. [ABSTRACT FROM AUTHOR]

Atractylodin is one of the main active ingredients of Atractylodis Rhizoma. It has various pharmacological properties, such as antigastric ulcer, immune regulation, antibacterial, anti-inflammatory, antitumor, anti-oxidant, and neuroprotective properties. In the past few decades, atractylodin has attracted the attention of researchers due to its excellent therapeutic effects. This paper aims to review the pharmacology of atractylodin, focusing mainly on its pharmacological effects in tumor treatment. Atractylodin exerts its antitumor effect by regulating different signaling pathways to induce important biological events such as apoptosis, cell cycle arrest, and autophagy, inhibiting cancer cell invasion and metastasis. In the process of cell apoptosis, atractylodin mainly induces cancer cell apoptosis by downregulating the Notch signaling pathway, affecting multiple upstream and downstream targets. In addition, atractylodin induces autophagy in cancer cells by regulating various signaling pathways such as PI3K/AKT/mTOR, p38MAPK, and hypothalamic Sirt1 and p-AMPK. Atractylodin effectively induces G1/M and G2/M phase arrest under the action of multiple signaling pathways. Among them, the pathways related to G1/M are more widely stagnated. In inhibiting the migration and invasion of cancer cells, atractylodin mainly regulates the Wnt signaling pathway, downregulates the expression of N-cadherin in cancer cells, and then blocks the PI3K/AKT/mTOR signaling pathway, inhibiting the phosphorylation of PI3K, AKT, and mTOR proteins, thereby having a significant impact on the invasion and migration of cancer cells. This paper systematically reviews the research progress on the antitumor effects and mechanisms of atractylodin, hoping to provide a reference and theoretical basis for its clinical application and new drug development. [ABSTRACT FROM AUTHOR]

Rational: Basal cells (BCs) are bronchial progenitor/stem cells that can regenerate injured airway that, in smokers, may undergo malignant transformation. As a model for early stages of lung carcinogenesis, we set out to characterize cytologically normal BC outgrowths from never-smokers and ever-smokers without cancers (controls), as well as from the normal epithelial "field" of ever-smokers with anatomically remote cancers, including lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) (cases). Methods: Primary BCs were cultured and expanded from endobronchial brushings taken remote from the site of clinical or visible lesions/tumors. Donor subgroups were tested for growth, morphology, and underlying molecular features by qRT-PCR, RNAseq, flow cytometry, immunofluorescence, and immunoblot. Results: (a) the BC population includes epithelial cell adhesion molecule (EpCAM) positive and negative cell subsets; (b) smoking reduced overall BC proliferation corresponding with a 2.6-fold reduction in the EpCAMpos/ITGA6 pos/CD24pos stem cell fraction; (c) LUSC donor cells demonstrated up to 2.8-fold increase in dysmorphic BCs; and (d) cells procured from LUAD patients displayed increased proliferation and S-phase cell cycle fractions. These differences corresponded with: (i) disparate NOTCH1/NOTCH2 transcript expression and altered expression of potential downstream (ii) E-cadherin (CDH1), tumor protein-63 (TP63), secretoglobin family 1a member 1 (SCGB1A1), and Hairy/enhancer-of-split related with YRPW motif 1 (HEY1); and (iii) reduced EPCAM and increased NK2 homeobox-1 (NKX2-1) mRNA expression in LUAD donor BCs. Conclusions: These and other findings demonstrate impacts of donor age, smoking, and lung cancer case-control status on BC phenotypic and molecular traits and may suggest Notch signaling pathway deregulation during early human lung cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Esophageal carcinosarcoma (ECS) is a relatively rare malignancy, accounting for < 1% of all esophageal cancers. Its etiopathogenesis remains unknown. This study analyzed the genomic abnormalities in sarcomatous tumors from two patients undergoing subtotal esophagectomy using whole genome sequencing to elucidate the key characteristics of ECS. Case presentation: We identified TP53 driver mutations, copy number gains in 11q13 (including CCND1), and Apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) signature enrichment in both ECS patients. Along with common genetic abnormalities, we identified CDKN2A driver mutations in case 1 and RAC1, NOTCH1, and TTC28 as novel fusion gene partners of MECOM in case 2. Notably, we detected germline pathogenic variant in Fanconi anemia (FA) complementation group I (FANCI) and group G (FANCG), which are involved in repairing DNA double-strand breaks by homologous recombination, for the first time, in ECS blood samples. These germline variants were truncating-type, Lys1221fs of FANCI (rs1567179036) for case 1 and Gln365Ter of FANCG (rs121434426) for case 2. We also identified somatic changes in cancer-associated pathways, such as PI3K/Akt/mTOR, cell cycle, and NOTCH signaling pathways, and structural chromosomal defects such as chromosome doubling. Conclusions: Our findings indicate that therapeutic drugs targeting the activation signal or FA pathway might be effective in treating ECS, however, their therapeutic significance should be elucidated in future studies. [ABSTRACT FROM AUTHOR]

Introduction: The immunological characteristics that could protect children with coronavirus disease 2019 (COVID-19) from severe or fatal illnesses have not been fully understood yet. Methods: Here, we performed single-cell RNA sequencing (scRNA-seq) analysis on peripheral blood samples of 15 children (8 with COVID-19) and compared them to 18 adults (13 with COVID-19). Results: The child-adult integrated single cell data indicated that children with the disease presented a restrained response to type I interferon in most of the major immune cell types, along with suppression of upstream interferon regulatory factor and toll-like receptor expression in monocytes, which was confirmed by in vitro interferon stimulation assays. Unlike adult patients, children with COVID-19 showed lower frequencies of activated proinflammatory CD14+ monocytes, possibly explaining the rareness of cytokine storm in them. Notably, natural killer (NK) cells in pediatric patients displayed potent cytotoxicity with a rich expression of cytotoxic molecules and upregulated cytotoxic pathways, whereas the cellular senescence, along with the Notch signaling pathway, was significantly downregulated in NK cells, all suggesting more robust cytotoxicity in NK cells of children than adult patients that was further confirmed by CD107a degranulation assays. Lastly, a modest adaptive immune response was evident with more naïve T cells but less activated and proliferated T cells while less naïve B cells but more activated B cells in children over adult patients. Conclusion: Conclusively, this preliminary study revealed distinct cell frequency and activation status of major immune cell types, particularly more robust NK cell cytotoxicity in PBMC that might help protect children from severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a severe obstetric disorder that significantly affects the maternal and neonatal peri-partum safety and long-term quality of life. However, there is limited research exploring the common mechanisms and potential clinical significance between early-onset preeclampsia and full-term preeclampsia from an immunological perspective. Methods: In this study, data analysis was conducted. Initially, immune-related co-expressed genes involving both subtypes of preeclampsia were identified through Weighted Gene Co-expression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were further employed to investigate the shared pathways regulated by immune-related genes. Binary logistic regression identified co-expressed genes with diagnostic value for preeclampsia, and a diagnostic model was constructed. Gene Set Enrichment Analysis (GSEA) predicted the potential biological functions of the selected genes. Lasso and Cox regression analyses identified genes closely associated with gestational duration, and a risk score model was established. A 4-gene feature, immune-related gene model for predicting the risk of preterm birth in preeclamptic pregnant women, was developed and validated through qPCR experiments. Immune cell infiltration analysis determined differences in immune cell infiltration between the two subtypes of preeclampsia. Results: This study identified 4 immune-related co-expressed genes (CXCR6, PIK3CB, IL1RAP, and OSMR). Additionally, diagnostic and preterm birth risk prediction models for preeclampsia were constructed based on these genes. GSEA analysis suggested the involvement of these genes in the regulation of galactose metabolism, notch signaling pathway, and RIG-I like receptor signaling pathway. Immune pathway analysis indicated that the activation of T cell co-inhibition could be a potential intervention target for immunotherapy in early-onset preeclampsia. Conclusion: Our study provides promising insights into immunotherapy and mechanistic research for preeclampsia, discovering novel diagnostic and intervention biomarkers, and offering personalized diagnostic tools for preeclampsia. [ABSTRACT FROM AUTHOR]

Ferroptosis has been observed to play an important role during erythrocyte differentiation (ED). However, the biological gene markers and ferroptosis mechanisms in ED remain unknown. We downloaded the datasets of ED in human umbilical cord blood-derived CD34+ cells from the Gene Expression Omnibus database. Using median differentiation time, the sample was categorized into long and short groups. The differentially expressed ferroptosis-related genes (DE-FRGs) were screened using differential expression analysis. The enrichment analyses and a protein-protein interaction (PPI) network were conducted. To predict the ED stage, a logistic regression model was constructed using the least absolute shrinkage and selection operator (LASSO). Overall, 22 DE-FRGs were identified. Ferroptosisrelated pathways were enriched using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Gene Set Enrichment Analysis and Gene Set Variation Analysis revealed the primary involvement of DE-FRGs in JAK-STAT, MAPK, PI3K-AKT-mTORC1, WNT, and NOTCH signaling pathways. Ten-hub DE-FRGs were obtained using PPI analysis. Furthermore, we constructed mRNA-microRNA (miRNA) and mRNA-transcription factor networks. Immune cell infiltration levels differed significantly during ED. LASSO regression analysis established a signature using six DE-FRGs (ATF3, CDH2, CHAC1, DDR2, DPP4, and GDF15) related to the ED stage. Bioinformatic analyses identified ferroptosis-associated genes during ED, which were further validated. Overall, we identified ferroptosis-related genes to predict their correlations in ED. Exploring the underlying mechanisms of ferroptosis may help us better understand pathophysiological changes in ED and provide new evidence for clinical transformation. [ABSTRACT FROM AUTHOR]

Objectives: Fibroleukin (FGA) and NOTCH3 are vital in both exercise-induced muscle adaptation and colon adenocarcinoma (COAD) progression. This study aims to elucidate the roles of FGA and NOTCH3 in phenotypic variations of striated muscle induced by exercise and in COAD development. Additionally, it seeks to evaluate the prognostic significance of these proteins. Methods: Gene Set Variation Analysis (GSVA) and protein-protein interaction (PPI) network analysis were employed to identify differentially expressed genes (DEGs). Molecular docking studies were conducted to assess the binding affinities of 39 compounds to the NOTCH3 protein. In vitro assays, including mobileular viability, gene expression, and apoptosis assays, were performed to evaluate the effects of glycerophosphoinositol on FGA and NOTCH3 expression. Additionally, copy number variation (CNV), methylation status, and survival analyses were conducted across multiple cancers types. Results: The NOTCH signaling pathway was consistently upregulated in exercise-induced muscle samples. High NOTCH3 expression was associated with poor prognosis in COAD, extracellular matrix organization, immune infiltration, and activation of the PI3K-Akt pathway. Molecular docking identified gamma-Glu-Trp, gamma-Glutamyltyrosine, and 17-Deoxycortisol as strong binders to NOTCH3. Glycerophosphoinositol treatment modulated FGA and NOTCH3 expression, influencing cell proliferation and apoptosis. CNV and methylation analyses revealed specific changes in FGA and NOTCH3 across 20 cancers types. Survival analyses showed strong associations between FGA/NOTCH3 expression and survival metrics, with negative correlations for FGA and positive correlations for NOTCH3. Conclusion: FGA and NOTCH3 play significant roles in exercise-induced muscle adaptation and colon cancer progression. The expression profiles and interactions of these proteins provide promising prognostic markers and therapeutic targets. These findings offer valuable insights into the post-translational modifications (PTMs) in human cancer, highlighting novel pharmacological and therapeutic opportunities. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D/Vitamin D receptor (VD/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD/VDR and the Notch pathways in intestinal barrier protection. Methods: Genetic Vdr knockout (VDR KO) and VD deficient (VDd) mice were established, and colitis was induced by feeding 2.5% dextran sodium sulfate (DSS) water. Mechanistic studies, including real-time PCR, immunofluorescence, Western blotting and dual-luciferase reporter assays, were performed on cultured Caco-2 cells and intestinal organoids. Results: VD deficiency and VDR genetical KO increased the severity of DSS-induced colitis in mice, which presented a higher disease activity index score, increased intestinal permeability, and more severe intestinal histological damage than controls, accompanied by decreased and disrupted claudin-1 and claudin-3. Moreover, inhibition of Notch pathway by LY411,575 aggravated the severity of DSS-induced colitis and intestinal injury. In Caco-2 cells and intestinal organoids, the expression of Notch-1, N1ICD and Hes1 decreased upon downregulation or KO of VDR but increased upon paricalcitol (PAR, a VDR agonist) treatment. Meanwhile, PAR rescued claudin-1 and claudin-3 impairments that resulted from TNF-α exposure but failed to restore claudin-3 upon Notch inhibition. The dual-luciferase reporter assay further suggested that VD/VDR positively regulated the Notch signaling pathway by modulating Notch-1 transcription. Conclusion: VD/VDR positively modulates Notch activation by promoting Notch-1 transcription to maintain intestinal tight junction integrity and barrier function. This highlights the VD/VDR-Notch pathway as a potential new therapeutic target for protecting the intestinal barrier against ulcerative colitis. [ABSTRACT FROM AUTHOR]

Aortic aneurysm/ dissection is the primary cause of mortality in patients with Marfan syndrome (MFS). Though aberrant activation of the transforming growth factor-β(TGF-β) pathway has been considered the central pathogenic mechanism for MFS aortic aneurysms, recent research has gradually revealed the involvement of other signaling pathways in MFS. This review summarizes the latest researches on the molecular mechanisms of MFS, including classical TGF-β and related signaling pathways such as Notch and nitric oxide(NO), as well as epigenetics and gene therapy, which provide new insights for the prevention and treatment of MFS. [ABSTRACT FROM AUTHOR]

Papua New Guinea (PNG) hosts distinct environments mainly represented by the ecoregions of the Highlands and Lowlands that display increased altitude and a predominance of pathogens, respectively. Since its initial peopling approximately 50,000 years ago, inhabitants of these ecoregions might have differentially adapted to the environmental pressures exerted by each of them. However, the genetic basis of adaptation in populations from these areas remains understudied. Here, we investigated signals of positive selection in 62 highlanders and 43 lowlanders across 14 locations in the main island of PNG using whole-genome genotype data from the Oceanian Genome Variation Project (OGVP) and searched for signals of positive selection through population differentiation and haplotype-based selection scans. Additionally, we performed archaic ancestry estimation to detect selection signals in highlanders within introgressed regions of the genome. Among highland populations we identified candidate genes representing known biomarkers for mountain sickness (SAA4 , SAA1 , PRDX1 , LDHA) as well as candidate genes of the Notch signaling pathway (PSEN1 , NUMB , RBPJ , MAML3), a novel proposed pathway for high altitude adaptation in multiple organisms. We also identified candidate genes involved in oxidative stress, inflammation, and angiogenesis, processes inducible by hypoxia, as well as in components of the eye lens and the immune response. In contrast, candidate genes in the lowlands are mainly related to the immune response (HLA-DQB1 , HLA-DQA2 , TAAR6 , TAAR9 , TAAR8 , RNASE4 , RNASE6 , ANG). Moreover, we find two candidate regions to be also enriched with archaic introgressed segments, suggesting that archaic admixture has played a role in the local adaptation of PNG populations. [ABSTRACT FROM AUTHOR]

Introduction: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications. Objectives: N6‐methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. Methods and results: This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi‐omics analysis revealed that HSC‐specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split‐1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%–62% and protein levels to 28%–35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%–38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression. Conclusion: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. Key Points/Highlights: IGF2BP3 deficiency inactivates Jag1 signalling.IGF2BP3 deficiency‐mediated m6A modifications promote HSC ferroptosis.IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis.IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis. [ABSTRACT FROM AUTHOR]

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi’s sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta’s ability to redistribute RBP-Jk DNA binding to the virus during reactivation. [ABSTRACT FROM AUTHOR]

Purpose: Preeclampsia (PE) is a serious complication of obstetrics and represents a significant challenge in terms of understanding its underlying mechanism. It has been shown that a number of disorders involve dysregulation of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2). However, the relationship between PE and CITED2 is still mostly unclear. This work aimed to confirm the hub genes linked to PE and explore the roles of CITED2 in trophoblast using experimental and bioinformatic methods. Methods: To determine the hub genes, bioinformatics research was performed on two datasets from the Gene Expression Omnibus (GEO) public database. Immune infiltration analysis and enrichment analysis were also used to identify the related pathways and immune cells. PCR and WB were then used to validate the mRNA and protein levels of CITED2 in the PE samples. Finally, the expression of CITED2 was knocked down using siRNA to investigate the function of CITED2 in trophoblast development in vitro. Results: The study's findings showed that the NOTCH signaling pathways, glycolysis, and hypoxia were the main areas of enrichment for the six PE-related genes that were tested. The results of immune infiltration suggest that activated NK cells and regulatory T cells may play an important role in this process. CITED2 was significantly upregulated in the PE placenta. In functional tests, the knockdown of CITED2 may enhance apoptosis while suppressing migration, invasion, and proliferation of cells. Conclusion: This study offers important proof that CITED2 influences trophoblast cell function and may one day be a therapeutic target for PE. [ABSTRACT FROM AUTHOR]

Background: Salidroside is the major bioactive and pharmacological active substance in Rhodiola rosea L. It has been reported to have neuroprotective effects on cerebral ischemia/reperfusion (I/R). However, whether salidroside can enhance neural regeneration after cerebral I/R is still unknown. This study investigated the effects of salidroside on the endogenous neural regeneration after cerebral I/R and the related mechanism. Methods: Focal cerebral I/R was induced in rats by transient middle cerebral artery occlusion/reperfusion (MCAO/R). The rats were intraperitoneally treated salidroside once daily for 7 consecutive days. Neurobehavioral assessments were performed at 3 days and 7 days after the injury. TTC staining was performed to assess cerebral infarct volume. To evaluate the survival of neurons, immunohistochemical staining of Neuronal Nuclei (NeuN) in the ischemic hemisphere were conducted. Also, immunofluorescence double or triple staining of the biomarkers of proliferating neural progenitor cells in Subventricular Zone (SVZ) and striatum of the ischemia hemisphere were performed to investigate the neurogenesis. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of neurotrophic factors (NTFs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Expression of Notch1 and its target molecular Hes1 were also analyzed by western-blotting and RT-PCR. Results: Salidroside treatment ameliorated I/R induced neurobehavioral impairment, and reduced infarct volume. Salidroside also restored NeuN positive cells loss after I/R injury. Cerebral I/R injury significantly increased the expression of 5-Bromo-2'-Deoxyuridine (BrdU) and doublecotin (DCX), elevated the number of BrdU/Nestin/DCX triple-labeled cells in SVZ, and BrdU/Nestin/glial fibrillary acidic protein (GFAP) triple-labeled cells in striatum. Salidroside treatment further promoted the proliferation of BrdU/DCX labeled neuroblasts and BrdU/Nestin/GFAP labeled reactive astrocytes. Furthermore, salidroside elevated the mRNA expression and protein concentration of BDNF and NGF in ischemia periphery area, as well. Mechanistically, salidroside elevated Notch1/Hes1 mRNA expression in SVZ. The protein levels of them were also increased after salidroside administration. Conclusions: Salidroside enhances the endogenous neural regeneration after cerebral I/R. The mechanism of the effect may involve the regulation of BDNF/NGF and Notch signaling pathway. [ABSTRACT FROM AUTHOR]

Notch signaling pathway is activated abnormally in solid and hematological tumors, which perform essential functions in cell differentiation, survival, proliferation, and angiogenesis. The activation of Notch signaling and communication among Notch and other oncogenic pathways heighten malignancy aggressiveness. Thus, targeting Notch signaling offers opportunities for improved survival and reduced disease incidence. Already, most attention has been given to its role in the cancer cells. Recent research shows that natural bioactive compounds can change signaling molecules that are linked to or interact with the Notch pathways. This suggests that there may be a link between Notch activation and the growth of tumors. Here, we sum up the natural bioactive compounds that possess inhibitory effects on human cancers by impeding the Notch pathway and preventing Notch crosstalk with other oncogenic pathways, which provoke further study of these natural products to derive rational therapeutic regimens for the treatment of cancer and develop novel anticancer drugs. This review revealed Notch as a highly challenging but promising target in oncology. [ABSTRACT FROM AUTHOR]

Abstract Background The role of Mediator complex subunit 1 (MED1), a pivotal transcriptional coactivator implicated in diverse biological pathways, remains unexplored in the context of oral squamous cell carcinoma (OSCC). This study aims to elucidate the contributory mechanisms and potential impact of MED1 on the progression of OSCC. Methods The expression and clinical significance of MED1 in OSCC tissues were evaluated through the bioinformatics analyses. The effects of MED1 on the biological behavior of OSCC cancer cells were assessed both in vitro and in vivo. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, bioinformatic analysis, CD8+ T cell isolation experiment, coculture experiment, enzyme-linked immunosorbent assay (ELISA), and flow cytometric analysis were employed to elucidate the underlying mechanism through which MED1 operates in the progression of OSCC. Results MED1 exhibited upregulation in both OSCC tissues and multiple OSCC cell lines, which correlated with decreased overall survival in patients. In vitro experiments demonstrated that knockdown of MED1 in metastatic OSCC cell lines SCC-9 and UPCI-SCC-154 hindered cell migration and invasion, while overexpression of MED1 promoted these processes. Whereas, MED1 knockdown had no impact on proliferation of cell lines mentioned above. In vivo studies further revealed that downregulation of MED1 effectively suppressed distant metastasis in OSCC. Mechanistically, MED1 enhanced the binding of transcription factors c-Jun and c-Fos to the matrix metalloprotein 9 (MMP9) promoters, resulting in a significant upregulation of MMP9 transcription. This process contributes to the migration and invasion of SCC-9 and UPCI-SCC-154 cells. Furthermore, MED1 modulated the expression of programmed death-ligand 1 (PD-L1) through the Notch signaling pathway, consequently impacting the tumor-killing capacity of CD8+ T cells in the tumor microenvironment. Conclusions Our findings indicate that MED1 plays a pivotal role in OSCC progression through the activation of MMP9 transcription and suppression of CD8+ T cell antitumor immunity, suggesting that MED1 may serve as a novel prognostic marker and therapeutic target in OSCC.

Abstract Background Salidroside is the major bioactive and pharmacological active substance in Rhodiola rosea L. It has been reported to have neuroprotective effects on cerebral ischemia/reperfusion (I/R). However, whether salidroside can enhance neural regeneration after cerebral I/R is still unknown. This study investigated the effects of salidroside on the endogenous neural regeneration after cerebral I/R and the related mechanism. Methods Focal cerebral I/R was induced in rats by transient middle cerebral artery occlusion/reperfusion (MCAO/R). The rats were intraperitoneally treated salidroside once daily for 7 consecutive days. Neurobehavioral assessments were performed at 3 days and 7 days after the injury. TTC staining was performed to assess cerebral infarct volume. To evaluate the survival of neurons, immunohistochemical staining of Neuronal Nuclei (NeuN) in the ischemic hemisphere were conducted. Also, immunofluorescence double or triple staining of the biomarkers of proliferating neural progenitor cells in Subventricular Zone (SVZ) and striatum of the ischemia hemisphere were performed to investigate the neurogenesis. Furthermore, reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of neurotrophic factors (NTFs) brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Expression of Notch1 and its target molecular Hes1 were also analyzed by western-blotting and RT-PCR. Results Salidroside treatment ameliorated I/R induced neurobehavioral impairment, and reduced infarct volume. Salidroside also restored NeuN positive cells loss after I/R injury. Cerebral I/R injury significantly increased the expression of 5-Bromo-2’-Deoxyuridine (BrdU) and doublecotin (DCX), elevated the number of BrdU/Nestin/DCX triple-labeled cells in SVZ, and BrdU/Nestin/glial fibrillary acidic protein (GFAP) triple-labeled cells in striatum. Salidroside treatment further promoted the proliferation of BrdU/DCX labeled neuroblasts and BrdU/Nestin/GFAP labeled reactive astrocytes. Furthermore, salidroside elevated the mRNA expression and protein concentration of BDNF and NGF in ischemia periphery area, as well. Mechanistically, salidroside elevated Notch1/Hes1 mRNA expression in SVZ. The protein levels of them were also increased after salidroside administration. Conclusions Salidroside enhances the endogenous neural regeneration after cerebral I/R. The mechanism of the effect may involve the regulation of BDNF/NGF and Notch signaling pathway.

Background: Asthma, a prevalent chronic respiratory disorder, remains enigmatic, notwithstanding considerable advancements in our comprehension. Continuous efforts are crucial for discovering novel molecular targets and gaining a comprehensive understanding of its pathogenesis. Materials and methods: In this study, we analyzed gene expression data from 212 individuals, including asthma patients and healthy controls, to identify 267 differentially expressed genes, among which C1orf64 and C7orf26 emerged as potential key genes in asthma pathogenesis. Various bioinformatics tools, including differential gene expression analysis, pathway enrichment, drug target prediction, and single-cell analysis, were employed to explore the potential roles of the genes. Results: Quantitative PCR demonstrated differential expression of C1orf64 and C7orf26 in the asthmatic airway epithelial tissue, implying their potential involvement in asthma pathogenesis. GSEA enrichment analysis revealed significant enrichment of these genes in signaling pathways associated with asthma progression, such as ABC transporters, cell cycle, CAMs, DNA replication, and the Notch signaling pathway. Drug target prediction, based on upregulated and downregulated differential expression, highlighted potential asthma treatments, including Tyrphostin-AG-126, Cephalin, Verrucarin-a, and Emetine. The selection of these drugs was based on their significance in the analysis and their established anti-inflammatory and antiviral invasion properties. Utilizing Seurat and Celldex packages for single-cell sequencing analysis unveiled disease-specific gene expression patterns and cell types. Expression of C1orf64 and C7orf26 in T cells, NK cells, and B cells, instrumental in promoting hallmark features of asthma, was observed, suggesting their potential influence on asthma development and progression. Conclusion: This study uncovers novel genetic aspects of asthma, highlighting potential therapeutic pathways. It exemplifies the power of integrative bioinformatics in decoding complex disease patterns. However, these findings require further validation, and the precise roles of C1orf64 and C7orf26 in asthma warrant additional investigation to validate their therapeutic potential. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alzheimer’s disease is a degenerative neurological disorder characterized primarily by cognitive impairment. Acupuncture is a kind of traditional Chinese medicine therapy for treating Alzheimer’s disease, but its mechanism is not yet clear. OBJECTIVE: To observe the effects of electroacupuncture with “Zhi San Zhen” on the Notch signaling pathway, β-amyloid protein (Aβ) and synaptic plasticity in 5xFAD mice. METHODS: Sixteen male, 6-month-old 5xFAD mice, SPF-grade, were randomly divided into the electroacupuncture with “Zhi San Zhen” group (electroacupuncture group) and the model group, with eight mice in each group. Eight SPF-grade, male, 6-month-old C57BL/6 mice were used as the wild control (wild) group. The electroacupuncture group received electroacupuncture with “Zhi San Zhen” intervention, 5 times a week for 4 consecutive weeks. The model group and the wild group did not receive electroacupuncture intervention. The Morris water maze was used to preliminarily assess their learning and memory abilities. Thioflavin S staining was performed to detect Aβ plaque deposition. Western blot and real-time quantitative polymerase chain reaction (RT-qPCR) were used to measure the expression levels of transmembrane receptor protein Notch-1, Notch 1 intracellular domain (NICD), hairy and enhancer of split 1 (Hes 1), hairy and enhancer of split 5 (Hes 5), synaptophysin (SYN), postsynaptic density protein-95 (PSD-95), and Aβ. RESULTS AND CONCLUSION: Compared with the model group, the wild group and the electroacupuncture group showed shortened escape latency, increased platform crossing times, and longer target quadrant dwell time (P < 0.05). Compared with the wild group, the model group had significantly increased deposition of Aβ plaques, while electroacupuncture with “Zhi San Zhen” inhibited the deposition of Aβ plaques in the hippocampus of 5xFAD mice (P < 0.05). Compared with the wild group, the model group had decreased mRNA levels of SYN, PSD-95, Notch 1, NICD, Hes 1, and Hes 5 in the hippocampal tissue of mice, and increased mRNA levels of Aβ (P < 0.05). Electroacupuncture with “Zhi San Zhen” increased the mRNA levels of SYN, PSD-95, Notch 1, NICD, Hes 1, and Hes 5 in the hippocampal tissue, and decreased the mRNA level of Aβ (P < 0.05). Compared with the Wild group, the model group had decreased protein expression levels of SYN, PSD-95, Notch 1, NICD, Hes 1, and Hes 5 in the hippocampal tissue of mice, and increased protein expression levels of Aβ (P < 0.05). Electroacupuncture with “Zhi San Zhen” upregulated the protein expression levels of SYN, PSD-95, Notch 1, NICD, Hes 1, and Hes 5, and inhibited the protein expression of Aβ (P < 0.05). To conclude, electroacupuncture with “Zhi San Zhen” can improve the learning and memory abilities of 5xFAD mice, possibly by inhibiting the deposition of Aβ protein and activating the Notch signaling pathway in the hippocampus to enhance synaptic plasticity. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) often leads to significant functional impairment. Here, we investigated the impact of epidermal growth factor‐like domain‐containing protein 7 (EGFL7) on angiogenesis and nerve regeneration following PNI. Using a sciatic nerve injury model, we assessed nerve function using the sciatic nerve function index. We analyzed the expression levels of EGFL7, forkhead box proteins A1 (FOXA1), nerve growth factor (NGF), brain‐derived neurotrophic factors (BDNF), Neurofilament 200 (NF200), myelin protein zero (P0), cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), and NOTCH‐related proteins in tissues and cells. Cell proliferation, migration, and angiogenesis were evaluated through cell counting kit assays, 5‐ethynyl‐2′deoxyuridine staining, and Transwell assays. We investigated the binding of FOXA1 to the EGFL7 promoter using dual‐luciferase assays and chromatin immunoprecipitation. We observed decreased EGFL7 expression and increased FOXA1 expression in PNI, and EGFL7 overexpression alleviated gastrocnemius muscle atrophy, increased muscle weight, and improved motor function. Additionally, EGFL7 overexpression enhanced Schwann cell and endothelial cell proliferation and migration, promoted tube formation, and upregulated NGF, BDNF, NF200, P0, CD31, and VEGF expression. FOXA1 was found to bind to the EGFL7 promoter region, inhibiting EGFL7 expression and activating the NOTCH signaling pathway. Notably, FOXA1 overexpression counteracted the effects of EGFL7 on Schwann cells and endothelial cells. In conclusion, EGFL7 holds promise as a therapeutic molecule for treating sciatic nerve injury. [ABSTRACT FROM AUTHOR]

• PPE inhibited the development of glomeruli and promoted compensatory growth of renal tubules. • PPE at clinical dose disturbed fetal kidney development with a time-effect difference, manifested as full-term pregnancy exposure > early pregnancy exposure > mid-late pregnancy exposure. • The developmental toxicity of PPE on fetal kidney was more serious to the female fetuses than the males. Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication. Now, it is also recognized as an emerging environmental contaminant. Pregnant women may be exposed to prednisone actively or passively through multiple pathways and cause developmental toxicity to the fetus. However, the impact of prenatal prednisone exposure (PPE) on fetal kidney development remains unclear. In this study, pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses (0.25, 0.5, or 1 mg/(kg·day)), or at the dose of 1 mg/(kg·day) in different gestational days (GD) (GD0-9, GD10-18, or GD0-18). The pregnant mice were euthanized on GD18. HE staining revealed fetal kidney dysplasia, with an enlarged glomerular Bowman's capsule space and a reduced capillary network in the PPE groups. The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups. However, overall gene expression in renal tubules and collecting ducts were markedly increased. All of the above effects were more pronounced in high-dose, full-term pregnancy, and female fetuses. Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2, increased the expression of Hnf1β, Hnf4α, and Wnt9b, and inhibited the expression of glial cell line-derived neurotrophic factor (GDNF) and Notch signaling pathways. In conclusion, this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney, and the time effect is manifested as full-term pregnancy > early pregnancy > mid-late pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

The document discusses the increased risk of skin cancers, specifically basal-cell carcinomas (BCC) and squamous-cell carcinomas (SCC), in solid organ transplant recipients (SOTR) due to immunosuppression. Treatment primarily involves surgical excision, with adjuvant radiotherapy for aggressive SCC. Immune-checkpoint inhibitors (ICI) are used for advanced SCC in non-immunosuppressed patients, but their use in SOTR requires careful consideration due to the risk of allograft rejection. Prevention strategies include treating precancerous lesions and implementing photoprotection measures. Future perspectives include new immunotherapies, HPV vaccination, and local blockade of tacrolimus for tumor rejection. [Extracted from the article]

The colonic mucosal barrier is an important component of the intestinal barrier, and its integrity is crucial for maintaining digestive tract homeostasis and normal metabolism in the body. This study aimed to elucidate the mechanisms by which malvidin-3-O-galactoside (M3G) might ameliorate colonic mucosal barrier function, from the perspective of physical barrier function and immune barrier function. Male C57BL/6J mice were given dextran sulfate sodium (DSS) to establish a mice model for colitis and then administrated with or without M3G for one week. The results showed that M3G supplementation significantly improved the disease activity index (DAI) score and colon tissue injury in mice with DSS-induced colitis. M3G improved the colonic physical barrier function by modulating the expression of mucin2 (MUC2), claudin-1, occludin, zona occludens 1 (ZO-1), and intestinal fatty acid binding protein (iFABP) in the colonic mucosa. Additionally, M3G also relieved the colonic immune barrier of mice by increasing the level of secretory immunoglobulin A (SIgA) in colon tissue and the percentages of CD4+T (CD3+CD4+) and CD8+T (CD3+CD8+) cells in colon lamina propria monocytes in mice. Furthermore, M3G down-regulated Notch signaling pathway-related proteins such as Notch1, notch intracellular domain (NICD), delta-like ligand 4 (DLL4), delta-like ligand 1 (DLL1), and hairy/enhancer of split 1 (Hes1) of colon tissue. The present results demonstrated that M3G can improve colonic mucosal barrier function by inhibiting the Notch signaling pathway.

Magnesium phosphate bone cements (MPC) have been recognized as a viable alternative for bone defect repair due to their high mechanical strength and biodegradability. However, their poor porosity and permeability limit osteogenic cell ingrowth and vascularization, which is critical for bone regeneration. In the current study, we constructed a novel hierarchically-porous magnesium phosphate bone cement by incorporating extracellular matrix (ECM)-mimicking electrospun silk fibroin (SF) nanofibers. The SF-embedded MPC (SM) exhibited a heterogeneous and hierarchical structure, which effectively facilitated the rapid infiltration of oxygen and nutrients as well as cell ingrowth. Besides, the SF fibers improved the mechanical properties of MPC and neutralized the highly alkaline environment caused by excess magnesium oxide. Bone marrow stem cells (BMSCs) adhered excellently on SM, as illustrated by formation of more pseudopodia. CCK8 assay showed that SM promoted early proliferation of BMSCs. Our study also verified that SM increased the expression of OPN, RUNX2 and BMP2, suggesting enhanced osteogenic differentiation of BMSCs. We screened for osteogenesis-related pathways, including FAK signaing, Wnt signaling and Notch signaling, and found that SM aided in the process of bone regeneration by suppressing the Notch signaling pathway, proved by the downregulation of NICD1, Hes1 and Hey2. In addition, using a bone defect model of rat calvaria, the study revealed that SM exhibited enhanced osteogenesis, bone ingrowth and vascularization compared with MPC alone. No adverse effect was found after implantation of SM in vivo. Overall, our novel SM exhibited promising prospects for the treatment of critical-sized bone defects.