USP18 orchestrates malignant progression in nasopharyngeal carcinoma through UBR5-driven attenuation of p53 signaling.

ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications.

Myocardial infarction (MI) is a complex pathological process characterized by vascular injury, myocardial necrosis, and dynamic immune interactions. Migrasomes are recently identified organelles generated during cell migration, serving as key mediators of intercellular communication. However, the contribution of migrasomes to immune-mediated myocardial injury remains largely unexplored. This study demonstrated an increase in migrasome production following MI. Migrasomes can be produced by macrophages, and M1 macrophage-derived migrasomes (M1-Migs) were particularly found to exacerbate myocardial tissue injury. Quantitative proteomic sequencing demonstrated increased levels of guanylate binding protein 5 (GBP5) within M1-Migs. Viral knockdown experiments demonstrated that M1-Migs mediate their deleterious effects predominantly via GBP5. Pathway enrichment analysis further indicated that GBP5 activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, thereby promoting myocardial cell apoptosis. Analysis of clinical samples has also demonstrated a positive correlation between macrophage-derived migrasomes and MI. Notably, colchicine may mitigate post-infarction myocardial injury by suppressing migrasome production by M1 macrophages. Overall, these findings identify macrophage-derived migrasomes as key amplifiers of myocardial injury, providing potential therapeutic targets for MI and may provide additional evidence for the clinical application of colchicine.

Colorectal cancer (CRC) is a major health threat with limited therapies for advanced stages. Crocetin, a natural compound from saffron, has broad anticancer potential, but its mechanisms in CRC are unclear. A CRC xenograft mouse model was established to evaluate the antitumor effect of crocetin. Next, transcriptomic analysis was performed to identify differentially expressed genes (DEGs) in tumor tissues of tumor-bearing mice between the crocetin treatment and control groups. Through the integration of network pharmacology, and protein-protein interaction (PPI) network analysis, potential key target genes regulated by crocetin in CRC were identified. Functional assays (e.g. CCK-8 and transwell assays) were employed to assess the biological role of crocetin and its target gene, TGM2, in CRC cells. Crocetin significantly inhibited tumor growth in HCT116-tumor-bearing mice in vivo. Transcriptomic analysis identified 2,577 DEGs in tumor tissues between the crocetin and control groups. Through integrated network pharmacology, transcriptomics, and molecular docking analyses, we identified five potential crocetin-targeted genes-ADAM17, DNMT1, MTOR, TGM2, and XRCC6-all of which showed significant downregulation following crocetin treatment. Furthermore, in vitro experiments demonstrated that crocetin notably suppressed cell viability, migration, and invasion, as well as reduced the expression of TGM2, p-JAK2, and p-STAT3 in HCT116 cells; however, the tumor-suppressive effects of crocetin were markedly abolished by TGM2 overexpression. Collectively, crocetin could suppress CRC progression by targeting TGM2/JAK2/STAT3 signaling pathway, supporting its potential as a therapeutic agent for CRC.

Schlafen family member 11 (SLFN11), implicated in cancer drug resistance, may improve poly(ADP-ribose) polymerase inhibitor (PARPi) efficacy. This study investigates SLFN11's role in epithelial ovarian cancer (EOC) progression and its influence on PARPi sensitivity, particularly in BRCA-wild-type contexts, with a focus on its emerging function in proteostasis regulation. SLFN11 expression in EOC and adjacent tissues was evaluated via immunohistochemistry, quantitative polymerase chain reaction (PCR), and Western blot. Functional assays-including cell viability, transwell migration, wound healing, and colony formation-assessed SLFN11's effects on SKOV3 cells (BRCA-wild-type) proliferation and invasiveness. PARPi sensitivity in SKOV3 cells with SLFN11 knockdown or overexpression (OE) was tested using Cell Counting Kit (CCK)-8 and Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assays. Protein stability and ubiquitination levels of PARP1/2 were analyzed as the central mechanism. SLFN11 mRNA and protein levels were markedly lower in EOC tissues compared with normal tissues. Silencing SLFN11 enhanced EOC cell proliferation, migration, and invasion, whereas OE inhibited these malignant behaviors. SLFN11 knockdown reduced PARPi-induced apoptosis and drug sensitivity, while its OE amplified these responses. Mechanistically, we demonstrate that SLFN11 suppresses global proteotoxic ubiquitination, thereby specifically stabilizing PARP1/2 proteins and potentiating PARPi-mediated DNA damage through enhanced chromatin trapping. SLFN11 enhances PARPi sensitivity in EOC by stabilizing PARP1/2 via inhibition of proteotoxic ubiquitination, supporting its role as a biomarker in a BRCA-wild-type EOC cell model where PARPi efficacy is limited by intrinsic resistance. While the application of PARPi in other subtypes of EOC still requires further validation, SLFN11 may improve PARPi response and could be explored as a strategy to address PARPi resistance.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and a poor prognosis. Resveratrol (RES), a natural polyphenolic compound, has demonstrated antitumor activity in multiple cancer types; however, its underlying mechanisms in pancreatic cancer remain incompletely understood. In this study, we investigated the effects of RES on pancreatic cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), with a particular focus on the role of inhibitor of growth family member 5 (ING5). Pancreatic cancer cell lines PANC1 and SW1990 were treated with RES, and cell viability, clonogenic growth, migration, and invasion were assessed using CCK-8, colony formation, wound-healing, and Transwell assays, respectively. ING5 expression and localization were evaluated by immunofluorescence, RT-qPCR, and Western blotting, and its functional significance was further examined using siRNA-mediated knockdown. RES treatment significantly suppressed pancreatic cancer cell proliferation, migration, invasion, and EMT in vitro, accompanied by upregulation of ING5 expression and increased E-cadherin levels with concomitant reduction of N-cadherin expression. Silencing ING5 enhanced malignant cellular behaviors and partially reversed the inhibitory effects of RES on EMT-associated phenotypes and cell growth. These findings indicate that ING5 contributes to the antitumor effects of RES and functions as an important mediator in the suppression of pancreatic cancer progression. Collectively, our results suggest that RES restrains pancreatic cancer cell aggressiveness at least in part through upregulation of ING5, highlighting the RES-ING5 axis as a potential therapeutic target for pancreatic cancer intervention.

Biocompatibility between bone cells and biomred for the process of osteogenesis. The aim of this study was to assess the effect of Photobiomodulation (PBM) in vitro on dental pulp stem cells (DPSCs) treated with Bio-Oss® (BO) bone substitute xenograft. DPSC cultures were obtained from third molars extracted from healthy volunteers and characterized by flow cytometry. The effects of PBM (5, 7, or 10J/cm2) on DPSCs treated with BO (5mg/ml) were assessed using cytotoxicity assays, viability staining, cell migration, alkaline phosphatase activity, and Alizarin red S staining. PBM restored the lost migration ability of DPSCs treated with BO; however, this combined therapy was associated with significantly lower levels of DPSC viability, alkaline phosphatase expression, and mineralization compared to controls. PBM therapy did not improve the biocompatibility of DPSCs treated with BO bone substitute. The effect of interaction between these treatments seemed to be cytotoxic to DPSCs. Our results suggest that the interaction between BO and PBM therapy could impair bone regeneration.

Disruption of nuclear-cytoskeletal connection impairs epithelial cell mechanosensing and collective migration.

Rosa roxburghii Tratt. (Cili), a medicinal-edible herb predominantly distributed in Guizhou Province, exhibits diverse pharmacological properties, including anti-inflammatory, antioxidant, and cell proliferation-promoting effects. Despite its recognized pharmacological value, the therapeutic efficacy and underlying mechanisms in fracture healing remain unexplored. This study aims to systematically investigate its potential mechanisms by integrating network pharmacology and molecular docking. The components of R. roxburghii Tratt. were retrieved from the PubChem, CNKI, VIP, and WANFANG databases, and their corresponding targets were screened from public databases. The targets of fracture healing were obtained from the GeneCards and OMIM databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed the mechanisms of R. roxburghii Tratt. in fracture healing. The potential targets and core components were identified by constructing a protein-protein interaction network and a series of topological networks. Finally, molecular docking was performed to validate the binding of the core targets to the components. Gene Ontology analysis highlighted its regulation of vascular endothelial growth factor signaling pathway, cell migration, epidermal growth factor receptor signaling pathways, and fibroblast growth factor receptor signaling pathways. Kyoto Encyclopedia of Genes and Genomes analysis suggested that R. roxburghii Tratt.'s mechanism may involve key pathways, such as hypoxia-inducible factor 1, phosphoinositide 3-kinase/protein kinase B, mitogen-activated protein kinase, tumor necrosis factor, and ras-associated protein-1 signaling pathway, while topological network analysis identified 4 core targets (tumor necrosis factor, prostaglandin G/H synthase 2, epidermal growth factor receptor, and proto-oncogene tyrosine-protein kinase Src) and 21 core components (naringenin, quercetin, kaempferol, isorhamnetin, luteolin, myricetin, etc), all critically associated with osteogenesis and angiogenesis. Molecular docking confirmed strong binding between these components and targets. These findings propose that R. roxburghii Tratt. may accelerate fracture healing by multitarget, components, and pathways regulating osteogenesis and angiogenesis, providing a scientific basis for its development and utilization.

Tissue-resident lymphocytes can recirculate, but the underlying molecular mechanism is poorly understood. During helminth infection, intestinal group 2 innate lymphoid cells (ILC2s) rapidly proliferate and give rise to inflammatory ILC2s (iILC2s), which migrate from the intestine to distal tissues. Here, we show in mice that the redistribution of iILC2s requires access to lymphatic vessels. Interleukin-25 (IL-25) induces a substantial change in the epigenetic landscape of iILC2s, with transcription factors KLF2 and ZEB2 driving increased expression of sphingosine-1-phosphate receptor 1 (S1PR1) and S1PR5, respectively. S1PR5 regulates iILC2 exit from the intestine to the lymph, whereas S1PR1 is critical for iILC2 egress from the mesenteric lymph nodes to the blood and then to distal tissues including the lung, where iILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of CD69, which mediates S1PR1 internalization. Thus, S1PRs modulate iILC2 emigration from nonlymphoid and lymphoid organs in a stage-specific manner, which provides a framework for understanding the multistep migration of tissue-resident immune cells.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer and seriously threatens the lives of many people worldwide. The difficulty in early diagnosis of lung cancer has always been a difficulty in lung cancer treatment, and basic leucine zipper nuclear factor 1 (BLZF1) has been shown to promote the occurrence and development of various cancers. This study used 505 LUAD patients in TCGA (TCGA dataset) and 60 LUAD patients in Yunnan Cancer Hospital (Clinical dataset) as research subjects to explore the role of BLZF1 in LUAD. The study found that the expression levels of mRNA and protein of the BLZF1 gene in cancer tissues were significantly higher than those in para-cancer tissues in the TCGA dataset and clinical dataset (P < 0.001). Receiver operating characteristic (ROC) curves analysis found that the AUC value of BLZF1 was 0.759 (95% CI = 0.7049-0.8140, P < 0.0001) in the TCGA dataset, and the AUC value was 0.9985 (95% CI = 0.9954-1.0000, P < 0.0001) in the clinical dataset. Moreover, the BLZF1 gene expression level in the two data sets was significantly correlated with the patient's T stage, and survival analysis showed that high BLZF1 gene expression levels were associated with decreased recurrence-free survival (RFS) (HR = 1.510, 95% Cl = 1.095-2.083, P = 0.012) and overall survival (OS) (HR = 1.472, 95% Cl = 1.099-1.973, P = 0.010). Protein-protein interaction (PPI) and enrichment analysis showed that the BLZF1 gene was closely associated with biological processes such as Golgi function, vesicle transport and cell membrane system maintenance. The expression correlation of BLZF1 with glycolysis-related genes indicated that BLZF1 may play a role in LUAD by participating in the sugar metabolism pathway. In addition, this study downregulated the expression of BLZF1 by small interfering RNA (si-BLZF1), and downregulation of BLZF1 expression significantly inhibited the proliferation, cloning, migration and invasion of LUAD cells. Therefore, BLZF1 may be involved in the occurrence and development of lung adenocarcinoma, which can be a potential diagnostic biomarker in clinical practice.

Collagen, a crucial structural protein in the extracellular matrix (ECM), exhibits exceptional biocompatibility with broad applications in biomedicine and cosmetics, of which type III collagen exhibits ubiquitous distribution across crucial tissues including vasculature and skin, where it performs essential physiological functions. However, high-efficiency production of bioactive recombinant human type III collagen (rhCOLIII) remains challenging. This study developed an effective strategy for synthesizing functional rhCOLIII in genetically engineered silkworms, which was driven by fibroin heavy chain (FibH) expression system, making rhCOLIII specifically expressed in the posterior silk gland (PSG) of silkworms. Moreover, rhCOLIII was successfully secreted into the cocoons at the yield of 7.8 mg/g cocoon shell weight. RNA-seq analysis revealed that differentially expressed genes (DEGs) enriched predominantly in endoplasmic reticulum protein processing pathways. Notably, the purified rhCOLIII protein exhibited excellent cytocompatibility and significantly promoted cell proliferation and migration of NIH/3T3, indicating its potential for accelerating wound healing. Additionally, the commercially important traits of the silkworms also remained unchanged, while the existence of rhCOLIII significantly improved the extensibility and toughness of silk fibers. These findings establish the silkworm bioreactor as a viable platform for high-efficiency production of bioactive rhCOLIII and provide a strategy for synthesizing other functional recombinant proteins.

N6,2'-O-dimethyladenosine (m6Am) is a prevalent RNA modification located at the first transcribed nucleotide adjacent to the 5' cap of mRNAs, where it has been implicated in gene regulation. However, the lack of methods for precise, transcript-specific manipulation of m6Am has limited its functional dissection. Here, we develop a programmable RNA-editing platform, termed Targeted m6Am Methylation (TAmM), that enables site-specific installation of m6Am on selected cellular transcripts. TAmM is engineered by fusing the catalytically inactive RfxCas13d (dCasRx) with the m6Am methyltransferase PCIF1, allowing guided deposition of m6Am at cap-proximal nucleotides. Using TAmM, we achieve efficient and specific m6Am installation at single-nucleotide resolution, as validated by LC-MS/MS. Targeted m6Am editing does not alter steady-state mRNA abundance but modulates protein output in a transcript-dependent manner. Mechanistically, m6Am installation enhances polysome association, indicating a direct role in translational regulation. Functional interrogation demonstrates that cap-proximal m6Am deposition on CTNNB1 increases β-catenin protein expression, promoting cell proliferation, clonogenicity, and migration in cancer cell models. Importantly, TAmM exhibits high fidelity, with negligible effects on the global m6Am landscape, transcriptome, or proteome. Our study establishes TAmM as a precise and versatile platform for programmable m6Am manipulation and reveals transcript-specific roles of m6Am in gene regulation.

The inhibitory effects of evodiamine on GBC cells were evaluated in vitro using a cell viability assay. Cell migration capacity was assessed via wound healing and Transwell assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry and Western blotting (WB). The molecular mechanisms were investigated using Quantitative polymerase chain reaction (qPCR) and WB to quantify ZEB1 gene expression. In vivo, the anti-tumor activity of evodiamine was verified in a nude mouse model. Evodiamine significantly inhibited the proliferation of GBC cells. Flow cytometry and Western blotting revealed that evodiamine induced G2/M phase arrest and promoted apoptosis. mRNA-sequencing (mRNA-seq) demonstrated that evodiamine suppressed the transcription of ZEB1 and genes in the PI3K-Akt signaling pathway. Consistent with in vitro findings, evodiamine exhibited remarkable antitumor effects in a nude mouse model. This study confirms that evodiamine inhibits GBC cell proliferation and induces apoptosis. The mechanism involves suppression of ZEB1 expression and inactivation of the PI3K-Akt signaling pathway.

Moderate-to-vigorous physical activity (MVPA) is inversely associated with risks of cancer, cardiovascular diseases (CVD), type 2 diabetes (T2D), and their co-occurrence, defined as multimorbidity; however, the underlying biological pathways remain unclear. In 33,806 UK Biobank participants with 2911 measured blood proteins, a proteomic signature of MVPA was derived with linear and LASSO regressions. Multivariable Cox models, adjusted for MVPA, estimated prospective associations with cancer, CVD, T2D, and multimorbidity. We show that after multiple testing corrections, 220 proteins are retained in the MVPA signature. Proteins related to food intake, metabolism, and cell growth (e.g., LEP, MSTN) are inversely associated, while those involved in immune cell migration and musculoskeletal integrity (e.g., integrins, COMP) are positively associated with MVPA. Several proteins positively associated with MVPA are inversely associated with disease risk (e.g., integrins, CLEC4A for cancer; LPL, LEP for T2D), while proteins negatively associated with MVPA are positively associated with disease risk (e.g., CD38, TGFA for CVD). The proteomic signature score is inversely associated with cancer risk (hazard ratio per interquartile range: 0.87; 95% confidence interval: 0.78, 0.96) and T2D (0.66; 0.60, 0.72). For multimorbidity, proteins inversely related to MVPA align with expected risk patterns (e.g., GGT1, HR: 1.32; 95% CI: 1.12, 1.57), but the proteomic signature score is not associated. This study identifies several proteins associated with MVPA that are also associated with cancer, CVD, T2D, and the multimorbidity of these conditions. Further studies investigating the causal nature of these associations are welcome.

Transcription factor Engrailed-1 (EN1) has been implicated as an oncogene in various solid tumors; however, its role in papillary thyroid carcinoma (PTC) is unknown. In the present study, the authors investigate the EN1 expression in PTC clinical specimens and its correlation with clinical outcomes, and then explore its function in PTC progression using in vitro and invivo models. A retrospective cohort of 376 paired PTC was collected with informed consent. Immunohistochemistry for EN1 protein expression was evaluated. Clinic pathological data were recorded. EN1-specific shRNAs (or siRNAs) and overexpression plasmids were used. Using En-1 knockdown and overexpression, cell invasion, migration, proliferation, and apoptosis in vitro were detected using Transwell and wound healing assays, MTT, colony formation assay, and flow cytometry assay, respectively. Xenograft tumor models (subcutaneous) and tail-vein injection metastasis models (lung colonization) were established in mice. EN1 is significantly overexpressed in PTC tissues; high EN1 expression is correlated with lymphovascular invasion (p < 0.05), lymph node metastasis (p < 0.05), TNM stage (p < 0.05), and recurrence (p < 0.05). Functionally enhanced EN1 expression promotes PTC cell invasion and migration, and promotes cell proliferation in vitro. Conversely, EN1 knockdown potently inhibited this invasive phenotype, induced significant apoptosis, and inhibited cell proliferation. EN1 silencing reduced tumor growth and lung metastatic potential in murine models invivo. EN1 overexpression enhanced these malignant phenotypes invivo. EN1 may be a novel driver of PTC aggressiveness and metastasis, suggesting its potential utility as a prognostic biomarker and therapeutic target.

Colorectal cancer (CRC) represents a major cause of cancer-related mortality worldwide. Exosomes derived from cancer-associated fibroblasts (CAFs-Exo) transfer oncogenic signals to cancer cells, promoting tumor growth, metastasis, and glutamine metabolism. However, the specific contribution of CAFs-Exo to the pathogenesis of CRC is still largely unexplored. The conditioned medium of CAFs (CAF-CM) and CAFs-Exo were used to treat CRC cells. The effects on cell behaviors were evaluated by measuring cell viability, proliferation, migration, invasion, and sphere formation. The influence on glutamine metabolism was assessed by detecting glutamine consumption and glutamine and α-ketoglutarate production. MeRIP, RIP, RNA pull-down, and mRNA stability assays were used to assess the METTL1/SLC1A5 mRNA interaction. Animal experiments were used to evaluate the function of CAFs-Exo invivo. CAF-CM promoted CRC cell proliferation, migration, invasion, sphere formation, and glutamine metabolism invitro. CAF-CM increased METTL1 expression and m7G modification levels in CRC cells. Si-METTL1-CAF-CM exerted inhibitory effects on CRC cell malignant behaviors and glutamine metabolism. Mechanistically, METTL1 stabilized SLC1A5 mRNA by mediating its m7G modification. SLC1A5 overexpression reversed the inhibitory effects of si-METTL1-CAF-CM on CRC cell malignant behaviors and glutamine metabolism. Furthermore, CAFs-Exo increased METTL1 protein levels in CRC cells. Sh-METTL1-CAFs-Exo suppressed tumor growth and lung metastasis invivo. Our findings identify a novel CAFs-Exo/METTL1/SLC1A5 axis that drives CRC progression partially by reprogramming glutamine metabolism, revealing new potential therapeutic targets for CRC treatment.

Spatio-Temporal Multi-Scale Cell Modeling of Skin Wound Healing.

Longitudinal, label-free tracking of stem cell differentiation is hindered by destructive end point assays and variability from cell migration and uncontrolled contacts. Here, we introduce an integrated single-cell array-electrochemical platform that standardizes the microenvironment while enabling repeated, nondestructive readouts on the same culture. Human bone marrow-derived mesenchymal stem cells (hBMSCs) were seeded onto a conductive single-cell array of polydopamine microdots microcontact-printed on poly(vinyl alcohol)-modified indium tin oxide (PVA-ITO). A thin methylcellulose overlay preserved viability and differentiation while limiting migration. Integrated with the electrochemical detection platform, the same substrate serves as the working electrode, enabling nondestructive electrochemical quantification of the osteogenic marker alkaline phosphatase (ALP) via conversion of l-ascorbic acid 2-phosphate (AAP) to electroactive ascorbic acid (AA). This integration enables standardized, label-free time-course measurements and is readily extensible to other enzymatic reporters and lineage programs.

Ophiopogonin B inhibits triple-negative breast cancer progression via suppressing PTP1B and regulating the PI3K/Akt pathway.