Ling Qi

Laminin (LN), a major component of the extracellular matrix (ECM), modulates tissue morphogenesis and is known to act as a reservoir for growth factors (GFs). Here we show, for the first time, that laminins and fibronectin also bind interleukins (ILs), through sites and binding behaviours distinct from those governing GF binding and independent of heparin. This finding extends the reservoir function of the ECM beyond growth factor biology and opens a matrix-biology perspective on immune regulation. We further show that LN111 potentiates IL-10 signalling during M2c macrophage polarization via crosstalk with the integrin α6 (ITGA6) axis. As a translational application, a PEG-maleimide (PEG-MAL) hydrogel functionalized with LN111 for IL-10 delivery significantly improves wound healing in a murine model of type 2 diabetes. During this work, we found that IL-binding sites sterically interfere with commercial antibodies. To address this, we developed a high-throughput approach that replaces immunolabelling with chemical labelling and combines AI-assisted docking with wet-lab validation to screen binding sites within large ECM proteins.

Pancreatic cancer (PC) is a lethal malignant tumor of the digestive system with a low survival rate. Current therapies provide only modest benefits for patients and new therapeutic options are urgently needed. Schisandrin B (Sch B) has demonstrated novel antitumor activity in several preclinical models; however, its effects on PC remain unclear. In the present study, the anti‑proliferative effects of Sch B in vitro were evaluated in PC cell lines. The underlying molecular mechanisms were explored using RNA sequencing, drug affinity responsive target stability (DARTS), molecular docking and small interfering RNA transfection. The antitumor effects of Sch B in vivo were evaluated using both a subcutaneous xenograft mouse model and an orthotopic genetically engineered mouse model. The in vitro studies showed that Sch B significantly inhibited the proliferation of PC cells and induced cell death in a dose‑dependent manner. Mechanistically, transcriptome Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that differentially expressed genes were significantly enriched in the ‘ferroptosis’ signaling pathway. Sch B triggered ferroptosis by promoting iron overload, lipid peroxidation and glutathione (GSH) depletion, as well as regulating the expression of ferroptosis‑related proteins [including GSH peroxidase 4, solute carrier family 3 member 2, acyl‑CoA synthetase long‑chain family member 4 (ACSL4), γ‑glutamyl‑cysteine ligase catalytic subunit and GSH synthetase]. Furthermore, pre‑treatment with the ferroptosis inhibitor ferrostatin‑1 partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. DARTS assays and molecular docking analyses confirmed the direct interaction between Sch B and ACSL4. Notably, silencing ACSL4 expression also partially reversed the anti‑proliferative effects and ferroptosis‑related events induced by Sch B. The in vivo studies demonstrated that Sch B suppressed tumor growth in subcutaneous xenograft models with good biosafety, and inhibited metastasis in orthotopic genetically engineered mice. In conclusion, Sch B may exert anti‑proliferative effects at least partially by inducing ACSL4‑dependent ferroptosis in PC.

Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis largely due to therapy-resistant stem-like cells that drive recurrence. While N6-methyladenosine modifications in GBM are well-studied, the role of 5-methylcytosine (m5C) modifications specifically in circular RNAs (circRNAs) remains poorly understood. Bioinformatic analysis, qRT-PCR and Western blot assays were used to investigate the expression of NSUN7, circNTRK2, YBX3, STK31, IKZF1 in GBM tissues and cell lines. m5C dot blot assays, m5C-bisulfite sequence assays, Sanger’s sequencing, RNA pull down and RIP assays, in vitro kinase assays, chromatin immunoprecipitation and luciferase reporter gene assays are used to clarify the interaction between factors above. Colony formation assays, sphere formation assays, and stemness marker (OCT4, DCLK1) analysis were utilized to assess the impact of the factors above on GBM stemness. Subcutaneous heterotopic and orthotopic xenograft are utilized to demonstrate the function of YBX3/circNTRK2/STK31/IKZF1 axis in GBM in vivo. NSUN7 and YBX3 are both upregulated in GBM tissues and cell lines. NSUN7 catalyzes m5C modification of circNTRK2. YBX3 decreasing circNTRK2 stability and function via binding m5C of circNTRK2. CircNTRK2 binds to and activates STK31, leading to phosphorylation of IKZF1 at S63, which decreases the O-GlcNAc levels and transcriptional activity of IKZF1, thereby promoting the stem cell characteristics of GBM cells. This study unveils that NSUN7-mediated m5C modification of circNTRK2 fuels GBM stemness via circNTRK2-dependent STK31 activation, thus identifying potential biomarkers for targeted molecular therapy of GBM and providing novel therapeutic targets for GBM treatment.

The subventricular zone (SVZ) is a region surrounding the lateral ventricles that contains neural stem cells and neural progenitor cells, which can proliferate and differentiate into various neural and glial cells. SVZ cells play important roles in neurological diseases like neurodegeneration, neural injury, and glioblastoma multiforme. Investigating the anatomy, structure, composition, physiology, disease associations, and related mechanisms of SVZ is significant for neural stem cell therapy and treatment/prevention of neurological disorders. However, challenges remain regarding the mechanisms regulating SVZ cell proliferation, differentiation, and migration, delivering cells to damaged areas, and immune responses. In-depth studies of SVZ functions and related therapeutic developments may provide new insights and approaches for treating brain injuries and degenerative diseases, as well as a scientific basis for neural stem cell therapy. This review summarizes research findings on SVZ and neurological diseases to provide references for relevant therapies.

Introduction: In recent years, natural compounds have attracted wide attention for the treatment of liver cancer due to their therapeutic potential and reduced toxicity. Among these, Schisandrin B (Sch B), a primary bioactive component derived from Schisandra chinensis, has shown notable antitumor activity; however, its specific mechanism remains unclear.Methods: The effect of Sch B on the growth of hepatocellular carcinoma(HCC) cells were assessed using CCK-8 assay, colony formation assay and EdU assay, and apoptosis was detected by flow cytometry. The co-culture system of macrophages and HCC cells was established to detect the effect of Sch B on the cell viability and cell cycle changes of HCC cells in the co-culture system. Then, the migration of HCC cells in the co-culture system was studied using a subtoxic concentration of Sch B. Exosomes of the co-culture system with or without Sch B effect were collected for identification and protein spectrum analysis. The differential protein was analyzed by KEGG enrichment analysis and protein interaction network, which was verified by western blotting. Meanwhile, the expression changes of macrophage polarization markers were detected. Finally, the inhibitory effect of Sch B on HCC and the changes of FN1 were verified by in vivo experiments.Results: Sch B inhibited HCC cell growth; moreover, it significantly suppressed HCC cell proliferation in the co-culture system and induced S-phase cell cycle arrest by downregulating CDK4, CDK2, and cyclin A2 while upregulating p27 Kip1. Additionally, Sch B inhibited the migration of HCC cells in the co-culture system.The differentially expressed protein fibronectin 1(FN1) in liver cancer patients was higher than that in healthy people. Moreover, after SchB treatment, the expression of FN1 protein in exosomes decreased and the macrophages exhibited M1 polarization. In vivo experiments also verified that Sch B inhibited HCC growth and downregulated the expression of FN1 protein in tumor tissues.Conclusion: Sch B may inhibit the development of HCC by inhibiting the expression of exosomal FN1during interactions between macrophages and HCC cells.

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field.

This study investigates platelet‐related subtypes in non‐small cell lung cancer (NSCLC) and seeks to identify genes associated with prognosis, focusing on the clinical significance of the chloride ion channel gene BEST3. We utilised sequencing and clinical data from GEO, TCGA and the Xena platform, building a risk model based on genetic features. TCGA and GSE37745 served as training cohorts, while GSE50081, GSE13213, GSE30129 and GSE42127 were validation cohorts. Immunotherapy datasets (GSE135222, TCGA‐SKCM) were also analysed. Differentially expressed genes (DEGs) were identified using Limma, subtypes through ConsensusClusterPlus and key prognostic genes using COX regression, Random Forest and LASSO‐COX. BEST3 expression was validated by flow cytometry (FCM) and functional assays in A549 cells with lentiviral overexpression evaluated its impact on apoptosis, proliferation and migration. Three platelet‐related subtypes were identified, with ten key prognostic genes (including BEST3). Gene Ontology (GO) analysis showed six genes involved in platelet pathways. BEST3 was highly expressed in the platelet subtype 1. Flow cytometry confirmed elevated BEST3 levels in NSCLC (35.9% vs. 27.3% in healthy individuals). Overexpression of BEST3 in NSCLC cells suppressed apoptosis and promoted proliferation and migration. The discovery of three platelet subtypes and the role of BEST3 in promoting tumour growth and migration highlights its potential as a therapeutic target and prognostic marker in NSCLC.

[This corrects the article DOI: 10.3389/fonc.2024.1347123.].