Lina Chen

Neutrophil extracellular traps (NETs), the DNA-protein structures released by neutrophils within the tumor microenvironment (TME), play a role in cancer that extends far beyond their traditional antimicrobial function. Specifically, NETs exert multifaceted and context-dependent effects on tumor progression, metastasis, immune regulation, and therapeutic response, showing their robust activity in shaping the complex landscape of tumor biology. This review systematically elucidates how NETs promote tumorigenesis by inducing DNA damage and epithelial-mesenchymal transition (EMT), and drive metastatic spread through mechanisms such as trapping circulating tumor cells, remodeling the pre-metastatic microenvironment, and reactivating dormant cells. Concurrently, NETs shape an immunosuppressive TME by modulating T cells, NK cells, and macrophages, while mediating resistance to chemotherapy, radiotherapy, and immunotherapy. Based on these mechanisms, targeting NET formation (such as inhibiting PAD4 or NE) or degrading their structures (such as using DNase I) has emerged as a potential strategy to enhance the efficacy of existing therapies. Therefore, deepening the understanding of the multifunctional regulatory networks underlying NETs within the TME holds significant implications for developing novel precision cancer therapies.

There was a mistake in figure 6 as published. In Figure 6, the GAPDH band shown in panels E and F, as well as GAPDH in panels H and J, are identical. This is because the representative images of target proteins were obtained from the same batch of gels, and therefore the corresponding GAPDH controls were displayed. However, due to our layout mistake, the reuse of these internal controls was not clearly indicated, which may have appeared as repeated patterns during review. The corrected figure will not affect the results and conclusions. The corrected figure 6 appears below.The original version of this article has been updated.There was a mistake in the caption of figure 6 as published. Due to the correction of panels E, F, H and J in figure 6. The relevant caption will also need to be adjusted. The original caption of figure 6 The original version of this article has been updated.Adding/removing text Due to the correction of figure 6, the related figure information in the main text of this paper will also need to be adjusted. The original text is "According to the in vitro results, the protective effects of EPO on mesangial cells exposed to HG were associated with PINK1/Parkin-mediated mitophagy. So we further detected the mRNA and protein levels of genes in PINK1/Parkinmediated mitophagy in the kidney tissues. Compared with mice in the control group, the ratio of LC3B-Ⅱ/LC3B-Ⅰ (Figure 6E), the mRNA and protein levels of PINK1 (Figures 6C,G), and Mfn-2 protein level (Figure 6J) in the kidney tissues of mice of Model group were significantly decreased, while P62 and Drp-1 were significantly increased in terms of the mRNA and protein levels (Figures 6B,F,I), resulting in the blockage of autophagic flux and inhibited level of PINK1/Parkin-mediated mitophagy. However, there was no difference in the mRNA expression of LC3 in these two groups (Figure 6A), and the mRNA and protein levels of Parkin were elevated in the model group (Figures 6D,H). Of note, EPO administration partly reversed these changes as indicated by the significantly increased ratio of LC3B-II/LC3B-I (Figure 6E) as well as expressions of PINK1 (Figures 6C,G) and Mfn-2 (Figure 6J), and decreased expressions of P62 (Figures 6B,F) and Drp-1 (Figure 6I). These results suggested that EPO could mitigate the blockage of autophagic flux and improve the level of PINK1/Parkin-mediated mitophagy".A correction has been made to the section 3.6 (paragraph number 255):"According to the in vitro results, the protective effects of EPO on mesangial cells exposed to HG were associated with PINK1/Parkin-mediated mitophagy. So we further detected the mRNA and protein levels of genes in PINK1/Parkin-mediated mitophagy in the kidney tissues. Compared with mice in the control group, the ratio of LC3B-Ⅱ/LC3B-Ⅰ (Figure . 6E,F), the mRNA and protein levels of PINK1 (Figure . 6C,E,F), and Mfn-2 protein level (Figure . 6G,H) in the kidney tissues of mice of Model group were significantly decreased, while P62 and Drp-1 were significantly increased in terms of the mRNA and protein levels (Figure . 6B, E-H), resulting in the blockage of autophagic flux and inhibited level of PINK1/Parkin-mediated mitophagy. However, there was no difference in the mRNA expression of LC3 in these two groups (

Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial‐derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular–osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron‐derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single‐cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line‐1 in vitro through the FAK–AKT–VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular‐mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable progress in treating hematologic malignancies, yet its broader application faces challenges such as manufacturing complexity, solid tumor microenvironment barriers, and immune toxicity. Nanoparticles (NPs), leveraging their precise delivery, immunomodulation, and multifunctional integration capabilities, offer innovative strategies to optimize CAR-T cell therapy. This review provides a comprehensive elucidation of the fundamental framework of CAR-T cell therapy and the challenges in oncological applications. Subsequently, we systematically summarized the synergistic mechanisms between NPs and CAR-T cell therapy, including optimization of genetic modification, enhancement of tumor site infiltration, modulation of immunosuppressive tumor microenvironments, mitigation of tumor antigen heterogeneity, real-time monitoring, and dynamic control of cellular activity. Ultimately, it highlights the emerging paradigm of artificial intelligence integration within this domain while discussing the associated technical obstacles and future prospects of this combined therapeutic approach.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD. Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway. Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000-000.

Tangerine peel is a traditional Chinese herb and has been widely applied in foods and medicine for its multiple pharmacological effects. Erythropoietin receptor (EPOR), a member of the cytokine receptor family, is widely expressed in multiple tissues in especial kidney and plays protective effects in adverse physiological and pathological conditions. We hypothesized that it might be EPOR agonists existing in Tangerine peel bring such renal benefits. To test our hypothesis, an EPOR/cell membrane chromatography (CMC)-high performance liquid chromatography (HPLC)-mass spectrometry (MS) analytical system was developed to screen EPOR targeted compounds from tangerine peel extra out. A fraction was retained on the EPOR/CMC column, separated, and further identified as nobiletin. Frontal analysis, non-linear chromatography, and molecular docking assay were applied to determine the binding force and sites between nobiletin and EPOR. Intracellular Ca²⁺ mobilization, cAMP accumulation, and phosphorylation of JAK2 and STAT5 were determined to confirm the EPOR activation effect of nobiletin. CoCl₂ was applied to construct a renal hypoxic cell model, and cell viability and apoptosis of human glomerular mesangial cells (HMC) were carried out to assess the pharmacological effect of nobiletin. Apoptosis-related proteins including Bcl-2, Bcl-xL, Bax, Cleaved caspase 3, caspase 3, caspase 9, and Cytochrome C were determined. SiRNA and lentivirus were used to silence or overexpress EPOR. Our results indicated that nobiletin is a potential EPOR agonist, reflected on its explicit binding force and downstream signal activating effects. Furthermore, EPOR-overexpressing enhanced the hypoxia-tolerance of renal cells. Our mechanism research indicated that the protective effect of nobiletin against hypoxia was depended on its pro-proliferation and anti-apoptosis effects. In conclusion, nobiletin, a potential small molecular agonist of EPOR, protects HMC against hypoxia through positively activating EPOR.

Insulin resistance (IR) is the principal pathophysiological change occurring in diabetes mellitus (DM). Baicalein, a bioactive flavonoid primarily extracted from the medicinal plant Scutellaria baicalensis Georgi, has been shown in our previous research to be a potential natural glucagon-like peptide-1 receptor (GLP-1R) agonist. However, the exact therapeutic effect of baicalein on DM and its underlying mechanisms remain elusive. In this study, we investigated the therapeutic effects of baicalein on diabetes and sought to clarify its underlying molecular mechanisms. Our results demonstrated that baicalein improves hyperglycemic, hyperinsulinemic, and glucometabolic disorders in mice with induced diabetes via GLP-1R. This was confirmed by the finding that baicalein’s effects on improving IR were largely diminished in mice with whole-body Glp1r ablation. Complementarily, network pharmacology analysis highlighted the pivotal involvement of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) insulin signaling pathway in the therapeutic actions of baicalein on IR. Our mechanism research significantly confirmed that baicalein mitigates hepatic and muscular IR through the PI3K/AKT signal pathway, both in vitro and in vivo. Furthermore, we demonstrated that baicalein enhances glucose uptake in skeletal muscle cells under IR conditions through the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-adenosine 5′-monophosphate-activated protein kinase (AMPK)-glucose transporter 4 (GLUT4) signaling pathway in a GLP-1R-dependent manner. In conclusion, our findings confirm the therapeutic effects of baicalein on IR and reveal that it improves IR in liver and muscle tissues through the PI3K/AKT insulin signaling pathway in a GLP-1R dependent manner. Moreover, we clarified that baicalein enhances the glucose uptake in skeletal muscle tissue through the Ca²⁺/CaMKII-AMPK-GLUT4 signal pathway.

Ulcerative colitis (UC) is defined by persistent inflammatory processes within the gastrointestinal tract of uncertain etiology. Current therapeutic approaches are limited in their ability to address oxidative stress, inflammation, barrier function restoration, and modulation of gut microbiota in a coordinated manner to maintain intestinal homeostasis. This study involves the construction of a metal-phenolic nanozyme (Cur-Fe) through a ferric ion-mediated oxidative coupling of curcumin. Cur-Fe nanozyme exhibits superoxide dismutase (SOD)-like and •OH scavenging activities, demonstrating significant anti-inflammatory and anti-oxidant properties for maintaining intracellular redox balance in vitro. Drawing inspiration from Escherichia coli Nissle 1917 (EcN), a biomimetic Cur-Fe nanozyme (CF@EM) is subsequently developed by integrating Cur-Fe into the EcN membrane (EM) to improve the in vivo targeting ability and therapeutic effectiveness of the Cur-Fe nanozyme. When orally administered, CF@EM demonstrates a strong ability to colonize the inflamed colon and restore intestinal redox balance and barrier function in DSS-induced colitis models. Importantly, CF@EM influences the gut microbiome towards a beneficial state by enhancing bacterial diversity and shifting the compositional structure toward an anti-inflammatory phenotype. Furthermore, analysis of intestinal microbial metabolites supports the notion that the therapeutic efficacy of CF@EM is closely associated with bile acid metabolism. Inspired by gut microbes, we have successfully synthesized a biomimetic Cur-Fe nanozyme with the ability to inhibit inflammation and restore intestinal homeostasis. Collectively, without appreciable systemic toxicity, this work provides an unprecedented opportunity for targeted oral nanomedicine in the treatment of ulcerative colitis.