TISSUE & CELL
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2024
·
IF 2.7
Xiuchao Shang,Yesheng Jin,Yuan Xue,Xiaoyun Pan,Haiquan Zhu,Xiangsheng Meng,Zhihai Cao,Yongjun Rui
This study aimed to investigate the effects of E26-transformation-specific variant-2 (ETV2) overexpression on wound healing in a cutaneous wound (CW) model and clarify associated mechanisms. pLVX-ETV2 lentivirus expressing ETV2 was constructed and infected into BMSCs to generate ETV2-overexpressed BMSCs (BMSCs+pLVX+ETV2). The RT-PCR assay was applied to amplify ETV2, VE-cadherin, vWF, ARG-1, IL-6, iNOS, TGF-β, IL-10, TNF-α. Western blot was used to determine expression of VE-cadherin and vWF. ETV2 induced differentiation of BMSCs into ECs by increasing CDH5/CD31, triggering tube-like structures, inducing Dil-Ac-LDL positive BMSCs. ETV2 overexpression increased the gene transcription and expression of VE-cadherin and vWF (P<0.01). Transcription of M1 phenotype specific iNOS gene was lower and transcription of M2 phenotype specific ARG-1 gene was higher in the RAW264.7+BMSCs+ETV2 group compared to the RAW264.7+BMSCs+pLVX group (P<0.01). ETV2 overexpression (RAW264.7+BMSCs+ETV2) downregulated IL-6 and TNF-α, and upregulated IL-10 and TGF-β gene transcription compared to RAW264.7+BMSCs+pLVX group (P<0.01). ETV2-overexpressed BMSCs promoted wound healing in CW mice and triggered the migration of BMSCs to the wound region and macrophage activation. ETV2-overexpressed BMSCs promoted collagen fibers and blood vessel formation in the wound region of CW mice. In conclusion, this study revealed a novel biofunction of ETV2 molecule in the wound healing process. ETV2 overexpression in BMSCs promoted wound healing in CW mice by triggering BMSCs differentiation into endothelial cells and modulating the transformation of M1 pro-inflammatory and M2 anti-inflammatory macrophages in vitro and in vivo .
研究领域:
细胞生物学
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分子生物学
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伤口愈合
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干细胞研究
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免疫学
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JOURNAL OF FLUORESCENCE
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2026
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IF 3.4
Wen Lei,Li Yuan,Wu Ting,Yu Yue,Wu Yong,Wang Yue,Wang Deguo
Macrophage polarization into M 1 and M 2 phenotypes plays critical roles in homeostasis and disease pathogenesis. M 2 macrophages are characterized by high expression of the mannose receptor (CD206), which specifically binds and internalizes mannosylated ligands. In this study, we developed a novel fluorescent probe by conjugating Rhodamine B (RhB) to mannan isolated from Tremella fuciformis (RhB-mannan). The probe was thoroughly characterized by FTIR, NMR, and fluorescence spectroscopy. Using Raw 264.7 macrophages polarized to M 1 (LPS) or M 2 (IL-4) phenotypes, we demonstrated that the RhB-mannan probe selectively labels M 2 cells, correlating with CD206 expression confirmed by immunofluorescence. The specificity of the probe was further validated by competitive inhibition with free mannose, which abolished the fluorescent labeling. This probe provides a valuable tool for live-cell imaging of M 2 macrophages and studying their role in disease progression.
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ARCHIVES OF MICROBIOLOGY
·
2024
·Vol. 206
·期 6
·1-11
·
IF 2.3
Zhuang Cuicui,Zhang Ruoqing,Bai Jiangang,Zhang Xinying,Zhao Jinhui
Escherichia coli ( E. coli ) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli -induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 μmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 μmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1β and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 μmol/L lycopene significantly increased E. coli -induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli -treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli -caused bovine mastitis, providing the new angle of the prevention and management of mastitis.
研究领域:
免疫学
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微生物学
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药理学
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细胞生物学
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兽医学
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2025
·
IF 5.9
Jing Bai,Shengli Liu,Zhiguo Mang,Xueqing Duan,Changfeng Song,Weiyi Tian
Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, is frequently overexpressed in colorectal cancer (CRC) and has emerged as a promising therapeutic target. In this study, a series of Tanshinone IIA derivatives were designed and synthesized through simultaneous modification of rings A and D, and their anti-CRC activities were evaluated. The optimized derivative 23 exhibited PKM2 activation (AC 50 = 92.12 nM) and significantly inhibited the proliferation of CRC cells. Molecular docking analysis revealed that the piperidinothiophene moiety in 23 strengthens binding through a salt bridge interaction with Asp295. Furthermore, 23 suppressed the PKM2/STAT3 signaling pathway both in vitro and in vivo. Together, these findings highlight derivative 23 as a promising anticancer candidate for the treatment of CRC.
研究领域:
肿瘤学
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药物化学
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分子生物学
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癌症药理学
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MICROBIAL PATHOGENESIS
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2026
·
IF 3.5
Cangcang Zhang,Dinghui Wang,Yang Shan,Chenggui Miao,Changzhong Wang,Weifan Wei,Tianming Wang,Jian Wang,Daqiang Wu
Pseudomonas aeruginosa , which is one of the most common opportunistic pathogenic bacteria, poses severe clinical risks for individuals with compromised immune systems, particularly concerning lung infections. Sodium houttuyfonate (SH), an active constituent isolated from Houttuynia cordata , exhibits limited direct antibacterial efficacy in vitro yet demonstrates notable therapeutic effects against bacterial infections in vivo. Nevertheless, the precise mechanisms underlying in vivo antibacterial pharmacological activity of SH remain unclear. Thus, here we investigate the mechanism by which SH alleviates P. aeruginosa -induced acute pulmonary infection, focusing on its influence on macrophage polarization signaling pathways. First, our findings demonstrate that SH effectively alleviated P. aeruginosa -induced acute pulmonary infection in mice, as evidenced by reduced inflammatory infiltration and alveolar damage in vivo. The results indicate that SH significantly modulated the expression of inflammatory mediators (IL-6, TNF-α, IL-1β, IL-10, TGF-β, Arg-1) and key signaling molecules (NF-κB, TLR4, STAT6, p38MAPK). In vitro, 24-h SH treatment decreased NO production and attenuated macrophage phagocytosis, while shifting cytokine profiles from M1 to M2 phenotypes. Immunofluorescence and flow cytometry confirmed decreased CD86 (M1 marker) and increased CD206 (M2 marker) expression, indicating enhanced M2 polarization. Mechanistically, SH suppressed the TLR-4/MyD88/NF-κB pathway while activating the p38MAPK/STAT6 axis. Genetic manipulation further verified that SH regulates TLR-4 and p38MAPK, thereby controlling downstream signaling and inflammatory responses to combat infection. In conclusion, our study suggests that SH promotes macrophage M2 polarization and reduces excessive inflammation in late-stage P. aeruginosa -induced acute pulmonary infection by modulating macrophage polarization through the suppression of pro-inflammatory signaling via the TLR4/MyD88/NF-κB pathway and activation of the p38 MAPK/STAT6 pathway.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Kaili Liu,Jianli Li,Zhiwei Sun,Yuheng Sun,Xuerui Zhang,Yang Sui,Zhongyuan Qu,Xiang Zou
Background Chelidonium majus L., a traditional herbal medicine listed in the Pharmacopoeia of China (2025), has remarkable anticancer properties. Chelidonine (CHE), its primary bioactive alkaloid, can inhibit the proliferation of breast cancer (BC) cells; however, whether its antitumor effect in BC is mediated through regulating M2 macrophage polarization remains unexplored. Purpose To investigate the effect of CHE on M2 macrophage polarization in BC and to identify key molecular targets and pathways involved in its immunomodulatory effects. Methods The effect of CHE on tumour progression was evaluated in vivo using a 4T1 BC mouse model. In addition, the effects of CHE on M2 macrophage polarization were investigated both in vitro and in vivo via immunofluorescence and Western blotting. Coculture assays were conducted to elucidate the mechanism by which CHE exerts antiproliferative and antimetastatic effects through the inhibition of M2 macrophage polarization. An integrated analysis of network pharmacology, single-cell, and bulk RNA-seq data was performed to identify potential molecular targets of CHE in the suppression of M2 macrophage polarization. Molecular docking, Western blotting, and ELISA were utilized for target validation to elucidate the roles in M2 macrophage polarization. Results CHE effectively impeded tumour progression in BC mice. Both in vitro and in vivo experiments demonstrated that CHE significantly inhibited M2 macrophage polarization, as evidenced by the altered expression of key polarization markers, including CD86, CD206, Arg-1, and CD11c. Under coculture conditions, CHE disrupted the mitochondrial membrane potential and compromised membrane integrity in BC cells, triggering pyroptosis via activation of the NLRP3/Caspase-1/GSDMD signaling axis. Additionally, CHE attenuated the epithelial–mesenchymal transition (EMT) process, thus reducing the migratory and invasive capacities of BC cells. An integrated analysis of network pharmacology, single-cell, and bulk RNA sequencing data revealed FBP1 as a potential molecular target through which CHE suppresses M2 macrophage polarization. Molecular docking studies revealed a relatively strong binding affinity between CHE and FBP1. Experimental validation further confirmed that CHE downregulated the expression of FBP1 and its downstream target p-STAT3 in macrophages, thereby inhibiting M2 polarization. Conclusions CHE might suppress M2 polarization and tumour progression by targeting FBP1. These findings highlight its potential as a therapeutic agent in immunotherapy and BC treatment.
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ACS Omega
·
2026
·
IF 5.2
Yuhan Yang,Yanlin Zhu,Hongyan Yuan,Zun Yang,Jie Zhou
Emerging evidence highlights a bidirectional relationship between diabetes and periodontitis, with both conditions sharing common pathogenic mechanisms. Biomaterials capable of modulating macrophage polarization hold significant therapeutic potential for promoting tissue repair in diabetic periodontitis. Asiatic acid (AA), a clinically proven compound with potent antioxidant and antiinflammatory properties, presents an attractive therapeutic candidate. In this study, we developed a multifunctional hybrid hydrogel, AA@GO (AA@GO/SA/CCS, abbreviated as AA@GO), composed of sodium alginate (SA), carboxymethyl chitosan (CCS), and graphene oxide (GO) for effective AA delivery. The AA@GO hydrogel demonstrated remarkable mitophagy-enhancing capabilities, effectively reducing intracellular ROS levels and restoring mitochondrial function in macrophages. Notably, this material significantly increased the M2/M1 polarization ratio by facilitating macrophage phenotype switching from M1 to M2, thereby attenuating inflammatory responses. Our findings elucidate the unique mechanism of AA@GO hydrogel action and propose a promising novel strategy for diabetic periodontitis treatment through macrophage polarization regulation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Wei Li,Xiao Wang,Xiaoli Liu,Luoyang Wang,Jie Liang,Yu Cui,Yi Liu,Mengting Zhou,Zijie Yang,Meiying Song,Yanyan Yang,Li Zhang,Bei Zhang
Persistent inflammation impedes peripheral nerve regeneration, in which infiltrating macrophages play pivotal roles by regulating the M1/M2 phenotypic balance. M2 macrophages facilitate repair, yet factors driving M1-to-M2 transition remain unclear. Lactate, a key metabolic byproduct in injured tissue, dynamically regulates microenvironmental signaling. Here, we observed a correlation between M2 macrophage accumulation and lactate elevation within 5 days post-sciatic nerve injury. In vitro, both Schwann cells and macrophages were identified as important lactate producers. In vivo, low-dose lactate (10–20 mM) enhanced M2 polarization and accelerated regeneration, whereas high-dose lactate (50 mM) showed no benefit. Transcriptomic analysis revealed that 10 mM lactate upregulated M2 markers (arginase 1 (Arg1), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β)) and oxidative phosphorylation (OXPHOS)-related genes in M1 macrophages. Seahorse analysis and adenosine triphosphate (ATP) quantification confirmed lactate-driven OXPHOS activation. Conversely, 50 mM lactate induced excessive reactive oxygen species (ROS) and reduced mitochondrial membrane potential which may explain its lack of regenerative efficacy. Furthermore, CCAAT/enhancer-binding protein beta (Cebpb), a transcription factor can promote Arg1 and VEGF expression in M1 cells under 20 mM lactate. Our findings demonstrate that low-dose lactate promotes M1-to-M2 transition via OXPHOS metabolic reprogramming and Cebpb upregulation, whereas excessive lactate disrupts mitochondrial function. This highlights lactate concentration-dependent modulation of macrophage polarization, a finding that provides insights into metabolic regulation of inflammatory responses during nerve repair. The current data, which focus on macrophage polarization outcomes, support further investigation into whether targeting metabolic rewiring could optimize regenerative microenvironments for functional nerve regeneration.
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TISSUE & CELL
·
2026
·
IF 2.5
Haifeng Hong,Cuiyun Zhou,Haibing Wang,Changhui Lin,Min Fang,Juntian Liu,Minhui Yang
Purpose M2 macrophage-derived exosomes (M2-Exo) have emerged as promising mediators of bone repair due to their anti-inflammatory and pro-regenerative properties. However, the molecular mechanisms underlying the interaction between M2-Exo and bone marrow mesenchymal stem cells (BMSCs) are awaiting clarification. Our previous study found that protein arginine methyltransferase 1 (PRMT1) in fracture-derived exosomes promotes bone healing. This study aimed to determine whether PRMT1-containing M2-Exo exerts an osteoprotective effect during fracture healing and elucidate underlying mechanisms. Methods Following knockdown of PRMT1 in M2-Exo and treating BMSCs, osteogenic differentiation ability of BMSCs was evaluated by qRT-PCR, western blot, Alizarin Red S, and Alkaline phosphatase (ALP). Immunoprecipitation was employed to clarify regulatory effect of PRMT1 on Src-associated in mitosis 68 KDa (Sam68) and its asymmetric dimethylarginine (ADMA) modification. Results M2-Exo extracted from serum samples of fracture rats were enriched in PRMT1. M2-Exo delivered PRMT1 to BMSCs. PRMT1 knockdown in M2-Exo impaired osteogenic differentiation, as evidenced by suppressing mineral deposition and ALP activity (42.3% and 60.8% reduction vs. sh-NC; p < 0.01), with a decrease in expression of Bone Morphogenetic Protein 2 (BMP2) and RUNX Family Transcription Factor 2 (RUNX2) (74.9% and 61.8% decline vs. sh-NC; p < 0.01). PRMT1 interacted with Sam68, and its knockdown reduced ADMA modification and Sam68 protein expression. Sam68 overexpression partially rescued the osteogenic defects caused by PRMT1 knockdown, with increased mineralization level and ALP (44.3% and 87.6% increase vs. M2-Exo-sh-PRMT1 + oe-NC; p < 0.05), along with elevated BMP2 and RUNX2 expression (79.5% and 98.8% increase vs. M2-Exo-sh-PRMT1 + oe-NC; p < 0.01). Conclusion PRMT1 released by M2-Exo is delivered to BMSCs, which enhances the osteogenic differentiation by catalyzing Sam68 ADMA. These findings provide a mechanistic and preclinical rationale for the potential use of M2-Exo to improve bone healing.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2025
·Vol. 48
·期 10
·1503-1513
·
IF 1.7
Xinyue Zhou,Wei Zhou,Changhong Qu,Yisha Jiang,Wenzhu Liu,Lipeng Pei
Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.
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CELL CYCLE
·
2026
·
IF 3.9
Yan Liu,Yue-Qi Geng,Li Jiang,Ai-Chun Liu
Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells. Tumor-associated macrophages (TAMs) are the predominant immune cells in the bone marrow microenvironment of MM and play important roles in MM. The effect of RBMS1 on MM has not yet been reported. This study aimed to investigate the function of RBMS1 in MM. Through the analysis of GSE datasets, we identified RBMS1 as a potential pathogenic factor in MM. We further investigated the effects of RBMS1 on the proliferation of MM cells (RPMI8226, MM1S, and KMS11) and its regulation of TAM polarization. An animal model was established by intravenous injection of MM cells into 6-week-old male NOG mice. Bioinformatics analyses, including RRA, WGCNA, and GO enrichment, screened for potential pathogenic genes in MM. Kaplan – Meier survival identified RBMS1 as a prognostic marker associated with poor outcomes in MM. Functionally, RBMS1 enhanced MM cell proliferation, colony formation, and cell cycle. Moreover, RBMS1 promoted M2 polarization of macrophages, as evidenced by elevated levels of M2 macrophage markers, as well as increased CCL2 secretion. Consistently, in a male NOD/Shi-scid IL-2 Rγnull mouse xenograft model, RBMS1 accelerated tumor growth and enhanced M2 macrophage polarization. Mechanistically, RBMS1 bound to the 3’UTR of PDPK1 mRNA, enhancing its stability and activating the pro-tumorigenic β-catenin signaling pathway, thereby promoting tumor growth. Collectively, this study is the first to report the functional role of RBMS1 in MM and highlights the importance of the RBMS1/PDPK1/β-catenin signaling axis in MM, providing new insights for basic research on MM.
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Stem Cell Research & Therapy
·
2026
·Vol. 17
·期 1
·103
·
IF 7.8
Yao Bao,Nie Hai,Zhou Ji,Guo Lixia,Li Jiahong,Liang Weimin,Feng Junwei,Hao Peng
Objective Heterotopic ossification (HO) is a pathological condition characterized by dysregulated regenerative processes in skeletal muscle, resulting in the formation of mature bone within ectopic sites. Accumulating studies indicate that M2 macrophages facilitate endothelial-mesenchymal transition (EndMT), which contributes centrally to HO pathogenesis. This study explored the mechanism of M2 macrophage involvement in EndMT-mediated HO and analyzed the underlying molecular pathways. Methods Clinical samples of immature, mature, and autologous cancellous bones were collected to analyze macrophage infiltration and the cellular origin of HO. Using the GEO and GeneCards databases, MSX2 was identified as a candidate regulatory factor. An endothelial-macrophage co-culture system was established to investigate the specific molecular mechanisms by which macrophages affect EndMT by modulating MSX2 expression. Achilles tendon incision surgery was performed in C57BL/6 mice to simulate trauma-induced HO. Histological examination, immunohistochemistry, immunofluorescence, and ELISA were performed to verify the role of macrophages in influencing HO progression via MSX2. The STRING database was used to predict LEF1 as a downstream target gene of MSX2. Regulatory interactions between MSX2 and LEF1 were examined using dual-luciferase reporter assays, western blotting, and quantitative real-time PCR. Results Compared to autologous cancellous bone, there was an increase in M2 macrophage infiltration in HO tissues, accompanied by the transformation of endothelial cells at the injury site into mesenchymal stem cells. The degree of HO positively correlated with elevated levels of BMP-2, SP, Act A, TGF-β, OSM, and NT-3 in the serum. In vitro experiments demonstrated that under co-culture conditions, M2 macrophages induced mouse aortic endothelial cells (MAOECs) to exhibit elevated expression of mesenchymal markers (N-cadherin, vimentin) and mesenchymal stem cell markers (CD44, CD90), while reducing levels of endothelial markers (E-cadherin, occludin). Moreover, M2 macrophage-driven EndMT activation further promoted the upregulation of chondrogenic (Sox9, SP7) and osteogenic (OPN, OCN, Runx2) markers. However, MSX2 depletion rescued M2 macrophage-induced EndMT activation. In vivo, MSX2 inhibition or macrophage depletion reduced the osteogenic capacity in mice and decreased HO formation, whereas injection of a lentivirus overexpressing MSX2 promoted HO formation. Mechanistically, MSX2 directly binds to the LEF1 promoter to enhance its transcriptional activity, thereby activating Wnt signaling and maintaining EndMT. Conclusions Our findings suggest that M2 macrophages regulate EndMT-driven osteogenesis through MSX2/LEF1/Wnt axis, providing new insights into future therapeutic strategies for HO.
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