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Batur A, Novak R, Salai G, Hrkač S, Ćosić V, Grgurević L. Extracellular vesicles in the pathogenesis and future diagnostics of oral squamous cell carcinoma. Future Sci OA 2025; 11:2461940. [PMID: 39920887 PMCID: PMC11812389 DOI: 10.1080/20565623.2025.2461940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025] Open
Abstract
Extracellular vesicles are a group of heterogeneous particles secreted during both physiological and pathological conditions which serve in intercellular communication and play a role in the development and progression of oral squamous cell carcinoma, the most common malignant tumor of the head and neck with a high mortality rate. Extensive research is being conducted in order to determine the precise role of extracellular vesicles in oncogenic processes and to explore the possible application of extracellular vesicles as early tumor biomarkers. In this review, we aimed to systematize observed roles extracellular vesicles might play in organizing of tumor microenvironment, tumor invasion and metastasis, as well as the impact of extracellular vesicles on immune dysregulation and development of resistance to chemotherapeutics. Additionally, we summarized findings involving the potential use of extracellular vesicles cargo proteins as early disease biomarkers.
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Affiliation(s)
- Anđela Batur
- School of Dental Medicine, University of Zagreb, Zagreb, Croatia
| | - Ruđer Novak
- Center for Translational and Clinical Research, Department of Proteomics, University of Zagreb, School of Medicine, Zagreb, Croatia
- BIMIS – Biomedical Research Center Šalata, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Grgur Salai
- Department of Pulmonology, University Hospital Dubrava, Zagreb, Croatia
| | - Stela Hrkač
- Department of Clinical Immunology, Allergology and Rheumatology, University Hospital Dubrava, Zagreb, Croatia
| | - Vesna Ćosić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Lovorka Grgurević
- Center for Translational and Clinical Research, Department of Proteomics, University of Zagreb, School of Medicine, Zagreb, Croatia
- BIMIS – Biomedical Research Center Šalata, University of Zagreb School of Medicine, Zagreb, Croatia
- Department of Anatomy, “Drago Perović”, University of Zagreb, School of Medicine, Zagreb, Croatia
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2
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Zhen L, Quiroga E, Creason SA, Chen N, Sapre TR, Snyder JM, Lindhartsen SL, Fountaine BS, Barbour MC, Faisal S, Aliseda A, Johnson BW, Himmelfarb J, Ratner BD. Synthetic vascular graft that heals and regenerates. Biomaterials 2025; 320:123206. [PMID: 40058247 DOI: 10.1016/j.biomaterials.2025.123206] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/15/2025] [Accepted: 02/23/2025] [Indexed: 04/06/2025]
Abstract
Millions of synthetic vascular grafts (sVG) are needed annually to address vascular diseases (a leading cause of death in humans) and kidney failure (as vascular access). However, in 70+ years since the first sVG in humans, we still do not have sVGs that fully endothelialize (the "holy grail" for truly successful grafts). The lack of healthy endothelium is believed to be a main cause for thrombosis, stenosis, and infection (the major reasons for graft failure). The immune-mediated foreign body response to traditional sVG materials encapsulates the materials in fibrotic scar suppressing vascularized healing. Here, we describe the first sVG optimized for vessel wall vascularization via uniform, spherical 40 μm pores. This sVG induced unprecedented rapid healing of luminal endothelium in a demanding and clinically relevant sheep model, probably by attracting and modulating macrophages and foreign body giant cells towards diverse, pro-healing phenotypes. Both this sVG and the control (PTFE grafts) remained 100 % patent during the implantation period. This advancement has broad implications beyond sVGs in tissue engineering and biocompatibility.
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Affiliation(s)
- Le Zhen
- Department of Bioengineering, University of Washington, Seattle, WA, USA; Department of Chemical Engineering, University of Washington, Seattle, WA, USA; Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA
| | - Elina Quiroga
- Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Department of Surgery, School of Medicine, University of Washington, Seattle, WA, USA
| | - Sharon A Creason
- Department of Bioengineering, University of Washington, Seattle, WA, USA; Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA
| | - Ningjing Chen
- Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, USA
| | - Tanmay R Sapre
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Jessica M Snyder
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | | | | | - Michael C Barbour
- Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
| | - Syed Faisal
- Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
| | - Alberto Aliseda
- Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
| | - Brian W Johnson
- Histology and Imaging Core, University of Washington, Seattle, WA, USA
| | - Jonathan Himmelfarb
- Department of Bioengineering, University of Washington, Seattle, WA, USA; Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, USA; Kidney Research Institute, Seattle, WA, 98104, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Kidney Disease Innovation at Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Buddy D Ratner
- Department of Bioengineering, University of Washington, Seattle, WA, USA; Department of Chemical Engineering, University of Washington, Seattle, WA, USA; Center for Dialysis Innovation (CDI), University of Washington, Seattle, WA, USA; University of Washington Engineered Biomaterials (UWEB21), University of Washington, Seattle, WA, USA
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3
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Wu J, Zhang F, Li Z, Gan L, Cao H, Cao H, Hao C, Sun Z, Wang W. Multiple omics-based machine learning reveals specific macrophage sub-clusters in renal ischemia-reperfusion injury and constructs predictive models for transplant outcomes. Comput Biol Chem 2025; 117:108421. [PMID: 40086342 DOI: 10.1016/j.compbiolchem.2025.108421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) is closely associated with numerous severe postoperative complications, including acute rejection, delayed graft function (DGF) and graft failure. Macrophages are central to modulating the aseptic inflammatory response during the IRI process. The objective of this study is to conduct an analysis of the developmental and differentiation characteristics of macrophages in IRI, identify distinct molecules subtypes of IRI, and establish robust predictive strategies for DGF and graft survival. METHOD We analyzed scRNA-Seq data from GEO database to identify macrophage sub-clusters specific to renal IRI, and use the hdWGCNA algorithm to screen gene modules closely associated with this sub-cluster. Integrating these module genes with the results from bulk RNA-Seq differential analysis to obtain hub genes, and delineating the different IRI molecular subtypes through consensus clustering based on the expression profiles of hub genes. Innovatively, the gene expression matrix was transformed into a unique graphic pixel module and applied advanced computer vision processing algorithms to construct a DGF predictive model. Additionally, we also employed 111 combinations of 10 machine learning algorithms to develop a predictive signature for graft survival. Finally, we validated the expression of the key gene ANXA1 in a mouse IRI model using qRT-PCR, WB, and IHC. RESULT This study successfully identified a subset of macrophages closely associated with renal IRI, and cell communication and pseudo-time analysis implied that they may be instrumental in both the maintenance and exacerbation of the IRI process. Utilizing the expression patterns of hub genes, recipients can be clustered into two subtypes (CI and C2) with unique clinical and molecular features. We innovatively applied deep learning algorithms to construct a model for DGF prediction, which can effectively mitigate batch effects among IRI recipients. Compared to other existing models, our model demonstrated superior performance with AUC of 0.816 and 0.845 in the training and validation set. Furthermore, we also used the random survival forest algorithm to develop a high-precision predictive signature for graft failure. The mouse IRI model confirmed a marked upregulation of ANXA1 mRNA and protein expression in renal tissue following IRI. CONCLUSION This study successfully revealed the macrophage sub-cluster closely associated with renal IRI. Two distinct IRI subgroups with different characteristics were identified and robust strategies were constructed for predicting DGF and graft survival, which can offer potential therapeutic targets for the treatment of IRI and reference for early prevention of various postoperative complications.
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Affiliation(s)
- Jiyue Wu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Feilong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Zhen Li
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Lijian Gan
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Haoyuan Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Huawei Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Changzhen Hao
- Department of Urology, Peking University International Hospital, Beijing, China.
| | - Zejia Sun
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China.
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China.
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Liu Z, Yang J, Tan G, Shi Y, Tao D, Wang W, Li B, Jin F, He X. Methotrexate loaded extracellular vesicles attenuate periodontitis by suppressing ACSL1 and promoting anti-inflammatory macrophage. Mol Immunol 2025; 182:83-95. [PMID: 40245705 DOI: 10.1016/j.molimm.2025.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/31/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
Macrophages are crucial immune cells in periodontal tissues, which play key roles in both the destruction and repair of associated with periodontitis. Targeted modulation of macrophage function has emerged as a potentially effective approach to influence periodontitis progression. This study investigates the effects of methotrexate-loaded extracellular vesicles (MTX-EVs) on inflammatory macrophage polarization both in vivo and in vitro. In a murine periodontitis model, MTX-EVs inhibited alveolar bone resorption, suppressed pro-inflammatory macrophage activation, and promoted anti-inflammatory macrophages. Mechanistically, MTX-EVs reduced acyl-CoA synthetase-1 (ACSL1) expression, which was elevated during inflammation. Inhibition of ACSL1 with triacsin-C in macrophages suppressed the inflammatory phenotype through the promotion of the oxidative phosphorylation (OXPHOS). In contrast, MTX-EVs counteracted the effects of ACSL1 overexpression on macrophage polarization and metabolism. Our findings suggest that targeting ACSL1 via MTX-EVs represents a therapeutic strategy for modulating macrophage polarization and improving periodontitis treatment outcomes.
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Affiliation(s)
- Zhi Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Jianhua Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Guodong Tan
- Air Force Medical Center, The Fourth Military Medical University, Beijing 100142, China
| | - Yuanyuan Shi
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Dihao Tao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Wenzhe Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Bei Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
| | - Fang Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
| | - Xiaoning He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China.
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Lu J, Zhou Y, Song YX, Wang JY, Xian JX. Natural alkaloids modulating macrophage polarization: Innovative therapeutic strategies for inflammatory, cardiovascular, and cancerous diseases. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156709. [PMID: 40250001 DOI: 10.1016/j.phymed.2025.156709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/21/2025] [Accepted: 03/29/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND Macrophage polarization, switching between pro-inflammatory M1 and anti-inflammatory M2 states, is crucial for disease dynamics in inflammatory, metabolic, and cancer contexts. Modulating this polarization is a clinical challenge, but natural alkaloids, with their potent anti-inflammatory and immunomodulatory effects, show promise in reprogramming macrophage phenotypes. PURPOSE This review explores the applications of natural alkaloids-such as matrine, berberine, koumine, sophoridine, and curcumin-in modulating macrophage polarization. It aims to highlight their potential in reprogramming macrophage phenotypes and improving therapeutic outcomes across various diseases. METHODS A comprehensive literature review was conducted using databases like PubMed, Web of Science, Science Direct and Google Scholar, employing targeted keywords related to natural alkaloids, macrophage polarization, and disease treatment. The analysis primarily focused on articles published between 2020 and 2024. RESULTS This review summarizes how natural alkaloids regulate macrophage polarization, promoting the M2 phenotype to reduce inflammation, thereby playing a therapeutic role in anti-inflammatory, cardiovascular, and metabolic diseases. At the same time, they also promote M1 polarization to inhibit tumor development. CONCLUSION Accumulating evidence demonstrates that macrophage polarization regulation by natural alkaloids holds notable clinical value for disease intervention. They alleviate inflammation, enhance antitumor immunity, and improve treatment outcomes, demonstrating their importance in innovative therapeutic strategies. Moreover, combining alkaloids with immunotherapy enhances treatment efficacy, further highlighting their versatility in a variety of therapeutic applications.
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Affiliation(s)
- Jing Lu
- Department of Pharmacy, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China
| | - Ying Zhou
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yi-Xuan Song
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jie-Ying Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jia-Xun Xian
- Traditional Chinese Medicine Hospital of Meishan, Meishan 620010, China.
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Kibet M, Abebayehu D. Crosstalk between T cells and fibroblasts in biomaterial-mediated fibrosis. Matrix Biol Plus 2025; 26:100172. [PMID: 40226302 PMCID: PMC11986236 DOI: 10.1016/j.mbplus.2025.100172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 02/28/2025] [Accepted: 03/19/2025] [Indexed: 04/15/2025] Open
Abstract
Biomaterial implants are a critical aspect of our medical therapies and biomedical research and come in various forms: stents, implantable glucose sensors, orthopedic implants, silicone implants, drug delivery systems, and tissue engineered scaffolds. Their implantation triggers a series of biological responses that often times lead to the foreign body response and subsequent fibrotic encapsulation, a dense ECM-rich capsule that isolates the biomaterial and renders it ineffective. These responses lead to the failure of biomaterials and is a major hurdle to overcome and in promoting their success. Much attention has been given to macrophage populations for the inflammatory component of these responses to biomaterials but recent work has identified an important role of T cells and their ability to modulate fibroblast activity and vice versa. In this review, we focus on T cell-fibroblast crosstalk by exploring T cell subsets, critical signaling pathways, and fibroblast populations that have been shown to dictate biomaterial-mediated fibrosis. We then highlight emerging technologies and model systems that enable new insights and avenues to T cell-fibroblast crosstalk that will improve biomaterial outcomes.
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Affiliation(s)
- Mathew Kibet
- Department of Biomedical Engineering, School of Engineering and Medicine, University of Virginia, Charlottesville, VA 22908, United States
| | - Daniel Abebayehu
- Department of Biomedical Engineering, School of Engineering and Medicine, University of Virginia, Charlottesville, VA 22908, United States
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Perry M, Hamza I. Heme and immunity: The heme oxygenase dichotomy. J Inorg Biochem 2025; 267:112844. [PMID: 39978176 DOI: 10.1016/j.jinorgbio.2025.112844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 01/12/2025] [Accepted: 02/02/2025] [Indexed: 02/22/2025]
Abstract
Heme, an iron containing organic ring, is required for a diverse range of biological processes across all forms of life. Although this nutrient is essential, its pro-inflammatory and cytotoxic properties can lead to cellular damage. Heme oxygenase 1 (HO-1) is an endoplasmic reticulum (ER)-anchored enzyme that degrades heme, releasing equimolar amounts of carbon monoxide (CO), biliverdin (BV), and iron. The induction of HO-1 by heme presents an interesting dichotomy in the cell: CO and BV possess anti-inflammatory and antioxidant properties while free iron can be detrimental as it can generate hydroxyl radicals through the Fenton reaction. The heme/HO-1 axis is tightly regulated, and can influence cell fate, local tissue environments, and disease outcomes during pathogen infection. In this review we explore the role of heme during macrophage polarization and its ability to act as an immune activator while also examining the contribution of HO-1 and heme during infections with intracellular and extracellular pathogens. We highlight work from the emerging field of nutritional immunity of heme and iron, and how the substrates and byproducts of heme metabolism via HO-1 can be beneficial to the host or the pathogen depending on the context.
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Affiliation(s)
- Melissa Perry
- Graduate Program in Biological Sciences, University of Maryland, College Park, MD 20742, USA; Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Iqbal Hamza
- Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
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Tang Y, Feng S, Yao K, Cheung SW, Wang K, Zhou X, Xiang L. Exogenous electron generation techniques for biomedical applications: Bridging fundamentals and clinical practice. Biomaterials 2025; 317:123083. [PMID: 39798242 DOI: 10.1016/j.biomaterials.2025.123083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/14/2024] [Accepted: 01/01/2025] [Indexed: 01/15/2025]
Abstract
Endogenous bioelectrical signals are quite crucial in biological development, governing processes such as regeneration and disease progression. Exogenous stimulation, which mimics endogenous bioelectrical signals, has demonstrated significant potential to modulate complex biological processes. Consequently, increasing scientific efforts have focused on developing methods to generate exogenous electrons for biological applications, primarily relying on piezoelectric, acoustoelectric, optoelectronic, magnetoelectric, and thermoelectric principles. Given the expanding body of literature on this topic, a systematic and comprehensive review is essential to foster a deeper understanding and facilitate clinical applications of these techniques. This review synthesizes and compares these methods for generating exogenous electrical signals, their underlying principles (e.g., semiconductor deformation, photoexcitation, vibration and relaxation, and charge separation), biological mechanisms, potential clinical applications, and device designs, highlighting their advantages and limitations. By offering a comprehensive perspective on the critical role of exogenous electrons in biological systems, elucidating the principles of various electron-generation techniques, and exploring possible pathways for developing medical devices utilizing exogenous electrons, this review aims to advance the field and support therapeutic innovation.
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Affiliation(s)
- Yufei Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Shuqi Feng
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Keyi Yao
- School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, China
| | - Sze Wing Cheung
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Kai Wang
- School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, China
| | - Xuemei Zhou
- School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, China.
| | - Lin Xiang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
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Yu F, Gong Z, Li Y, Naseem DF, Li C, Wen M, Zhao B, Xu Z, Zhang S, Zang R, Wu A, Han Q, Wu S, Li H, Song Y. Association of SIRT6 Expression With Risk of Pneumonitis Induced by Radiotherapy in Cancer Patients. Mol Carcinog 2025; 64:1104-1118. [PMID: 40170513 PMCID: PMC12074565 DOI: 10.1002/mc.23900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/06/2025] [Accepted: 02/18/2025] [Indexed: 04/03/2025]
Abstract
Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients in this study, 124 developed NSRP, and 46 experienced SRP. The univariate analysis showed that SIRT6 expression (cOR, 0.33, 95%CI, 0.18-0.97 before RT and 0.31, 0.19-0.98 after RT), clinical factors, dosimetric parameters and haematological/serological parameters were associated with SRP before and after RT. Our multivariable logistic regression showed that SIRT6 expression was significantly associated with risk of SRP before (aOR, 0.32, 95%CI, 0.15-0.96) and after RT (aOR, 0.32, 95%CI, 0.18-0.99) after adjustment with other confounders. Moreover, the receiver operating characteristic curve analysis revealed that the combined multivariable model exhibited superior predictive capability compared to any single predictor (overall AUC, 0.93, 95%CI, 0.90-0.97 before RT and AUC, 0.91, 95%CI, 0.87-0.96 after RT). The expression of SIRT6 alone or in combination with other risk factors was associated with an increased risk of SRP, suggesting a novel approach for the prevention and treatment of radiation pneumonitis in clinical practice.
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Affiliation(s)
- Fengyuan Yu
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zheng Gong
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Yuan Li
- Department of RadiologyAffiliated Hospital of Nanjing University of Chinese MedicineNanjingPR China
| | - Danial F. Naseem
- Department of Head and Neck SurgeryMD Anderson Cancer CenterHoustonTexasUSA
| | - Chen Li
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Miaowei Wen
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Bingying Zhao
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Zhezhe Xu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shanshan Zhang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Rukun Zang
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Ailu Wu
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Qingxin Han
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
| | - Shuhui Wu
- Department of OtorhinolaryngologyBaoshan Hospital Affiliated with Shanghai University of Traditional Chinese MedicineShanghaiPR China
| | - Hongwei Li
- Department of RadiotherapyQingdao UniversityQingdaoChina
| | - Yipeng Song
- Department of RadiotherapyQingdao UniversityQingdaoChina
- Department of RadiotherapyThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantaiChina
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10
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Wu Y, Wang X, Song L, Zhao Z, Xia Y, Tang K, Wang H, Liu J, Wang Z. Tuning macrophage phenotype for enhancing patency rate and tissue regeneration of vascular grafts. Acta Biomater 2025; 198:245-256. [PMID: 40158766 DOI: 10.1016/j.actbio.2025.03.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 03/14/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025]
Abstract
Macrophages are primary immune cells that play a crucial role in tissue regeneration during the early stages of biomaterial implantation. They create a microenvironment that facilitates cell infiltration, angiogenesis, and tissue remodeling. In the field of vascular tissue engineering, numerous studies have been conducted to modulate the macrophage phenotype by designing various biomaterials, which in turn enhances the regenerative capacity and long-term patency of vascular grafts. However, the mechanism underlying the different phenotypes of macrophages involved in the tissue regeneration of vascular grafts remains unclear. In this study, vascular grafts loaded with various macrophage phenotypes were developed, and their effects were evaluated both in vivo and in vitro. The RAW 264.7 macrophages (M0) were initially treated with LPS or IL-4/IL-10 and polarized into M1 and M2 phenotypes. Subsequently, M0, M1, and M2 macrophages were seeded onto electrospun PCL scaffolds to obtain macrophage-loaded vascular grafts (PCL-M0, PCL-M1, and PCL-M2). As prepared vascular grafts were implanted into the mouse carotid artery for up to one month. The results indicate that the loading of M2 macrophages effectively enhances the patency rate and neotissue formation of vascular grafts. This is achieved through the development of a well-defined endothelium and smooth muscle layer. RNA sequencing was used to investigate the mechanisms of action of different macrophages on tissue regeneration. The study found that M1 macrophages inhibited tissue regeneration by mediating angiogenesis and chronic inflammation through upregulation of VEGFa, IL-1β, and IL-6 expression. In contrast, M2 macrophages regulate the immune microenvironment by upregulating the expression of IL-4 and TGF-β, thereby promoting tissue regeneration. In conclusion, our study demonstrates how different macrophage phenotypes contribute to the initial inflammatory microenvironment surrounding vascular grafts, thereby modulating the biological process of vascular remodeling. STATEMENT OF SIGNIFICANCE: Regulating the biophysical and biochemical characteristics of biomaterials can induce macrophage polarization and enhance vascular remodeling. In previous work, we fabricated a vascular graft with a macroporous structure that promoted macrophage infiltration and polarization into a pro-regenerative phenotype. To illustrate the mechanism, we established a new mouse model and evaluated the effects of different macrophages on vascular regeneration. The study revealed that tuning macrophage phenotype can impact the initial inflammatory microenvironment by secreting cytokines, which can increase the patency rate and regenerative capacity of vascular grafts. These findings provide essential theoretical support for the development of immunoregulatory scaffolds for vascular and other tissue regeneration.
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Affiliation(s)
- Yifan Wu
- College of Life Sciences, Tiangong University, Tianjin 300387, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
| | - Xixi Wang
- College of Life Sciences, Tiangong University, Tianjin 300387, China; Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Lili Song
- College of Life Sciences, Tiangong University, Tianjin 300387, China; Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Zhe Zhao
- College of Life Sciences, Tiangong University, Tianjin 300387, China
| | - Ying Xia
- College of Life Sciences, Tiangong University, Tianjin 300387, China
| | - Kai Tang
- Department of Cardiovascular Surgery, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Fuwai Hospital, Beijing 100037, China
| | - Huiquan Wang
- College of Life Sciences, Tiangong University, Tianjin 300387, China
| | - Jing Liu
- Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Zhihong Wang
- Institute of Transplant Medicine, School of Medicine, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin 300071, China.
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Moldovan A, Wagner F, Schumacher F, Wigger D, Kessie DK, Rühling M, Stelzner K, Tschertok R, Kersting L, Fink J, Seibel J, Kleuser B, Rudel T. Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes. mBio 2025; 16:e0398124. [PMID: 40249190 PMCID: PMC12077188 DOI: 10.1128/mbio.03981-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/19/2025] [Indexed: 04/19/2025] Open
Abstract
Chlamydiae are obligate intracellular pathogens that utilize host cell metabolites for catabolic and anabolic processes. The bacteria replicate in epithelial cells from which they take up sphingolipids (SL) and incorporate them into the chlamydial membrane and the vacuole (termed inclusion). SL uptake is essential for Chlamydia trachomatis (Ctr) in epithelial cells; however, they can also infect phagocytes, but the consequences for the SL metabolism have not yet been investigated in these cells. We performed a quantitative sphingolipidome analysis of infected primary neutrophils, macrophages, and immortalized fallopian tube epithelial cells. Sphingosine (Sph) levels are elevated in primary M2-like macrophages and human neutrophils infected with C. trachomatis. Human neutrophils respond to the pathogen by markedly upregulating sphingosine kinase 1 (SPHK1). We show in M2-like macrophages, by RNAseq, that two counteracting pathways involving upregulation of SPHK1, but also sphingosine-1-phosphate phosphatases 1 and 2 (SGPP1 and SGPP2) and sphingosine-1-phosphate lyase (SGPL1), maintain a steady pool of S1P. Using click chemistry, we show that exogenously added sphingomyelin (SM) and ceramide (Cer) are efficiently taken up into the chlamydial inclusion and are integrated into bacterial membranes in infected M2-like macrophages. Exogenous Sph reduces chlamydial infectivity, is transported into the inclusion lumen, and integrates into chlamydial membranes, suggesting that this particular SL species could represent a host defense mechanism. Taken together, our data indicate an important role for Sph/Sph kinase vs S1P/S1P phosphatase balance in infected phagocytes and a previously unrecognized role for sphingosine in the immune defense against chlamydial infection.IMPORTANCEChlamydia trachomatis (Ctr) is the leading cause of sexually transmitted diseases worldwide. Left untreated, it can cause severe complications such as blindness, pelvic inflammatory disease, or infertility. To date, no vaccines are available, and antibiotic treatment represents the only therapeutic approach to cure the infection. Limited access to antibiotics and displaced antibiotic intake increase the risk of developing recurring infections. Immune cells which fail to clear the infection and serve as a niche for chlamydial survival and replication, favor this outcome. Our research aims to elucidate the influence of sphingolipids (SL) during chlamydial infection, especially of phagocytic cells. Identifying relevant targets offers new strategies to develop alternative treatment methods.
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Affiliation(s)
- Adriana Moldovan
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabienne Wagner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Dominik Wigger
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - David Komla Kessie
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Marcel Rühling
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Kathrin Stelzner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Regina Tschertok
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Louise Kersting
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Julian Fink
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Jürgen Seibel
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Burkhard Kleuser
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Thomas Rudel
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
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12
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Zhang L, Liu J. Spironolactone protects against hypertension-induced renal fibrosis by promoting autophagy and inhibiting the NLRP3 inflammasome. J Hypertens 2025:00004872-990000000-00683. [PMID: 40366120 DOI: 10.1097/hjh.0000000000004020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 03/16/2025] [Indexed: 05/15/2025]
Abstract
INTRODUCTION We aimed to investigate the mechanism by which spironolactone protects against hypertensive renal fibrosis. METHODS For in-vivo experiments, we established Control, SHR, and SHR+spironolactone (20 mg/kg/day) groups. For in-vitro experiments, we established Control, TGF-β1-induced (10 ng/ml), and spironolactone (1 μmol/l) intervention groups. Renal function and serum potassium, estradiol, testosterone, and plasma aldosterone levels were assessed, along with autophagy indicators LC3 and p62, and NLRP3 inflammasome-related proteins (NLRP3, caspase-1, IL-1β and IL-18). Additionally, changes in macrophage polarization and T cell and dendritic cell populations were determined. RESULTS 20 mg/kg/day of spironolactone effectively maintained systolic pressure and renal function by lowering aldosterone levels and significantly reducing testosterone levels. Hypertensive renal fibrosis was predominant in the glomeruli, tubules, and interstitium, and was associated with autophagy inhibition in renal tubules, NLRP3 inflammasome activation, both M1 and M2 macrophage polarization, with a predominant effect on M1 polarization, decreased CD4+ T cell population and CD4/CD8 ratio, and increased CD8+ T cell and dendritic cell population. Autophagy negatively regulated the NLRP3 inflammasome. Spironolactone inhibited both M1 and M2 macrophages polarization, mainly M1 macrophage polarization, reduced CD8+ T and dendritic cell population, increased CD4+ T cell population, negatively regulated the release of NLRP3 inflammasome-related proteins in macrophages, and restored autophagy in the glomeruli and renal tubules. CONCLUSION Spironolactone acts on sites where the mineralocorticoid receptor is present. A dose of 20 mg/kg/day spironolactone is well tolerated and protects against hypertension-induced renal fibrosis by restoring autophagy and suppressing NLRP3 inflammasome activation.
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Affiliation(s)
- Lin Zhang
- Department of Clinical Laboratory, North China University of Science and Technology Affiliated Hospital
| | - Jianchang Liu
- Tangshan People's Hospital, Tangshan, Hebei Province, China
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13
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Xia L, Pan Y, Wang X, Hu R, Gao J, Chen W, He K, Cui D, Zhao Y, Liu L, Lai L, Su M. ERMAP attenuates DSS-induced colitis in mice by regulating macrophage and T cell functions. BMC Gastroenterol 2025; 25:362. [PMID: 40355813 PMCID: PMC12070682 DOI: 10.1186/s12876-025-03840-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/02/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND & AIMS Both macrophages and T cells play a critical role in inflammatory bowel disease (IBD) development. Since our previous studies have shown that a novel immune checkpoint molecule erythrocyte membrane-associated protein (ERMAP) affects macrophage polarization and negatively regulates T cell responses, we investigated the effects of ERMAP on DSS-induced colitis progression in mice. METHODS C57BL/6 mice developed a dextran sodium sulfate (DSS) colitis model, treated with control Fc protein (Control Ig) and ERMAP-Fc fusion protein (ERMAP-Ig) for 12 days to assess colitis severity by disease activity index (DAI), weight loss, colon length, histology, flow cytometry, Q-PCR, WB, ELISA, and the effect of adoptive transfer of ERMAP knockout mice (ERMAP-/-) peritoneal macrophages on DSS colitis mice. In vitro, the effects of the RAW264.7 macrophage cell line that interfered with ERMAP expression on macrophage polarization and T cells were analyzed by flow cytometry. RESULTS We show here that administration of ERMAP protein significantly increases the proportion of anti-inflammatory M2-type macrophages and inhibits T cell activation and proliferation in DSS-induced colitis mice. Knockdown of ERMAP in RAW264.7 macrophages reduces M2-type macrophage polarization and increases T cell responses. Adoptive transfer of macrophages from ERMAP-/- exacerbates DSS-induced colitis. Global gene expression analysis by RNA-seq shows that ERMAP inhibits the NOD-like receptor (NLR) protein family pathway in macrophages. CONCLUSIONS In summary, our results suggest that administration of ERMAP can protect DSS-induced colitis in mice by regulating T cell and macrophage functions. This study adds to the evidence for various mechanistic pathways associated to the pathogenesis of IBD, which could subsequently be translated to novel therapeutics.
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Affiliation(s)
- Lu Xia
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
- Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Yiwen Pan
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Xianbin Wang
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Rong Hu
- Translational Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Jie Gao
- Translational Medicine Research Center of Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Wei Chen
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Keke He
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Dongbin Cui
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Youbo Zhao
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China
| | - Lu Liu
- The Public Health Clinical Center of Guiyang City, 6 Daying Road, Guiyang City, 550004, Guizhou, China.
| | - Laijun Lai
- Department of Allied Health Sciences, University of Connecticut, 1390 Storrs Road, Storrs, CT, 06269, USA.
| | - Min Su
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China.
- Department of Histology and Embryology, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China.
- Key Laboratory for Research on Autoimmune Diseases of Higher Education schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China.
- Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guizhou, 561113, China.
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Liu Y, Zhai Y, Zhang Y, Song L, Zhang H, Cao J, Zhao S, Wu Y, Liang R, Zhu R, Wang W, Sun Y. High metastatic tumor-derived CXCL16 mediates liver colonization metastasis by inducing Kupffer cell polarization via the PI3K/AKT/FOXO3a pathway. Neoplasia 2025; 65:101174. [PMID: 40347803 DOI: 10.1016/j.neo.2025.101174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 04/30/2025] [Accepted: 04/30/2025] [Indexed: 05/14/2025]
Abstract
Liver metastases represent a late-stage manifestation of numerous cancers, often associated with poor patient prognosis. Kupffer cells (KCs), resident liver macrophages, play a critical role in liver metastasis (LM). However, the mechanisms by which the polarization of KCs facilitate colorectal cancer (CRC) liver metastases remain elusive. Here, we established a CRC liver metastasis mouse model and employed a co-culture system, found that KCs were recruited and polarized to M2 phenotype. We isolated and purified highly metastatic cell lines to reveal potential changes in CRC cells during metastasis. Through bulk RNA sequencing, we identified and validated CXCL16 as a positive mediator in liver-metastatic CT26-LM cells that induced an M2-like KC phenotype. Knock down of CXCL16 reduced the M2 polarization of KCs and inhibited the formation of liver metastasis lesions. Next, this polarization process was shown to be achieved through the PI3K/AKT/FOXO3a pathway. Further investigation revealed FOXO3a transcriptionally activates CD206(MRC1) in this process. Pharmacological inhibition of the CXCL16-PI3K-FOXO3a axis to disrupt the polarization of KCs attenuated CRC liver metastasis in vivo. Our findings collectively indicate that targeting the CXCL16/PI3K/AKT/FOXO3a pathway in KCs may represent a promising therapeutic strategy for preventing CRC liver metastasis.
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Affiliation(s)
- Yin Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yunpeng Zhai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Liming Song
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hanyue Zhang
- Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jiahui Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Senfeng Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yahui Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ruopeng Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Rongtao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Weijie Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuling Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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Liu S, Wang M, Xu L, Deng D, Lu L, Tian J, Zhou D, Rui K. New insight into the role of SOCS family in immune regulation and autoimmune pathogenesis. J Adv Res 2025:S2090-1232(25)00313-3. [PMID: 40349956 DOI: 10.1016/j.jare.2025.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 04/07/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Suppressor of cytokine signaling (SOCS) proteins regulate signal transduction by interacting with cytokine receptors and signaling proteins and targeting associated proteins for degradation. Recent studies have demonstrated that the SOCS proteins serve as crucial inhibitors in cytokine signaling networks and play a pivotal role in both innate and adaptive immune responses. AIM OF REVIEW In this review, we aim to discuss recent advancements in understanding the complex functions of SOCS proteins in various immune cells, as well as the effects of SOCS proteins in human health and diseases. Increasing evidence indicates that SOCS proteins are frequently dysregulated in developing autoimmune diseases, suggesting that therapeutic targeting of SOCS proteins could provide clinical benefit. KEY SCIENTIFIC CONCEPTS OF REVIEW This review provides a comprehensive understanding of SOCS proteins in immune regulation and autoimmune pathogenesis, it also highlights the role of SOCS-related mimetic peptides in immunotherapy.
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Affiliation(s)
- Shiyi Liu
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China; Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Mingwei Wang
- Department of Emergency, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Liangjie Xu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Daihua Deng
- Department of Rheumatology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Chongqing International Institute for Immunology, China
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Dongmei Zhou
- Department of Rheumatology and Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Ivy A, Bess SN, Agrawal S, Kochar V, Stokes AL, Muldoon TJ, Nelson CE. A dual-fluorescence assay for gene delivery vehicle screening in macrophages with an inflammation-inducible reporter construct. BMC METHODS 2025; 2:8. [PMID: 40352095 PMCID: PMC12062070 DOI: 10.1186/s44330-025-00030-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 05/01/2025] [Indexed: 05/14/2025]
Abstract
Background Macrophages are a promising target for therapeutics in various applications such as regenerative medicine and immunotherapy for cancer. Due to their plastic nature, macrophages can switch from a non-activated state to activated with the smallest environmental change. For macrophages to be effective in their respective applications, screening for phenotypic changes is necessary to elucidate the cell response to different delivery vehicles, vaccines, small molecules, and other stimuli. Methods We created a sensitive and dynamic high-throughput screening method for macrophages based on the activation of NF-κB. For this reporter, we placed an mRFP1 fluorescence gene under the control of an inflammatory promoter, which recruits NF-κB response elements to promote expression during the inflammatory response in macrophages. We characterized the inflammatory reporter based on key markers of an inflammatory response in macrophages including TNF-α cytokine release and immunostaining for inflammatory and non-inflammatory cell surface markers. We compared gene delivery and inflammation of several clinically relevant viral vehicles and commercially available non-viral vehicles. Statistical analysis between groups was performed with a one-way ANOVA with post-hoc Tukey's test. Results The reporter macrophages demonstrated a dynamic range after LPS stimulation with an EC50 of 0.61 ng/mL that was highly predictive of TNF-α release. Flow cytometry revealed heterogeneity between groups but confirmed population level shifts in pro-inflammatory markers. Finally, we demonstrated utility of the reporter by showing divergent effects with various leading gene delivery vehicles. Discussion This screening technique developed here provides a dynamic, high-throughput screening technique for determining inflammatory response by mouse macrophages to specific stimuli. The method presented here provides insight into the inflammatory response in mouse macrophages to different viral and non-viral gene delivery methods and provides a tool for high-throughput screening of novel vehicles. Supplementary Information The online version contains supplementary material available at 10.1186/s44330-025-00030-x.
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Affiliation(s)
- Allie Ivy
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
| | - Shelby N. Bess
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
| | - Shilpi Agrawal
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
| | - Varun Kochar
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
| | - Abbey L. Stokes
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
| | - Timothy J. Muldoon
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR USA
| | - Christopher E. Nelson
- Department of Biomedical Engineering, University of Arkansas, 120 John A. White Jr. Engineering Hall, Fayetteville, AR 72701 USA
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR USA
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Zhang S, Guo R, Li Y, Liu K, Gong S. Mutual inhibitory interaction between M1 macrophages and Schwann cells in the myelin sheath of auditory nerves. Neuroscience 2025; 573:399-407. [PMID: 40147621 DOI: 10.1016/j.neuroscience.2025.03.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
OBJECTIVES To explore the interaction between the M1 macrophages and Schwann cells (SCs) in auditory nerve myelin. METHODS We conducted co-culture experiments using SCs from the auditory nerve myelin and induced M1 macrophages from 6-week-old C57BL/6 mice. The co-cultured group was set up as an experimental group, while the control groups were assigned as separated cultures of SCs and macrophages alone. The cultured cells were evaluated by cell number and morphology; further, the functions of the cells were detected by the secretion of Brain-Derived Neurotrophic Factor (BDNF) and phagocytic ability. RESULTS SCs from the auditory nerve were purified and cultured, showing exponential growth. The BDNF secretion value of SCs was 0.444 ± 0.031 ng/ml. M1 polarization of mouse bone marrow macrophages was successfully induced, and the absorbance value of the macrophages phagocytosis was 0.144 ± 0.003. The co-cultured model presented significant shortening of the spindle-shaped bipolar protrusions of SCs, and the SCs number in co-cultured group was reduced by about 50 % compared with the SCs in control group. the secretion of BDNF value in the co-cultured group was reduced to 0.02 ± 0.007 ng/ml (P < 0.001). In addition, the absorbance value of M1 macrophages phagocytosis in the co-cultured group was significantly reduced to 0.104 ± 0.001 (P < 0.001). CONCLUSION Both M1 macrophages and SCs in auditory nerve myelin were significantly damaged in the co-cultured group.
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Affiliation(s)
- Si Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, China
| | - Rui Guo
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, China
| | - Yang Li
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, China.
| | - Ke Liu
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, China.
| | - Shusheng Gong
- Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Clinical Center for Hearing Loss, Capital Medical University, Beijing, China.
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18
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Wang Y, Gao J, Wu T, Wang Z. M2 Macrophages Mitigate Ocular Surface Inflammation and Promote Recovery in a Mouse Model of Dry Eye. Ocul Immunol Inflamm 2025:1-10. [PMID: 40327794 DOI: 10.1080/09273948.2025.2497484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 03/27/2025] [Accepted: 04/21/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE Dry eye disease (DED) is a chronic, progressive, multifactorial condition characterized by tear film instability and ocular surface damage. Ocular surface inflammation is one of the main mechanisms of DED. This study aims to investigate the therapeutic effects of anti-inflammatory M2 macrophages on ocular surface inflammation and their potential mechanisms in improving dry eye symptoms in a mouse model. METHODS Mouse macrophages (RAW264.7) were polarized into M2 macrophages by IL-4 under different osmolarities, and M2 macrophage conditioned medium (M2-CM) was collected. Flow cytometry and ELISA were applied to measure the cytokine expression of the M2 macrophages. Primary mouse corneal epithelial cells (CECs) were co-cultured with RAW264.7 and M2 macrophages using a Transwell system. The viability and migration of CECs were assessed using CCK-8 and scratch assays. Mouse DED was established by subcutaneous injection of scopolamine, and the therapeutic effects of M2-CM were evaluated by phenol red thread test, fluorescein staining, and tear film breakup time (BUT). PCR and immunofluorescence staining were applied to observe inflammatory factors and cells on the ocular surface. RESULTS M2 macrophages enhanced CEC viability, proliferation, and migration, but hyperosmolarity inhibited M2 macrophage polarization. In the DED model, M2-CM improved ocular surface conditions, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory factors. Immunofluorescence revealed reduced pro-inflammatory cells (M1 macrophages, Th1, and Th17) and increased M2 macrophages in the ocular tissues after M2-CM treatment. CONCLUSION These results suggest that M2-CM ameliorates ocular surface inflammation and promotes recovery in DED, offering a potential therapeutic strategy for DED.
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Affiliation(s)
- Yingming Wang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jing Gao
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tianhong Wu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhenyu Wang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Droździk A, Barczak K, Bosiacki M, Kupnicka P, Cenariu D, Uriciuc WA, Chlubek D, Lipski M, Droździk M, Baranowska-Bosiacka I. Analysis of the Expression and Activity of Cyclooxygenases COX-1 and COX-2 in THP-1 Monocytes and Macrophages Cultured with Xenogenic Collagen Matrices Biofunctionalized with the Injectable Platelet-Rich Fibrin. Int J Mol Sci 2025; 26:4386. [PMID: 40362624 PMCID: PMC12073069 DOI: 10.3390/ijms26094386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/30/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Xenogenic collagen matrices are used in clinical practice for soft tissue augmentation around teeth and implants, either alone or biofunctionalized with injectable platelet-rich fibrin (iPRF). Their direct interaction with inflammatory cells may influence both healing and destructive inflammation processes. Therefore, expression of cyclooxygenases (COX-1 and COX-2) and prostanoids (PGE2 and TXB2) was studied in THP-1 monocyte/macrophage cultures exposed to porcine collagen matrices (a non-cross-linked monolayer scaffold composed of collagen type I, collagen type III, and elastin (MLCM), a bilayer scaffold made of collagen types I and III (BLCM), and a volume-stable cross-linked monolayer scaffold (VSCM)). The study showed that VSCM and MLCM significantly reduced PGE2 concentrations in THP-1 monocyte cultures. iPRF further reduced PGE2 concentrations when exposed to MLCM. In contrast, incubation of THP-1 monocytes with VSCM and BLCM resulted in a significant increase in TXB2 concentrations compared with control conditions. Incubation of macrophages with MLCM, VSCM, and BLCM increased PGE2 concentrations, with VSCM and BLCM additionally increasing TXB2 concentrations. iPRF in macrophage cultures with VSCM and BLCM also resulted in increased PGE2 and TXB2 concentrations compared with control conditions. Confocal microscopy revealed no visible differences in COX-1 immunoexpression in monocytes and macrophages cultured with collagen matrices, either with or without iPFR. Weak positive COX-2 immunofluorescence was observed in monocytes, while moderate positive immunofluorescence was detected in macrophages. In conclusion, it can be suggested that the studied collagen matrices interact with monocytes/macrophages, with MLCM exhibiting the highest compatibility.
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Affiliation(s)
- Agnieszka Droździk
- Laboratory of Preclinical Periodontology, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland;
| | - Mateusz Bosiacki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland; (M.B.); (D.C.); (I.B.-B.)
| | - Patrycja Kupnicka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland; (M.B.); (D.C.); (I.B.-B.)
| | - Diana Cenariu
- MEDFUTURE—Research Center for Advanced Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania;
| | - Willi Andrei Uriciuc
- Faculty of Nursing and Science of Health, “Iuliu-Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland; (M.B.); (D.C.); (I.B.-B.)
| | - Mariusz Lipski
- Department of Preclinical Conservative Dentistry and Preclinical Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland;
| | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111, Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp 72, 70-111 Szczecin, Poland; (M.B.); (D.C.); (I.B.-B.)
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20
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Froom ZSCS, Callaghan NI, Davenport Huyer L. Cellular crosstalk in fibrosis: insights into macrophage and fibroblast dynamics. J Biol Chem 2025:110203. [PMID: 40334985 DOI: 10.1016/j.jbc.2025.110203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025] Open
Abstract
Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function through the release of their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.
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Affiliation(s)
- Zachary S C S Froom
- School of Biomedical Engineering, Faculties of Medicine and Engineering, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Neal I Callaghan
- Department of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Locke Davenport Huyer
- School of Biomedical Engineering, Faculties of Medicine and Engineering, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Microbiology & Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; Department of Biomaterials & Applied Oral Sciences, Faculty of Dentistry, Dalhousie University, Halifax, NS B3H 4R2, Canada; Nova Scotia Health, Halifax, NS B3S 0H6, Canada.
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21
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Zhao W, Zhang Z, Xie M, Ding F, Zheng X, Sun S, Du J. Exploring tumor-associated macrophages in glioblastoma: from diversity to therapy. NPJ Precis Oncol 2025; 9:126. [PMID: 40316746 PMCID: PMC12048723 DOI: 10.1038/s41698-025-00920-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/22/2025] [Indexed: 05/04/2025] Open
Abstract
Glioblastoma is the most aggressive and lethal cancer of the central nervous system, presenting substantial treatment challenges. The current standard treatment, which includes surgical resection followed by temozolomide and radiation, offers limited success. While immunotherapies, such as immune checkpoint inhibitors, have proven effective in other cancers, they have not demonstrated significant efficacy in GBM. Emerging research highlights the pivotal role of tumor-associated macrophages (TAMs) in supporting tumor growth, fostering treatment resistance, and shaping an immunosuppressive microenvironment. Preclinical studies show promising results for therapies targeting TAMs, suggesting potential in overcoming these barriers. TAMs consist of brain-resident microglia and bone marrow-derived macrophages, both exhibiting diverse phenotypes and functions within the tumor microenvironment. This review delves into the origin, heterogeneity, and functional roles of TAMs in GBM, underscoring their dual roles in tumor promotion and suppression. It also summarizes recent progress in TAM-targeted therapies, which may, in combination with other treatments like immunotherapy, pave the way for more effective and personalized strategies against this aggressive malignancy.
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Affiliation(s)
- Wenwen Zhao
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhi Zhang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Mingyuan Xie
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Feng Ding
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xiangrong Zheng
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shicheng Sun
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianyang Du
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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22
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Wang T, Wang X, Ren W, Sun Z, Zhang Y, Wu N, Diao H. Cardiomyocyte proliferation: Advances and insights in macrophage-targeted therapy for myocardial injury. Genes Dis 2025; 12:101332. [PMID: 39935606 PMCID: PMC11810708 DOI: 10.1016/j.gendis.2024.101332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/18/2024] [Accepted: 03/20/2024] [Indexed: 02/13/2025] Open
Abstract
In the mammalian heart, cardiomyocytes undergo a transient window of proliferation that leads to regenerative impairment, limiting cardiomyocyte proliferation and myocardial repair capacity. Cardiac developmental patterns exacerbate the progression of heart disease characterized by myocardial cell loss, ultimately leading to cardiac dysfunction and heart failure. Myocardial infarction causes the death of partial cardiomyocytes, which triggers an immune response to remove debris and restore tissue integrity. Interestingly, when transient myocardial injury triggers irreversible loss of cardiomyocytes, the subsequent macrophages responsible for proliferation and regeneration have a unique immune phenotype that promotes the formation of pre-existing new cardiomyocytes. During mammalian regeneration, mononuclear-derived macrophages and self-renewing resident cardiac macrophages provide multiple cytokines and molecular signals that create a regenerative environment and cellular plasticity capacity in postnatal cardiomyocytes, a pivotal strategy for achieving myocardial repair. Consistent with other human tissues, cardiac macrophages originating from the embryonic endothelium produce a hierarchy of contributions to monocyte recruitment and fate specification. In this review, we discuss the novel functions of macrophages in triggering cardiac regeneration and repair after myocardial infarction and provide recent advances and prospective insights into the phenotypic transformation and heterogeneous features involving cardiac macrophages. In conclusion, macrophages contribute critically to regeneration, repair, and remodeling, and are challenging targets for cardiovascular therapeutic interventions.
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Affiliation(s)
- Tao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
| | - Xueyao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
| | - Weibin Ren
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
| | - Zeyu Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yanhui Zhang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
| | - Nanping Wu
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
| | - Hongyan Diao
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
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23
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Mezouar S, Mege J. Monitoring Macrophage Polarization in Infectious Disease, Lesson From SARS-CoV-2 Infection. Rev Med Virol 2025; 35:e70034. [PMID: 40148134 PMCID: PMC11976041 DOI: 10.1002/ird3.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/11/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
The concept of macrophage polarization has been largely used in human diseases to define a typology of activation of myeloid cells reminiscent of lymphocyte functional subsets. In COVID-19, several studies have investigated myeloid compartment dysregulation and macrophage polarization as an indicator of disease prognosis and monitoring. SARS-CoV-2 induces an in vitro activation state in monocytes and macrophages that does not match the polarization categories in most studies. In COVID-19 patients, monocytes and macrophages are activated but they do not show a polarization profile. Therefore, the investigation of polarization under basic conditions was not relevant to assess monocyte and macrophage activation. The analysis of monocytes and macrophages with high-throughput methods has allowed the identification of new functional subsets in the context of COVID-19. This approach proposes an innovative stratification of myeloid cell activation. These new functional subsets of myeloid cells would be better biomarkers to assess the risk of complications in COVID-19, reserving the concept of polarization for pharmacological programme evaluation. This review reappraises the polarization of monocytes and macrophages in viral infections, particularly in COVID-19.
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Affiliation(s)
- Soraya Mezouar
- Centre National de la Recherche ScientifiqueÉtablissement Français du SangAnthropologie Bio‐Culturelle, Droit, Éthique et SantéAix‐Marseille UniversityMarseilleFrance
- Faculty of Medical and Paramedical SciencesAix‐Marseille UniversityHIPE Human LabMarseilleFrance
| | - Jean‐Louis Mege
- Centre National de la Recherche ScientifiqueÉtablissement Français du SangAnthropologie Bio‐Culturelle, Droit, Éthique et SantéAix‐Marseille UniversityMarseilleFrance
- Department of ImmunologyLa Timone HospitalMarseilleFrance
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24
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Zhang H, Yu Y, Qian C. Oligonucleotide-Based Modulation of Macrophage Polarization: Emerging Strategies in Immunotherapy. Immun Inflamm Dis 2025; 13:e70200. [PMID: 40325939 PMCID: PMC12053320 DOI: 10.1002/iid3.70200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 03/10/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Recent advances in immunotherapy have spotlighted macrophages as central mediators of disease treatment. Their polarization into pro‑inflammatory (M1) or anti‑inflammatory (M2) states critically influences outcomes in cancer, autoimmunity, and chronic inflammation. Oligonucleotides have emerged as highly specific, scalable, and cost‑effective agents for reprogramming macrophage phenotypes. OBJECTIVE To review oligonucleotide strategies-including ASOs, siRNAs, miRNA mimics/inhibitors, and aptamers-for directing macrophage polarization and their therapeutic implications. REVIEW SCOPE We examine key signaling pathways governing M1/M2 phenotypes, describe four classes of oligonucleotides and their mechanisms, and highlight representative preclinical and clinical applications. KEY INSIGHTS Agents such as AZD9150, MRX34, and AS1411 demonstrate macrophage reprogramming in cancer, inflammation, and infection models. Advances in ligand‑conjugated nanoparticles and chemical modifications improve delivery and stability, yet immunogenicity, off‑target effects, and formulation challenges remain significant barriers. FUTURE PERSPECTIVES Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation.
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Affiliation(s)
- Hanfu Zhang
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
- School of Molecular SciencesUniversity of Western AustraliaCrawleyWAAustralia
| | - Yizhi Yu
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
| | - Cheng Qian
- National Key Laboratory of Immunity & Inflammation, Institute of ImmunologyNaval Medical UniversityShanghaiChina
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25
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Luo G, Li J, Chen S, Yuan Z, Sun Z, Lou T, Chen Z, Liu H, Zhou C, Fan C, Ruan H. Polylactic acid electrospun membranes coated with chiral hierarchical-structured hydroxyapatite nanoplates promote tendon healing based on a macrophage-homeostatic modulation strategy. Bioact Mater 2025; 47:460-480. [PMID: 40034408 PMCID: PMC11872693 DOI: 10.1016/j.bioactmat.2025.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/30/2024] [Accepted: 01/21/2025] [Indexed: 03/05/2025] Open
Abstract
Tendon injury is a common and challenging problem in the motor system that lacks an effective treatment, affecting daily activities and lowering the quality of life. Limited tendon regenerative capability and immune microenvironment dyshomeostasis are considered the leading causes hindering tendon repair. The chirality of biomaterials was proved to dictate immune microenvironment and dramatically affect tissue repair. Herein, chiral hierarchical structure hydroxylapatite (CHAP) nanoplates are innovatively synthesized for immunomodulatory purposes and further coated onto polylactic acid electrospinning membranes to achieve long-term release for tendon regeneration adaption. Notably, levorotatory-chiral HAP (L-CHAP) nanoplates rather than dextral-chiral or racemic-chiral exhibit good biocompatibility and bioactivity. In vitro experiments demonstrate that L-CHAP induces macrophage M2 polarization by enhancing macrophage efferocytosis, which alleviates inflammatory damage to tendon stem cells (TDSCs) through downregulated IL-17-NF-κB signaling. Meanwhile, L-CHAP-mediated macrophage efferocytosis also promotes TDSCs proliferation and tenogenic differentiation. By establishing a rat model of Achilles tendon injury, L-CHAP was demonstrated to comprehensively promoting tendon repair by enhancing macrophage efferocytosis and M2 polarization in vivo, finally leading to improvement of tendon ultrastructural and mechanical properties and motor function. This novel strategy highlights the role of L-CHAP in tendon repair and thus provides a promising therapeutic strategy for tendon injury.
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Affiliation(s)
- Gang Luo
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Juehong Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Shuai Chen
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Zhengqiang Yuan
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Ziyang Sun
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Tengfei Lou
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Zhenyu Chen
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Hang Liu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Chao Zhou
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Cunyi Fan
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
| | - Hongjiang Ruan
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Rd, Shanghai, 200233, PR China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Building 3, Langu Science and Technology Park, Lane 70, Haiji 6th Road, Shanghai, PR China
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Sun Z, Wang X, Shi C, Yu T, Xu W, Ji X, Su K, Yan H, Shan Y, Xie T, Xu J, Zhao X, Shan J. TREM2 modulates lipid metabolism to alleviate airway inflammation in asthma: A potential therapeutic target. Int J Biol Macromol 2025; 308:142306. [PMID: 40154695 DOI: 10.1016/j.ijbiomac.2025.142306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/23/2025] [Accepted: 03/18/2025] [Indexed: 04/01/2025]
Abstract
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR) and immune cell infiltration. TREM2 (Triggering Receptor Expressed on Myeloid cells 2), known for its role in lipid metabolism and inflammation, was found to be upregulated in asthma. Using Trem2-/- mice, we observed that TREM2 deletion significantly reduces airway inflammation and AHR. This effect is achieved through the modulation of triglyceride (TG) metabolism, leading to increased TG synthesis, decreased lipolysis, and reduced release of pro-inflammatory free fatty acids (FFAs), particularly arachidonic acid. The study reveals a novel role for TREM2 in regulating lipid metabolism in asthma, suggesting that targeting TREM2 may offer new therapeutic opportunities for managing asthma and related inflammatory conditions.
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Affiliation(s)
- Zhengpeng Sun
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xuan Wang
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chen Shi
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tao Yu
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Weichen Xu
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xinyu Ji
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Ke Su
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Hua Yan
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yiwen Shan
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tong Xie
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jianya Xu
- Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Xia Zhao
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
| | - Jinjun Shan
- Jiangsu Key Laboratory of Children's Health and Chinese Medicine, State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China; Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
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27
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Parolini C. Pathophysiology of bone remodelling cycle: Role of immune system and lipids. Biochem Pharmacol 2025; 235:116844. [PMID: 40044049 DOI: 10.1016/j.bcp.2025.116844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/31/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Osteoporosis is the most common skeletal disease worldwide, characterized by low bone mineral density, resulting in weaker bones, and an increased risk of fragility fractures. The maintenance of bone mass relies on the precise balance between bone synthesis and resorption. The close relationship between the immune and skeletal systems, called "osteoimmunology", was coined to identify these overlapping "scientific worlds", and its function resides in the evaluation of the mutual effects of the skeletal and immune systems at the molecular and cellular levels, in both physiological and pathological states. Lipids play an essential role in skeletal metabolism and bone health. Indeed, bone marrow and its skeletal components demand a dramatic amount of daily energy to control hematopoietic turnover, acquire and maintain bone mass, and actively being involved in whole-body metabolism. Statins, the main therapeutic agents in lowering plasma cholesterol levels, are able to promote osteoblastogenesis and inhibit osteoclastogenesis. This review is meant to provide an updated overview of the pathophysiology of bone remodelling cycle, focusing on the interplay between bone, immune system and lipids. Novel therapeutic strategies for the management of osteoporosis are also discussed.
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Affiliation(s)
- Cinzia Parolini
- Department of Pharmacological and Biomolecular Sciences, 'Rodolfo Paoletti', via Balzaretti 9 - Università degli Studi di Milano 20133 Milano, Italy.
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Breitenstein P, Visser VL, Motta SE, Martin M, Generali M, Baaijens FPT, Loerakker S, Breuer CK, Hoerstrup SP, Emmert MY. Modulating biomechanical and integrating biochemical cues to foster adaptive remodeling of tissue engineered matrices for cardiovascular implants. Acta Biomater 2025; 197:48-67. [PMID: 40118167 DOI: 10.1016/j.actbio.2025.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/15/2025] [Accepted: 03/18/2025] [Indexed: 03/23/2025]
Abstract
Cardiovascular disease remains one of the leading causes of mortality in the Western world. Congenital heart disease affects nearly 1 % of newborns, with approximately one-fourth requiring reconstructive surgery during their lifetime. Current cardiovascular replacement options have significant limitations. Their inability to grow poses particular challenges for pediatric patients. Tissue Engineered Matrix (TEM)-based in situ constructs, with their self-repair and growth potential, offer a promising solution to overcome the limitations of current clinically used replacement options. Various functionalization strategies, involving the integration of biomechanical or biochemical components to enhance biocompatibility, have been developed for Tissue Engineered Vascular Grafts (TEVG) and Tissue Engineered Heart Valves (TEHV) to foster their capacity for in vivo remodeling. In this review, we present the current state of clinical translation for TEVG and TEHV, and provide a comprehensive overview of biomechanical and biochemical functionalization strategies for TEVG and TEHV. We discuss the rationale for functionalization, the implementation of functionalization cues in TEM-based TEVG and TEHV, and the interrelatedness of biomechanical and biochemical cues in the in vivo response. Finally, we address the challenges associated with functionalization and discuss how interdisciplinary research, especially when combined with in silico models, could enhance the translation of these strategies into clinical applications. STATEMENT OF SIGNIFICANCE: Cardiovascular disease remains one of the leading causes of mortality, with current replacements being unable to grow and regenerate. In this review, we present the current state of clinical translation for tissue engineered vascular grafts (TEVG) and heart valves (TEHV). Particularly, we discuss the rationale and implementation for functionalization cues in tissue engineered matrix-based TEVGs and TEHVs, and for the first time we introduce the interrelatedness of biomechanical and biochemical cues in the in-vivo response. These insights pave the way for next-generation cardiovascular implants that promise better durability, biocompatibility, and growth potential. Finally, we address the challenges associated with functionalization and discuss how interdisciplinary research, especially when combined with in silico models, could enhance the translation of these strategies into clinical applications .
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Affiliation(s)
- Pascal Breitenstein
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland
| | - Valery L Visser
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland
| | - Sarah E Motta
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland
| | - Marcy Martin
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland
| | - Melanie Generali
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland
| | - Frank P T Baaijens
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Sandra Loerakker
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Christopher K Breuer
- Center for Regenerative Medicine, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Surgery, Nationwide Children's Hospital, Columbus, OH, USA; Department of Surgery, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Simon P Hoerstrup
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland; Wyss Zurich Translational Center, University of Zurich and ETH Zurich, Zurich 8092, Switzerland
| | - Maximilian Y Emmert
- Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren 8952, Switzerland; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin 13353, Germany; Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
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Liu C, Luo Y, Zhou H, Lin M, Zang D, Chen J. Immune cell-derived exosomal non-coding RNAs in tumor microenvironment: Biological functions and potential clinical applications. Chin J Cancer Res 2025; 37:250-267. [PMID: 40353080 PMCID: PMC12062983 DOI: 10.21147/j.issn.1000-9604.2025.02.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/25/2025] [Indexed: 05/14/2025] Open
Abstract
The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy. Within the tumor microenvironment, exosomes have emerged as pivotal mediators of intercellular communication, with their cargo of non-coding RNAs (ncRNAs) serving as key regulatory elements. This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology. The involvement of various immune cells, including T cells, B cells, natural killer cells, macrophages, neutrophils, and myeloid-derived suppressor cells, in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored. Additionally, the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed, alongside their potential clinical applications in cancer.
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Affiliation(s)
- Chenguang Liu
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Yawen Luo
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Huan Zhou
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Meixi Lin
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Dan Zang
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
| | - Jun Chen
- Department of Oncology, the Second Hospital of Dalian Medical University, Dalian 116023, China
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Matsui T, Tanaka Y. Pathophysiology and healing of insertional Achilles tendinopathy: Current concepts. J ISAKOS 2025:100867. [PMID: 40316256 DOI: 10.1016/j.jisako.2025.100867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 04/04/2025] [Accepted: 04/18/2025] [Indexed: 05/04/2025]
Abstract
Insertional Achilles tendinopathy (IAT) is a challenging condition that significantly impacts athletes and physically active individuals, often leading to chronic pain and impaired performance. IAT is characterized by a complex interplay of mechanical stress, vascular impairment, inflammatory responses, and extracellular matrix (ECM) dysregulation at the Achilles tendon insertion. This review integrates recent advancements in the understanding of IAT pathophysiology with focus on the effects of tensile and compressive loads, intra-tendinous pressure changes, tissue hypoxia, and ECM water balance. Emerging evidence indicates that mechanical loading influences tendon homeostasis through mechanotransduction, leading to ECM remodelling and fibrocartilaginous adaptation. Although appropriate compressive loading is necessary to maintain ECM homeostasis and fibrocartilage regeneration, excessive or abnormal loading disrupts tendon repair mechanisms and contributes to degenerative changes. Furthermore, increased intra-tendinous pressure impairs capillary perfusion, thereby promoting a hypoxic microenvironment that exacerbates the inflammatory response. Dysregulated water retention due to glycosaminoglycans (GAGs) and hyaluronic acid affects intra-tendinous pressure, highlighting potential therapeutic strategies targeting ECM hydration. This review also explores the roles of macrophage polarisation, cytokine regulation, and growth factors in tendon healing, emphasising their potential therapeutic implications. By integrating the anatomical, biomechanical, and molecular insights, this review provides a comprehensive perspective of IAT pathophysiology and its healing mechanisms. Understanding these mechanisms is essential to optimising conservative treatments, refining surgical approaches, and developing novel therapeutic strategies to enhance tendon repair and prevent disease progression.
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31
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Gao Z, Shao S, Xu Z, Nie J, Li C, Du C. IDO1 induced macrophage M1 polarization via ER stress-associated GRP78-XBP1 pathway to promote ulcerative colitis progression. Front Med (Lausanne) 2025; 12:1524952. [PMID: 40370742 PMCID: PMC12075526 DOI: 10.3389/fmed.2025.1524952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/17/2025] [Indexed: 05/16/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder distinguished by alternating phases of remission and exacerbation. Restoring immune balance through the modulation of M1 macrophage polarization represents a potentially valuable therapeutic strategy for UC. Indoleamine 2,3-dioxygenase-1 (IDO1) has been shown to contribute to macrophage plasticity, but its role in the pathogenesis of UC via regulating M1 macrophage polarization has not been studied yet. For the clinical component, we analyzed IDO1 expression in UC using bioinformatics analysis of Gene Expression Omnibus (GEO) datasets and validated the result using western blotting of colonic tissues from new recruited UC patients. Colitis was induced in mice via dextran sulfate sodium (DSS) treatment and subsequently treated with oral administration of 1-methyl-DL-tryptophan (1-MT), an inhibitor of IDO1 pathway. The results indicated that IDO1 expression was significantly elevated in UC patients and correlated with M1 macrophage polarization observed in both human data and colitis mice. Furthermore, 1-MT markedly ameliorated DSS-induced weight loss, colonic shortening and disease severity via inhibiting IDO1 expression level, downregulating GRP78-XBP1 pathway and reducing M1 proportion. Notably, in vitro study revealed that overexpressing IDO1 in RAW264.7 cells induced macrophage M1 polarization with increased expression levels of GRP78 and XBP1, which was attenuated by 1-MT treatment. Additionally, the catalytic effect exerted by IDO1 overexpression on M1 polarization was neutralized by employing an inhibitor targeting the endoplasmic reticulum (ER) stress pathway. Thus, our findings suggest that IDO1 may promote UC progression by skewing macrophages towards M1 polarization through ER stress-associated GRP78-XBP1 pathway.
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Affiliation(s)
- Zijian Gao
- Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
- Department of Gastroenterology, Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
| | - Shuai Shao
- Department of Gastroenterology, Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
| | - Zhen Xu
- Department of Gastroenterology, Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
| | - Jiao Nie
- Department of Gastroenterology, Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
| | - Chenglin Li
- Department of Oncology, Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
| | - Chao Du
- Linyi People’s Hospital, Shandong Second Medical University, Linyi, China
- Department of Gastroenterology, Weihai Municipal Hospital, Shandong University, Weihai, China
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32
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Jolfayi AG, Beheshti AT, Hosseini SM, Fakhrabadi AA, Mohebbi B, Malakootian M, Maleki M, Pouraliakbar H, Hosseini S, Arabian M. Epicardial adipose tissue features as a biomarker and therapeutic target in coronary artery disease. Sci Rep 2025; 15:14786. [PMID: 40295726 PMCID: PMC12037875 DOI: 10.1038/s41598-025-99600-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 04/21/2025] [Indexed: 04/30/2025] Open
Abstract
This study aimed to examine the interplay between epicardial adipose tissue (EAT) features, macrophage polarization, and the cytokines Resistin and Apelin in the context of coronary artery disease (CAD). Using a case-control design with 21 CAD and 20 non-CAD individuals, the study collected demographic data, cardiovascular risk factors, and medical histories. Metabolic risk factors were assessed through laboratory tests, and CAD presence was confirmed by imaging studies. Detailed measurements of epicardial adipose characteristics were obtained through CT scans. Blood samples were analyzed for Resistin and Apelin levels, and tissue samples from EAT for macrophage polarization. The results revealed no significant differences in EAT volume and density between CAD and non-CAD groups, but the CAD group exhibited a significantly higher Calcium score. Apelin and Resistin mRNA expression levels in the right ventricular epicardial and atrioventricular fat tissue showed significantly lower Apelin and higher Resistin levels in CAD patients. CD206 expression levels in EAT were substantially lower in the CAD group, while CD11c expression levels were significantly higher. The CAD group exhibited a significantly higher CD11c/CD206 ratio in adipose tissue macrophages. This investigation highlights the significance of molecular characteristics of EAT in CAD development. While no significant differences were found in EAT volume and density, lower Apelin and higher Resistin mRNA expression in CAD patients' right ventricular fat tissue were observed. Changes in macrophage polarization markers, lower CD206 and higher CD11c, along with a higher CD11c/CD206 ratio in the macrophages of CAD patients have been shown in two investigated regions of EAT.
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Affiliation(s)
| | | | | | | | - Bahram Mohebbi
- Cardiovascular Research Center, Rajaie Cardiovascular Institute, Tehran, Iran
| | - Mahshid Malakootian
- Cardiogenetic Research Center, Rajaie Cardiovascular Institute, Tehran, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Institute, Tehran, Iran
| | | | - Saeid Hosseini
- Heart Valve Disease Research Center, Rajaie Cardiovascular Institute, Tehran, Iran
| | - Maedeh Arabian
- Cardiogenetic Research Center, Rajaie Cardiovascular Institute, Tehran, Iran.
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Petrilli JD, Estevão P, De Araújo LE, Muller I, Yoshinaga MY, Ramos PIP, Chaves-Filho AB, Horta T, Sorgi CA, Miyamoto S, Riley L, Arruda S, Queiroz A. Immunoregulatory macrophages induced by mycobacterial nonpolar lipids. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025:vkae058. [PMID: 40280187 DOI: 10.1093/jimmun/vkae058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 12/16/2024] [Indexed: 04/29/2025]
Abstract
The capacity of Mycobacterium tuberculosis (Mtb) to establish long-term survival is attributed to its ability to subvert host defense mechanisms, especially macrophages. Although Mtb lipids are believed to play a role in this host-pathogen crosstalk, how mycobacterial lipids drive this complex interaction is poorly characterized. Here, we cultured macrophages with nonpolar cell wall Mtb lipids and applied high-throughput expression profiling (RNA sequencing), mass spectrometry-based targeted eicosanoid, and untargeted lipidomics analysis. This system-level analysis revealed that Mtb nonpolar lipid triggered the expression of phenotypic markers for classically and alternatively activated macrophages, a state previously referred as immunoregulatory. Specifically, under lipid stimulation, macrophages expressed high levels of proinflammatory markers, activated components of the interleukin-1 family, underwent an imbalance in lipid metabolism, and shifted the eicosanoid synthesis pathway toward the prostaglandin axis. Taken together, these results suggest an intricate mechanism of Mtb-driven macrophage immunomodulation that may favor its long-term survival.
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Affiliation(s)
- Jéssica Dias Petrilli
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
| | - Paulo Estevão
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
| | | | - Igor Muller
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
| | - Marcos Yukio Yoshinaga
- Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil
| | | | | | - Thainá Horta
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
| | - Carlos Arterio Sorgi
- Department of Chemistry, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Sayuri Miyamoto
- Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, Brazil
| | - Lee Riley
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
| | - Sérgio Arruda
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
| | - Adriano Queiroz
- Advanced Laboratory of Public Health, Gonçalo Moniz Institute/Fiocruz, Salvador, Brazil
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, United States
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34
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Yoo NH, Baek YS, Kim HK, Lee CO, Kim MJ. Antioxidant and Anti-Inflammatory Activities of Astilboides tabularis (Hemsl.) Engl. Root Extract. Molecules 2025; 30:1892. [PMID: 40363699 DOI: 10.3390/molecules30091892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/12/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
Here, we examined the antioxidant and anti-inflammatory activities of the ethyl acetate (EtOAc) fraction of Astilboides tabularis (Hemsl.) Engl. root extracts, initially prepared from a 70% ethanol extraction. This EtOAc fraction exhibited significant scavenging activity against DPPH radicals (IC50: 11.38 ± 0.48 µg/mL) and ABTS radicals (IC50: 7.46 ± 0.58 µg/mL), and had a high total phenolic content (i.e., 407.02 ± 13.56 mg GAE/g). In addition, the EtOAc fraction demonstrated concentration-dependent protective effects in a RAW264.7 macrophage cell model subjected to oxidative stress. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, nitric oxide (NO) production and the expression of inflammatory mediators (iNOS, COX-2, TNF-α, IL-1β, IFN-β) were inhibited in a concentration-dependent manner. Western blot and real-time PCR (RT-PCR) analyses revealed that the EtOAc fraction also suppressed inflammatory mediator expression via inhibiting the activation of the NF-κB and MAPK signaling pathways. Finally, LC-QTOF-MS and LC-MS/MS analyses identified gallic acid and bergenin as compounds contributing to observed antioxidant and anti-inflammatory effects. In conclusion, the EtOAc fraction of A. tabularis root extracts exhibited strong anti-oxidant and anti-inflammatory properties, suggesting potential usage for treating various inflammatory diseases.
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Affiliation(s)
- Nam Ho Yoo
- Department of Bio-Resource Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Young Sun Baek
- Department of Bio-Resource Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Hee Kyu Kim
- Gangwondo Forest Science Institute, Chuncheon 24207, Republic of Korea
| | - Chan Ok Lee
- Gangwondo Forest Science Institute, Chuncheon 24207, Republic of Korea
| | - Myong Jo Kim
- Department of Bio-Resource Sciences, Kangwon National University, Chuncheon 24341, Republic of Korea
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Zhang X, Zhu Y, Xiong Z, Xie W, Shao M, Liu Z. Broad-Spectrum ROS/RNS Scavenging Catalase-Loaded Microreactors for Effective Oral Treatment of Inflammatory Bowel Diseases. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025:e2501341. [PMID: 40263925 DOI: 10.1002/smll.202501341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/20/2025] [Indexed: 04/24/2025]
Abstract
Inflammatory bowel disease (IBD) such as ulcerative colitis (UC) is an autoimmune disease characterized by persistent inflammation along the gastrointestinal tract with excessive generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. Here, catalase (CAT)-containing microreactor capsules with long-lasting broad-spectrum ROS/RNS-scavenging capability are developed for the treatment of IBD. In this design, CAT is encapsulated in the dense hydrogel network of calcium alginate (ALG) microspheres, which provides long-term protection of CAT activity in protease-rich intestinal environment. Afterward, the polydopamine (PDA) modification on the surface of CAT@ALG microspheres can provide them bioadhesiveness to achieve prolonged retention in the intestinal tract and broad-spectrum scavenging capability against various types of ROS/RNS beyond hydrogen peroxide. Enteric capsules are further used to protect the CAT@ALG-PDA microspheres from gastric fluid for selective release at the intestinal site. The combined action of PDA and CAT in CAT@ALG-PDA microreactors results in the broad-spectrum scavenging of excess ROS/RNS and regulates redox balance in acute UC rat model, showing satisfactory therapeutic effects superior to the mesalazine and adalimumab at clinically relevant doses without obvious side effects. This work highlights that these CAT@ALG-PDA capsules can act as long-acting broad-spectrum ROS/RNS reactors, promising for IBD treatment.
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Affiliation(s)
- Xiangyu Zhang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Yujie Zhu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Zijian Xiong
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Wenjie Xie
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Ming Shao
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Zhuang Liu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
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Zhao Y, Zhang Y, Li J, Zhang Y, Qu Y. The role of IGF2BP2 in macrophage-mediated NLRP3 inflammasome activation in the pathogenesis of dry AMD. Biol Direct 2025; 20:57. [PMID: 40264207 PMCID: PMC12016075 DOI: 10.1186/s13062-025-00648-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/05/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Dry age-related macular degeneration (AMD) is a common chronic degenerative eye disease for which there is currently no effective treatment. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is a recently identified m6A reader that binds RNA and maintains its stability, thereby participating in various biological processes. However, its role in dry AMD remains unclear. METHODS In this study, we investigated the role of IGF2BP2 in macrophage NLRP3 inflammasomes using a sodium iodate-induced dry AMD model. RESULTS Our results demonstrated that IGF2BP2 is highly expressed in the retinal-choroidal tissue induced by sodium iodate, with its effects primarily occurring in macrophages. The loss of IGF2BP2 ameliorating dry AMD. Mechanistically, methylated NLRP3 transcripts were subsequently directly recognized by the specific m 6 A "reader", IGF2BP2, to prevent NLRP3 mRNA degradation. Furthermore, in in vivo experiments, to maintain the eye's "immune privilege", we employed mesoporous silica-based cell therapy to target and regulate macrophage IGF2BP2, providing a foundation for the evaluation and translation of therapies targeting this gene. CONCLUSION our study reveals that the molecular mechanism of dry AMD pathogenesis involves IGF2BP2-mediated NLRP3 inflammasome activation in macrophages, highlighting IGF2BP2 as a promising biomarker and therapeutic target for dry AMD treatment.
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Affiliation(s)
- Yuqing Zhao
- Department of Geriatrics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China
- Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Zhang
- Department of Geriatrics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China
- Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Junfang Li
- Department of Geriatrics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China
- Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Yifei Zhang
- Department of Geriatrics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China
- Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, China
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China
| | - Yi Qu
- Department of Geriatrics, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, China.
- Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, China.
- Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, China.
- Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China.
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Qin H, Yu S, Han R, He J. Age-dependent glial heterogeneity and traumatic injury responses in a vertebrate brain structure. Cell Rep 2025; 44:115508. [PMID: 40198221 DOI: 10.1016/j.celrep.2025.115508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/11/2024] [Accepted: 03/12/2025] [Indexed: 04/10/2025] Open
Abstract
The progression of traumatic brain injury (TBI) pathology is significantly influenced by age and involves a complex interplay of glial cells. However, the influence of age on the glial dynamics and their TBI responses remains mostly unexplored. Here, we obtain a comprehensive single-cell transcriptome atlas of three major glial types under the physiological and TBI conditions across four post-embryonic life stages in the zebrafish midbrain optic tectum. We identify a library of glial subtypes and states with specific age-dependent patterns that respond distinctly to TBI. Combining the glial interactome analysis and CRISPR-Cas9-mediated gene disruption, we reveal the essential roles of dla-notch3 and cxcl12a-cxcr4b interactions in the early-larval-stage-specific unresponsiveness of radial astrocytes to TBI and the TBI-induced age-independent recruitment of microglia to injury sites, respectively. Overall, our findings provide the molecular and cellular framework of TBI-induced age-related glial dynamics in vertebrate brains.
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Affiliation(s)
- Huiwen Qin
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuguang Yu
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruyi Han
- Department of Ophthalmology, Eye, ENT Hospital of Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment, Restoration, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia, Fudan University, Shanghai 200031, China
| | - Jie He
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
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Nelson DE, Olszewski MA. Editorial: Exploring the molecular mechanisms that regulate macrophage polarization. Front Immunol 2025; 16:1599215. [PMID: 40308610 PMCID: PMC12041800 DOI: 10.3389/fimmu.2025.1599215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Accepted: 04/07/2025] [Indexed: 05/02/2025] Open
Affiliation(s)
- David E. Nelson
- Department of Biology, Middle Tennessee State University, Murfreesboro, TN, United States
| | - Michal A. Olszewski
- Department of Veterans’ Affairs, Ann Arbor Health System, Ann Arbor, MI, United States
- Division of Pulmonary & Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
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Herta T, Bhattacharyya A, Hippenstiel S, Zahlten J. The role of KLF4 in phagocyte activation during infectious diseases. Front Immunol 2025; 16:1584873. [PMID: 40313940 PMCID: PMC12044337 DOI: 10.3389/fimmu.2025.1584873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Phagocytes, including granulocytes (especially neutrophils), monocytes, macrophages, and dendritic cells, are essential components of the innate immune system, bridging innate and adaptive immunity. Their activation and function are tightly regulated by transcription factors that coordinate immune responses. Among these, Krüppel-like factor 4 (KLF4) has gained attention as a regulator of phagocyte differentiation, polarization, and inflammatory modulation. However, its role is highly context-dependent, exhibiting both pro- and anti-inflammatory properties based on environmental signals, cellular states, and the invading pathogen. KLF4 influences monocyte-to-macrophage differentiation and shapes macrophage polarization, promoting either inflammatory or regulatory phenotypes depending on external cues. In neutrophils, it affects reactive oxygen species production and immune activation, while in dendritic cells, it regulates monocyte-to-dendritic cell differentiation and cytokine secretion. Its diverse involvements in immune responses suggests that it contributes to maintaining a balance between effective pathogen defense and the prevention of excessive and potentially harmful inflammation. This review summarizes current knowledge on the function of KLF4 in phagocytes during infections, highlighting its regulatory mechanisms, context-dependent roles, and its impact on immune activation and resolution. Additionally, potential implications for therapeutic interventions targeting KLF4 are discussed.
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Affiliation(s)
- Toni Herta
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité –Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Aritra Bhattacharyya
- Department of Respiratory Medicine and Critical Care Medicine with Sleep Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Hippenstiel
- Department of Respiratory Medicine and Critical Care Medicine with Sleep Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Janine Zahlten
- Department of Respiratory Medicine and Critical Care Medicine with Sleep Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
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40
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Liu X, Harbison RA, Varvares MA, Puram SV, Peng G. Immunotherapeutic strategies in head and neck cancer: challenges and opportunities. J Clin Invest 2025; 135:e188128. [PMID: 40231472 PMCID: PMC11996880 DOI: 10.1172/jci188128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Abstract
HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.
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Affiliation(s)
- Xia Liu
- Department of Otolaryngology–Head and Neck Surgery
- Rob Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center and
| | - R. Alex Harbison
- Department of Otolaryngology–Head and Neck Surgery
- Rob Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center and
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Mark A. Varvares
- Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Sidharth V. Puram
- Department of Otolaryngology–Head and Neck Surgery
- Rob Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center and
- Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Guangyong Peng
- Department of Otolaryngology–Head and Neck Surgery
- Rob Ebert and Greg Stubblefield Head and Neck Tumor Center at Siteman Cancer Center and
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
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Zhang Z, Li L, Ge Y, Chen A, Diao S, Yang Y, Chen Q, Zhou Y, Shao J, Meng F, Yu L, Tian M, Qian X, Lin Z, Xie C, Liu B, Li R. Verteporfin-Mediated In Situ Nanovaccine Based on Local Conventional-Dose Hypofractionated Radiotherapy Enhances Antitumor and Immunomodulatory Effect. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2413387. [PMID: 40231790 DOI: 10.1002/advs.202413387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/06/2025] [Indexed: 04/16/2025]
Abstract
In situ radiotherapy is the most successful cytotoxic therapy available for the treatment of solid tumors, while high-dose radiotherapy per fraction is not yet widely and reliably used. To some extent, the major considerations of the disappointing results are on the risk of high-dose irradiation-induced damage to the surrounding normal tissues and the difficulty in distant metastasis control. To break these restraints, a gelatinase-responsive amphiphilic methoxypolyethyleneglycol-PVGLIG-polycaprolactone (mPEG-PVGLIG-PCL) nanoparticles' loading verteporfin (N@VP), a special photosensitizer that can also be excited by X-rays to produce cytotoxic singlet oxygen and greatly enhance radiotherapy efficacy, is prepared in this study. Herein, it is shown that the formed N@VP combined with conventional-dose radiation therapy (RT, 2 Gy (gray, a radiation dose unit)) can realize an antitumor effect no less than high-dose RT (8 Gy) and minimize radiation dose necessary to achieve local tumor control. Moreover, this radiosensitive nanosystem can exert excellent systemic antitumor immunity and abscopal effect, providing a preferable "in situ vaccine" strategy based on conventional-dose RT to achieve efficient systemic management of distant tumor metastasis. When combined with immunotherapy, this novel strategy for radiosensitization results in better immunotherapy sensitivity by stimulating significant immunogenic tumor cell death and synergistic antitumor immune responses.
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Affiliation(s)
- Zhifan Zhang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Yuchen Ge
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Anni Chen
- Nanjing International Hospital, Medical School of Nanjing University, Nanjing, 210019, China
| | - Shanchao Diao
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Yueling Yang
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Qianyue Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Yingling Zhou
- Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Jie Shao
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Fanyan Meng
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Lixia Yu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Manman Tian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Xiaoping Qian
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Zhaoyu Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, 210061, China
| | - Chen Xie
- State Key Laboratory for Organic Electronics and Information Displays & Institute of Advanced Materials (IAM), Jiangsu Key Laboratory for Biosensors, Nanjing University of Posts & Telecommunications, Nanjing, 210023, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
| | - Rutian Li
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute, Nanjing University, Nanjing, 210008, China
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Yan D, Li X, Wang H, Li B, Wang W, Liao Y, Tang BZ, Wang D. NIR-II aggregation-induced emission nanoparticles camouflaged with preactivated macrophage membranes for phototheranostics of pulmonary tuberculosis. Nat Protoc 2025:10.1038/s41596-025-01146-8. [PMID: 40210746 DOI: 10.1038/s41596-025-01146-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 01/10/2025] [Indexed: 04/12/2025]
Abstract
Phototheranostics, which allows simultaneous diagnosis and therapy, offers notable advantages in terms of noninvasiveness, controllability and negligible drug resistance, presenting a promising approach for disease treatment. By integrating second near-infrared (NIR-II, 1,000-1,700 nm) phototheranostic agents characterized by aggregation-induced emission (AIE) and cell membranes with specific targeting capacity, we have developed a versatile type of biomimetic nanoparticle (NP) for precise phototheranostics of pulmonary tuberculosis (TB). Coating the phototheranostic agents with preactivated macrophage membranes results in the formation of biomimetic NPs, which exhibit specific binding to TB through a lesion-pathogen dual-targeting strategy, allowing the accurate detection of Mycobacterium tuberculosis via NIR-II fluorescence imaging and precise photothermal therapy using the irradiation of a 1,064 nm laser. In comparison with traditional treatments, small individual granulomas (0.2 mm in diameter) in TB-infected mice are visualized, and improved antibacterial effects are achieved upon NP administration. Here we present a standardized workflow for the synthesis of the NIR-II AIE agents, their use for the fabrication of the biomimetic NPs and their in vitro and in vivo applications as phototheranostics against M. tuberculosis. The preparation and characterization of the NIR-II AIE agents requires ~8 d, the synthesis and characterization of the phototheranostic NPs requires ~8 d, the validation of in vitro targeting capacity and photothermal eradication requires ~26 d, and the in vivo NIR-II fluorescence imaging and imaging-guided photothermal therapy requires ~74 d. All procedures are straightforward and suitable for clinicians or researchers with prior training in organic synthesis and biomedical engineering.
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Affiliation(s)
- Dingyuan Yan
- Center for AIE Research, Guangdong Provincial Key Laboratory of New Energy Materials Service Safety, College of Materials Science and Engineering, Shenzhen University, Shenzhen, China
| | - Xue Li
- Center for AIE Research, Guangdong Provincial Key Laboratory of New Energy Materials Service Safety, College of Materials Science and Engineering, Shenzhen University, Shenzhen, China
| | - Huanhuan Wang
- Institute for Engineering Medicine, Kunming Medical University, Kunming, China
| | - Bin Li
- Institute for Engineering Medicine, Kunming Medical University, Kunming, China
| | - Wei Wang
- Institute for Engineering Medicine, Kunming Medical University, Kunming, China
| | - Yuhui Liao
- Institute for Engineering Medicine, Kunming Medical University, Kunming, China.
| | - Ben Zhong Tang
- Center for AIE Research, Guangdong Provincial Key Laboratory of New Energy Materials Service Safety, College of Materials Science and Engineering, Shenzhen University, Shenzhen, China.
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong, China.
| | - Dong Wang
- Center for AIE Research, Guangdong Provincial Key Laboratory of New Energy Materials Service Safety, College of Materials Science and Engineering, Shenzhen University, Shenzhen, China.
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43
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Hissen KL, He W, Wu G, Criscitiello MF. Dietary L-glutamate modulates intestinal mucosal immunity of juvenile hybrid striped bass ( Morone saxatilis ♀ × Morone chrysops ♂). Front Immunol 2025; 16:1575644. [PMID: 40276506 PMCID: PMC12018413 DOI: 10.3389/fimmu.2025.1575644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 03/10/2025] [Indexed: 04/26/2025] Open
Abstract
Introduction L-Glutamate is a conditionally essential amino acid, meaning it can become essential under specific conditions, like stress or disease. It is an abundant intracellular amino acid crucial in immune responses. Supplementation of feed with key amino acids, such as glutamate, can optimize growth and have other health benefits for production animals. Most research on dietary amino acid supplementation has focused on mammalian models, thus this research turned to hybrid striped bass, a teleost fish of growing importance to the aquaculture industry. The study investigated the effects of dietary supplementation with 0% or 5% glutamate in hybrid striped bass on intestinal mucosal immunity. Methods The basal purified diet contained crystalline amino acids, including 3% L-glutamate. After an 8-week period of dietary supplementation with 5% glutamate followed by lipopolysaccharide stimulation, the intestinal mucosa was analyzed at the cellular and molecular levels to compare with the head kidney to assess potential changes in immune reactivity. Results One week after lipopolysaccharide stimulation, glutamate supplementation enhanced (P < 0.05) the whole-body growth of fish without lipopolysaccharide challenge, total respiratory burst (the sum of O2 - and H2O2 production) in head kidney leukocytes, the net production of H2O2 in intestinal mucosal leukocytes, and upregulation of expression of mRNAs for IL-1β, TNF-α, and IgT in the gut mucosa. Discussion Dietary supplementation with 5% L-glutamate may modulate intestinal mucosal immunity and improve growth in HSB to enhance disease resistance. Further research is needed to clarify the mechanism and cost-effective application.
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Affiliation(s)
- Karina L. Hissen
- Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States
| | - Wenliang He
- Amino Acids Laboratory, Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - Guoyao Wu
- Amino Acids Laboratory, Department of Animal Science, Texas A&M University, College Station, TX, United States
| | - Michael F. Criscitiello
- Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Bryan, TX, United States
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Tovar-Parra D, McDermott A, Juarez MN, Cardot J, Sylla MS, Berthiaume L, Delbès G, Pelletier M, Audet-Walsh É, Plante I. The rat mammary gland undergoes dynamic transcriptomic and lipidomic modifications from pre-puberty to adulthood. Sci Rep 2025; 15:12222. [PMID: 40210913 PMCID: PMC11986145 DOI: 10.1038/s41598-025-97532-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 04/04/2025] [Indexed: 04/12/2025] Open
Abstract
Mammary gland development is a complex process involving dynamic interaction between the epithelial and stromal components at different critical stages, particularly around puberty. While epithelial tissue changes are well-documented, stromal mechanisms are less understood. To address this gap, this study employed histology, lipidomic, and transcriptomic analyses to investigate molecular and cellular dynamics in the mammary gland during pre-puberty (Post Natal Day (PND21)), peri-puberty (PND46), and adulthood (PND90) in rats. The epithelial area was significantly smaller at PND21 than at PND46 and PND90, with a higher complexity at PND21 compared to PND46. Significant differences in adipocyte number and size were observed between PND21, PND46, and PND90. Transcriptomic analysis revealed that 1563 genes changed significantly between PND21 and PND46, with only 14 genes altered between PND46 and PND90. Enrichment analyses indicated dynamic regulation of pathways related to proliferation, differentiation, lipid metabolism, and immune responses. In lipidomic analysis, 29/43 and 7/43 fatty acids differed significantly between PND21 - PND46 and PND46 - PND90, respectively. These results suggest that mammary gland development involves complex interactions between metabolic demands, hormonal regulation, and immune responses.
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Affiliation(s)
- David Tovar-Parra
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Alec McDermott
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Melany N Juarez
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Jysiane Cardot
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Mame Sokhna Sylla
- Axe Endocrinologie-Néphrologie, Centre de recherche du CHU de Québec-Université Laval, Québec City, Canada
| | - Line Berthiaume
- Axe Endocrinologie-Néphrologie, Centre de recherche du CHU de Québec-Université Laval, Québec City, Canada
| | - Géraldine Delbès
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Martin Pelletier
- Axe Maladies infectieuses et immunitaires, Centre de recherche du CHU de Québec-Université Laval, Québec City, Canada
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Québec City, Canada
| | - Étienne Audet-Walsh
- Axe Endocrinologie-Néphrologie, Centre de recherche du CHU de Québec-Université Laval, Québec City, Canada
- Department of molecular medicine, Faculty of Medicine, Université Laval, Québec City, Canada
| | - Isabelle Plante
- Institut National de la Recherche Scientifique INRS, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada.
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Jonsson A, Korsgren O, Hedin A. Transcriptomic characterization of human pancreatic CD206- and CD206 + macrophages. Sci Rep 2025; 15:12037. [PMID: 40199933 PMCID: PMC11978877 DOI: 10.1038/s41598-025-96313-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. CD206- and CD206 + macrophages were sorted separately from pancreatic islets and exocrine tissue to high purity using flow cytometry, followed by RNA-seq analysis. Comparing CD206- with CD206 + macrophages, CD206- showed enrichment in histones, proliferation and cell cycle regulation, glycolysis and SPP1-associated immunosuppressive polarization while CD206 + showed enrichment in complement and coagulation-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Comparing islet CD206- with exocrine CD206-, enrichments in islet samples included two sets involved in immune regulation, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Fewer differences were found between CD206 + macrophages, with enrichments in islet samples including two IL2-RA related gene sets, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206 + macrophage populations within the human pancreas.
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Affiliation(s)
- Alexander Jonsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Anders Hedin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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46
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Parbin NS, Banik B. Copper peroxide incorporated BSA-NPs: a pH-responsive, self-supplying source of reactive oxygen species for cancer cell destruction via polarization of macrophages to the M1 phenotype. Chem Commun (Camb) 2025; 61:5605-5608. [PMID: 40105257 DOI: 10.1039/d5cc00216h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Herein, we produced self-assembled CuPer-BSA nanoparticles (NPs) formed as a result of incorporation of copper peroxide into bovine serum albumin (BSA) and serving as a self-supplying source of Cu2+ and H2O2 at biologically relevant acidic pH, and in these conditions activating a Fenton-type reaction to generate hydroxyl radicals (˙OH). ROS-induced polarization of RAW 264.7 macrophages to the M1 phenotype resulted in cellular secretions that showed significant anti-cancer efficacy against HeLa cells.
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Affiliation(s)
- Nursaima Sultana Parbin
- Department of Chemistry, Cotton University, Panbazar, Guwahati-781001, Assam, India.
- Department of Chemistry, Gauhati University, Gopinath Bordoloi Nagar, Guwahati-781014, Assam, India
| | - Bhabatosh Banik
- Department of Chemistry, Cotton University, Panbazar, Guwahati-781001, Assam, India.
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Zhang C, Wang H, Li X, Jiang Y, Sun G, Yu H. Enhancing antitumor immunity: the role of immune checkpoint inhibitors, anti-angiogenic therapy, and macrophage reprogramming. Front Oncol 2025; 15:1526407. [PMID: 40260303 PMCID: PMC12009726 DOI: 10.3389/fonc.2025.1526407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.
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Affiliation(s)
- Chong Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xinying Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuxin Jiang
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hanqing Yu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Chen L, Yin J, Xu K, Cui Y, Zhu S, Li T, Lv T, Song Y, Zhan P. Novel bioengineered drugs with immunotherapies for malignant pleural effusion: Remodulate tumor immune microenvironment and activate immune system. Crit Rev Oncol Hematol 2025; 211:104717. [PMID: 40194717 DOI: 10.1016/j.critrevonc.2025.104717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/09/2025] Open
Abstract
Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.
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Affiliation(s)
- Lu Chen
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jie Yin
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ke Xu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - YuTing Cui
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - SuHua Zhu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China.
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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49
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Zhao F, Su Y, Liu H, Zhao Y, Zhang L, Zhuge N, Zhao P, Ning Z, Kang Q, Liu D. Facile Nanocomposite Hydrogel Scaffold with Sustained Drug Release and Osteo-Immunomodulatory Effects to Enhance Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2025; 17:19286-19303. [PMID: 40116446 DOI: 10.1021/acsami.4c20390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
High-quality repair of critical bone defects without exogenous cells remains a major clinical challenge worldwide. Herein, we fabricated a nanocomposite hydrogel scaffold (ASA/MSNs/CSH) by incorporating aspirin (ASA)-loaded mesoporous silica nanoparticles (MSNs) into genipin-cross-linked chitosan hydrochloride (CSH). The resulting scaffold was designed to provide immunomodulatory support during the process of bone regeneration. ASA-loaded MSNs were encapsulated in CSH, forming a composite hydrogel capable of sustained drug release for over 35 days. This composite hydrogel was able to meet key criteria for physicochemical properties, mechanical strength, biocompatibility, and cell affinity. The study showed that the scaffolds could create a beneficial immune microenvironment through reducing inflammation and inducing macrophages toward M2-polarized phenotype in vitro. The scaffold also enhanced the osteogenesis of bone marrow mesenchymal stromal cells, as demonstrated by enhancing the alkaline phosphatase activity and the formation of calcium nodules. Meanwhile, the TGF-β/Smad pathway was identified as an important regulatory mechanism via Western blot analysis. Moreover, the critical size defect models were established in rat skulls, and the results demonstrated that the ASA/MSNs/CSH nanocomposite scaffolds exhibited adequate biocompatibility, superior anti-inflammatory effect, and an admirable capacity for bone regeneration in vivo.
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Affiliation(s)
- Fang Zhao
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Disease, Ji'nan 250012, P. R. China
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Yuxuan Su
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Disease, Ji'nan 250012, P. R. China
| | - Hong Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Disease, Ji'nan 250012, P. R. China
| | - Yong Zhao
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Liao Zhang
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Nanshan Zhuge
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Peng Zhao
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Zhaoliang Ning
- Department of Orthodontics, Tai'an Stomatological Hospital, Tai' an 271000, P. R. China
| | - Qi Kang
- Department of Radiology, the Affiliated Tai'an City Central Hospital of Qingdao University, Tai'an 271000, P. R. China
| | - Dongxu Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Disease, Ji'nan 250012, P. R. China
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50
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Jia B, Xu Y, Zhu X. Cognitive resilience in Alzheimer's disease: Mechanism and potential clinical intervention. Ageing Res Rev 2025; 106:102711. [PMID: 40021093 DOI: 10.1016/j.arr.2025.102711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
Alzheimer's disease (AD) is a globally recognized neurodegenerative disorder that severely impairs cognitive function and imposes substantial psychological and financial burdens on patients and their families. The hallmark pathological features of AD include progressive neurodegeneration, extracellular beta-amyloid (Aβ) plaque accumulation, and intracellular hyperphosphorylated tau protein tangles. However, recent studies have identified a subset of patients exhibiting cognitive resilience, characterized by a slower cognitive decline or the preservation of high cognitive function despite the presence of AD pathology. Cognitive resilience is influenced by a complex interplay of genetic, environmental, and lifestyle factors. In addition, cognitive resilience contributes to the new perspectives on the diagnosis and personalized treatment of AD. This review aims to provide a comprehensive analysis of current studies on cognitive resilience in AD and to explore future research directions of AD diagnosis and treatment.
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Affiliation(s)
- Bin Jia
- Department of Neurology, Nanjing Drum Tower Hospital, School of Medicine, Jiangsu University, Nanjing, Jiangsu, China; Department of Neurology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital, School of Medicine, Jiangsu University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China; Nanjing Neurology Clinical Medical Center, and Nanjing Drum Tower Hospital Brain Disease and Brain Science Center, Nanjing, China
| | - Xiaolei Zhu
- Department of Neurology, Nanjing Drum Tower Hospital, School of Medicine, Jiangsu University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Molecular Medicine and Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China; Nanjing Neurology Clinical Medical Center, and Nanjing Drum Tower Hospital Brain Disease and Brain Science Center, Nanjing, China.
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