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Venkatesh SB, Shetty SS. Role of genetic polymorphisms in residual ridge resorption of mandible - A scoping review. JAPANESE DENTAL SCIENCE REVIEW 2025; 61:22-30. [PMID: 40125334 PMCID: PMC11927421 DOI: 10.1016/j.jdsr.2025.02.002] [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: 04/27/2024] [Revised: 01/20/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Residual ridge (RR) refers to the clinical alveolar ridge that remains after the bone and soft tissues have healed following tooth extraction. This ridge undergoes resorption, which is most rapid during the first six months of post-extraction. Subsequently, bone resorption continues at a slower pace throughout life, leading to significant loss of jaw structure over time. This process is commonly known as residual ridge resorption (RRR). RRR is a major factor contributing to the loss of stability and retention, especially in mandibular complete dentures. Severe resorption of the maxillary and mandibular ridges can also lead to a sunken cheek appearance, poorly fitting and unstable dentures, and associated pain and discomfort. Though the etiology of residual ridge resorption remains unclear. It is believed that certain cytokines and individual genetic variations may influence the RRR process. Thus, reviewing the studies that discuss genetic association with the health and resorption of alveolar bone may give clear view on the etiology, help to define the risk and strategize preventive and personalized management of the disease. Hence, we undertook a scoping review to understand the potential genetic factors influencing the Residual ridge resorption (RRR). This review employed PRISMA-ScR extension protocols for scoping review. The results of the study provided significant association between genetic polymorphisms, especially of single gene nucleotide polymorphisms with mandibular residual ridge resorption. Hence understanding the genetic predisposition of patients can guide the clinicians in identifying patients at higher risk of RRR, enabling preventive measures, proactive intervention and careful designing of the prothesis.
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Affiliation(s)
- Swapna B. Venkatesh
- Department of Prosthodontics and Crown & Bridge, Manipal College of Dental Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India
| | - Smitha Sammith Shetty
- Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India
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Yang Y, Rao T, Jiang Y, Zhan Y, Cheng J, Yin Z, Ma K, Zhong X, Guo X, Yang S. Electroacupuncture ameliorates cognitive impairment and white matter injury in vascular dementia rats via activating HIF-1α/VEGF/VEGFR2 pathway. Neuroscience 2025; 573:364-380. [PMID: 40164280 DOI: 10.1016/j.neuroscience.2025.03.063] [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: 11/30/2024] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025]
Abstract
Vascular dementia (VaD) significantly impairs patients' quality of life and imposes a major social and economic burden. Electroacupuncture (EA), a contemporary modification of traditional acupuncture, has demonstrated potential in improving cognitive function in VaD, particularly when applied at the Shenting and Baihui. However, the underlying mechanisms remain inadequately understood. Elucidating how EA ameliorates cognitive deficits is critical for validating its clinical application and advancing non-pharmacological interventions for neurodegenerative disorders. This study aimed to investigate the neuroprotective mechanisms of electroacupuncture at these acupoints on cognitive function in VaD rats. VaD was induced in male Sprague-Dawley rats through bilateral common carotid artery occlusion (BCAO), with sham rats serving as controls. Rats were subsequently divided into three groups: BCAO, BCAO + EA and BCAO + EA + YC-1 (a HIF-1α inhibitor). Electroacupuncture was applied to the Shenting and Baihui. Cerebral blood flow (CBF) was measured using dynamic susceptibility contrast functional MRI, and cognitive recovery was evaluated through the Morris water maze. Immunohistochemical analysis quantified myelin repair and angiogenesis, while expression of HIF-1α, VEGF and VEGFR2 in white matter was quantified using PCR and Western blot. The results indicated that electroacupuncture improved learning and memory, increased CBF, enhanced myelin recovery and promoted angiogenesis in VaD rats. The expression of HIF-1α, VEGF and VEGFR2 in the white matter was significantly elevated in VaD rats. Electroacupuncture at Shenting and Baihui activates the HIF-1α/VEGF/VEGFR2 pathway, enhances angiogenesis, white matter perfusion and myelin repair, thereby restoring cognitive function in VaD rats.
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Affiliation(s)
- Yihan Yang
- The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Ting Rao
- The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China; Fujian Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou, China; Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, China
| | - Yijing Jiang
- Fujian Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou, China; Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, China
| | - Ying Zhan
- The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Jing Cheng
- Fujian Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou, China; Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, China
| | - Zihan Yin
- The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Ke Ma
- The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xiaoling Zhong
- Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinran Guo
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu 226001, China
| | - Shanli Yang
- Fujian Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou, China; Fujian Key Laboratory of Rehabilitation Technology, Fuzhou, China.
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Lu X, Friedrich LJ, Efferth T. Natural products targeting tumour angiogenesis. Br J Pharmacol 2025; 182:2094-2136. [PMID: 37680009 DOI: 10.1111/bph.16232] [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: 06/23/2023] [Revised: 08/15/2023] [Accepted: 08/28/2023] [Indexed: 09/09/2023] Open
Abstract
Tumour angiogenesis is the formation of new blood vessels to support the growth of a tumour. This process is critical for tumour progression and metastasis, making it an attractive approach to cancer therapy. Natural products derived from plants, animals or microorganisms exert anti-angiogenic properties and can be used to inhibit tumour growth and progression. In this review, we comprehensively report on the current status of natural products against tumour angiogenesis from four perspectives until March 2023: (1) the role of pro-angiogenic factors and antiangiogenic factors in tumour angiogenesis; (2) the development of anti-tumour angiogenesis therapy (monoclonal antibodies, VEGFR-targeted small molecules and fusion proteins); (3) the summary of anti-angiogenic natural agents, including polyphenols, polysaccharides, alkaloids, terpenoids, saponins and their mechanisms of action, and (4) the future perspectives of anti-angiogenic natural products (bioavailability improvement, testing of dosage and side effects, combination use and discovery of unique natural-based compounds). Our review aims to better understand the potential of natural products for drug development in inhibiting tumour angiogenesis and further aid the effective transition of these outcomes into clinical trials. LINKED ARTICLES: This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.
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Affiliation(s)
- Xiaohua Lu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Lara Johanna Friedrich
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz, Germany
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Li JZ, Zhan X, Sun HB, Chi C, Zhang GF, Liu DH, Zhang WX, Sun LH, Kang K. L-arginine from elder human mesenchymal stem cells induces angiogenesis and enhances therapeutic effects on ischemic heart diseases. World J Stem Cells 2025; 17:103314. [DOI: 10.4252/wjsc.v17.i4.103314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/06/2025] [Accepted: 03/17/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapy may be a future treatment for myocardial infarction (MI). However, few studies have assessed the therapeutic efficacy of adipose tissue-derived MSCs (ADSCs) obtained from elderly patients in comparison to that of bone marrow-derived MSCs (BMSCs) from the same elderly patients. The metabolomics results revealed a significantly higher L-arginine excretion from aged ADSCs vs BMSCs in hypoxic conditions. This was hypothesized as the possible mechanism that ADSCs showed an improved angiogenic capacity and enhanced the therapeutic effect on ischemic heart diseases.
AIM To investigate the role of L-arginine in enhancing angiogenesis and cardiac protection by comparing ADSCs and BMSCs in hypoxic conditions for MI therapy.
METHODS Metabolomic profiling of supernatants from ADSCs and BMSCs under hypoxic conditions were performed. Then, arginine succinate lyase (ASL) overexpression and short hairpin RNA plasmid were prepared and transfected into BMSCs. Subsequently, in vitro wound healing and Matrigel tube formation assays were used to verify the proangiogenetic effects of ADSC positive control, BMSCs, BMSCs ASL short hairpin RNA, BMSCs ASL overexpressed, and BMSC negative control on cocultured human umbilical vein endothelial cells. All sample sizes, which were determined to meet the statistical requirements and be greater than 3, were established on the basis of previously established literature standards. The protein levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor, etc. were detected. In vivo, the five types of cells were transplanted into the infarcted area of MI rat models, and the therapeutic effects of the transplanted cells were evaluated by echocardiography on cardiac function and by Masson’s staining/terminal-deoxynucleotidyl transferase mediated nick end labeling assay/immunofluorescence detection on the infarcted area.
RESULTS Metabolomic analysis showed that L-arginine was increased. Using ASL gene transfection, we upregulated the production of L-arginine in aged patient-derived BMSCs in vitro, which in turn enhanced mitogen activated protein kinase and VEGF receptor 2 protein expression, VEGF and basic fibroblast growth factor secretion, and inductive angiogenesis to levels comparable to donor-matched ADSCs. After the cell transplantation in vivo, the modified BMSCs as well as ADSCs exhibited decreased apoptotic cells, enhanced vessel formation, reduced scar size, and improved cardiac function in the MI rat model. The therapeutic efficacy decreased by inhibiting L-arginine synthesis.
CONCLUSION L-arginine is important for inducing therapeutic angiogenesis for ADSCs and BMSCs in hypoxic conditions. ADSCs have higher L-arginine secretion, which leads to better angiogenesis induction and cardiac protection. ADSC transplantation is a promising autologous cell therapy strategy in the context of the present aging society.
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Affiliation(s)
- Jian-Zhong Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Key Laboratory of Cell Transplantation of the National Ministry of Public Health, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710014, Shaanxi Province, China
| | - Xu Zhan
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Key Laboratory of Cell Transplantation of the National Ministry of Public Health, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Hao-Bo Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Key Laboratory of Cell Transplantation of the National Ministry of Public Health, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Chao Chi
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Guo-Fu Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Dong-Hui Liu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wen-Xi Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Li-Hua Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University and Pharmacology Department of Pharmacy College of Harbin Medical University, Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Kai Kang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Key Laboratory of Cell Transplantation of the National Ministry of Public Health, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin 150001, Heilongjiang Province, China
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Akbarian M, Kianpour M, Yu KW, Sidow SJ, Vashaee D, Tayebi L. Synergistic Prevascularization with Proangiogenic Silica Nanoparticles and VEGF-Mimetic Aptamer in Tailored GelMA Hydrogels. ACS APPLIED BIO MATERIALS 2025. [PMID: 40258621 DOI: 10.1021/acsabm.4c01911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2025]
Abstract
Angiogenesis is a crucial and challenging requirement for the regeneration and repair of damaged tissues, particularly for critical-sized ones. To address this challenge, in this study, we fabricated a cell-communicating gelatin methacryloyl (GelMA) hydrogel using core-shell silica nanoparticles conjugated with roxadustat (FG-4592) and a VEGF-mimetic aptamer (Apt02). This hydrogel promotes tube formation and prevascularization synergistically through both extracellular and intracellular pathways in human umbilical vein endothelial cells (HUVEC), with FG-4592 acting via the extracellular pathway and Apt02 via the intracellular pathway. Fluorophore carbon quantum dot was synthesized and used as a core for constructing core-shell amine-functionalized silica nanoparticles (CQD@MSN-NH2). Using human serum albumin (HSA) as a protein linker, FG-4592 was conjugated on the surface of the nanoparticles to the finalized CQD@MSN@HSA@FG-4592 (CMHF) theranostic proangiogenic nanoparticle. Several techniques were used to characterize structural and cytotoxic properties of CMHF nanoparticles. On the other hand, Apt02 was incorporated into the GelMA hydrogel to induce angiogenesis extracellularly. Results showed that the CMHF nanoparticle and Apt02 are cyto-compatible in periodontal ligament fibroblasts (PDLF) and HUVEC. The HUVEC tube formation assay indicated that 1.0 μM Apt02, 20 μM FG-4592, and 35 μg/mL of CMHF individually induced angiogenesis in HUVEC when 10 ng/mL VEGF was used as a positive control. Western blot and quantitative polymerase chain reaction assays of four genes revealed Apt02 to have an extracellular mechanism of action while FG-4592 increases cellular concentration of the hypoxia-inducible factor-1α (Hif-1α) transcription factor intercellularly and recruits HUVEC to form tube-like vessels both in vitro and ex ovo. In summary, our study introduces an injectable hydrogel containing a blend of 5% GelMA, 1.0 μM Apt02, and 35 μg/mL CMHF nanoparticles, which effectively enhances angiogenesis by activating both extracellular (through VEGFR) and intracellular (by Hif-1α overexpression) pathways and is more effective when targeting only one pathway.
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Affiliation(s)
- Mohsen Akbarian
- School of Dentistry, Marquette University, Milwaukee, Wisconsin 53233, United States
| | - Maryam Kianpour
- School of Dentistry, Marquette University, Milwaukee, Wisconsin 53233, United States
| | - Kevin W Yu
- Department of Surgical and Diagnostic Sciences, School of Dentistry, Marquette University, Milwaukee, Wisconsin 53233, United States
| | - Stephanie J Sidow
- Department of Surgical and Diagnostic Sciences, School of Dentistry, Marquette University, Milwaukee, Wisconsin 53233, United States
| | - Daryoosh Vashaee
- Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, North Carolina 27606, United States
- Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina 27606, United States
| | - Lobat Tayebi
- School of Dentistry, Marquette University, Milwaukee, Wisconsin 53233, United States
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Zhang L, Lin Y, Hu L, Wang Y, Hu C, Shangguan X, Tang S, Chen J, Hu P, Chen ZS, Ke ZF, Chen Z. Transient intracellular expression of PD-L1 and VEGFR2 bispecific nanobody in cancer cells inspires long-term T cell activation and infiltration to combat tumor and inhibit cancer metastasis. Mol Cancer 2025; 24:119. [PMID: 40253320 PMCID: PMC12008900 DOI: 10.1186/s12943-025-02253-6] [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: 11/04/2024] [Accepted: 01/30/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND PD-L1, an immune checkpoint inhibitor, and VEGFR2, essential for cancer metastasis, play pivotal roles in tumorigenesis. However, their miniature bispecific intracellular nanobodies for combining check-point blockade and anti-metastasis anticancer therapy remain underexplored. METHODS The intrabodies were developed using gene cloning technology. Specificity of the intrabodies was testified using Western blot, co-immunoprecipitation (co-IP) analysis, antibody competitive binding assay, flow cytometry analysis, etc. Checkpoint blockade was demonstrated using antibody-antigen competitive binding assay. Cancer cell migration was determined using scratch assay. Combined anti-cancer therapeutic efficacy of FAP1V2 was determined in vivo of mice models. The PD-1hi immune cells, TCR βhi and CD25hi T-cells were analyzed by flow cytometry, and cancer cell metastasis was performed using immune-fluorescence analysis on lung and liver tissues. Transcriptome analysis was performed to explore signaling pathways associated with the enhanced anticancer efficiency. RESULTS Bispecific intrabody FAP1V2 fused with antibody VH regions, was successfully developed and verified with its ability to target and block human and mouse PD-L1 and VEGFR2, inhibiting cancer cell binding to PD-1 and reducing their migratory capacity. Compared to the other treatment, two-rounds of transient FAP1V2 expression in LLC cells in experimental mice models achieved remarkable tumor inhibition, which brought about complete immune inhibition on growth of secondary-round of LLC tumor in 1/6 of the tested mice, inspired long-term activation of TCR βhi T cells and increased their infiltration to tumors, inhibited the emergence of PD-1hi immune cells, indicating prevented T cell depletion. The elevated CD25 expression also supported the success in enhancing immune response reported by elevated T cell activity in spleen. Transcriptome analysis identified critical intracellular pathways regulated by the concurrent blockade of PD-L1 and VEGFR2. CONCLUSION PD-L1 and VEGFR2- bispecific VH intracellular nanobody was highly biocompatible and showed the potential for combined anti-cancer therapy through long-term immune activation mediated by PD-L1/PD-1 checkpoint blockade and anti-metastasis mediated by VEGFR2 blockade.
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Affiliation(s)
- Lei Zhang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yunfeng Lin
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Li Hu
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Yanan Wang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Chaohua Hu
- National Engineering Research Center for Sugarcane, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Xinyi Shangguan
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
- College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Shuzhi Tang
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
| | - Jincan Chen
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
| | - Ping Hu
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Zun-Fu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China.
| | - Zhuo Chen
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350108, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Liu X, Zhang J, Yi T, Li H, Tang X, Liu D, Wu D, Li Y. Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies. Biomark Res 2025; 13:62. [PMID: 40251641 PMCID: PMC12007322 DOI: 10.1186/s40364-025-00779-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: 11/26/2024] [Accepted: 04/13/2025] [Indexed: 04/20/2025] Open
Abstract
Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.
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Affiliation(s)
- Xueru Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Juan Zhang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Ting Yi
- Department of Trauma Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Hui Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Xing Tang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Dan Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Daichao Wu
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
| | - Yukun Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China.
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Teufelsbauer M, Stickler S, Eggerstorfer MT, Hammond DC, Lang C, Hamilton G. Markers for the angiogenic potential of fat grafts. Wien Klin Wochenschr 2025:10.1007/s00508-025-02532-8. [PMID: 40232500 DOI: 10.1007/s00508-025-02532-8] [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: 01/20/2025] [Accepted: 03/19/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND Fat grafting is widely utilized in reconstructive and esthetic plastic surgery, typically with minimal complications. Nevertheless, the occurrence of fat necrosis is dependent on the technique used for fat extraction, tissue processing and the volume of the graft. The longevity of the graft critically depends on the presence of adipose-derived stromal cells (ADSC) and their promotion of a reconstituted vascular supply. OBJECTIVE This study seeks to determine whether there are differences in 13 angiogenesis-related adipokines based on their grouping by vascular endothelial growth factor (VEGF) expression levels. METHODS The expression of 14 adipokines related to angiogenesis in 12 cultured ADSCs was evaluated using Human Adipokine Profiler kits, which simultaneously detect 58 mediators. Adipokines of the high and low VEGF expression groups were evaluated for their expression of the remaining 13 angiogenic proteins. RESULTS We were able to show that there are significant differences in VEGFlow and VEGFhigh ADSCs regarding fibroblast growth factor 19 (p = 0.043) and insulin like growth factor binding protein 3 (p = 0.028). Furthermore, ADSCs with differentially highly expressed VEGF show a different pattern in the amount of protein levels regarding the 13 other adipokines observed. CONCLUSION The VEGF has been described as a key angiogenic factor in fat grafts that may be linked to successful grafting; however, two of the fat samples analyzed exhibited high expression of VEGF but lacked significant co-expression of a range of other angiogenic factors. Thus, the assessment of the expression of predisposing mediators for graft angiogenesis for wound healing or contouring should include further angiogenesis promoters aside VEGF as parameters.
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Affiliation(s)
- Maryana Teufelsbauer
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, 1090, Vienna, Austria
| | - Sandra Stickler
- Institute of Pharmacology, Medical University of Vienna, Waehringerstraße 13A, 1090, Vienna, Austria
| | | | - Dennis C Hammond
- Center for Breast and Body Contouring, 49546, Grand Rapids, MI, USA
| | - Clemens Lang
- Department of Trauma Surgery, Hospital Donaustadt, 1220, Vienna, Austria
| | - Gerhard Hamilton
- Institute of Pharmacology, Medical University of Vienna, Waehringerstraße 13A, 1090, Vienna, Austria.
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Murakami J, Tanaka T, Tani K, Ueno K, Yamamoto N, Yoshimine S, Purba MS, Sunahara H, Hoshii Y, Hamano K. Pilot study of autologous multilayered fibroblast sheet transplantation for reinforcing bronchial stump healing after pulmonary lobectomy in a canine model. Gen Thorac Cardiovasc Surg 2025:10.1007/s11748-025-02145-y. [PMID: 40232674 DOI: 10.1007/s11748-025-02145-y] [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: 03/01/2025] [Accepted: 04/02/2025] [Indexed: 04/16/2025]
Abstract
OBJECTIVE Bronchopleural fistula (BPF) is a serious complication that can occur after lung resection. This pilot study aimed to evaluate the effectiveness of autologous multilayered fibroblast sheet transplantation in reinforcing bronchial stump healing after lung resection in a canine model. METHODS Four beagles underwent left caudal lobe excision. Two dogs received autologous multilayered fibroblast sheet transplantation on the stapled bronchial stump, while two served as controls. Fibroblast sheets generated from autologous oral mucosal fibroblasts were optimized for growth factor secretion. Fourteen days after lobectomy, the bronchial stumps were histologically and immunohistochemically analyzed to assess connective tissue formation, blood vessel formation, and inflammation. RESULTS Fibroblast sheets secreted high levels of pro-healing and pro-angiogenic factors in vitro. No adverse events or serious postoperative complications associated with the fibroblast sheet transplantation were observed. The cell sheet-transplanted group exhibited a layered structure of newly formed tissue around the bronchial stump. This was associated with enhanced blood vessel formation, as indicated by increased CD31-positive cells and high VEGF levels. The untreated control group showed a localized nodule of inflammation near the bronchial stump, which lacked evidence of blood vessel formation. CONCLUSION Autologous multilayered fibroblast sheet transplantation promoted connective tissue formation and blood vessel growth around the bronchial stump after lobectomy in a canine model. These findings suggest that fibroblast sheet transplantation is a promising therapeutic approach for preventing BPF after lung resection.
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Affiliation(s)
- Junichi Murakami
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
- Division of Advanced Cell Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan.
| | - Toshiki Tanaka
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Kenji Tani
- Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
- Division of Translational Research for One Medicine, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| | - Koji Ueno
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
- Division of Advanced Cell Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
| | - Naohiro Yamamoto
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Sota Yoshimine
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
| | - Melpa Susanti Purba
- Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Hiroshi Sunahara
- Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Yoshinobu Hoshii
- Department of Diagnostic Pathology, Yamaguchi University Hospital, Yamaguchi, Japan
| | - Kimikazu Hamano
- Department of Surgery and Clinical Science, Division of Chest Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan
- Division of Advanced Cell Therapy, Research Institute for Cell Design Medical Science, Yamaguchi University, Yamaguchi, Japan
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10
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Li F, Song L, He Y, Chen P, Wang J, Zeng M, Li C, Chen J, Chen H, Guo Q, Fan J, Huang X, Wang Q, Zhang Q. FLT1-enriched extracellular vesicles induce a positive feedback loop between nasopharyngeal carcinoma cells and endothelial cells to promote angiogenesis and tumour metastasis. Oncogene 2025:10.1038/s41388-025-03389-x. [PMID: 40223024 DOI: 10.1038/s41388-025-03389-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 03/29/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Distant metastasis is one of the main reasons for treatment failure in nasopharyngeal carcinoma (NPC) patients. Tumour angiogenesis is a key basis for the distant metastasis of NPC. However, the molecular mechanisms underlying the mutual interaction between endothelial and NPC cells in tumour angiogenesis and NPC metastasis are still unclear. Here, we found that extracellular vesicles (EVs) mediate intercellular communication between endothelial cells and NPC cells, thereby promoting NPC cell migration, invasion, colony formation, and angiogenesis. Further experiments indicated that EV-mediated information exchange between endothelial cells and NPC cells upregulated the expression of the vascular endothelial growth factor receptor FLT1 in both types of cells. Mechanistically, FLT1-enriched EVs promoted NPC metastasis through the PI3K/AKT pathway and increased tumour angiogenesis, tumour growth, and distant lung and liver metastasis of NPC in xenografted mice. This effect was achieved through the delivery and upregulation of FLT1 in both endothelial and NPC cells. Thus, our findings reveal that FLT1-enriched EVs induce a positive feedback loop between NPC cells and endothelial cells to promote tumour angiogenesis and tumour metastasis. These results increase our understanding of the intricate interplay between tumour angiogenesis and distant metastasis and have major implications for the diagnosis and management of NPC patients with increased levels of FLT1-enriched EVs.
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Affiliation(s)
- Fei Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Lin Song
- School of Life Sciences, Huizhou University, Huizhou, China
| | - Yue He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peiling Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiasheng Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Maozhen Zeng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Chunmou Li
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Junru Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Haisheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qiqi Guo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiaxi Fan
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xuan Huang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qi Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Qing Zhang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
- Research Institute of Sun Yat-sen University in Shenzhen, Shenzhen, China.
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11
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Yang S, Zhang G, Hong X, Li T, Liu Y, Hong H, Liu L, Wang H, Wu S, Wang Y, Wang P, Sun Q, Liu C. Effects of maternal PM 2.5 exposure during pregnancy on cardiovascular maldevelopment in rat offspring. Reprod Toxicol 2025; 135:108906. [PMID: 40220971 DOI: 10.1016/j.reprotox.2025.108906] [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: 01/11/2025] [Revised: 03/24/2025] [Accepted: 04/02/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Epidemiological studies suggest a link between maternal exposure to PM2.5 during pregnancy and a higher incidence of fetal cardiovascular abnormalities. However, experimental data on the underlying mechanisms remain scarce. OBJECTIVE This study aims to explore the effects of maternal PM2.5 exposure during pregnancy on fetal cardiovascular maldevelopment in a rat model. METHODS Twenty-eight pregnant rats were divided into control and PM2.5-exposed groups according the exposure doses (N = 7 per group). Rats were administered with PM2.5 suspensions corresponding to 0, 2.6, 5.5, and 11 μg/d, respectively, during gestation. On gestational day 21, neonatal hearts were collected, and levels of cardiac transcription factors (Tbx2, Tbx20, Hand2 and Gata6), MMP9, TN-C, VEGF-A, NF-κB, apoptotic markers (Bax/Bcl-2 ratio), catalase (CAT), and lipid metabolism indicators were measured. RESULTS In the 11 μg/d group, the mRNA levels of Tbx2, Tbx20, Hand2, Gata6, MMP9, TN-C and VEGF-A, the protein levels of Tbx2, Hand2, and TN-C, and blood CAT activity were significantly reduced (P < 0.05). Conversely, NF-κB, Bax/Bcl-2, and serum markers of dyslipidemia (TC, TG, LDH, LDL-C/HDL-C) were significantly elevated (P < 0.05). Additionally, TN-C and Hand2 mRNA levels were reduced in the 2.6 μg/d group, and LDH level was increased in the 5.5 μg/d group (P < 0.05). CONCLUSIONS Maternal PM2.5 exposure during pregnancy is associated with fetal cardiovascular maldevelopments, possibly through the changes of cardiac transcription factors, vascular dysfunction, oxidative stress, apoptosis, and abnormalities of lipid metabolism.
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Affiliation(s)
- Shengying Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan Province, China; Department of Obstetrics and Gynecology, Dongfang Affiliated Hospital of Xiamen University, 900 Hospital of the Joint Logistics Team, Fuzhou, Fujian Province, China
| | - Guiming Zhang
- The People's Hospital of Huili, Huili, Sichuan Province, China
| | - Xinru Hong
- Department of Obstetrics and Gynecology, Dongfang Affiliated Hospital of Xiamen University, 900 Hospital of the Joint Logistics Team, Fuzhou, Fujian Province, China
| | - Tao Li
- Department of Obstetrics and Gynecology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan Province, China
| | - Yang Liu
- Department of Obstetrics and Gynecology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan Province, China
| | - Huangfeng Hong
- Department of Obstetrics and Gynecology, Dongfang Affiliated Hospital of Xiamen University, 900 Hospital of the Joint Logistics Team, Fuzhou, Fujian Province, China
| | - Lina Liu
- Department of Obstetrics and Gynecology, Dongfang Affiliated Hospital of Xiamen University, 900 Hospital of the Joint Logistics Team, Fuzhou, Fujian Province, China
| | - Hailong Wang
- Department of Basic Medicine, School of Medicine, Xiamen University, Xiamen, Fujian Province, China
| | - Shuiping Wu
- College of the Environment and Ecology, Xiamen University, Xiamen, Fujian Province, China
| | - Yulan Wang
- Fuzhou Changle District Hospital, Fuzhou, Fujian Province, China
| | - Ping Wang
- Department of Pediatrics, the Military Hospital of 92435 Unit of PLA, Ningde, Fujian Province, China
| | - Qinghua Sun
- School of Public Health and Joint China-US Research Center for Environment and Pulmonary Diseases, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Chaobin Liu
- The Fourth Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, China International Science & Technology Cooperation Base for Environmental Factors on Early Development, Fuzhou, Fujian Province, China.
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12
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Brunmaier LAE, Ozdemir T, Walker TW. Angiogenesis: Biological Mechanisms and In Vitro Models. Ann Biomed Eng 2025:10.1007/s10439-025-03721-2. [PMID: 40210793 DOI: 10.1007/s10439-025-03721-2] [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: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.
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Affiliation(s)
- Laura A E Brunmaier
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Tugba Ozdemir
- Nanoscience and Biomedical Engineering Department, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA
| | - Travis W Walker
- Karen M. Swindler Department of Chemical and Biological Engineering, South Dakota School of Mines & Technology, 501 E St. Joseph St., Rapid City, SD, 57701, USA.
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13
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Xu MZ, Ke F, Chai JP, A JD, Tan QL. Progress on the HIF-1α/VEGF/VEGFR2 signal pathway in hepatic alveolar echinococcosis. Front Oncol 2025; 15:1553125. [PMID: 40265025 PMCID: PMC12011584 DOI: 10.3389/fonc.2025.1553125] [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: 12/30/2024] [Accepted: 03/17/2025] [Indexed: 04/24/2025] Open
Abstract
Alveolar echinococcosis (AE), a lethal parasitic zoonosis mimicking malignant tumors, progresses via hepatic infiltration and metastatic spread, causing multiorgan failure. Despite its clinical resemblance to cancer, molecular drivers of its aggressiveness remain poorly defined. Recent studies highlight perilesional angiogenesis as pivotal for lesion invasiveness, mediated by VEGF-driven pathological vascularization. VEGF not only fuels parasitic proliferation by creating nutrient-rich microenvironments but also engages crosstalk with host-parasite interactions, including immune evasion by Echinococcus multilocularis, germinal layer hyperplasia, and periparasitic inflammation.Targeting the HIF-1α/VEGF/VEGFR2 axis emerges as a promising therapeutic strategy. Mechanistically, VEGF/VEGFR2 blockade may simultaneously disrupt angiogenesis-dependent parasitic expansion and survival pathways. Preclinical evidence shows that inhibiting HIF-1α (VEGF's upstream regulator) suppresses metacestode proliferation and tissue invasion by starving lesions of vascular support while modulating immune-inflammatory responses. This dual action addresses both parasitic resource acquisition and host defence subversion.This review synthesizes molecular insights into HIF-1α/VEGF-mediated pathogenesis with clinical observations, proposing anti-angiogenic therapy as a rational adjunct to current treatments. By delineating VEGF's role in sustaining parasitic metabolic demands and immune regulation, we underscore the translational potential of pathway-specific inhibitors. Such approaches could mitigate limitations of conventional therapies (e.g., benzimidazoles), particularly for advanced-stage AE with microvascular proliferation. Systematic analysis of angiogenesis signalling networks advances our understanding of AE's "parasitic cancer" paradigm while guiding development of targeted interventions to improve patient outcomes.
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Affiliation(s)
- Meng-Zhao Xu
- The Graduate School, Qinghai University, Xining, China
| | - Fei Ke
- The Graduate School, Qinghai University, Xining, China
| | - Jin-Ping Chai
- Department of Internal Medicine-Cardiovascular, Qinghai Provincial People’s Hospital, Xining, China
| | - Ji-De A
- Department of Hepatic Hydatidosis, Qinghai Provincial People’s Hospital, Xining, China
| | - Qing-Long Tan
- Department of General Surgery, Qinghai Provincial People’s Hospital, Xining, China
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14
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Ferroni M, De Gaetano F, Zonfrillo M, Bono N, Cereda MG, Pierimarchi P, Sferrazza G, Candiani G, Boschetti F. Assessment of magnesium-based components for intraocular drug delivery by in vitrobiocompatibility and drug-device interaction. Biomed Mater 2025; 20:035012. [PMID: 40101366 DOI: 10.1088/1748-605x/adc21f] [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: 06/27/2024] [Accepted: 03/18/2025] [Indexed: 03/20/2025]
Abstract
The development of magnesium-based intraocular drug delivery devices holds significant promise for biomedical applications, particularly in treating wet age-related macular degeneration (AMD) using vascular endothelial growth factor inhibitors such as bevacizumab. Magnesium's rapid degradation, which can be finely tuned to achieve the controlled release required for AMD treatment, along with its well-established biocompatibility and biodegradable properties, positioning it as an ideal material for these applications. The study aimed to evaluate magnesium's potential as a carrier for ocular drug delivery systems by demontrating the stability of monoclonal antibodies, specifically bevacizumab, in the presence of magnesium corrosion products and the biocompatibility of these products with various cell lines, including murine fibroblasts (3T3), rat retinal Müller cells, and human retinal pigment epithelial cells (ARPE19). The stability of bevacizumab with pure magnesium (Mg) was investigated through an indirect enzyme-linked immunosorbent assay protocol, developed and customized for this specific aim. The biocompatibility of Mg corrosion products was assessed by toxicological evaluations through MTT and Trypan Blue Viability assays, along with cell cycle analysis. Results demonstrated no significant impact of Mg corrosion products on bevacizumab stability, with changes in mean values consistently below or equal to 10%. Furthermore, Mg extracts showed minimal cytotoxicity, as metabolic activity exceeded 80% across all cell lines, classified as Grade 0/1 cytotoxicity under ISO 10993-5 standards. Cell viability, proliferation, and morphology remained unaffected for up to 72 h of exposure. This study provides the firstin vitroevaluation of bevacizumab's stability in the presence of magnesium corrosion products and its biocompatibility with retinal cell lines, laying the foundation for future ophthalmic research and underscoring magnesium's potential as a material for intraocular drug delivery systems.
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Affiliation(s)
- Marco Ferroni
- LaBS, Chemistry, Materials and Chemical Engineering Department 'Giulio Natta', Politecnico di Milano, Piazza L. da Vinci 32, 20133 Milan, Italy
- MgShell S.r.l., Viale Romagna 59, 20133 Milan, Italy
| | - Francesco De Gaetano
- LaBS, Chemistry, Materials and Chemical Engineering Department 'Giulio Natta', Politecnico di Milano, Piazza L. da Vinci 32, 20133 Milan, Italy
- MgShell S.r.l., Viale Romagna 59, 20133 Milan, Italy
| | - Manuela Zonfrillo
- Institute of Translational Pharmacology, National Research Council, Via del Fosso del Cavaliere 100, 00133 Rome, Italy
| | - Nina Bono
- genT_LΛB, Chemistry, Materials and Chemical Engineering Department 'Giulio Natta', Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy
| | | | - Pasquale Pierimarchi
- Institute of Translational Pharmacology, National Research Council, Via del Fosso del Cavaliere 100, 00133 Rome, Italy
| | - Gianluca Sferrazza
- Institute of Translational Pharmacology, National Research Council, Via del Fosso del Cavaliere 100, 00133 Rome, Italy
- Department of Biomedical Science, National Council Research Council, Rome, Piazzale Aldo Moro 7, 00185 Rome, Italy
| | - Gabriele Candiani
- genT_LΛB, Chemistry, Materials and Chemical Engineering Department 'Giulio Natta', Politecnico di Milano, Via Mancinelli 7, 20131 Milan, Italy
| | - Federica Boschetti
- LaBS, Chemistry, Materials and Chemical Engineering Department 'Giulio Natta', Politecnico di Milano, Piazza L. da Vinci 32, 20133 Milan, Italy
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15
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Zhou K, Liu Y, Tang C, Zhu H. Pancreatic Cancer: Pathogenesis and Clinical Studies. MedComm (Beijing) 2025; 6:e70162. [PMID: 40182139 PMCID: PMC11965705 DOI: 10.1002/mco2.70162] [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: 06/24/2024] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 04/05/2025] Open
Abstract
Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.
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Affiliation(s)
- Kexun Zhou
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yingping Liu
- Department of RadiotherapyCancer HospitalChinese Academy of Medical SciencesBeijingChina
| | - Chuanyun Tang
- The First Clinical Medical College of Nanchang UniversityNanchang UniversityNanchangChina
| | - Hong Zhu
- Department of Medical OncologyCancer CenterWest China HospitalSichuan UniversityChengduChina
- Division of Abdominal Tumor Multimodality TreatmentCancer CenterWest China HospitalSichuan UniversityChengduChina
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16
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Platt JR, Pennycook S, Muthoo CE, Westwood AC, Frood R, Beggs AD, Scarsbrook A, Seligmann JF, Tolan DJM. Colon cancer biology and treatment in the era of precision oncology: A primer for Radiologists. Eur J Radiol 2025; 185:112000. [PMID: 39978239 DOI: 10.1016/j.ejrad.2025.112000] [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: 12/20/2024] [Revised: 02/07/2025] [Accepted: 02/12/2025] [Indexed: 02/22/2025]
Abstract
In the era of precision oncology, systemic therapies for colon cancer are becoming increasingly biomarker-led, with implications for patients in the neoadjuvant, adjuvant and metastatic settings. As the landscape for colon cancer treatment evolves and becomes more complex, it is important that all members of the multidisciplinary team keep abreast of developments to ensure the most effective care is delivered to patients. As core members of the colorectal multidisciplinary team, Radiologists play a central role throughout the patient journey. This review serves as an educational summary of current and emerging treatment pathways in colon cancer, standards for biomarker testing, mechanisms of action for key drugs, important treatment-related complications, relevant tumour biology that underpins patterns of disease and treatment response, and the specific implications systemic therapies have for cancer imaging and Radiologists. We also highlight the increasing role for radiology in patient stratification and the importance of imaging biomarkers. It is crucial that Radiologists understand the current landscape of colon cancer treatment and emerging strategies on the horizon in clinical trials. Only through engagement across the wider multidisciplinary team will we deliver true personalised medicine for patients with colon cancer.
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Affiliation(s)
- James R Platt
- Division of Oncology, Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Stephanie Pennycook
- Department of Medical Oncology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Chand E Muthoo
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
| | - Alice C Westwood
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Russell Frood
- Leeds Institute of Clinical Trials Research, School of Medicine, University of Leeds, Leeds, UK.
| | - Andrew D Beggs
- Department of Cancer and Genomics, University of Birmingham, Birmingham, UK.
| | - Andrew Scarsbrook
- Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Jenny F Seligmann
- Division of Oncology, Leeds Institute of Medical Research at St James's, School of Medicine, University of Leeds, Leeds, UK.
| | - Damian J M Tolan
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
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17
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Nahm WJ, Falanga V. The Adverse Impact of Tyrosine Kinase Inhibitors on Wound Healing and Repair. Int Wound J 2025; 22:e70513. [PMID: 40251464 PMCID: PMC12008022 DOI: 10.1111/iwj.70513] [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: 08/21/2024] [Revised: 02/20/2025] [Accepted: 04/02/2025] [Indexed: 04/20/2025] Open
Abstract
Tyrosine kinase inhibitors (TKIs) can treat various cancers, primarily through their antiangiogenic effects. However, as angiogenesis is crucial for successful wound healing, TKIs may adversely impact wound repair. This review analysed all 63 FDA-approved TKIs and identified evidence for wound healing and repair implications in 24 agents. The primary mechanism contributing to impaired wound healing appears to be the inhibition of vascular endothelial growth factor receptors, with secondary targets, such as epidermal growth factor receptors and platelet-derived growth factor receptors, potentially playing a role. Information from safety package inserts, preclinical studies, case reports and clinical trials suggests that these TKIs can cause delayed or impaired wound healing. The safety information generally recommends discontinuing treatment for at least one to 2 weeks before elective surgery and resuming treatment only after adequate wound healing has occurred. Neoadjuvant therapy with TKIs may be feasible if sufficient time is allowed between the cessation of the TKI and the onset of surgery. As the use of TKIs continues to increase, healthcare professionals should be aware of their potential impact on wound healing and take appropriate precautions to minimise the risk of wound-related complications.
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Affiliation(s)
- William J. Nahm
- New York University Grossman School of MedicineNew YorkNew YorkUSA
| | - Vincent Falanga
- Department of DermatologyBoston University Chobanian and Avedisian School of MedicineBostonMassachusettsUSA
- Department of Biochemistry & Cell BiologyBoston University Chobanian and Avedisian School of MedicineBostonMassachusettsUSA
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18
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Li K, Wang Y, Huang P. Association of Four VEGFA Gene Variants with Rheumatoid Arthritis Risk: A Meta-analysis and Trial Sequential Analysis. Biochem Genet 2025; 63:984-1013. [PMID: 38814384 DOI: 10.1007/s10528-024-10834-1] [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: 12/21/2023] [Accepted: 05/08/2024] [Indexed: 05/31/2024]
Abstract
The association between rheumatoid arthritis (RA) risk and specific variants of the Vascular Endothelial Growth Factor A (VEGFA) gene remains contentious. This study sought to elucidate the correlations between RA risk and several VEGFA gene variants, including VEGFA-634 (rs2010963), VEGFA-C936 (rs3025039), VEGFA-2578 (rs699947), VEGFA-1154 (rs1570360), through a comprehensive meta-analysis. We systematically reviewed literature from the Cochrane Library database, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and the Wanfang Data Information Service platform to gather relevant case-control studies. Using odds ratio (OR) and 95% confidence interval (95% CI), we analyzed the data to assess potential correlations. Sensitivity analysis and the Egger's test were employed to ensure the results stability and to evaluate potential publication bias. Additionally, trial sequential analysis (TSA) was conducted to validate the findings. Our meta-analysis incorporated ten studies involving 2817 patients and 2855 controls. Results indicated that the AA genotype of VEGFA-1154 (rs1570360) is associated with a reduced risk of RA in the overall population (AG + GG vs AA: P = 0.032 OR = 1.932 95% CI 1.059-3.523). However, no significant association is found for VEGFA-634 (rs2010963), VEGFA-C936 (rs3025039), and VEGFA-2578 (rs699947) variants with RA risk. Subgroup analysis revealed a significant association between the VEGF rs3025039(C936) variant and RA risk in the PCR-RFLP group under the TC vs. CC model. TSA confirmed the sufficiency of the sample size for robust conclusions. These findings suggest that the G allele of VEGFA-1154 (rs1570360) may increase RA risk, whereas the A allele appears to confer a protective effect. This study enhances our understanding of the genetic predispositions to RA and underscores the potential role of VEGFA gene variants in its pathogenesis.
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Affiliation(s)
- Ke Li
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Yilu Wang
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Peng Huang
- Center for Evidence-Based Medicine, School of Public Health, Jiangxi Medical College, Nanchang University, No. 461, Bayi Avenue, Donghu District, Nanchang, 330006, China.
- Jiangxi Province Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
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19
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Shang L, Ao Y, Huang X, Wu H, Feng K, Wang J, Yue Y, Zhou Z, Liu Q, Li H, Fu G, Liu K, Pan J, Huang Y, Chen J, Chen G, Liang M, Yao J, Huang S, Hou J, Wu Z. sVEGFR3 alleviates myocardial ischemia/reperfusion injury through regulating mitochondrial homeostasis and immune cell infiltration. Apoptosis 2025; 30:894-911. [PMID: 39863719 DOI: 10.1007/s10495-024-02068-8] [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] [Accepted: 12/23/2024] [Indexed: 01/27/2025]
Abstract
Recent studies have suggested that sVEGFR3 is involved in cardiac diseases by regulating lymphangiogenesis; however, results are inconsistent. The aim of this study was to investigate the function and mechanism of sVEGFR3 in myocardial ischemia/reperfusion injury (MI/RI). sVEGFR3 effects were evaluated in vivo in mice subjected to MI/RI, and in vitro using HL-1 cells exposed to oxygen-glucose deprivation/reperfusion. Echocardiography, TTC-Evans blue staining, ELISA, electron microscopy, immunofluorescence, western blotting, and flow cytometry were used to investigate whether sVEGFR3 attenuates I/R injury. Transcriptome sequencing was used to investigate the downstream mechanism of sVEGFR3. Results showed that, in vivo, sVEGFR3 pretreatment reduced cardiac dysfunction, infarct area, and myocardial injury indicators by reducing ROS production, AIF expression, and apoptosis. In vitro, sVEGFR3 restored mitochondrial homeostasis by stabilizing the mitochondrial membrane potential (MMP) and preventing the opening of mitochondrial permeability transition pores (mPTP). And sVEGFR3 inhibits mitochondrial apoptosis through the Ras/MEK/ERK pathway. Furthermore, I/R injury increased the proportion of M1 macrophages and CD4 + T cells in myocardial tissue, as well as serum IFN-γ and TNF-α levels, whereas sVEGFR3 treatment attenuated these effects. sVEGFR3 attenuates MI/RI by regulating mitochondrial homeostasis and immune cell infiltration, and reduces intrinsic ROS-mediated mitochondrial apoptosis via the Ras/MEK/ERK pathway.
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Affiliation(s)
- Liqun Shang
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Yuanhan Ao
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Xiaolin Huang
- Department of Thoracic Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Huawei Wu
- Department of Surgery, Columbia University, New York, NY, USA
| | - Kangni Feng
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Junjie Wang
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Yuan Yue
- Department of Cardiovascular Surgery, Shenzhen People's Hospital, Shenzhen, China
| | - Zhuoming Zhou
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Quan Liu
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Huayang Li
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Guangguo Fu
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Kaizheng Liu
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Jinyu Pan
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Yang Huang
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Jiantao Chen
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Guangxian Chen
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Mengya Liang
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Jianping Yao
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China
| | - Suiqing Huang
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China.
| | - Jian Hou
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China.
- Department of Cardiology, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Zhongkai Wu
- Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan II Rd, Guangzhou, 510080, China.
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20
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Wu J, Wen M, Wang Z, Yu K, Jin X, Liu C, Song Q, Zhang G, Wu B, Li Y. Network pharmacological analysis and experimental verification of Zisheng Tongmai decoction in the treatment of premature ovarian failure. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3667-3680. [PMID: 39352532 DOI: 10.1007/s00210-024-03476-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/19/2024] [Indexed: 04/10/2025]
Abstract
Premature ovarian failure (POF) is a disease that seriously jeopardizes women's physical and mental health worldwide. Zisheng Tongmai decoction (ZSTMD), a famous Traditional Chinese Medicine (TCM) formula, has a marked effect on the clinical treatment of POF. This study investigated the potential mechanism of ZSTMD to improve POF through network pharmacology and experimental validation. The active components, key targets and potential mechanisms of ZSTMD against POF were predicted by network pharmacology and molecular docking. The POF model was induced in rats by cyclophosphamide (CTX) and subsequently gavaged with different doses of ZSTMD. KGN cells were treated with different concentrations of quercetin and CTX. Histopathological were observed via hematoxylin and eosin (H&E) staining and immunofluorescence staining. Serum estrogen levels were detected via ELISA. Protein expression was detected via Western blot. We identified quercetin as the main active ingredients targeting VEGFA. Molecular docking showed that VEGFA interacted well with the main active components of ZSTMD. In vivo experiments, ZSTMD significantly increased body weight and the ovarian index, significantly increased E2 and AMH, and decreased FSH and LH in POF rats. Histologic results showed that ZSTMD increased the number of follicles and vascular density in the ovary. It also increased VEGFA and CD31 protein expression. In vitro experiments, quercetin suppressed CTX-induced apoptosis in KGN cells and increased VEGFA protein expression. Our study demonstrated that ZSTMD improves POF by promoting angiogenesis through VEGFA target.
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Affiliation(s)
- Jiaru Wu
- School of Integrative Medicine, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Mengjie Wen
- School of Integrative Medicine, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Zecheng Wang
- School of Integrative Medicine, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Kun Yu
- School of Experimental Center, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Xinyue Jin
- School of Integrative Medicine, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Chenxu Liu
- School of Integrative Medicine, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Qiuhang Song
- School of Basic Medical Sciences, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Guohong Zhang
- School of Basic Medical Sciences, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China
| | - Beibei Wu
- Department of Dermatology, Hebei Province Chinese Medicine Hospital. Shijiazhuang, Hebei, China
| | - Yunfeng Li
- School of Basic Medical Sciences, Hebei University of Chinese Medicine. Shijiazhuang, Hebei, China.
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21
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Hsu CY, Altalbawy FMA, Oghenemaro EF, Uthirapathy S, Chandra M, Nathiya D, Kaur P, Ravi Kumar M, Kadhim AJ, Kariem M. Exosomal lncRNAs in the Tumor Angiogenesis: As Therapeutic Targets in Cancer Treatment. Arch Pharm (Weinheim) 2025; 358:e202400940. [PMID: 40165644 DOI: 10.1002/ardp.202400940] [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: 12/12/2024] [Revised: 02/12/2025] [Accepted: 03/05/2025] [Indexed: 04/02/2025]
Abstract
Exosomes, as mediators of intercellular communication, can be released from different types of cells and regulate the function of the target cell by transferring cargo, such as proteins, DNA, and RNA. Recent investigations have revealed a preponderance of long noncoding RNAs (lncRNAs), a subclass of noncoding RNAs, within exosomes, where they exhibit notable stability and are implicated in the development and progression of neoplastic processes, such as tumor angiogenesis. Angiogenesis, as a hallmark of cancer, provides diffusible nutrients and oxygen to the distant cells and guarantees tumorigenesis and metastasis. Exosomal lncRNAs, including MALAT1, OIP5-AS1, PART1, SNHG family, FAM225A, ATB, RAMP2-AS1, UCA1, TRPM2-AS, FGD5-AS1, and LINC0016, could modulate tumor angiogenesis by activating signaling cascades and mediators within the target cells, such as microRNAs (miRNAs). Regulation of tumor angiogenesis through modulation of exosomal lncRNAs could be a reliable strategy for cancer therapy. In this review, we discuss the characteristics and biogenesis of exosomes and lncRNAs and how exosomal lncRNAs are involved in various processes of tumorigenesis. Our primary focus is on exosomal lncRNAs, their impact on tumor angiogenesis, and their potential as novel diagnostic markers and therapeutic targets for various cancers.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona, USA
| | - Farag M A Altalbawy
- Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
- National Institute of Laser Enhanced Sciences (NILES), University of Cairo, Giza, Egypt
| | - Enwa Felix Oghenemaro
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Delta State University, Abraka, Delta State, Nigeria
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Muktesh Chandra
- Marwadi University Research Center, Department of Bioinformatics, Faculty of Engineering and Technology, Marwadi University, Rajkot, Gujarat, India
| | - Deepak Nathiya
- Department of Pharmacy Practice, Institute of Pharmacy, NIMS University, Jaipur, India
| | - Parjinder Kaur
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India
| | - M Ravi Kumar
- Department of Basic Science & Humanities, Raghu Engineering College, Visakhapatnam, India
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq
| | - Muthena Kariem
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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22
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Luo H, Zhang W, Zeng W, Wang Y, Feng J, Lan Y, Dong X, Liu T, Sun Y, Lu H. OPN3-mediated positive regulation of angiogenesis in HUVECs through VEGFR2 interaction. Commun Biol 2025; 8:529. [PMID: 40164822 PMCID: PMC11958745 DOI: 10.1038/s42003-025-07958-4] [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: 06/03/2024] [Accepted: 03/19/2025] [Indexed: 04/02/2025] Open
Abstract
Many rhodopsin-like G-protein-coupled receptors (Rh-GPCRs) are known to either promote or inhibit angiogenesis. Among these, Opsin 4 and Opsin 5 are specifically involved in vascular development within the eye. Opsin 3 (OPN3), another member of Rh-GPCRs, performs a variety of light-dependent and light-independent functions in extraocular tissue. However, its role in endothelial cells and angiogenesis remains unclear. Here, we found that OPN3 knockdown or knockout in zebrafish impairs embryonic angiogenesis and vascular development. Similarly, silencing OPN3 in human umbilical vein endothelial cells (HUVECs) inhibits cellular proliferation, migration, sprouting, and tube formation, while OPN3 overexpression promotes these cellular processes. Moreover, OPN3 regulates angiogenesis in HUVECs through the VEGFR2-AKT pathway, with OPN3 and VEGFR2 co-localizing at the plasma membrane and forming a physical complex. These findings provide new insights into the non-light-dependent functions of OPN3 in angiogenesis, expanding our understanding of its physiological roles and offering potential therapeutic strategies for angiogenesis-related diseases.
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Affiliation(s)
- Huanhuan Luo
- School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wei Zhang
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Wen Zeng
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yu Wang
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Jianglong Feng
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yinghua Lan
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Xian Dong
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Ting Liu
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Yan Sun
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Hongguang Lu
- School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China.
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
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23
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Mahaki H, Nobari S, Tanzadehpanah H, Babaeizad A, Kazemzadeh G, Mehrabzadeh M, Valipour A, Yazdinezhad N, Manoochehri H, Yang P, Sheykhhasan M. Targeting VEGF signaling for tumor microenvironment remodeling and metastasis inhibition: Therapeutic strategies and insights. Biomed Pharmacother 2025; 186:118023. [PMID: 40164047 DOI: 10.1016/j.biopha.2025.118023] [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: 01/22/2025] [Revised: 03/18/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in cancer progression and metastasis, with vascular endothelial growth factor (VEGF) signaling serving as a key regulator of tumor angiogenesis and immune evasion. VEGF induces abnormal blood vessel formation, promoting tumor growth, immune suppression, and metastasis through epithelialmesenchymal transition (EMT). As a result, VEGF signaling has become a critical therapeutic target in cancer treatment. This review examines the molecular mechanisms driving VEGF-mediated tumor growth and angiogenesis, with a focus on the interaction between tumor and endothelial cells and the dual role of VEGF in fostering vascularization and immune suppression. Current anti-VEGF therapies, including monoclonal antibodies (e.g., bevacizumab) and tyrosine kinase inhibitors (TKIs), have demonstrated efficacy and have received FDA approval for various cancers; however, therapeutic resistance remains a significant challenge. Strategies to overcome resistance, such as novel VEGF inhibitors, vascular normalization approaches, and combination therapies with immune checkpoint inhibitors, have been explored. Additionally, future directions emphasize the need for personalized approaches to improve treatment efficacy and reduce metastasis. A comprehensive understanding of VEGF signaling in the TME may pave the way for more effective cancer therapies.
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Affiliation(s)
- Hanie Mahaki
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sima Nobari
- Deputy of Health, Iran University of Medical Science, Tehran, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Babaeizad
- Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Gholamhosein Kazemzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Mehrabzadeh
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arezoo Valipour
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nader Yazdinezhad
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Piao Yang
- Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210, USA
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
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24
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Chitoran E, Rotaru V, Stefan DC, Gullo G, Simion L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab-20 Years of Therapeutic Success and Controversy. Cancers (Basel) 2025; 17:1126. [PMID: 40227654 PMCID: PMC11988089 DOI: 10.3390/cancers17071126] [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: 01/07/2025] [Revised: 03/22/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.
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Affiliation(s)
- Elena Chitoran
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Daniela-Cristina Stefan
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
| | - Laurentiu Simion
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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25
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Nishida A, Andoh A. The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis. Cells 2025; 14:488. [PMID: 40214442 PMCID: PMC11987742 DOI: 10.3390/cells14070488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/14/2025] Open
Abstract
Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.
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Affiliation(s)
- Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Seta-Tsukinowa, Otsu 520-2192, Shiga, Japan;
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26
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Nadora D, Ezzati S, Bol B, Aboud O. Serendipity in Neuro-Oncology: The Evolution of Chemotherapeutic Agents. Int J Mol Sci 2025; 26:2955. [PMID: 40243541 PMCID: PMC11988343 DOI: 10.3390/ijms26072955] [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: 01/08/2025] [Revised: 03/01/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
The development of novel therapeutics in neuro-oncology faces significant challenges, often marked by high costs and low success rates. Despite advances in molecular biology and genomics, targeted therapies have had limited impact on improving patient outcomes in brain tumors, particularly gliomas, due to the complex, multigenic nature of these malignancies. While significant efforts have been made to design drugs that target specific signaling pathways and genetic mutations, the clinical success of these rational approaches remains sparse. This review critically examines the landscape of neuro-oncology drug discovery, highlighting instances where serendipity has led to significant breakthroughs, such as the unexpected efficacy of repurposed drugs and off-target effects that proved beneficial. By exploring historical and contemporary cases, we underscore the role of chance in the discovery of impactful therapies, arguing that embracing serendipity alongside rational drug design may enhance future success in neuro-oncology drug development.
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Affiliation(s)
- Denise Nadora
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Shawyon Ezzati
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Brandon Bol
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA; (S.E.); (B.B.)
| | - Orwa Aboud
- Department of Neurology, Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;
- Department of Neurological Surgery, Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
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27
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Tanaka K, Sugisaka J, Shiraishi Y, Watanabe Y, Daga H, Azuma K, Nishino K, Mori M, Ota T, Saito H, Hata A, Sakaguchi T, Kozuki T, Akamatsu H, Matsumoto H, Tachihara M, Wakuda K, Sato Y, Ozaki T, Tsuchiya-Kawano Y, Yamamoto N, Nakagawa K, Okamoto I. Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC. Nat Commun 2025; 16:2825. [PMID: 40121197 PMCID: PMC11929838 DOI: 10.1038/s41467-025-58186-7] [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: 04/06/2024] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.
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Affiliation(s)
- Kentaro Tanaka
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
| | - Jun Sugisaka
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | - Yoshimasa Shiraishi
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Haruko Daga
- Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kazumi Nishino
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Masahide Mori
- Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center, Toyonaka, Japan
| | - Takayo Ota
- Department of Breast Medical Oncology, Izumi City General Hospital, Izumi, Japan
| | - Haruhiro Saito
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Akito Hata
- Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan
| | | | - Toshiyuki Kozuki
- Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Hiroaki Akamatsu
- Internal Medicine III, Wakayama Medical University, Wakayama, Japan
| | - Hirotaka Matsumoto
- Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
| | - Motoko Tachihara
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazushige Wakuda
- Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Nagaizumi, Japan
| | - Yuki Sato
- Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Tomohiro Ozaki
- Department of Medical Oncology, Kishiwada City Hospital, Osaka, Japan
| | - Yuko Tsuchiya-Kawano
- Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Nobuyuki Yamamoto
- Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Wang C, Fan X, Shi Y, Tang F. Radiation-Induced Brain Injury with Special Reference to Astrocytes as a Therapeutic Target. J Integr Neurosci 2025; 24:25907. [PMID: 40152565 DOI: 10.31083/jin25907] [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: 07/30/2024] [Revised: 10/22/2024] [Accepted: 11/06/2024] [Indexed: 03/29/2025] Open
Abstract
Radiotherapy is one of the primary modalities for oncologic treatment and has been utilized at least once in over half of newly diagnosed cancer patients. Cranial radiotherapy has significantly enhanced the long-term survival rates of patients with brain tumors. However, radiation-induced brain injury, particularly hippocampal neuronal damage along with impairment of neurogenesis, inflammation, and gliosis, adversely affects the quality of life for these patients. Astrocytes, a type of glial cell that are abundant in the brain, play essential roles in maintaining brain homeostasis and function. Despite their importance, the pathophysiological changes in astrocytes induced by radiation have not been thoroughly investigated, and no systematic or comprehensive review addressing the effects of radiation on astrocytes and related diseases has been conducted. In this paper, we review current studies on the neurophysiological roles of astrocytes following radiation exposure. We describe the pathophysiological changes in astrocytes, including astrogliosis, astrosenescence, and the associated cellular and molecular mechanisms. Additionally, we summarize the roles of astrocytes in radiation-induced impairments of neurogenesis and the blood-brain barrier (BBB). Based on current research, we propose that brain astrocytes may serve as potential therapeutic targets for treating radiation-induced brain injury (RIBI) and subsequent neurological and neuropsychiatric disorders.
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Affiliation(s)
- Caiping Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 226001 Nantong, Jiangsu, China
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
| | - Xingjuan Fan
- Department of Neurology, Affiliated Hospital of Nantong University, 226001 Nantong, Jiangsu, China
| | - Yunwei Shi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, 226001 Nantong, Jiangsu, China
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
| | - Fengru Tang
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 138602 Singapore, Singapore
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29
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Shaikh S, Chary PS, Mehra NK. Tyrosine Kinase Inhibitor Lenvatinib Based Nano Formulations and Cutting-Edge Scale-Up Technologies in revolutionizing Cancer Therapy. ACS APPLIED BIO MATERIALS 2025; 8:1749-1784. [PMID: 40091597 DOI: 10.1021/acsabm.4c01527] [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] [Indexed: 03/19/2025]
Abstract
Lenvatinib (LEN), a tyrosine kinase inhibitor, has emerged as a promising therapeutic agent for various solid tumors. Nevertheless, a number of constraints, including diminished bioavailability, incapacity to elicit localized inflammation, and inability to selectively accumulate at the tumor site, may impede the comprehensive exploitation of its versatile tyrosine kinase inhibitory capabilities. In order to achieve targeted delivery of LEN while also reducing its high dose used in conventional therapeutics, nanoformulation approaches can be adopted. The integration of LEN into various nanoformulations, such as nanoparticles, nanocrystals, high density lipoproteins (HDLs), liposomes, and micelles, is discussed, highlighting the advantages of these innovative approaches in a comparative manner; however, given that the current methods of nanoformulation synthesis employ toxic organic solvents and chemicals, there is an imperative need for exploring alternative, environmentally friendly approaches. The multifaceted effects of nanocarriers have rendered them profoundly applicable within the biomedical domain, serving as instrumental entities in various capacities such as vehicles for drug delivery and genetic material, diagnostic agents, facilitators of photothermal therapy, and radiotherapy. However, the scalability of these nanotechnological methodologies must be rigorously investigated and addressed to refine drug delivery mechanisms. This endeavor offers promising prospects for revolutionizing strategies in cancer therapeutics, thereby laying the foundation for future research in scale-up techniques in the pursuit of more effective and less toxic therapies for cancer.
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Affiliation(s)
- Samia Shaikh
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500029, India
| | - Padakanti Sandeep Chary
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500029, India
| | - Neelesh Kumar Mehra
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500029, India
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30
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Satpati D. Cancer Targeting Radiopeptidomimetics in Molecular Nuclear Medicine. Mol Pharm 2025. [PMID: 40078059 DOI: 10.1021/acs.molpharmaceut.4c01180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
Peptides are highly receptor-affine molecules exhibiting suitable pharmacokinetics. Additionally, low-cost production, simple protocols allowing easy modifications, and tolerance toward harsh reaction conditions make peptides ideal ligands for preparation of radiopharmaceuticals for cancer detection and treatment. However, natural peptides being substrates for enzymes are susceptible to proteolysis, which limits the in vivo lifetime and the target uptake. Therefore, the majority of peptides are not able to progress beyond preclinical research. Advancement of peptides for clinical analysis needs modification to instill improved features. Continuous increase and further expected rise in cancer cases in the next decade require development of more disease-directed and promising radiopharmaceuticals. Redesigned peptide, mimicking the original peptide with similar or improved affinity and high metabolic stability, shall have significant edge. This review outlines the design of peptidomimetics by incorporation of D-amino acids (inverso); reversal of D-amino acid sequence (retro-inverso), and reversal of L-amino acid sequence (retro). Clinically successful radiopeptidomimetics prepared using the three approaches have been elaborated to elucidate the important role of peptidomimetics in cancer management.
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Affiliation(s)
- Drishty Satpati
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085, India
- Homi Bhabha National Institute, Mumbai 400094, India
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31
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Cheng L, Zhang H, Zhou B, Wang H, Sun Y, Pang Y, Dong B. Polydopamine-modified hydroxyapatite and manganese tetroxide nanozyme incorporated gelatin methacryloyl hydrogel: A multifunctional platform for anti-bacteria, immunomodulation, angiogenesis, and enhanced regeneration in infected wounds. Int J Biol Macromol 2025; 307:141834. [PMID: 40081722 DOI: 10.1016/j.ijbiomac.2025.141834] [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: 12/27/2024] [Revised: 02/18/2025] [Accepted: 03/05/2025] [Indexed: 03/16/2025]
Abstract
Intensive inflammation induced via bacterial infection seriously disturbs the immune-microenvironment and compromise the neovascularization in the skin wound. On the basis of reducing bacterial infections, alleviating inflammatory response and rebuild the crosstalk between macrophages and vascular endothelial cell (VEC) serve as the key strategy for facilitating infected wound healing. Herein, manganese tetroxide (Mn3O4) nanozymes and polydopamine-coated hydroxyapatite (PHA) nanoparticles were loaded on the gelatin methacryloyl (GelMA) hydrogel, which was subsequently crosslinked by the UV light to construct a multifunctional hydrogel wound dressing GelMA-PHA-Mn3O4 with excellent anti-bacterial, immuno-regulation and angiogenic properties. Triggered by near infrared (NIR), PHA exhibited photothermal effect and effectively eradicated Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) biofilm. On the other hand, Mn3O4 nanozymes in hydrogel exhibit desirable reactive oxygen species (ROS) scavenging capacity due to the redox cycle between Mn2+ and Mn3+, which successfully transform the LPS-induced macrophage phenotype from pro-inflammation M1 to anti-inflammation M2. Notably, the interaction between macrophages and VECs was subsequently reconstructed and exhibited an evident pro-angiogenic phenomenon along with the improvement of local immuno-microenvironment. In vivo study further verified that the GelMA-PHA-Mn3O4 hydrogel combined with NIR irradiation could accelerate the healing of infected wound through the prominent anti-bacterial and immuno-regulation effect. The collagen deposition and formation of blood vessel in the wound were active. Above, this study demonstrated that the GelMA-PHA-Mn3O4 hydrogel represents a promising approach for managing infected wounds, with an anticipated prospect in clinical application.
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Affiliation(s)
- Liang Cheng
- Department of Prosthodontics, School and Hospital of Stomatology, Jilin University, Changchun 130021, China; State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun 130021, China
| | - Huan Zhang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, 999077, Hong Kong
| | - Bingshuai Zhou
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun 130021, China
| | - Huaiwu Wang
- Director of Surgery Center, The Changchun hospital of Guowen Medical Group, Changchun 130022, China
| | - Yue Sun
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun 130021, China; Department of Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China, 130021.
| | - Yuxuan Pang
- Department of Prosthodontics, School and Hospital of Stomatology, Jilin University, Changchun 130021, China.
| | - Biao Dong
- State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun 130021, China.
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Grobbelaar C, Steenkamp V, Mabeta P. Vascular Endothelial Growth Factor Receptors in the Vascularization of Pancreatic Tumors: Implications for Prognosis and Therapy. Curr Issues Mol Biol 2025; 47:179. [PMID: 40136433 PMCID: PMC11941243 DOI: 10.3390/cimb47030179] [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: 01/31/2025] [Revised: 03/01/2025] [Accepted: 03/03/2025] [Indexed: 03/27/2025] Open
Abstract
In pancreatic cancer (PC), vascular endothelial growth factor (VEGF) and its primary receptor, vascular endothelial growth factor receptor (VEGFR)-2, are central drivers of angiogenesis and metastasis, with their overexpression strongly associated with poor prognosis. In some PC patients, VEGF levels correlate with disease stage, tumor burden, and survival outcomes. However, therapies targeting VEGF and VEGFR-2, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have demonstrated limited efficacy, partly due to the emergence of resistance mechanisms. Resistance appears to stem from the activation of alternative vascularization pathways. This review explores the multifaceted roles of VEGFRs in pancreatic cancer, including VEGFR-1 and VEGFR-3. Potential strategies to improve VEGFR-targeting therapies, such as combination treatments, the development of more selective inhibitors, and the use of biomarkers, are discussed as promising approaches to enhance treatment efficacy and outcomes.
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Affiliation(s)
- Craig Grobbelaar
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Vanessa Steenkamp
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
| | - Peace Mabeta
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa;
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Aksan B, Mauceri D. Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure. J Biomed Sci 2025; 32:33. [PMID: 40050849 PMCID: PMC11884128 DOI: 10.1186/s12929-025-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/21/2025] [Indexed: 03/10/2025] Open
Abstract
Neurons rely on the bloodstream for essential nutrients and oxygen, which is facilitated by an intricate coupling of the neuronal and vascular systems. Central to this neurovascular interaction is the vascular endothelial growth factor (VEGF) family, a group of secreted growth factors traditionally known for their roles in promoting endothelial cell proliferation, migration, and survival in the cardiovascular and lymphatic systems. However, emerging evidence shows that VEGFs also play indispensable roles in the nervous system, extending beyond their canonical angiogenic and lymphangiogenic functions. Over the past two decades, VEGFs have been found to exert direct effects on neurons, influencing key aspects of neuronal function independently of their actions on vascular cells. In particular, it has become increasingly evident that VEGFs also play crucial functions in the development, regulation, and maintenance of neuronal morphology. Understanding the roles of VEGFs in neuronal development is of high scientific and clinical interest because of the significance of precise neuronal morphology for neural connectivity and network function, as well as the association of morphological abnormalities with neurological and neurodegenerative disorders. This review begins with an overview of the VEGF family members, their structural characteristics, receptors, and established roles in vasculature. However, it then highlights and focuses on the exciting variety of neuronal functions of VEGFs, especially their crucial role in the development, regulation, and maintenance of neuronal morphology.
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Affiliation(s)
- Bahar Aksan
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany
| | - Daniela Mauceri
- Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany.
- Institute of Anatomy and Cell Biology, Dept. Molecular and Cellular Neuroscience, University of Marburg, Robert-Koch-Str. 8, 35032, Marburg, Germany.
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34
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Liu F, Gu Z, Yi F, Liu X, Zou W, Xu Q, Yuan Y, Chen N, Tang J. Potential of Glycyrrhiza in the prevention of colitis-associated colon cancer. Fitoterapia 2025; 181:106398. [PMID: 39842555 DOI: 10.1016/j.fitote.2025.106398] [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: 10/16/2024] [Revised: 01/09/2025] [Accepted: 01/15/2025] [Indexed: 01/24/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Glycyrrhiza, a legume native to the Mediterranean region, has a long history of ethnomedicinal use in China. Due to its antiviral, antibacterial, anti-inflammatory, antioxidant, antitumor, anti-ulcer, and hepatoprotective properties, Glycyrrhiza is widely utilized in the treatment of gastrointestinal disorders. THE AIM OF THE REVIEW The specific mechanisms of the main active constituents of glycyrrhiza in the treatment of inflammatory bowel disease, precancerous lesions and colorectal cancer at all stages of the colitis-associated colon cancer "Inflammation-Dysplasia-Cancer" sequence, as well as its pharmacokinetics, toxicology, formulation improvements, and application studies, are reviewed to provide new insights and perspectives on glycyrrhiza as a dietary supplement to treat and prevent colitis-associated colon cancer. MATERIALS AND METHODS Information on Glycyrrhiza was retrieved from electronic databases, including PubMed and Web of Science. RESULTS Glycyrrhiza is a well-established medicinal plant with significant potential for applications in both the food and pharmaceutical industries. Over 400 active constituents have been identified in Glycyrrhiza, including terpenoids, flavonoids, isoflavones, coumarins, and polyphenols. Numerous studies have demonstrated that Glycyrrhiza and its active compounds can inhibit the "Inflammation-Dysplasia-Cancer" progression of colitis-associated colon cancer by mitigating inflammatory bowel disease, reducing the number of intestinal precancerous lesions, and counteracting colorectal cancer. Furthermore, derivatives and nanocarriers are crucial for the effective treatment of colitis-associated colon cancer using Glycyrrhiza and its active constituents. CONCLUSION In conclusion, Glycyrrhiza is a plant with both medicinal and nutritional value, making it a potential food ingredient and dietary supplement for the treatment of colitis-associated colon cancer.
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Affiliation(s)
- Fang Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China; North Sichuan Medical College, Nanchong, China.
| | - Zhili Gu
- North Sichuan Medical College, Nanchong, China
| | - Feiyang Yi
- North Sichuan Medical College, Nanchong, China
| | - Xue Liu
- North Sichuan Medical College, Nanchong, China
| | - Wenxuan Zou
- North Sichuan Medical College, Nanchong, China
| | - Qingxia Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yun Yuan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Nianzhi Chen
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jianyuan Tang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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35
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Kuronishi M, Ozawa Y, Kimura T, Li SD, Kato Y. Development of a Microvessel Density Gene Signature and Its Application in Precision Medicine. CANCER RESEARCH COMMUNICATIONS 2025; 5:398-408. [PMID: 39835481 PMCID: PMC11880750 DOI: 10.1158/2767-9764.crc-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/08/2024] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
SIGNIFICANCE A novel gene signature for MVD was developed. This MVD gene score enables the estimation of MVD, reflecting the sensitivity to antiangiogenic inhibitors, in transcriptomic datasets. We demonstrated the utility of the MVD gene score together with a T cell-inflamed gene signature for potential future use as a clinical biomarker.
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Affiliation(s)
| | - Yoichi Ozawa
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | - Takayuki Kimura
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
| | | | - Yu Kato
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan
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Wonkam A, Esoh K, Levine RM, Ngo Bitoungui VJ, Mnika K, Nimmagadda N, Dempsey EAD, Nkya S, Sangeda RZ, Nembaware V, Morrice J, Osman F, Beer MA, Makani J, Mulder N, Lettre G, Steinberg MH, Latanich R, Casella JF, Drehmer D, Arking DE, Chimusa ER, Yen JS, Newby GA, Antonarakis SE. FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries. Nat Commun 2025; 16:2092. [PMID: 40025045 PMCID: PMC11873275 DOI: 10.1038/s41467-025-57413-5] [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: 12/05/2023] [Accepted: 02/20/2025] [Indexed: 03/04/2025] Open
Abstract
Known fetal haemoglobin (HbF)-modulating loci explain 10-24% variation of HbF level in Africans with Sickle Cell Disease (SCD), compared to 50% among Europeans. Here, we report fourteen candidate loci from a genome-wide association study (GWAS) of HbF level in patients with SCD from Cameroon, Tanzania, and the United States of America. We present results of cell-based experiments for FLT1 candidate, demonstrating expression in early haematopoiesis and a possible involvement in hypoxia associated HbF induction. Our study employed genotyping arrays that capture a broad range of African and non-African genetic variation and replicated known loci (BCL11A and HBS1L-MYB). We estimated the heritability of HbF level in SCD at 94%, higher than estimated in unselected Europeans, and suggesting a robust capture of HbF-associated loci by these arrays. Our approach, which involved genotype imputation against six reference haplotype panels and association analysis with each of the panels, proved superior over selecting a best-performing panel, evidenced by a substantial proportion of panel-specific (up to 18%) and a low proportion of shared (28%) imputed variants across the panels.
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Affiliation(s)
- Ambroise Wonkam
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
| | - Kevin Esoh
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rachel M Levine
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | | | - Khuthala Mnika
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Nikitha Nimmagadda
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Erin A D Dempsey
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Siana Nkya
- Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania
| | - Raphael Z Sangeda
- Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania
| | - Victoria Nembaware
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Jack Morrice
- Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Fujr Osman
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael A Beer
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Julie Makani
- Sickle Cell Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health & Allied Sciences (MUHAS), Dar Es Salaam, Tanzania
- SickleInAfrica Clinical Coordinating Center, Muhimbili University of Health & Allied Sciences (MUHAS), Dar Es Salaam, Tanzania
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Nicola Mulder
- Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, CIDRI-Africa Wellcome Trust Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Guillaume Lettre
- Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada
| | - Martin H Steinberg
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Rachel Latanich
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James F Casella
- Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daiana Drehmer
- Armstrong Oxygen Biology Research Center, Institute for Cell Engineering, and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dan E Arking
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Emile R Chimusa
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle, Tyne and Wear, UK
| | - Jonathan S Yen
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Gregory A Newby
- McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Stylianos E Antonarakis
- Department of Genetic Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Wang F, Wei X, Zheng Y, Wang J, Ying J, Chen X, Luo S, Luo H, Yu X, Chen B, Ma L, Xu R. Safety, Pharmacokinetics, and Pharmacodynamics Evaluation of Ivonescimab, a Novel Bispecific Antibody Targeting PD-1 and VEGF, in Chinese Patients With Advanced Solid Tumors. Cancer Med 2025; 14:e70653. [PMID: 40114411 PMCID: PMC11925807 DOI: 10.1002/cam4.70653] [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: 05/06/2024] [Revised: 01/22/2025] [Accepted: 01/26/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Ivonescimab (AK112) is a first-in-class bispecific antibody that simultaneously targets programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF) with cooperative binding. We report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of ivonescimab in patients suffered from advanced solid tumors. METHODS A multicenter, open-label, dose-escalation, phase I study was conducted in five hospitals in China. Ivonescimab was used as a monotherapy. The dose of ivonescimab intravenously administered was 3, 5, 10, 20, and 30 mg/kg every 2 weeks (Q2W), and 10 and 20 mg/kg every 3 weeks (Q3W). Safety, PK, and PD of ivonescimab were evaluated. RESULTS A total of 59 patients treated in the study. Only one dose-limiting toxicity (DLT) occurred in 1 out of 9 patients in the 10 mg/kg Q2W cohort, indicating that no maximum tolerated dose was reached. Among the participants, 53 patients (89.8%) experienced treatment-related adverse events (TRAEs), with the most common being proteinuria (33.9%), aspartate aminotransferase elevation (27.1%), white blood cell count decrease (22.0%), alanine aminotransferase elevation (20.3%), and anemia (20.3%). Fourteen patients (23.7%) had ≥ Grade 3 TRAEs, and 7 patients (11.9%) experienced serious TRAEs. Notably, there were no reported deaths associated with the TRAEs, and no dose-dependent increase in adverse events was observed. The half-life of ivonescimab ranged from 5.0 to 7.3 days following single-dose administration across all dose levels. The serum concentrations of ivonescimab increased with escalating doses in an approximately dose-proportional manner. Following multiple doses, the accumulation ratio ranged from 1.1 to 1.7, suggesting mild accumulation of ivonescimab. The steady state was achieved after 5 doses. Ivonescimab occupancy on PD-1 sustained over 80% across the treatment period. Serum VEGF level was rapidly down-regulated after each administration. CONCLUSIONS In patients with advanced solid tumors, ivonescimab monotherapy was well-tolerated and demonstrated a linear PK characteristics. PD profiles showed the promising potential of ivonescimab for the management of advanced solid tumors. TRIAL REGISTRATION ClinicalTrials.gov (NCT04597541).
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MESH Headings
- Humans
- Male
- Female
- Middle Aged
- Neoplasms/drug therapy
- Neoplasms/pathology
- Aged
- Antibodies, Bispecific/pharmacokinetics
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/administration & dosage
- Antibodies, Bispecific/pharmacology
- Antibodies, Bispecific/therapeutic use
- Adult
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- China
- Maximum Tolerated Dose
- Dose-Response Relationship, Drug
- Antineoplastic Agents, Immunological/pharmacokinetics
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/pharmacology
- Immune Checkpoint Inhibitors/pharmacokinetics
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/administration & dosage
- Immune Checkpoint Inhibitors/pharmacology
- East Asian People
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Affiliation(s)
- Fenghua Wang
- Department of Medical Oncology, Cancer Prevention Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaoli Wei
- Department of Medical Oncology, Cancer Prevention Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yulong Zheng
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Jing Wang
- Department of Gynecology, Hunan Cancer Hospital, Changsha, Hunan, China
| | - Jieer Ying
- Department of Hepatobiliary Pancreatic Gastric Medicine, Zhejiang Cancer Hospital, Zhejiang, Hangzhou, China
| | - Xiaozhong Chen
- The Department of Head and Neck Radiation, Zhejiang Cancer Hospital, Zhejiang, Hangzhou, China
| | - Suxia Luo
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Huiyan Luo
- Department of Medical Oncology, Cancer Prevention Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xufang Yu
- Akeso Biopharma, Inc., Zhongshan, Guangdong, China
| | - Benchao Chen
- Akeso Biopharma, Inc., Zhongshan, Guangdong, China
| | - Lei Ma
- Akeso Biopharma, Inc., Zhongshan, Guangdong, China
| | - Ruihua Xu
- Department of Medical Oncology, Cancer Prevention Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
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Lei Y, Zhong C, Zhang J, Zheng Q, Xu Y, Li Z, Huang C, Ren T. Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1. Oncogene 2025; 44:769-781. [PMID: 39663393 PMCID: PMC11888990 DOI: 10.1038/s41388-024-03236-5] [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: 07/11/2024] [Revised: 11/13/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024]
Abstract
Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.
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Affiliation(s)
- Yuqiong Lei
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Cheng Zhong
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jingyuan Zhang
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Qi Zheng
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yongle Xu
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zhoubin Li
- Department of Lung Transplantation and Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
| | - Chenwen Huang
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Department of Clinical Research Centre, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Tao Ren
- Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Stem Cell Center, Shanghai Sixth People's Hospital, Shanghai, 200233, China.
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Chen J, Hu S, Liu J, Jiang H, Wang S, Yang Z. Exosomes: a double-edged sword in cancer immunotherapy. MedComm (Beijing) 2025; 6:e70095. [PMID: 39968497 PMCID: PMC11831209 DOI: 10.1002/mco2.70095] [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: 08/02/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 02/20/2025] Open
Abstract
Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.
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Affiliation(s)
- Jiayi Chen
- School of Life SciencesJilin UniversityChangchunChina
| | - Siyuan Hu
- School of Life SciencesJilin UniversityChangchunChina
| | - Jiayi Liu
- School of Life SciencesJilin UniversityChangchunChina
| | - Hao Jiang
- School of Life SciencesJilin UniversityChangchunChina
| | - Simiao Wang
- School of Life SciencesJilin UniversityChangchunChina
| | - Zhaogang Yang
- School of Life SciencesJilin UniversityChangchunChina
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Morris VK, Liu S, Lin K, Zhu H, Prasad S, Mahvash A, Bhosale P, Sun B, Parra ER, Wistuba I, Peddireddy A, Yao J, Mendoza-Perez J, Knafl M, Woodman SE, Eng C, Halperin D. Phase II trial of atezolizumab and bevacizumab for treatment of HPV-positive unresectable or metastatic squamous cell carcinoma of the anal canal. Clin Cancer Res 2025; 31:752145. [PMID: 40019482 PMCID: PMC12010964 DOI: 10.1158/1078-0432.ccr-24-1512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/31/2024] [Accepted: 02/26/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Anti-PD-(L)1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus (HPV)-associated malignancies. VEGF signaling causes intratumoral immune evasion and immune suppression. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer. PATIENTS AND METHODS For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST v1.1). The primary endpoint was best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pretreatment/on-treatment biopsies) using a log-rank test. RESULTS Among 20 participants, the overall response rate was 11% (95% confidence interval (CI): 1.2-32). Median PFS and OS were 4.1 months (95% CI: 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in interferon gamma (P=.03) and inflammatory response (P =.02) gene expression signatures with prolonged PFS, as did rises in CD3+CD8+PD1+ (P=.02) cells and decreases in CD3+FoxP3+ cells (P=.04) from 10 paired biopsies with multiplex immunoflorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter OS (HR 6.3, 95% CI 1.2-32; P=.01). CONCLUSIONS Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 monotherapy for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.
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Affiliation(s)
- Van K. Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Suyu Liu
- Department of Biostatistics, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Kangyu Lin
- Department of Gastrointestinal Medical Oncology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Haifeng Zhu
- Department of Genomic Medicine, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Seema Prasad
- Department of Gastrointestinal Medical Oncology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Armeen Mahvash
- Department of Radiology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Priya Bhosale
- Department of Radiology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Baohua Sun
- Department of Translational Molecular Pathology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Edwin R. Parra
- Department of Translational Molecular Pathology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Ignacio Wistuba
- Department of Translational Molecular Pathology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | | | - James Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Julia Mendoza-Perez
- Department of Translational Molecular Pathology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Mark Knafl
- Department of Genomic Medicine, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Scott E. Woodman
- Department of Genomic Medicine, The University of Texas – MD Anderson Cancer Center, Houston, Texas
| | - Cathy Eng
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Daniel Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas – MD Anderson Cancer Center, Houston, Texas
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Zhang M, Wang Z, Liu S, Li Y, Gong Y, Liu M. New options for targeting TRPV1 receptors for cancer treatment: odorous Chinese herbal medicine. Front Oncol 2025; 15:1488289. [PMID: 40007993 PMCID: PMC11850239 DOI: 10.3389/fonc.2025.1488289] [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: 08/29/2024] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Vanilloid1 (TRPV1), a subfamily of transient receptor channels, is one of the non-selective calcium channels, which is a bridge between cellular response and extracellular environmental networks, and is involved in a variety of pathophysiological processes. It is also involved in the process of cancer occurrence and progression, and researchers are revealing its role in cancer. In this paper, we review the expression and significance of TRPV1 receptor in various cancer cell types, the role of TRPV1 in the apoptosis-proliferation balance, cancer cell invasion and metastasis, and tumor micro-environment, with emphasis on the mechanisms by which TRPV1 receptor mediates inflammatory response, immune system, and thus regulates cancer. We discussed the latest directions and current challenges of TRPV1 receptor-targeting therapy for cancer, and summarized the odorous traditional herbs that modulate TRPV1 receptors, with a view to developing anti-tumor drugs targeting TRPV1 receptors in the future.
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Affiliation(s)
- Minghui Zhang
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Zongao Wang
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Shaojun Liu
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Yuxuan Li
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Yanting Gong
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
| | - Min Liu
- Nanjing University of Chinese Medicine, Suzhou, China
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
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42
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Hafeez MT, Gao H, Ju F, Qi F, Li T, Zhang S. Transcriptomic Analysis Divulges Differential Expressions of Microglial Genes After Microglial Repopulation in Mice. Int J Mol Sci 2025; 26:1494. [PMID: 40003960 PMCID: PMC11855859 DOI: 10.3390/ijms26041494] [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: 12/12/2024] [Revised: 02/02/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
Microglia are key immune cells in the central nervous system (CNS) and maintain hemostasis in physiological conditions. Microglial depletion leads to rapid repopulation, but the gene expression and signaling pathways related to repopulation remain unclear. Here, we used RNA sequencing (RNA-Seq) analysis to profile the transcriptome of microglia-depleted tissue by taking advantage of a conditional genetic microglial depletion model (CX3CR1CreER/+ system). Differential gene expression (DGE) sequencing analysis showed that 1226 genes were differentially up- and downregulated in both groups compared to control. Our data demonstrated that many microglial genes were highly regulated on day 3 after depletion but the numbers of differentially expressed genes were reduced by day 7. Gene ontology (GO) analysis categorized these differentially expressed genes on day 3 and day 7 to the specific biological processes, such as cell proliferation, cell activation, and cytokine and chemokine production. DGE analysis indicated that specific genes related to proliferation were regulated after depletion. Consistent with the changes in transcriptome, the histological analysis of transgenic mice revealed that the microglia after depletion undergo proliferation and activation from day 3 to day 7. Collectively, these results suggest that transcriptomic changes in microglial genes during depletion have a profound implication for the renewal and activation of microglia and may help to understand the regulatory mechanism of microglial activation in disease conditions.
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Affiliation(s)
| | | | | | | | | | - Shengxiang Zhang
- Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou 730000, China
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Wakita S, Horiguchi K, Nakano S, Higuchi Y. Successful Endoscopic Resection of a Chronic Expanding Hematoma Following Gamma Knife Surgery for Cerebral Arteriovenous Malformation: A Case Report. NMC Case Rep J 2025; 12:47-51. [PMID: 40017678 PMCID: PMC11867764 DOI: 10.2176/jns-nmc.2024-0216] [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: 09/09/2024] [Accepted: 11/14/2024] [Indexed: 03/01/2025] Open
Abstract
Gamma knife surgery is useful for treating cerebral arteriovenous malformations. However, some radiation-induced long-term complications have been reported. One of these is a chronic expanding hematoma. We present a case of chronic expanding hematoma, successfully treated with endoscopic resection. The patient, a woman in her 30s, experienced a cerebral hemorrhage 17 years ago associated with an arteriovenous malformation in the corpus callosum. The lesion was completely embolized with n-butyl-2-cyanoacrylate embolization twice, followed 2 years later by gamma knife surgery. The patient presented to the emergency room with headache and left hemiplegia. A computed tomography scan showed hemorrhagic changes consistent with the cystic lesion and worsening edematous changes around it. An endoscopic tumor resection (interhemispheric approach) was performed, and most of the lesion was removed. Pathology did not detect any neoplastic lesions, and a diagnosis of chronic expanding hematoma was performed based on the presence of abnormal vascular neoplasia. The postoperative course was uneventful, and the headache promptly resolved. The pathophysiology of chronic expanding hematoma involves slow and progressive hematoma expansion due to repeated local hemorrhage, causing intense cerebral edema around the lesion. Surgical removal is effective, and edematous changes and neurological symptoms can be quickly relieved after surgery. Endoscopic surgery is particularly effective for deep lesions owing to its ability to manipulate within a narrow surgical field. In this case, the lesion was removed with minimal invasiveness and no complications, leading to early symptom relief and resolution of the surrounding brain edema changes.
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Affiliation(s)
- Shogo Wakita
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
| | - Kentaro Horiguchi
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
| | - Shigeki Nakano
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
| | - Yoshinori Higuchi
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Chiba, Japan
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Perepletchikova D, Malashicheva A. Communication between endothelial cells and osteoblasts in regulation of bone homeostasis: Notch players. Stem Cell Res Ther 2025; 16:56. [PMID: 39920854 PMCID: PMC11806792 DOI: 10.1186/s13287-025-04176-x] [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: 07/25/2024] [Accepted: 01/23/2025] [Indexed: 02/09/2025] Open
Abstract
Endothelial cells coat blood vessels and release molecular signals to affect the fate of other cells. Endothelial cells can adjust their behavior in response to the changing microenvironmental conditions. During bone regeneration, bone tissue cells release factors that promote blood vessel growth. Notch is a key signaling that regulates cell fate decisions in many tissues and plays an important role in bone tissue development and homeostasis. Understanding the interplay between angiogenesis and osteogenesis is currently a focus of research efforts in order to facilitate and improve osteogenesis when needed. Our review explores the cellular and molecular mechanisms including Notch-dependent endothelial-MSC communication that drive osteogenesis-angiogenesis processes and their effects on bone remodeling and repair.
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Affiliation(s)
| | - Anna Malashicheva
- Institute of Cytology Russian Academy of Science, St. Petersburg, Russia, 194064.
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Hirakawa T, Yamaguchi K, Funaishi K, Shimoji K, Sakamoto S, Horimasu Y, Masuda T, Nakashima T, Iwamoto H, Hamada H, Yamada S, Hattori N. Predictive Value of Circulatory Total VEGF-A and VEGF-A Isoforms for the Efficacy of Anti-PD-1/PD-L1 Antibodies in Patients with Non-Small-Cell Lung Cancer. Cancers (Basel) 2025; 17:572. [PMID: 40002167 PMCID: PMC11853576 DOI: 10.3390/cancers17040572] [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: 01/09/2025] [Revised: 01/31/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Vascular endothelial growth factor (VEGF)-A promotes an immunosuppressive tumor microenvironment, potentially affecting the efficacy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody therapy. VEGF121 and VEGF165, VEGF-A isoforms, promote and inhibit tumor growth, respectively. Additionally, VEGF-A levels differ depending on whether they are measured in serum or plasma. However, whether the serum or plasma levels of total VEGF-A (tVEGF-A) or its isoforms are the most suitable for predicting anti-PD-1/PD-L1 antibody therapy efficacy remains unclear. METHODS Eighty-six patients with non-small-cell lung cancer (NSCLC) who were treated with anti-PD-1/PD-L1 antibody monotherapy between December 2015 and December 2023 were retrospectively enrolled. The association between the serum and plasma levels of tVEGF-A and its isoforms (VEGF121 and VEGF165) and treatment outcomes was analyzed. RESULTS The median progression-free survival (PFS) was 2.9 months, and the objective response rate (ORR) was 23.3%. PFS was significantly shorter in patients with higher tVEGF-A serum levels (≥484.2 pg/mL) than in those without (median PFS 2.1 vs. 3.7 months, p = 0.004). In contrast, plasma tVEGF-A levels could not be used to stratify PFS. Therefore, the serum levels of VEGF-A isoforms were measured. Patients with higher VEGF121 serum levels (≥523.5 pg/mL) showed both significantly shorter PFS (median PFS 2.3 vs. 3.3 months, p = 0.022) and a lower ORR (9.7% vs. 30.9%, p = 0.033) than those without. Multivariate Cox and logistic regression analyses showed that higher levels of serum VEGF121 were significantly associated with shorter PFS and a lower ORR. CONCLUSIONS Serum VEGF121 levels may be useful in predicting anti-PD-1/PD-L1 antibody monotherapy efficacy.
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Affiliation(s)
- Tetsu Hirakawa
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Kakuhiro Yamaguchi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Kunihiko Funaishi
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Kiyofumi Shimoji
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Shinjiro Sakamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Yasushi Horimasu
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Takeshi Masuda
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Taku Nakashima
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Hiroshi Iwamoto
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
| | - Hironobu Hamada
- Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | | | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (T.H.); (T.M.); (T.N.); (N.H.)
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Puzzo M, De Santo M, Morelli C, Leggio A, Catalano S, Pasqua L. Colorectal Cancer: Current and Future Therapeutic Approaches and Related Technologies Addressing Multidrug Strategies Against Multiple Level Resistance Mechanisms. Int J Mol Sci 2025; 26:1313. [PMID: 39941081 PMCID: PMC11818749 DOI: 10.3390/ijms26031313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.
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Affiliation(s)
- Marianna Puzzo
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
| | - Marzia De Santo
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Catia Morelli
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Antonella Leggio
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
| | - Stefania Catalano
- Laboratory of Clinical, Biomolecular and Genetic Analyses Unit, Annunziata Hospital, 87100 Cosenza, Italy; (M.P.); (S.C.)
- Department of Pharmacy, Health and Nutritional Sciences University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy; (M.D.S.); (C.M.); (A.L.)
| | - Luigi Pasqua
- NanoSiliCal Devices s.r.l., University of Calabria, 87036 Arcavacata di Rende, Italy
- Department of Environmental Engineering, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende, Italy
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Chen BD, Zhao Y, Wu JL, Zhu ZG, Yang XD, Fang RP, Wu CS, Zheng W, Xu CA, Xu K, Ji X. Exosomes in Skin Flap Survival: Unlocking Their Role in Angiogenesis and Tissue Regeneration. Biomedicines 2025; 13:353. [PMID: 40002766 PMCID: PMC11853446 DOI: 10.3390/biomedicines13020353] [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: 12/13/2024] [Revised: 01/22/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
This review explores the critical role of exosomes in promoting angiogenesis, a key factor in skin flap survival. Skin flaps are widely used in reconstructive surgery, and their survival depends heavily on the formation of new blood vessels. Exosomes, small extracellular vesicles secreted by various cells, have emerged as important mediators of intercellular communication and play a crucial role in biological processes such as angiogenesis. Compared to traditional methods of promoting angiogenesis, exosomes show more selective and targeted therapeutic potential as they naturally carry angiogenic factors and can precisely regulate the angiogenesis process. The review will delve into the molecular mechanisms by which exosomes facilitate angiogenesis, discuss their potential therapeutic applications in enhancing skin flap survival, and explore future research directions, particularly the challenges and prospects of exosomes in clinical translation. By highlighting the unique advantages of exosomes in skin flap survival, this review provides a new perspective in this field and opens up new research directions for future therapeutic strategies.
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Affiliation(s)
- Bo-da Chen
- Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (B.-d.C.); (J.-l.W.); (Z.-g.Z.); (X.-d.Y.); (R.-p.F.)
| | - Yue Zhao
- School of Public Health, Hangzhou Medical College, Hangzhou 310053, China;
| | - Jian-long Wu
- Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (B.-d.C.); (J.-l.W.); (Z.-g.Z.); (X.-d.Y.); (R.-p.F.)
| | - Zi-guan Zhu
- Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (B.-d.C.); (J.-l.W.); (Z.-g.Z.); (X.-d.Y.); (R.-p.F.)
| | - Xiao-dong Yang
- Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (B.-d.C.); (J.-l.W.); (Z.-g.Z.); (X.-d.Y.); (R.-p.F.)
| | - Ren-peng Fang
- Center for Plastic & Reconstructive Surgery, Department of Hand & Reconstructive Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (B.-d.C.); (J.-l.W.); (Z.-g.Z.); (X.-d.Y.); (R.-p.F.)
| | - Chen-si Wu
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (C.-s.W.); (W.Z.); (C.-a.X.)
| | - Wei Zheng
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (C.-s.W.); (W.Z.); (C.-a.X.)
| | - Cheng-an Xu
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (C.-s.W.); (W.Z.); (C.-a.X.)
| | - Keyang Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China;
| | - Xin Ji
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, China; (C.-s.W.); (W.Z.); (C.-a.X.)
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Shahbaz S, Rezaeifar M, Syed H, Redmond D, Terveart JWC, Osman M, Elahi S. Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients. Brain Behav Immun 2025; 124:97-114. [PMID: 39615603 DOI: 10.1016/j.bbi.2024.11.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/04/2024] [Accepted: 11/27/2024] [Indexed: 01/20/2025] Open
Abstract
A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses. Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.
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Affiliation(s)
- Shima Shahbaz
- Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada
| | - Maryam Rezaeifar
- Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada
| | - Hussein Syed
- Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton T6G 2E1, AB, Canada
| | - Desiree Redmond
- Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton T6G 2E1, AB, Canada
| | - Jan Willem Cohen Terveart
- Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton T6G 2E1, AB, Canada
| | - Mohammed Osman
- Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Women and Children Health Research Institute, University of Alberta, Edmonton T6G 2E1, AB, Canada.
| | - Shokrollah Elahi
- Mike Petryk School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton T6G 2E1, AB, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton T6G 2E1, AB, Canada; Women and Children Health Research Institute, University of Alberta, Edmonton T6G 2E1, AB, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2E1, AB, Canada; Glycomics Institute of Alberta, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G 2E1, AB, Canada.
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Feng Q, Yu C, Guo L, Liu X, Lin Y, Li C, Zhang W, Zong Y, Yang W, Ma Y, Wang R, Li L, Pei Y, Wang H, Liu D, Niu H, Han M, Nie L. DCBLD1 Modulates Angiogenesis by Regulation of the VEGFR-2 Endocytosis in Endothelial Cells. Arterioscler Thromb Vasc Biol 2025; 45:198-217. [PMID: 39665138 DOI: 10.1161/atvbaha.123.320443] [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: 11/17/2023] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Unwanted angiogenesis is involved in the progression of various malignant tumors and cardiovascular diseases, and the factors that regulate angiogenesis are potential therapeutic targets. We tested the hypothesis that DCBLD1 (discoidin, CUB, and LCCL domain-containing protein 1) is a coreceptor of VEGFR-2 (vascular endothelial growth factor receptor-2) and modulates angiogenesis in endothelial cells. METHODS A carotid artery ligation model and retinal angiogenesis assay were used to study angiogenesis using globe knockout or endothelial cell-specific conditional Dcbld1 knockout mice in vivo. Immunoblotting, immunofluorescence staining, plasma membrane subfraction isolation, Coimmunoprecipitation, and mass spectrum assay were performed to clarify the molecular mechanisms. RESULTS Loss of Dcbld1 impaired VEGF (vascular endothelial growth factor) response and inhibited VEGF-induced endothelial cell proliferation and migration. Dcbld1 deletion interfered with adult and developmental angiogenesis. Mechanistically, DCBLD1 bound to VEGFR-2 and regulated the formation of VEGFR-2 complex with negative regulators: protein tyrosine phosphatases, E3 ubiquitin ligases (neuronal precursor cell-expressed developmentally downregulated gene 4, Nedd4 and c-Casitas B-lineage lymphoma, c-Cbl), and also Dcbld1 knockdown promoted lysosome-mediated VEGFR-2 degradation in endothelial cells. CONCLUSION These findings demonstrated the essential role of endothelial DCBLD1 in regulating VEGF signaling and provided evidence that DCBLD1 promotes VEGF-induced angiogenesis by limiting the dephosphorylation, ubiquitination, and lysosome degradation after VEGFR-2 endocytosis. We proposed that endothelial DCBLD1 is a potential therapeutic target for ischemic cardiovascular diseases by the modulation of angiogenesis through regulation of the VEGFR-2 endocytosis.
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Affiliation(s)
- Qi Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Chao Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Lingling Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Xiaoning Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Yanling Lin
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Chenyang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Wenjun Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Yanhong Zong
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Weiwei Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Yuehua Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Runtao Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Lijing Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Yunli Pei
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Huifang Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Demin Liu
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
- Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China (D.L.)
| | - Honglin Niu
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
- School of Nursing, Hebei Medical University, Shijiazhuang, Hebei Province, China (H.N.)
| | - Mei Han
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
| | - Lei Nie
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Key Laboratory of Vascular Biology in Hebei Province, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., M.H., L.N.)
- Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei Province, China (Q.F., C.Y., L.G., X.L., Y.L., C.L., W.Z., Y.Z., W.Y., Y.M., R.W., L.L., Y.P., H.W., D.L., H.N., M.H., L.N.)
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Li X, Zhu D, Zhao B, Li Q, Jin P. Alternative splicing: Therapeutic target for vasculopathy in diabetic complications. Life Sci 2025; 362:123331. [PMID: 39734014 DOI: 10.1016/j.lfs.2024.123331] [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: 08/25/2024] [Revised: 12/03/2024] [Accepted: 12/19/2024] [Indexed: 12/31/2024]
Abstract
It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.
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Affiliation(s)
- Xiaoyue Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Dong Zhu
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Bingkun Zhao
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Peisheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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