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Zhang X, Artz N, Steindler DA, Hingtgen S, Satterlee AB. Exosomes: Traversing the blood-brain barrier and their therapeutic potential in brain cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189300. [PMID: 40097050 PMCID: PMC12124962 DOI: 10.1016/j.bbcan.2025.189300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 03/07/2025] [Accepted: 03/09/2025] [Indexed: 03/19/2025]
Abstract
The blood-brain barrier (BBB) presents a major challenge for the effective delivery of therapeutic agents to the brain tumor cells from the peripheral blood circulation, making the treatment of central nervous system (CNS)-related cancers more difficult and resistant to both standard treatments and emerging therapies. Exosomes, which serve as messengers for intercellular communication throughout the body, can naturally or be modified to penetrate the BBB. Recently, exosomes have been increasingly explored as an invasive or non-invasive approach for delivering therapeutic agents to the CNS. With their low immunogenicity, ease of modification, excellent cargo protection, and inherent ability to cross the BBB, exosomes hold great promise for revolutionizing targeted therapy for CNS-related diseases, including brain cancer. In this review, we highlight recent discoveries and insights into the mechanisms exosomes use to penetrate the BBB, the methods they employ to payload diverse therapeutics, and their roles in transporting therapeutic compounds for brain cancer and other neurological disorders.
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Affiliation(s)
- Xiaopei Zhang
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Nichole Artz
- Department of Pediatric Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Dennis A Steindler
- Steindler Consulting, Boston, MA, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Shawn Hingtgen
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Andrew Benson Satterlee
- Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Eshelman Institute for Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Li X, Ma Y, Jiang Q, Zhan H, Sun X. The associations between circulating amino acids and arterial aneurysms and dissection: A bidirectional Mendelian randomization study. INTERNATIONAL JOURNAL OF CARDIOLOGY. CARDIOVASCULAR RISK AND PREVENTION 2025; 25:200388. [PMID: 40160699 PMCID: PMC11951207 DOI: 10.1016/j.ijcrp.2025.200388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 04/02/2025]
Abstract
Background Circulating amino acid levels can be altered in arterial aneurysms and dissection, but the relationships between them is unclear. The present study investigated the causal relationship between circulating amino acid levels and arterial aneurysms and dissection via bidirectional two-sample Mendelian randomization (MR). Methods A bidirectional two-sample MR analysis was used. Forward analysis was performed with amino acid levels as the exposure and arterial aneurysms and dissection as outcomes. Reverse analysis was performed with arterial aneurysms and dissection as exposures and circulating amino acid levels as outcomes. MR data were analyzed using five analytical methods: the inverse-variance weighted (IVW), MR‒Egger, weighted median, simple, and weighted methods. IVW was used as the main analytical method, and the other methods were used for supplementary analyses. Heterogeneity was assessed using Cochran's Q test, and horizontal pleiotropy was assessed using intercepts from MR‒Egger regression. The genome-wide association study (GWAS) data for circulating amino acids were obtained from the IEU open GWAS database and the GWAS Catalog database. The GWAS data for arterial aneurysms and dissection were obtained from the Finngen consortium database version R10. Results The tyrosine level was negatively correlated with other aneurysms (P = 0.00211, OR: 0.57, 95 % CI: 0.40, 0.82). Aortic dissection decreased the circulating glycine level (P = 0.00168, OR: 0.98, 95 % CI: 0.98, 0.99). Conclusion Through bidirectional MR analysis, we found that tyrosine level was negatively correlated with other aneurysms and that aortic dissection reduced circulating glycine. Our findings support a possible interaction between circulating amino acid levels and arterial aneurysms and dissection.
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Affiliation(s)
- Xiaodong Li
- Department of Interventional Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yarong Ma
- Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Qiulin Jiang
- Department of Interventional Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Huizhi Zhan
- Department of Interventional Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xiaolei Sun
- Department of Interventional Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
- Laboratory of Nucleic Acids in Medicine for National High-level Talent, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China
- Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, 646000, China
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Research Excellence, Faculty of Life Science and Medicine, King's College London, London, SE5 9NU, United Kingdom
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Sule RO, Rivera GDT, Vaidya T, Gartrell E, Gomes AV. Environmental Toxins and Oxidative Stress: The Link to Cardiovascular Diseases. Antioxidants (Basel) 2025; 14:604. [PMID: 40427486 PMCID: PMC12108754 DOI: 10.3390/antiox14050604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 05/07/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Cardiovascular diseases (CVDs) remain a leading global health concern, responsible for substantial morbidity and mortality. In recent years, as our understanding of the multifaceted nature of CVDs has increased, it has become increasingly evident that traditional risk factors alone do not account for the entirety of cardiovascular morbidity and mortality. Environmental toxins, a heterogeneous group of substances ubiquitous in our surroundings, have now entered the spotlight as offenders in the development and progression of CVDs. Environmental toxins include heavy metals, air pollutants, pesticides, and endocrine-disrupting chemicals, among others. Upon exposure, they can elicit oxidative stress, a condition characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify and repair the resulting damage. Oxidative stress triggers a cascade of events, including inflammation, endothelial dysfunction, lipid peroxidation, and vascular remodeling, which can contribute to the development of atherosclerosis, hypertension, and other cardiovascular pathologies. This article delves into the molecular mechanisms underpinning oxidative stress-mediated cardiovascular damage induced by environmental toxins, emphasizing the role of specific toxins in this process. Further research is necessary to understand how individual susceptibility and genotype influence the impact of environmental toxins on oxidative stress and the risk of CVD.
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Affiliation(s)
- Rasheed O. Sule
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA; (R.O.S.); (G.D.T.R.)
- Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Gabriela Del Toro Rivera
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA; (R.O.S.); (G.D.T.R.)
| | - Tanishq Vaidya
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA; (R.O.S.); (G.D.T.R.)
| | - Emily Gartrell
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA; (R.O.S.); (G.D.T.R.)
| | - Aldrin V. Gomes
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, USA; (R.O.S.); (G.D.T.R.)
- Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA
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Jang WB, Rethineswaran VK, Kwon SM. Targeting Mitochondrial Dysfunction to Prevent Endothelial Dysfunction and Atherosclerosis in Diabetes: Focus on the Novel Uncoupler BAM15. Int J Mol Sci 2025; 26:4603. [PMID: 40429748 PMCID: PMC12111197 DOI: 10.3390/ijms26104603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/02/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to endothelial dysfunction and accelerated atherosclerosis. Mitochondrial dysfunction, oxidative stress, and dysregulated lipid metabolism contribute to endothelial cell (EC) injury, promoting plaque formation and increasing cardiovascular disease risk. Current lipid-lowering therapies have limited effectiveness in restoring endothelial function, highlighting the need for novel strategies. Mitochondrial uncoupling has emerged as a promising approach, with BAM15-a newly identified mitochondrial uncoupler-showing potential therapeutic benefits. BAM15 enhances fatty acid oxidation (FAO), reduces reactive oxygen species, and protects ECs from hyperglycemia-induced apoptosis. Unlike conventional uncouplers, BAM15 demonstrates improved tolerability and efficacy without severe off-target effects. It restores mitochondrial function, improves endothelial survival, and supports metabolic homeostasis under hyperglycemic conditions. This review uniquely integrates emerging evidence on mitochondrial dysfunction, endothelial metabolism, and FAO to highlight the novel role of BAM15 in restoring vascular function in diabetes. We provide the first focused synthesis of BAM15's mechanistic impact on EC bioenergetics and position it within the broader landscape of mitochondrial-targeted therapies for diabetic vascular complications. Further research is needed to elucidate the molecular mechanism through which BAM15 modulates EC metabolism and to evaluate its long-term vascular effects in diabetic models.
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Affiliation(s)
- Woong Bi Jang
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Vinoth Kumar Rethineswaran
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sang-Mo Kwon
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (W.B.J.); (V.K.R.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
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Jiao Q, Xu X, Xu L, Wang Y, Pang S, Hao J, Liu X, Zhao Y, Qi W, Qin L, Huang T, Li J, Wang T. Knockdown of eIF3a alleviates pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition via TGFβ1/SMAD pathway. J Transl Med 2025; 23:524. [PMID: 40346622 PMCID: PMC12065328 DOI: 10.1186/s12967-025-06505-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 04/13/2025] [Indexed: 05/11/2025] Open
Abstract
OBJECTIVE Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vascular remodeling and involves Endothelial-to-Mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs). EndMT is a complex cell differentiation process, mainly showing the detachment of endothelial cell migration and reducing endothelial cell characteristics to varying degrees, acquiring mesenchymal cell characteristics. In addition, numerous studies have reported that eIF3a over expression plays an important role in the occurrence and development of fibrotic diseases, cancer, and degenerative lesions, however, the mechanisms of eIF3a affecting the dysfunction of pulmonary arterial endothelial cells remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of eIF3a-knockdown inhibiting EndMT by regulating TGFβ1/SMAD signal pathway in PAH. METHODS In this study, we screened the potential target genes associated with idiopathic pulmonary arterial hypertension (IPAH) by WGCNA to provide a reference for the diagnosis and treatment of PAH. By constructing WGCNA, which indicated that the blue module (module-trait associations between modules and clinical feature information were calculated to selected the optimum module) is most closely associated with IPAH, we further screened out 10 up-regulated candidate biomarker genes. Male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), AAV1-shRNA-NC group and AAV1-shRNA-eIF3a group. The eIF3a-knockdown rat model was constructed by adeno-associated virus type-1 (AAV1) infection, PAH was evaluated according to hemodynamic alteration, right heart hypertrophy and histopathological changes in the lung tissue. Hematoxylin eosin (H&E) staining was used to assess the morphological changes of pulmonary arteries in rats of each treatment group. Co-localization of eIF3a with alpha-small muscle action (α-SMA) and co-localization of eIF3a with endothelial marker (CD31) were detected by double-label immunofluorescence. Immunohistochemistry (IHC) and Western blot (WB) experiments were performed to assess the expression of eIF3a, EndMT and TGFβ1/SMAD signal related proteins. In vitro, primary rat pulmonary artery endothelial cells (PAECs) were transfected with si-eIF3a to investigate the effects of eIF3a-knockdown on hypoxia-induced EndMT in PAECs and further elucidate its underlying molecular mechanisms. RESULTS By WGCNA analysis, we screened the up-regulated hub genes of TMF1, GOLGB1, ARMC8, PRPF40 A, EIF3 A, ROCK2, EIF5B, CCP110, and KRR1 associated with PAH, and in order to verify the potential role of eIF3a in the development of pulmonary arterial hypertension, MCT-induced PAH rat model was constructed successfully. The expression of eIF3a was increased in MCT-treated lungs. Knockdown of eIF3a significantly inhibited the pulmonary arterial hypertension and vascular remodeling in MCT-induced PAH rat model, ameliorated MCT-induced increases of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Double-labeled immunofluorescence showed eIF3a was mostly co-localized with CD31, this result indicated that the development of MCT-induced PAH was related to the regulation of PAECs function (most likely associated with the change of EndMT in endothelial cells). WB showed that the expressions of EndMT related proteins were significantly increased by regulating TGFβ1/SMAD signaling pathway in MCT-induced PAH rat lung tissues, however, knockdown of eIF3a markedly attenuated these changes. In addition, we observed the same results in rat PAECs with chronic hypoxia exposure. These results indicate that eIF3a-knockdown inhibited EndMT by regulating TGFβ1/SMAD signaling pathway in PAECs, thereby improving the development of MCT-induced PAH. CONCLUSIONS Knockdown of eIF3a inhibited EndMT in PAECs regulating TGFβ1/SMAD signaling pathway, significantly alleviated the changes of RVSP, RVH and vascular remodeling in MCT-induced PAH rats, eIF3a may be a promising and novel therapeutic target for the treatment of PAH.
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Affiliation(s)
- Qiuhong Jiao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Xiufeng Xu
- Department of Geriatrics, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Longwu Xu
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Yuying Wang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Shulan Pang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jie Hao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Xiaohong Liu
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Yudan Zhao
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Wanpeng Qi
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Limin Qin
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Tao Huang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Jingtian Li
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Tao Wang
- Department of Cardiology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China.
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Grego A, Fernandes C, Fonseca I, Dias-Neto M, Costa R, Leite-Moreira A, Oliveira SM, Trindade F, Nogueira-Ferreira R. Endothelial dysfunction in cardiovascular diseases: mechanisms and in vitro models. Mol Cell Biochem 2025:10.1007/s11010-025-05289-w. [PMID: 40259179 DOI: 10.1007/s11010-025-05289-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 04/08/2025] [Indexed: 04/23/2025]
Abstract
Endothelial cells (ECs) are arranged side-by-side to create a semi-permeable monolayer, forming the inner lining of every blood vessel (micro and macrocirculation). Serving as the first barrier for circulating molecules and cells, ECs represent the main regulators of vascular homeostasis being able to respond to environmental changes, either physical or chemical signals, by producing several factors that regulate vascular tone and cellular adhesion. Healthy endothelium has anticoagulant properties that prevent the adhesion of leukocytes and platelets to the vessel walls, contributing to resistance to thrombus formation, and regulating inflammation, and vascular smooth muscle cell proliferation. Many risk factors of cardiovascular diseases (CVDs) promote the endothelial expression of chemokines, cytokines, and adhesion molecules. The resultant endothelial activation can lead to endothelial cell dysfunction (ECD). In vitro models of ECD allow the study of cellular and molecular mechanisms of disease and provide a research platform for screening potential therapeutic agents. Even though alternative models are available, such as animal models or ex vivo models, in vitro models offer higher experimental flexibility and reproducibility, making them a valuable tool for the understanding of pathophysiological mechanisms of several diseases, such as CVDs. Therefore, this review aims to synthesize the currently available in vitro models regarding ECD, emphasizing CVDs. This work will focus on 2D cell culture models (endothelial cell lines and primary ECs), 3D cell culture systems (scaffold-free and scaffold-based), and 3D cell culture models (such as organ-on-a-chip). We will dissect the role of external stimuli-chemical and mechanical-in triggering ECD.
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Affiliation(s)
- Ana Grego
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Cristiana Fernandes
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Ivo Fonseca
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Marina Dias-Neto
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Angiology and Vascular Surgery, Unidade Local de Saúde de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Raquel Costa
- Universidade Católica Portuguesa, CBQF-Centro de Biotecnologia e Química Fina-Laboratório Associado, Escola Superior de Biotecnologia, Rua Diogo Botelho 1327, 4169-005, Porto, Portugal
| | - Adelino Leite-Moreira
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
- Department of Cardiothoracic Surgery, Unidade Local de Saúde de São João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Sandra Marisa Oliveira
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Fábio Trindade
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Rita Nogueira-Ferreira
- RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.
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Zhang X, Wang Y, Han J, Zhao W, Zhang W, Li X, Chen J, Song W, Wang L. Cardiac-Focused Multi-Organ Chips: Advanced Disease Modeling, Drug Testing, and Inter-Organ Communication. Adv Biol (Weinh) 2025; 9:e2400512. [PMID: 39913111 DOI: 10.1002/adbi.202400512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 12/18/2024] [Indexed: 02/07/2025]
Abstract
Heart disease remains a leading cause of mortality worldwide, posing a significant challenge to global healthcare systems. Traditional animal models and cell culture techniques are instrumental in advancing the understanding of cardiac pathophysiology. However, these methods are limited in their ability to fully replicate the heart's intricate functions. This underscores the need for a deeper investigation into the fundamental mechanisms of heart disease. Notably, cardiac pathology is often influenced by systemic factors, with conditions in other organs contributing to disease onset and progression. Cardiac-focused multi-organ chip technology has emerged to better elucidate these complex inter-organ communications and address the limitations of current in vitro models. This technology offers a novel approach by recreating the cardiac microenvironment and integrating it with other organ systems, thereby enabling more precise disease modeling and drug toxicity assessment. This review provides a comprehensive overview of the heart's structure and function, explores the advancements in cardiac organ chip development, and highlights the applications of cardiac-focused multi-organ chips in medical research. Finally, the future potential of this technology in enhancing disease modeling and therapeutic evaluation is discussed.
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Affiliation(s)
- Xiaolong Zhang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
| | - Yushen Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
| | - Junlei Han
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
| | - Weilong Zhao
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
| | - Wenhong Zhang
- College of Mechanical Engineering, Donghua University, Shanghai, 201 620, China
| | - Xinyu Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250 021, China
| | - Jun Chen
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
| | - Wei Song
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250 021, China
| | - Li Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250 353, China
- Shandong Institute of Mechanical Design and Research, Jinan, 250 353, China
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Premarathna AD, Robal M, Bai RG, Ahmed TAE, Rjabovs V, Hincke MT, Tuvikene R. Bioactivities of Nostoc sp. polysaccharides: Anti-inflammatory, wound healing, cytoprotective, and anticoagulant effects. Int J Biol Macromol 2025; 303:140350. [PMID: 39894132 DOI: 10.1016/j.ijbiomac.2025.140350] [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: 06/25/2024] [Revised: 01/09/2025] [Accepted: 01/24/2025] [Indexed: 02/04/2025]
Abstract
Polysaccharides from various cyanobacterial species have attracted attention for their potential health benefits. In this study, polysaccharide extracts from a freshwater Nostoc sp. were explored for their potential in immunomodulation relevant to skincare, and particularly wound care. Nostoc sp. polysaccharides (NSPs) were tested in various cellular and molecular assays using RAW264.7 macrophages and skin cell lines (HDF, HaCaT). Polysaccharides from the Nostoc sp. outer layer (OL) and inner fluid (IF) significantly enhanced cell proliferation and migration of HDF. HaCaT scratch-wound healing improved with certain polysaccharide extracts. Inner fluid fractions IF-2B and IF-3B polysaccharides demonstrated anti-inflammatory effects in RAW264.7 cells, while IF-1B reduced TNF-α and IL-8 expression in HaCaT cells. TNF-α, though not promoting cell proliferation, positively impacted phagocytosis and NO production. NSPs exhibited weak anticoagulation properties, and fraction IF-1B with monomer composition (Ara/3.0: Glc/23.7: Man/20.3: GlcA/28.0) accelerated wound healing; importantly, OL-1B along with all of the IF cold and hot-extracted fractions were non-cytotoxic, suggesting significant potential for developing skin therapeutics, including pharmaceutical and cosmetic products, based on active compounds from Nostoc sp.. The study underscores the underexplored potential of Nostoc sp. extracts in skincare and highlights the potential benefits of these bioactive components for therapeutic applications.
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Affiliation(s)
- Amal D Premarathna
- School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia.
| | - Marju Robal
- School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia
| | - Renu Geetha Bai
- School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia; Chair of Biosystems Engineering, Institute of Forestry and Engineering, Estonian University of Life Sciences, Kreutzwaldi 56, Tartu 51014, Estonia
| | - Tamer A E Ahmed
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ontario K1H 8M5, Canada; School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, Ontario K1H 8M5, Canada
| | - Vitalijs Rjabovs
- National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia; Institute of Chemistry and Chemical Technology, Riga Technical University, Paula Valdena iela 3/7, LV-1048 Riga, Latvia
| | - Maxwell T Hincke
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ontario K1H 8M5, Canada; Department of Innovation in Medical Education, Faculty of Medicine, University of Ottawa, Ontario K1H 8M5, Canada
| | - Rando Tuvikene
- School of Natural Sciences and Health, Tallinn University, Narva mnt 29, 10120 Tallinn, Estonia.
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Wu J, Wang J, Pei Z, Zhu Y, Zhang X, Zhou Z, Ye C, Song M, Hu Y, Xue P, Zhao G. Endothelial senescence induced by PAI-1 promotes endometrial fibrosis. Cell Death Discov 2025; 11:89. [PMID: 40050610 PMCID: PMC11885584 DOI: 10.1038/s41420-025-02377-0] [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: 01/14/2025] [Revised: 02/07/2025] [Accepted: 02/24/2025] [Indexed: 03/09/2025] Open
Abstract
Intrauterine adhesions (IUAs), also known as Asherman's syndrome (AS), represent a significant cause of uterine infertility for which effective treatment remains elusive. The endometrium's ability to regenerate cyclically depends heavily on the growth and regression of its blood vessels. However, trauma to the endometrial basal layer can disrupt the subepithelial capillary plexus, impeding regeneration. This damage results in the replacement of native cells with fibroblasts and myofibroblasts, ultimately leading to fibrosis. Endothelial cells (ECs) play a pivotal role in the vascular system, extending beyond their traditional barrier function. Through single-cell sequencing and experimental validation, we discovered that ECs undergo senescence in IUA patients, impairing angiogenesis and fostering stromal cell fibrosis. Further analysis revealed significant interactions between ECs and PAI-1+ stromal cells. PAI-1, derived from stromal cells, promotes EC senescence via the urokinase-type plasminogen activator receptor (uPAR). Notably, prior to fibrosis onset, TGF-β upregulates PAI-1 expression in stromal cells in a SMAD dependent manner. In an IUA mouse model, inhibiting PAI-1 mitigated EC senescence and endometrial fibrosis. Our findings underscore the crucial role of EC senescence in IUA pathogenesis, contributing to vascular reduction and fibrosis. Targeting PAI-1 represents a promising therapeutic strategy to suppress EC senescence and alleviate endometrial fibrosis, offering new insights into the treatment of IUAs.
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Affiliation(s)
- Jing Wu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jie Wang
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhongrui Pei
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yaru Zhu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xier Zhang
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zihan Zhou
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chunying Ye
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Minmin Song
- Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, China
| | - Yali Hu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Pingping Xue
- Department of Reproductive Medicine Center, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
| | - Guangfeng Zhao
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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10
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Santos F, Sum H, Yan DCL, Brewer AC. Metaboloepigenetics: Role in the Regulation of Flow-Mediated Endothelial (Dys)Function and Atherosclerosis. Cells 2025; 14:378. [PMID: 40072106 PMCID: PMC11898952 DOI: 10.3390/cells14050378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
Endothelial dysfunction is the main initiating factor in atherosclerosis. Through mechanotransduction, shear stress regulates endothelial cell function in both homeostatic and diseased states. Accumulating evidence reveals that epigenetic changes play critical roles in the etiology of cardiovascular diseases, including atherosclerosis. The metabolic regulation of epigenetics has emerged as an important factor in the control of gene expression in diseased states, but to the best of our knowledge, this connection remains largely unexplored in endothelial dysfunction and atherosclerosis. In this review, we (1) summarize how shear stress (or flow) regulates endothelial (dys)function; (2) explore the epigenetic alterations that occur in the endothelium in response to disturbed flow; (3) review endothelial cell metabolism under different shear stress conditions; and (4) suggest mechanisms which may link this altered metabolism to the regulation of the endothelial epigenome by modulations in metabolite availability. We believe that metabolic regulation plays an important role in endothelial epigenetic reprogramming and could pave the way for novel metabolism-based therapeutic strategies.
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Affiliation(s)
- Francisco Santos
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
| | - Hashum Sum
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
| | | | - Alison C. Brewer
- School of Cardiovascular and Metabolic Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK; (F.S.); (H.S.)
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11
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Dobariya KH, Goyal D, Kumar H. Molecular signature-based labeling techniques for vascular endothelial cells. Acta Histochem 2025; 127:152222. [PMID: 39644518 DOI: 10.1016/j.acthis.2024.152222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 11/14/2024] [Accepted: 11/26/2024] [Indexed: 12/09/2024]
Abstract
Vascular endothelial cells (VECs) play a crucial role in the development and maintenance of vascular biology specific to the tissue types. Molecular signature-based labeling and imaging of VECs help researchers understand potential mechanisms linking VECs to disease pathology, serving as valuable biomarkers in clinical settings and trials. Labeling techniques involve selectively tagging or marking VECs for visualization. Immunolabeled employs antibodies that specifically bind to VECs markers, while fluorescent tracers or dyes can directly label VECs for imaging. Some techniques use specific carbohydrate residues on cell surface, while others employ endothelial-specific promoters to express fluorescent proteins. Additionally, VEC can be labeled with contrast agents, radiolabeled tracers, and nanoparticles. The choice of labeling technique depends on study context, including whether it involves animal models, in vitro cell cultures, or clinical applications. Herein, we discussed the various labeling methods utilized to label VECs and the techniques to visualize them.
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Affiliation(s)
- Krutika H Dobariya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Divya Goyal
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India.
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12
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Zhao T, Su Y. Mechanisms and Therapeutic Potential of Myofibroblast Transformation in Pulmonary Fibrosis. JOURNAL OF RESPIRATORY BIOLOGY AND TRANSLATIONAL MEDICINE 2025; 2:10001. [PMID: 40190620 PMCID: PMC11970920 DOI: 10.70322/jrbtm.2025.10001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and fatal disease with an increasing incidence and limited therapeutic options. It is characterized by the formation and deposition of excess extracellular matrix proteins resulting in the gradual replacement of normal lung architecture by fibrous tissue. The cellular and molecular mechanism of IPF has not been fully understood. A hallmark in IPF is pulmonary fibroblast to myofibroblast transformation (FMT). During excessive lung repair upon exposure to harmful stimuli, lung fibroblasts transform into myofibroblasts under stimulation of cytokines, chemokines, and vesicles from various cells. These mediators interact with lung fibroblasts, initiating multiple signaling cascades, such as TGFβ1, MAPK, Wnt/β-catenin, NF-κB, AMPK, endoplasmic reticulum stress, and autophagy, contributing to lung FMT. Furthermore, single-cell transcriptomic analysis has revealed significant heterogeneity among lung myofibroblasts, which arise from various cell types and are adapted to the altered microenvironment during pathological lung repair. This review provides an overview of recent research on the origins of lung myofibroblasts and the molecular pathways driving their formation, with a focus on the interactions between lung fibroblasts and epithelial cells, endothelial cells, and macrophages in the context of lung fibrosis. Based on these molecular insights, targeting the lung FMT could offer promising avenues for the treatment of IPF.
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Affiliation(s)
- Tianming Zhao
- Department of Pharmacology & Toxicology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Yunchao Su
- Department of Pharmacology & Toxicology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Research Service, Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30912, USA
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13
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Michelutti L, Tel A, Robiony M, Vinayahalingam S, Agosti E, Ius T, Gagliano C, Zeppieri M. The Properties and Applicability of Bioprinting in the Field of Maxillofacial Surgery. Bioengineering (Basel) 2025; 12:251. [PMID: 40150715 PMCID: PMC11939734 DOI: 10.3390/bioengineering12030251] [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: 02/05/2025] [Revised: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Perhaps the most innovative branch of medicine is represented by regenerative medicine. It deals with regenerating or replacing tissues damaged by disease or aging. The innovative frontier of this branch is represented by bioprinting. This technology aims to reconstruct tissues, organs, and anatomical structures, such as those in the head and neck region. This would mean revolutionizing therapeutic and surgical approaches in the management of multiple conditions in which a conspicuous amount of tissue is lost. The application of bioprinting for the reconstruction of anatomical areas removed due to the presence of malignancy would represent a revolutionary new step in personalized and precision medicine. This review aims to investigate recent advances in the use of biomaterials for the reconstruction of anatomical structures of the head-neck region, particularly those of the oral cavity. The characteristics and properties of each biomaterial currently available will be presented, as well as their potential applicability in the reconstruction of areas affected by neoplasia damaged after surgery. In addition, this study aims to examine the current limitations and challenges and to analyze the future prospects of this technology in maxillofacial surgery.
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Affiliation(s)
- Luca Michelutti
- Clinic of Maxillofacial Surgery, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy; (L.M.); (A.T.)
| | - Alessandro Tel
- Clinic of Maxillofacial Surgery, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy; (L.M.); (A.T.)
| | - Massimo Robiony
- Clinic of Maxillofacial Surgery, Head-Neck and NeuroScience Department, University Hospital of Udine, p.le S. Maria della Misericordia 15, 33100 Udine, Italy; (L.M.); (A.T.)
| | | | - Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza Spedali Civili 1, 25123 Brescia, Italy
| | - Tamara Ius
- Academic Neurosurgery, Department of Neurosciences, University of Padova, 35121 Padova, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
- Mediterranean Foundation “G.B. Morgagni”, 95125 Catania, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34100 Trieste, Italy
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14
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Ament AL, Heiner M, Hessler MC, Alexopoulos I, Steeg K, Gärtner U, Vazquez-Armendariz AI, Herold S. Endothelialized Bronchioalveolar Lung Organoids Model Endothelial Cell Responses to Injury. Am J Respir Cell Mol Biol 2025; 72:124-132. [PMID: 39226154 DOI: 10.1165/rcmb.2023-0373ma] [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: 10/27/2023] [Accepted: 09/03/2024] [Indexed: 09/05/2024] Open
Abstract
Organoid three-dimensional systems are powerful platforms to study development and disease. Recently, the complexity of lung organoid models derived from adult mouse and human stem cells has increased substantially in terms of cellular composition and structural complexity. However, a murine lung organoid system with a clear integrated endothelial compartment is still missing. Here, we describe a novel method that adds another level of intricacy to our published bronchioalveolar lung organoid (BALO) model by microinjection of FACS-sorted lung endothelial cells (ECs) into differentiated organoid cultures. Before microinjection, ECs obtained from the lung homogenate of young mice expressed typical EC markers such as CD31 and vascular endothelial cadherin and showed tube formation capacity. Following microinjection, ECs surrounded the BALO's alveolar-like compartment, aligning with type I and type II alveolar epithelial cells, as demonstrated by confocal and electron microscopy. Notably, expression of Car4 and Aplnr was as well detected, suggesting the presence of EC microvascular phenotypes in the cultured ECs. Moreover, upon epithelial cell injury by LPS and influenza A virus, endothelialized BALOs released proinflammatory cytokines, leading to the upregulation ICAM-1 (intercellular adhesion molecule 1) in ECs. In summary, we characterized for the first time an organoid model that incorporates ECs into the alveolar structures of lung organoids, not only increasing our previous model's cellular and structural complexity but also providing a suitable niche to model lung endothelium responses to injury ex vivo.
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Affiliation(s)
- Anna-Lena Ament
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Organoid Biology, Life & Medical Sciences Institute (LIMES), Transdisciplinary Research Area (TRA) Life and Health, University of Bonn, Bonn, Germany
| | - Monika Heiner
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - Marie Christin Hessler
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
| | - Ioannis Alexopoulos
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Cardio-Pulmonary Institute (CPI), Giessen, Germany
- Member of the German Center for Lung Research (DZL), Institute of Lung Health (ILH), Giessen, Germany
| | - Katharina Steeg
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Department of Diagnostic and Interventional Radiology, University Hospital Giessen, and
| | - Ulrich Gärtner
- Institute for Anatomy and Cell Biology, Justus-Liebig-University Giessen, Giessen, Germany
| | - Ana Ivonne Vazquez-Armendariz
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Organoid Biology, Life & Medical Sciences Institute (LIMES), Transdisciplinary Research Area (TRA) Life and Health, University of Bonn, Bonn, Germany
| | - Susanne Herold
- Department of Medicine V (Internal Medicine, Infectious Diseases and Infection Control), Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
- Cardio-Pulmonary Institute (CPI), Giessen, Germany
- Member of the German Center for Lung Research (DZL), Institute of Lung Health (ILH), Giessen, Germany
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15
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Jimenez-Trinidad FR, Calvo-Gomez S, Sabaté M, Brugaletta S, Campuzano V, Egea G, Dantas AP. Extracellular Vesicles as Mediators of Endothelial Dysfunction in Cardiovascular Diseases. Int J Mol Sci 2025; 26:1008. [PMID: 39940780 PMCID: PMC11816526 DOI: 10.3390/ijms26031008] [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: 12/20/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors-such as sex and aging-along with significant cardiovascular risk factors, influence this process. The review covers studies ranging from the first description of EVs in 1945 to contemporary insights into their biological roles in intercellular signaling and endothelial dysfunction. A comprehensive analysis of peer-reviewed articles and reviews indexed in the PubMed database was conducted to compile the information. Initially, Medical Subject Headings (MeSH) terms included keywords aimed at providing general knowledge about the role of EVs in the regulation of endothelial signaling, such as "extracellular vesicles", "endothelium", and "intercellular signaling". Subsequently, terms related to the pathophysiological implications of EV interactions with endothelial dysfunction and cardiovascular disease were added, including "cardiovascular disease", "sex", "aging", "atherosclerosis", "obesity", and "diabetes". Additionally, the potential applications of EVs in cardiovascular disease were explored using the MeSH terms "extracellular vesicles", "cardiovascular disease", "biomarker", and "therapeutic strategy". The results of this bibliographical review reveal that EVs have the capacity to induce various cellular responses within the cardiovascular system and play a significant role in the complex landscape of endothelial dysfunction and cardiovascular disease. The composition of the EV cargo is subject to modification by pathophysiological conditions such as sex, aging, and cardiovascular risk factors, which result in a complex regulatory influence on endothelial function and neighboring cells when released from a dysfunctional endothelium. Moreover, the data suggest that this field still requires further exploration, as EV biology is continuously evolving, presenting a dynamic and engaging area for research. A deeper understanding of the molecular cargo involved in EV-endothelium interactions could yield valuable biomarkers for monitoring cardiovascular disease progression and facilitate the development of innovative bioengineered therapeutic strategies to enhance patient outcomes.
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Affiliation(s)
- Francisco Rafael Jimenez-Trinidad
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Sergi Calvo-Gomez
- Department of Biomedical Sciences, School of Medicine, Universitat Internacional de Catalunya (UIC), 08195 Barcelona, Spain;
| | - Manel Sabaté
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Salvatore Brugaletta
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Victoria Campuzano
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Rare Diseases Biomedical Research Network Center (CIBERER), Instituto de Salud Carlos III, 28222 Madrid, Spain
| | - Gustavo Egea
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center of Medical Genetics, University of Antwerpen, 2659 Edegem, Belgium
| | - Ana Paula Dantas
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain; (F.R.J.-T.); (V.C.); (G.E.)
- Institut Clínic Cardiovascular (ICCV), Hospital Clínic, 08036 Barcelona, Spain; (M.S.); (S.B.)
- Division of Respiratory, Cardiovascular and Renal Pathobiology and Bioengineering, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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16
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Wang W, Su W, Han J, Song W, Li X, Xu C, Sun Y, Wang L. Microfluidic platforms for monitoring cardiomyocyte electromechanical activity. MICROSYSTEMS & NANOENGINEERING 2025; 11:4. [PMID: 39788940 PMCID: PMC11718118 DOI: 10.1038/s41378-024-00751-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/04/2024] [Accepted: 06/26/2024] [Indexed: 01/12/2025]
Abstract
Cardiovascular diseases account for ~40% of global deaths annually. This situation has revealed the urgent need for the investigation and development of corresponding drugs for pathogenesis due to the complexity of research methods and detection techniques. An in vitro cardiomyocyte model is commonly used for cardiac drug screening and disease modeling since it can respond to microphysiological environmental variations through mechanoelectric feedback. Microfluidic platforms are capable of accurate fluid control and integration with analysis and detection techniques. Therefore, various microfluidic platforms (i.e., heart-on-a-chip) have been applied for the reconstruction of the physiological environment and detection of signals from cardiomyocytes. They have demonstrated advantages in mimicking the cardiovascular structure and function in vitro and in monitoring electromechanical signals. This review presents a summary of the methods and technologies used to monitor the contractility and electrophysiological signals of cardiomyocytes within microfluidic platforms. Then, applications in common cardiac drug screening and cardiovascular disease modeling are presented, followed by design strategies for enhancing physiology studies. Finally, we discuss prospects in the tissue engineering and sensing techniques of microfluidic platforms.
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Affiliation(s)
- Wei Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 250353, Jinan, China
- Shandong Institute of Mechanical Design and Research, 250353, Jinan, China
| | - Weiguang Su
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 250353, Jinan, China
- Shandong Institute of Mechanical Design and Research, 250353, Jinan, China
| | - Junlei Han
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 250353, Jinan, China
- Shandong Institute of Mechanical Design and Research, 250353, Jinan, China
| | - Wei Song
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
| | - Xinyu Li
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, China
| | - Chonghai Xu
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 250353, Jinan, China
- Shandong Institute of Mechanical Design and Research, 250353, Jinan, China
| | - Yu Sun
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, M5S3G8, Canada.
| | - Li Wang
- School of Mechanical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 250353, Jinan, China.
- Shandong Institute of Mechanical Design and Research, 250353, Jinan, China.
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17
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Espinosa G, Salinas-Varas C, Rojas-Barón L, Preußer C, Pogge von Strandmann E, Gärtner U, Conejeros I, Hermosilla C, Taubert A. Bovine PMN responses to extracellular vesicles released by Besnoitia besnoiti tachyzoites and B. besnoiti-infected host cells. Front Immunol 2024; 15:1509355. [PMID: 39749330 PMCID: PMC11693690 DOI: 10.3389/fimmu.2024.1509355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/03/2024] [Indexed: 01/04/2025] Open
Abstract
Bovine besnoitiosis is a re-emerging cattle disease caused by the apicomplexan parasite Besnoitia besnoiti, which severely affects individual animal welfare and profitability in cattle industry. We recently showed that B. besnoiti tachyzoite exposure to bovine polymorphonuclear neutrophils (PMN) effectively triggers neutrophil extracellular trap (NET) formation, leading to parasite immobilization hampering host cell infection. So far, the triggers of this defense mechanism remain unclear. Emerging evidence indicates that extracellular vesicles (EVs) modulate PMN effector functions, such as ROS production or NET formation. Therefore, we tested whether exposure of bovine PMN to EVs from different cellular sources affects classical PMN effector functions and cytokine/chemokine secretion. EVs were isolated from B. besnoiti-infected and non-infected host cells (bovine umbilical vein endothelial cells, BUVEC), from tachyzoite-exposed bovine PMN and from B. besnoiti tachyzoites. EV concentration and size was determined by Nano-Flow cytometry and EV nature was confirmed by both classical EV markers (CD9 and CD81) and transmission electron microscopy (TEM). Overall, PMN stimulation with both BUVEC- and tachyzoite-derived EVs significantly induced extracellular DNA release while EVs from PMN failed to affect NET formation. BUVEC and tachyzoite EV-driven NET formation was confirmed microscopically by the presence of DNA decorated with neutrophil elastase (NE) and histones in typical NET structures. Moreover, confocal microscopy revealed EVs to be internalized by bovine PMN. Referring to PMN activation, EVs from the different cellular sources all failed to affect glycolytic or oxidative responses of bovine PMN as detected by Seahorse®-based analytics and luminol-based chemoluminescence, thereby denying any role of NADPH oxidase (NOX) activity in EV-driven NET formation. Finally, exposure to B. besnoiti-infected BUVEC-derived EVs induced IL-1β and IL-6 release, but failed to drive CXCL8 release of bovine PMN. Hence, we overall demonstrated that EVs of selected cellular origin owned the capacity to trigger NOX-independent NET formation, were incorporated by PMN and selectively fostered IL-1β and IL-6 release.
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Affiliation(s)
- Gabriel Espinosa
- Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany
| | | | - Lisbeth Rojas-Barón
- Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany
| | - Christian Preußer
- Core Facility Extracellular Vesicles, Center for Tumor Biology and Immunology, Philipps University of Marburg, Marburg, Germany
| | - Elke Pogge von Strandmann
- Core Facility Extracellular Vesicles, Center for Tumor Biology and Immunology, Philipps University of Marburg, Marburg, Germany
| | - Ulrich Gärtner
- Institute of Anatomy and Cell Biology, Justus Liebig University Giessen, Giessen, Germany
| | - Iván Conejeros
- Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany
| | - Carlos Hermosilla
- Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany
| | - Anja Taubert
- Institute of Parasitology, Justus Liebig University Giessen, Giessen, Germany
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18
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Citrin KM, Chaube B, Fernández-Hernando C, Suárez Y. Intracellular endothelial cell metabolism in vascular function and dysfunction. Trends Endocrinol Metab 2024:S1043-2760(24)00296-0. [PMID: 39672762 DOI: 10.1016/j.tem.2024.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/04/2024] [Accepted: 11/11/2024] [Indexed: 12/15/2024]
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels that is crucial for vascular function and homeostasis. They regulate vascular tone, oxidative stress, and permeability. Dysfunction leads to increased permeability, leukocyte adhesion, and thrombosis. ECs undergo metabolic changes in conditions such as wound healing, cancer, atherosclerosis, and diabetes, and can influence disease progression. We discuss recent research that has revealed diverse intracellular metabolic pathways in ECs that are tailored to their functional needs, including lipid handling, glycolysis, and fatty acid oxidation (FAO). Understanding EC metabolic signatures in health and disease will be crucial not only for basic biology but can also be exploited when designing new therapies to target EC-related functions in different vascular diseases.
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Affiliation(s)
- Kathryn M Citrin
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
| | - Balkrishna Chaube
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Indian Institute of Technology Dharwad, Karnataka, India
| | - Carlos Fernández-Hernando
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
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19
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Mandal P, Kanthlal SK. Vascular targeting of constituents of commonly used spices and its molecular interactions in endothelial dysfunction: A review. PHYTOCHEMISTRY REVIEWS 2024; 23:1805-1834. [DOI: 10.1007/s11101-024-09939-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 02/23/2024] [Indexed: 05/12/2025]
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20
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Che Mohd Nassir CMN, Che Ramli MD, Jaffer U, Abdul Hamid H, Mehat MZ, Mohamad Ghazali M, Kottakal Cheriya EN. Neurological Sequelae of Post-COVID-19 Fatigue: A Narrative Review of Dipeptidyl Peptidase IV-Mediated Cerebrovascular Complications. Curr Issues Mol Biol 2024; 46:13565-13582. [PMID: 39727939 PMCID: PMC11727395 DOI: 10.3390/cimb46120811] [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: 10/11/2024] [Revised: 11/09/2024] [Accepted: 11/17/2024] [Indexed: 12/28/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) has been a global pandemic affecting millions of people's lives, which has led to 'post-COVID-19 fatigue'. Alarmingly, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) not only infects the lungs but also influences the heart and brain. Endothelial cell dysfunction and hypercoagulation, which we know occur with this infection, lead to thrombo-inflammation that can manifest as many myriad cardio-cerebrovascular disorders, such as brain fog, fatigue, cognitive dysfunction, etc. Additionally, SARS-CoV-2 has been associated with oxidative stress, protein aggregation, cytokine storm, and mitochondrial dysfunction in neurodegenerative diseases. Accordingly, the identification of molecular targets involved in these actions could provide strategies for preventing and treating this disease. In particular, the very common enzyme dipeptidyl peptidase IV (DPPIV) has recently been identified as a candidate co-receptor for the cell entry of the SARS-CoV-2 virus with its involvement in infection. In addition, DPPIV has been reported as a co-receptor for some viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV). It mediates immunologic reactions and diseases such as type 2 diabetes mellitus, obesity, and hypertension, which have been considered the prime risk factors for stroke among other types of cardio-cerebrovascular diseases. Unlike angiotensin-converting enzyme 2 (ACE2), DPPIV has been implicated in aggravating the course of infection due to its disruptive effect on inflammatory signaling networks and the neuro-glia-vascular unit. Regarding the neurological, physiological, and molecular grounds governing post-COVID-19 fatigue, this review focuses on DPPIV as one of such reasons that progressively establishes cerebrovascular grievances following SARS-CoV infection.
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Affiliation(s)
- Che Mohd Nasril Che Mohd Nassir
- Department of Anatomy and Physiology, Faculty of Medicine, School of Basic Medical Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia;
| | - Muhammad Danial Che Ramli
- Faculty of Health and Life Sciences, Management and Science University, Shah Alam 40150, Selangor, Malaysia
| | - Usman Jaffer
- Kulliyyah of Islamic Revealed Knowledge and Human Sciences, International Islamic University Malaysia, Kuala Lumpur 50728, Malaysia;
| | - Hafizah Abdul Hamid
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia; (H.A.H.); (M.Z.M.)
| | - Muhammad Zulfadli Mehat
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia; (H.A.H.); (M.Z.M.)
| | - Mazira Mohamad Ghazali
- Department of Anatomy and Physiology, Faculty of Medicine, School of Basic Medical Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu 20400, Terengganu, Malaysia;
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Kelantan, Malaysia
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21
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Chen N, Gao J, Zhao H, Liu S, Zhou Y, Liu Y, Zhang Z, Yang S. Stratifying by Blood Glucose Levels to Predict Hemorrhagic Transformation Risk Post-Rt-PA in Acute Ischemic Stroke. Clin Interv Aging 2024; 19:1807-1818. [PMID: 39525875 PMCID: PMC11550918 DOI: 10.2147/cia.s482060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Objective Stroke is a leading cause of disability and mortality worldwide, posing a significant public health challenge. While treatment of acute ischemic stroke (AIS) with recombinant tissue plasminogen activator (rt-PA) is effective but increases the risk of hemorrhagic transformation (HT). This study aimed to explore the determinants of HT in AIS patients treated with rt-PA and investigate the association between blood glucose levels and HT risk. Methods We conducted a prospective cohort study at the First Affiliated Hospital of Harbin Medical University from January 2018 to December 2021. Patients with AIS and who received rt-PA within 4.5 hours of symptom onset were included. Demographic, clinical, laboratory, and imaging data were collected. Results Of the 426 patients, 15% experienced HT post-rt-PA, occurred more frequently in patients with a history of cardiac embolism, higher prethrombolysis NIHSS scores, and elevated fasting blood glucose (FBG) levels. The frequency of HT was higher in non-diabetic patients with FBG levels ≥7.0 mmol/L compared to diabetic patients. Elevated blood glucose levels were significantly associated with HT, regardless of diabetes history. Conclusion The findings suggest importance of precise glycemic control during AIS management to improve patient outcomes, particularly in non-diabetic patients. Future protocols for AIS treatment should incorporate these findings to reduce HT risks. Further large-scale studies are needed to confirm these associations and guide clinical practices.
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Affiliation(s)
- Nan Chen
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Jiadi Gao
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Hanshu Zhao
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Sihan Liu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Yubing Zhou
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Yushuang Liu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Zhongling Zhang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
| | - Shanshan Yang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China
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22
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Hossen F, Geng X, Sun GY, Yao X, Lee JC. Oligomeric Amyloid-β and Tau Alter Cell Adhesion Properties and Induce Inflammatory Responses in Cerebral Endothelial Cells Through the RhoA/ROCK Pathway. Mol Neurobiol 2024; 61:8759-8776. [PMID: 38561558 PMCID: PMC11445398 DOI: 10.1007/s12035-024-04138-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 03/19/2024] [Indexed: 04/04/2024]
Abstract
Dysfunction of cerebral endothelial cells (CECs) has been implicated in the pathology of Alzheimer's disease (AD). Despite evidence showing cytotoxic effects of oligomeric amyloid-β (oAβ) and Tau (oTau) in the central nervous system, their direct effects on CECs have not been fully investigated. In this study, we examined the direct effects of oAβ, oTau, and their combination on cell adhesion properties and inflammatory responses in CECs. We found that both oAβ and oTau increased cell stiffness, as well as the p-selectin/Sialyl-LewisX (sLeX) bonding-mediated membrane tether force and probability of adhesion in CECs. Consistent with these biomechanical alterations, treatments with oAβ or oTau also increased actin polymerization and the expression of p-selectin at the cell surface. These toxic oligomeric peptides also triggered inflammatory responses, including upregulations of p-NF-kB p65, IL-1β, and TNF-α. In addition, they rapidly activated the RhoA/ROCK pathway. These biochemical and biomechanical changes were further enhanced by the treatment with the combination of oAβ and oTau, which were significantly suppressed by Fasudil, a specific inhibitor for the RhoA/ROCK pathway. In conclusion, our data suggest that oAβ, oTau, and their combination triggered subcellular mechanical alterations and inflammatory responses in CECs through the RhoA/ROCK pathway.
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Affiliation(s)
- Faruk Hossen
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Xue Geng
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Grace Y Sun
- Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
| | - Xincheng Yao
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - James C Lee
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
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23
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Wang H, Cui L, Luo Y, Chen H, Liu X, Shi Q. Inflammation-responsive PCL/gelatin microfiber scaffold with sustained nitric oxide generation and heparin release for blood-contacting implants. Int J Biol Macromol 2024; 281:136544. [PMID: 39414218 DOI: 10.1016/j.ijbiomac.2024.136544] [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: 06/25/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 10/18/2024]
Abstract
Delayed endothelialization, the excessive proliferation of smooth muscle cells (SMCs), and persistent inflammation are the main reasons for the implantation failure of blood-contacting materials. To overcome this problem, an inflammation-responsive, core-shell structured microfiber scaffold is developed using polycaprolactone (PCL), selenocystamine-modified gelatin (Gel-Se), L-ascorbyl 6-palmitate (AP), and dexamethasone as the fiber shell, with poly (l-lysine) (PLL) and heparin incorporated in the fiber core. Superhydrophilic microfiber scaffolds exhibit antifouling properties that inhibit protein adsorption and blood cell adhesion, thereby effectively mitigating the risk of acute thrombosis. The continuous release of heparin and sustained generation of nitric oxide (NO) through the catalytic decomposition of S-nitrosothiols by selenocystamine lead to a biomimetic endothelial function for the enhancement of blood compatibility. The inflammation-responsive compound AP can detoxify excess reactive oxygen species (ROS) while controlling the release of dexamethasone to reduce chronic inflammation. We demonstrate the ability of microfiber scaffolds to reduce thrombotic and inflammatory complications, inhibit SMC proliferation, and promote rapid endothelialization both in vitro and ex vivo. Hence, microfiber scaffolds are robust and promising for blood-contacting implants with enhanced antithrombogenicity and anti-inflammatory capabilities.
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Affiliation(s)
- Haozheng Wang
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, China.
| | - Lei Cui
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated the Third Center Hospital, Tianjin, China
| | - Honghong Chen
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiaoju Liu
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qiang Shi
- State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, China.
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24
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Hirano A, Kadoya H, Takasu M, Iwakura T, Kajimoto E, Tatsugawa R, Matsuura T, Kurumatani H, Yamamoto T, Kidokoro K, Kishi S, Nagasu H, Sasaki T, Kashihara N. Effects of Beraprost on Intestinal Microcirculation and Barrier Function in a Mouse Model of Renal Failure. Microcirculation 2024; 31:e12889. [PMID: 39348278 DOI: 10.1111/micc.12889] [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: 03/06/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 10/02/2024]
Abstract
OBJECTIVE Endothelial dysfunction plays an important role in the pathogenesis of chronic kidney disease. Prostacyclin (PGI2), an endothelial cell-produced endogenous prostaglandin, plays a crucial role in maintaining endothelial function. However, its effects on intestinal microcirculation and barrier function are not fully understood. We hypothesized that PGI2 improves intestinal microcirculation and barrier function via endothelial protective effects. METHODS ICR and ICGN (a spontaneous nephrotic model) mice were used in this study. Intestinal microcirculation was visualized in vivo to investigate PGI2 effects. Beraprost served as PGI2. PGI2 administration spanned 4 weeks, following which we assessed its influence on intestinal endothelial, intestinal barrier, and renal functions. RESULTS We visualized intestinal microcirculation and endothelial glycocalyx in the intestinal blood vessels. Beraprost administration induced a 1.2-fold dilatation of the vascular diameter of the small intestine. Intestinal blood flow in ICGN mice was significantly reduced compared that in ICR mice but improved with beraprost administration. ICGN mice exhibited reduced serum albumin levels, decreased ambulation, an imbalance in intestinal reactive oxygen species (ROS)/nitric oxide (NO), and impaired tight junctions; all were ameliorated by beraprost administration. CONCLUSIONS Beraprost improves intestinal microcirculation and barrier function by ameliorating ROS/NO imbalances, thereby reducing physical inactivity during renal failure.
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Affiliation(s)
- Akira Hirano
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hiroyuki Kadoya
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
- Department of General Geriatric Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Masanobu Takasu
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Tsukasa Iwakura
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Eriko Kajimoto
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Rie Tatsugawa
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | | | | | - Toshiya Yamamoto
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
- Department of General Geriatric Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kengo Kidokoro
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Seiji Kishi
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Hajime Nagasu
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Tamaki Sasaki
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Okayama, Japan
- Department of Medical Science, Kawasaki Medical School, Kurashiki, Okayama, Japan
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25
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Wesley UV, Dempsey RJ. Neuro-molecular perspectives on long COVID-19 impacted cerebrovascular diseases - a role for dipeptidyl peptidase IV. Exp Neurol 2024; 380:114890. [PMID: 39038507 DOI: 10.1016/j.expneurol.2024.114890] [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: 05/15/2024] [Revised: 07/01/2024] [Accepted: 07/14/2024] [Indexed: 07/24/2024]
Abstract
The coronavirus disease 2019 (COVID-19) has caused immense devastation globally with many outcomes that are now extending to its long-term sequel called long COVID. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects not only lungs, but also the brain and heart in association with endothelial cell dysfunction, coagulation abnormalities, and thrombosis leading to cardio-cerebrovascular health issues. Fatigue, cognitive decline, and brain fog are common neurological symptoms in persisting long COVID. Neurodegenerative processes and SARS-CoV-2 infection manifest overlapping molecular mechanisms, such as cytokine dysregulation, inflammation, protein aggregation, mitochondrial dysfunction, and oxidative stress. Identifying the key molecules in these processes is of importance for prevention and treatment of this disease. In particular, Dipeptidyl peptidase IV (DPPIV), a multifunctional peptidase has recently drawn attention as a potential co-receptor for SARS-CoV-2 infection and cellular entry. DPPIV is a known co-receptor for some other COVID viruses including MERS-Co-V. DPPIV regulates the immune responses, obesity, glucose metabolism, diabetes, and hypertension that are associated with cerebrovascular manifestations including stroke. DPPIV likely worsens persisting COVID-19 by disrupting inflammatory signaling pathways and the neurovascular system. This review highlights the neurological, cellular and molecular processes concerning long COVID, and DPPIV as a potential key factor contributing to cerebrovascular dysfunctions following SARS-CoV-2 infection.
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Affiliation(s)
- Umadevi V Wesley
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
| | - Robert J Dempsey
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA
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26
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Deng X, Wu Q, Liu Y. Eucommia ulmoidesOliv. leaves flavonoids attenuate methylglyoxal-induced endothelial cell apoptosis in vitro and in vivo by upregulating AKT-Nrf2 signaling and downregulating oxidative stress. Food Sci Nutr 2024; 12:7938-7953. [PMID: 39479661 PMCID: PMC11521679 DOI: 10.1002/fsn3.4416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/19/2024] [Accepted: 08/04/2024] [Indexed: 11/02/2024] Open
Abstract
Methylglyoxal (MGO) triggers oxidative stress responses in vascular endothelial cells, leading to apoptosis linked to diabetic vascular complications. Total flavonoids of Eucommia ulmoides leaves (TFEL) display antioxidant activity, yet its prevention of MGO-induced apoptosis and mechanisms are unclear. Our study used western blotting and ELISA to evaluate protein levels and enzyme activities. Cell viability and apoptosis were evaluated using CCK8 assay and PE Annexin V/7-AAD double staining. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured using fluorescence probes. Vascular pathological changes and apoptosis were analyzed through H&E and TUNEL staining. In vitro, MGO-stimulated human umbilical vein endothelial cells (HUVECs) were treated with varying TFEL concentrations. Our results demonstrated that TFEL significantly enhanced cell viability, reduced apoptosis, downregulated caspase-3 activity, and Bax/Bcl-2 ratio. Moreover, TFEL markedly suppressed MGO-induced ROS and malondialdehyde (MDA) production while restoring antioxidant enzyme activity and MMP. TFEL pretreatment promoted the expression of p-Akt, Nrf2, and HO-1 proteins. Pharmacological inhibition of p-Akt significantly suppressed the upregulation of Nrf2 and HO-1 protein levels mediated by TFEL. Consistently, pharmacological inhibition of Nrf2 or p-Akt partially abrogated the protective effects of TFEL against MGO-induced damage in HUVECs. In vivo studies revealed that TFEL (100 and 200 mg/kg) partially restored antioxidant capacity and reduced aortic thickness and apoptosis in MGO-injured mice. In conclusion, the findings indicate that TFEL mitigates MGO-induced apoptosis via activation of p-Akt/Nrf2/HO-1 and scavenging of oxidative stress, highlighting its potential in diabetic vascular complication management.
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Affiliation(s)
- Xin Deng
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of EducationSouthwest Medical UniversityLuzhouChina
| | - Qianfeng Wu
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Youping Liu
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
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27
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Krüger-Genge A, Harb K, Braune S, Jung CHG, Westphal S, Bär S, Mauger O, Küpper JH, Jung F. Effects of Arthrospira platensis on Human Umbilical Vein Endothelial Cells. Life (Basel) 2024; 14:1253. [PMID: 39459553 PMCID: PMC11508656 DOI: 10.3390/life14101253] [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: 07/24/2024] [Revised: 09/03/2024] [Accepted: 09/12/2024] [Indexed: 10/28/2024] Open
Abstract
Atherosclerosis is initiated by injury or damage to the vascular endothelial cell monolayer. Therefore, the early repair of the damaged vascular endothelium by a proliferation of neighbouring endothelial cells is important to prevent atherosclerosis and thrombotic events. Arthrospira platensis (AP) has been used as a dietary supplement, mainly due to its high content of vitamins, minerals, amino acids, and pigments such as chlorophylls, carotenoids, and phycocyanin, ingredients with antioxidant, anti-inflammatory, and anti-thrombotic properties. Therefore, in this prospective, placebo-controlled, data-driven, sample-size-estimated in vitro study, we tested whether an aqueous extract of AP at different concentrations (50, 100, and 200 µg/mL) had an effect on the different cellular parameters of human umbilical vein endothelial cells. Therefore, cell impedance measurement and cell proliferation were measured to investigate the monolayer formation. In addition, cell viability, integrity, and metabolism were analysed to evaluate singular cellular functions, especially the antithrombotic state. Furthermore, cell-cell and cell-substrate interactions were observed. The highest proliferation was achieved after the addition of 100 µg/mL. This was consistently confirmed by two independent optical experiments in cell cultures 48 h and 85 h after seeding and additionally by an indirect test. At this concentration, the activation or dysfunction of HUVECs was completely prevented, as confirmed by prostacyclin and interleukin-6 levels. In conclusion, in this study, AP induced a significant increase in HUVEC proliferation without inducing an inflammatory response but altered the hemostasiological balance in favour of prostacyclin over thromboxane, thereby creating an antithrombotic state. Thus, APE could be applied in the future as an accelerator of endothelial cell proliferation after, e.g., stent placement or atherosclerosis.
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Affiliation(s)
- Anne Krüger-Genge
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Kudor Harb
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Steffen Braune
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
| | - Conrad H. G. Jung
- Carbon Biotech, Social Enterprise Stiftungs AG, 01968 Senftenberg, Germany
| | - Sophia Westphal
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Stefanie Bär
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Olivia Mauger
- Life Science and Bioprocesses, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany; (K.H.); (S.W.); (S.B.); (O.M.)
| | - Jan-Heiner Küpper
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
- Carbon Biotech, Social Enterprise Stiftungs AG, 01968 Senftenberg, Germany
| | - Friedrich Jung
- Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany (J.-H.K.); (F.J.)
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28
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Chen L, Bai H, Zhao J, Zhang P, Zhang X, Kong D, Dong C, Zhang W. Lipid emulsion attenuates vasodilation by decreasing intracellular calcium and nitric oxide in vascular endothelial cells. Heliyon 2024; 10:e37353. [PMID: 39296045 PMCID: PMC11408769 DOI: 10.1016/j.heliyon.2024.e37353] [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: 04/10/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 09/21/2024] Open
Abstract
Lipid emulsion (LE), a widely used parenteral nutrition, exhibits a well-documented ability to reverse the vasodilatory effects induced by acetylcholine in blood vessels. However, the specific mechanisms underlying this action are not yet fully understood. This study aimed to elucidate the mechanism by which LE reverses vasodilation in vitro through dose-response curve experiments, calcium imaging, and fluorescence assays. The results revealed a significant attenuation of acetylcholine (Ach)-induced vasodilation in rat thoracic aortic rings following LE exposure. In human aortic endothelial cells, pretreatment with LE significantly suppressed ATP-induced calcium elevation. This suppression persisted even after elimination of extracellular calcium with a calcium chelator. Moreover, LE pre-exposure reduced the intracellular calcium concentration ([Ca2+]i) elevation in endothelial cells following cyclopiazonic acid (CPA) treatment, suggesting enhanced endoplasmic reticulum (ER) calcium reuptake. Additionally, nitric oxide (NO) fluorescence assays showed a decrease in NO production upon ATP stimulation post-LE pretreatment of endothelial cells. Taken together, these results indicate that the reversal of vasodilation by LE may involve enhanced ER calcium uptake, leading to a reduction in intracellular calcium concentration and suppression of NO (key vasodilatory agent) synthesis.
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Affiliation(s)
- Ling Chen
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
- Nursing Department, The Fourth Hospital of Hebei Medical University, China
| | - Hui Bai
- Department of Cardiac Ultrasound, The Second Hospital of Hebei Medical University, China
| | - Jing Zhao
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
| | - Panpan Zhang
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
| | - Xinhua Zhang
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
| | - Dezhi Kong
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
| | - Changzheng Dong
- Department of Neurosurgery, Hebei General Hospital, Shijiazhuang, Hebei Province, 050000, China
| | - Wei Zhang
- Department of Pharmacology, Institution of Chinese Integrative Medicine, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, China
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Desanlis J, Gordon D, French C, Calveyrac C, Cottin F, Gernigon M. Effects of occlusion pressure on hemodynamic responses recorded by near-infrared spectroscopy across two visits. Front Physiol 2024; 15:1441239. [PMID: 39324105 PMCID: PMC11422206 DOI: 10.3389/fphys.2024.1441239] [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: 05/30/2024] [Accepted: 08/21/2024] [Indexed: 09/27/2024] Open
Abstract
Ischemic Preconditioning (IPC) has emerged as a promising approach to mitigate the impact of hypoxia on physiological functions. However, the heterogeneity of occlusion pressures for inducing arterial occlusion has led to inconsistent hemodynamic outcomes across studies. This study aims to evaluate the peripheral hemodynamic responses to partial and total blood-flow occlusions on the left arm at rest, using absolute or individualized pressures, on two occasions. Thirty-five young males volunteered to participate in this study. IPC procedure (3 × 7-min) was performed on the left upper arm with cuff pressures at 50 mmHg (G1), 50 mmHg over the systolic blood pressure (SBP + 50 mmHg) (G2) or 250 mmHg (G3). NIRS-derived parameters were assessed for each occlusion and reperfusion phase in the brachioradialis. Results showed a significantly lower magnitude of deoxygenation (TSIAUC) for G1 compared to G2 (-1959.2 ± 1417.4 vs. -10908.1 ± 1607.5, P < 0.001) and G3 -1959.2 ± 1417.4 vs. -11079.3 ± 1828.1, P < 0.001), without differences between G2 and G3. However, G3 showed a significantly faster reoxygenation only for tissue saturation index (TSIslope) compared to G2 (1.3 ± 0.1 vs. 1.0 ± 0.2, P = 0.010), but without differences in the speed of recovery of deoxyhemoglobin [(HHb) slope], or in the magnitude of post-occlusive hyperemia (PORH). Besides TSI reoxygenation speed, G2 and G3 elicit comparable resting hemodynamic responses measured by NIRS. Thus, this study highlights the practicality and effectiveness of using relative occlusion pressures based on systolic blood pressure (SBP) rather than relying on excessively high absolute pressures.
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Affiliation(s)
- Julien Desanlis
- CIAMS, Université Paris-Saclay, Orsay, France
- CIAMS, Université d’Orléans, Orléans, France
- Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom
| | - Dan Gordon
- Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom
| | - Chloe French
- CIAMS, Université Paris-Saclay, Orsay, France
- CIAMS, Université d’Orléans, Orléans, France
- Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, United Kingdom
| | - Camille Calveyrac
- CIAMS, Université Paris-Saclay, Orsay, France
- CIAMS, Université d’Orléans, Orléans, France
| | - François Cottin
- CIAMS, Université Paris-Saclay, Orsay, France
- CIAMS, Université d’Orléans, Orléans, France
| | - Marie Gernigon
- CIAMS, Université Paris-Saclay, Orsay, France
- CIAMS, Université d’Orléans, Orléans, France
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Allen MF, Park SY, Kwak YS. Oxidative stress and vascular dysfunction: Potential therapeutic targets and therapies in peripheral artery disease. Microvasc Res 2024; 155:104713. [PMID: 38914307 DOI: 10.1016/j.mvr.2024.104713] [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: 11/13/2023] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024]
Abstract
Peripheral artery disease (PAD) is the manifestation of atherosclerosis characterized by the accumulation of plaques in the arteries of the lower limbs. Interestingly, growing evidence suggests that the pathology of PAD is multifaceted and encompasses both vascular and skeletal muscle dysfunctions, which contributes to blunted physical capabilities and diminished quality of life. Importantly, it has been suggested that many of these pathological impairments may stem from blunted reduction-oxidation (redox) handling. Of note, in those with PAD, excessive production of reactive oxygen species (ROS) outweighs antioxidant capabilities resulting in oxidative damage, which may have systemic consequences. It has been suggested that antioxidant supplementation may be able to assist in handling ROS. However, the activation of various ROS production sites makes it difficult to determine the efficacy of these antioxidant supplements. Therefore, this review focuses on the common cellular mechanisms that facilitate ROS production and discusses how excessive ROS may impair vascular and skeletal muscle function in PAD. Furthermore, we provide insight for current and potential antioxidant therapies, specifically highlighting activation of the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway as a potential pharmacological therapy to combat ROS accumulation and aid in vascular function, and physical performance in patients with PAD. Altogether, this review provides a better understanding of excessive ROS in the pathophysiology of PAD and enhances our perception of potential therapeutic targets that may improve vascular function, skeletal muscle function, walking capacity, and quality of life in patients with PAD.
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Affiliation(s)
- Michael F Allen
- School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, United States of America
| | - Song-Young Park
- School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, United States of America; Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Yi-Sub Kwak
- Department of Physical Education, College of Arts, Design, and Sports Science, Dong-Eui University, Busan, Republic of Korea.
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31
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Yang T, Peng J, Zhang Z, Chen Y, Liu Z, Jiang L, Jin L, Han M, Su B, Li Y. Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review. Front Immunol 2024; 15:1438984. [PMID: 39206200 PMCID: PMC11349558 DOI: 10.3389/fimmu.2024.1438984] [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: 05/27/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Extracellular histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.
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Affiliation(s)
- Tinghang Yang
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Jing Peng
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Zhuyun Zhang
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Yu Chen
- State Key Laboratory of Polymer Materials Engineering, College of Polymer Science and Engineering, Sichuan University, Chengdu, China
| | - Zhihui Liu
- Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, China
| | - Luojia Jiang
- Jiujiang City Key Laboratory of Cell Therapy, Department of Nephrology, Jiujiang No. 1 People’s Hospital, Jiujiang, China
| | - Lunqiang Jin
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Mei Han
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
| | - Baihai Su
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
- Med+ Biomaterial Institute of West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China
- Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Yupei Li
- Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China
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32
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Florido MHC, Ziats NP. Endothelial dysfunction and cardiovascular diseases: The role of human induced pluripotent stem cells and tissue engineering. J Biomed Mater Res A 2024; 112:1286-1304. [PMID: 38230548 DOI: 10.1002/jbm.a.37669] [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: 08/28/2023] [Revised: 12/07/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024]
Abstract
Cardiovascular disease (CVD) remains to be the leading cause of death globally today and therefore the need for the development of novel therapies has become increasingly important in the cardiovascular field. The mechanism(s) behind the pathophysiology of CVD have been laboriously investigated in both stem cell and bioengineering laboratories. Scientific breakthroughs have paved the way to better mimic cell types of interest in recent years, with the ability to generate any cell type from reprogrammed human pluripotent stem cells. Mimicking the native extracellular matrix using both organic and inorganic biomaterials has allowed full organs to be recapitulated in vitro. In this paper, we will review techniques from both stem cell biology and bioengineering which have been fruitfully combined and have fueled advances in the cardiovascular disease field. We will provide a brief introduction to CVD, reviewing some of the recent studies as related to the role of endothelial cells and endothelial cell dysfunction. Recent advances and the techniques widely used in both bioengineering and stem cell biology will be discussed, providing a broad overview of the collaboration between these two fields and their overall impact on tissue engineering in the cardiovascular devices and implications for treatment of cardiovascular disease.
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Affiliation(s)
- Mary H C Florido
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Harvard Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Nicholas P Ziats
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
- Departments of Biomedical Engineering and Anatomy, Case Western Reserve University, Cleveland, Ohio, USA
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Larionov A, Hammer CM, Fiedler K, Filgueira L. Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease. Cells 2024; 13:1276. [PMID: 39120307 PMCID: PMC11312403 DOI: 10.3390/cells13151276] [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] [Revised: 07/19/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.
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Affiliation(s)
- Alexey Larionov
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Christian Manfred Hammer
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
| | - Klaus Fiedler
- Independent Researcher, CH-1700 Fribourg, Switzerland;
| | - Luis Filgueira
- Faculty of Science and Medicine, Anatomy, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland; (C.M.H.); (L.F.)
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Han Q, Yu Y, Liu X, Guo Y, Shi J, Xue Y, Li Y. The Role of Endothelial Cell Mitophagy in Age-Related Cardiovascular Diseases. Aging Dis 2024:AD.2024.0788. [PMID: 39122456 DOI: 10.14336/ad.2024.0788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Aging is a major risk factor for cardiovascular diseases (CVD), and mitochondrial autophagy impairment is considered a significant physiological change associated with aging. Endothelial cells play a crucial role in maintaining vascular homeostasis and function, participating in various physiological processes such as regulating vascular tone, coagulation, angiogenesis, and inflammatory responses. As aging progresses, mitochondrial autophagy impairment in endothelial cells worsens, leading to the development of numerous cardiovascular diseases. Therefore, regulating mitochondrial autophagy in endothelial cells is vital for preventing and treating age-related cardiovascular diseases. However, there is currently a lack of systematic reviews in this area. To address this gap, we have written this review to provide new research and therapeutic strategies for managing aging and age-related cardiovascular diseases.
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Affiliation(s)
- Quancheng Han
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yiding Yu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiujuan Liu
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yonghong Guo
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jingle Shi
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yitao Xue
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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35
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Duranova H, Kuzelova L, Borotova P, Simora V, Fialkova V. Human Umbilical Vein Endothelial Cells as a Versatile Cellular Model System in Diverse Experimental Paradigms: An Ultrastructural Perspective. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2024; 30:419-439. [PMID: 38817111 DOI: 10.1093/mam/ozae048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/15/2024] [Accepted: 04/30/2024] [Indexed: 06/01/2024]
Abstract
Human umbilical vein endothelial cells (HUVECs) are primary cells isolated from the vein of an umbilical cord, extensively used in cardiovascular studies and medical research. These cells, retaining the characteristics of endothelial cells in vivo, serve as a valuable cellular model system for understanding vascular biology, endothelial dysfunction, pathophysiology of diseases such as atherosclerosis, and responses to different drugs or treatments. Transmission electron microscopy (TEM) has been a cornerstone in revealing the detailed architecture of multiple cellular model systems including HUVECs, allowing researchers to visualize subcellular organelles, membrane structures, and cytoskeletal elements. Among them, the endoplasmic reticulum, Golgi apparatus, mitochondria, and nucleus can be meticulously examined to recognize alterations indicative of cellular responses to various stimuli. Importantly, Weibel-Palade bodies are characteristic secretory organelles found in HUVECs, which can be easily distinguished in the TEM. These distinctive structures also dynamically react to different factors through regulated exocytosis, resulting in complete or selective release of their contents. This detailed review summarizes the ultrastructural features of HUVECs and highlights the utility of TEM as a pivotal tool for analyzing HUVECs in diverse research frameworks, contributing valuable insights into the comprehension of HUVEC behavior and enriching our knowledge into the complexity of vascular biology.
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Affiliation(s)
- Hana Duranova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
| | - Lenka Kuzelova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
- Faculty of Biotechnology and Food Sciences, Institute of Biotechnology, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
| | - Petra Borotova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
| | - Veronika Simora
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
| | - Veronika Fialkova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, 949 76 Nitra, Slovak Republic
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Li Y, Li YJ, Fang X, Chen DQ, Yu WQ, Zhu ZQ. Peripheral inflammation as a potential mechanism and preventive strategy for perioperative neurocognitive disorder under general anesthesia and surgery. Front Cell Neurosci 2024; 18:1365448. [PMID: 39022312 PMCID: PMC11252726 DOI: 10.3389/fncel.2024.1365448] [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: 01/04/2024] [Accepted: 06/19/2024] [Indexed: 07/20/2024] Open
Abstract
General anesthesia, as a commonly used medical intervention, has been widely applied during surgical procedures to ensure rapid loss of consciousness and pain relief for patients. However, recent research suggests that general anesthesia may be associated with the occurrence of perioperative neurocognitive disorder (PND). PND is characterized by a decline in cognitive function after surgery, including impairments in attention, memory, learning, and executive functions. With the increasing trend of population aging, the burden of PND on patients and society's health and economy is becoming more evident. Currently, the clinical consensus tends to believe that peripheral inflammation is involved in the pathogenesis of PND, providing strong support for further investigating the mechanisms and prevention of PND.
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Affiliation(s)
- Yuan Li
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Department of Anesthesiology, Mianyang Hospital of Traditional Chinese Medicine, Mianyang, China
| | - Ying-Jie Li
- Department of General Surgery, Mianyang Hospital of Traditional Chinese Medicine, Mianyang, China
| | - Xu Fang
- Department of Anesthesiology, Nanchong Central Hospital, The Second Clinical Medical School of North Sichuan Medical College, Zunyi, China
| | - Dong-Qin Chen
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wan-Qiu Yu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhao-Qiong Zhu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Early Clinical Research Ward of Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Burboa PC, Corrêa-Velloso JC, Arriagada C, Thomas AP, Durán WN, Lillo MA. Impact of Matrix Gel Variations on Primary Culture of Microvascular Endothelial Cell Function. Microcirculation 2024; 31:e12859. [PMID: 38818977 PMCID: PMC11227414 DOI: 10.1111/micc.12859] [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: 08/31/2023] [Revised: 04/05/2024] [Accepted: 04/25/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE The endothelium regulates crucial aspects of vascular function, including hemostasis, vasomotor tone, proliferation, immune cell adhesion, and microvascular permeability. Endothelial cells (ECs), especially in arterioles, are pivotal for flow distribution and peripheral resistance regulation. Investigating vascular endothelium physiology, particularly in microvascular ECs, demands precise isolation and culturing techniques. METHODS Freshly isolated ECs are vital for examining protein expression, ion channel behavior, and calcium dynamics. Establishing primary endothelial cell cultures is crucial for unraveling vascular functions and understanding intact microvessel endothelium roles. Despite the significance, detailed protocols and comparisons with intact vessels are scarce in microvascular research. We developed a reproducible method to isolate microvascular ECs, assessing substrate influence by cultivating cells on fibronectin and gelatin matrix gels. This comparative approach enhances our understanding of microvascular endothelial cell biology. RESULTS Microvascular mesenteric ECs expressed key markers (VE-cadherin and eNOS) in both matrix gels, confirming cell culture purity. Under uncoated conditions, ECs were undetected, whereas proteins linked to smooth muscle cells and fibroblasts were evident. Examining endothelial cell (EC) physiological dynamics on distinct matrix substrates revealed comparable cell length, shape, and Ca2+ elevations in both male and female ECs on gelatin and fibronectin matrix gels. Gelatin-cultured ECs exhibited analogous membrane potential responses to acetylcholine (ACh) or adenosine triphosphate (ATP), contrasting with their fibronectin-cultured counterparts. In the absence of stimulation, fibronectin-cultured ECs displayed a more depolarized resting membrane potential than gelatin-cultured ECs. CONCLUSIONS Gelatin-cultured ECs demonstrated electrical behaviors akin to intact endothelium from mouse mesenteric arteries, thus advancing our understanding of endothelial cell behavior within diverse microenvironments.
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Affiliation(s)
- Pía C. Burboa
- Department of Pharmacology; Physiology & Neuroscience; New Jersey Medical School; Rutgers, The State University of New Jersey, Newark, NJ 07103, U.S.A
| | - Juliana C. Corrêa-Velloso
- Department of Pharmacology; Physiology & Neuroscience; New Jersey Medical School; Rutgers, The State University of New Jersey, Newark, NJ 07103, U.S.A
| | - Cecilia Arriagada
- Departamento de Ciencias Biológicas y Químicas, Facultad de Medicina y Ciencia, Universidad San Sebastián, Campus Los Leones, Lota 2465, Providencia, Santiago, Chile
| | - Andrew P. Thomas
- Department of Pharmacology; Physiology & Neuroscience; New Jersey Medical School; Rutgers, The State University of New Jersey, Newark, NJ 07103, U.S.A
| | - Walter N. Durán
- Department of Pharmacology; Physiology & Neuroscience; New Jersey Medical School; Rutgers, The State University of New Jersey, Newark, NJ 07103, U.S.A
| | - Mauricio A. Lillo
- Department of Pharmacology; Physiology & Neuroscience; New Jersey Medical School; Rutgers, The State University of New Jersey, Newark, NJ 07103, U.S.A
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Fang Y, Zhu Y, Zhang M, Ying H, Xing Y. TLQP-21 facilitates diabetic wound healing by inducing angiogenesis through alleviating high glucose-induced injuries on endothelial progenitor cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4993-5004. [PMID: 38183447 PMCID: PMC11166834 DOI: 10.1007/s00210-023-02808-8] [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: 08/13/2023] [Accepted: 10/20/2023] [Indexed: 01/08/2024]
Abstract
Diabetes mellitus (DM) is a metabolic disease with multiple complications, including diabetic cutaneous wounds, which lacks effective treating strategies and severely influences the patients' life. Endothelial progenitor cells (EPCs) are reported to participate in maintaining the normal function of blood vessels, which plays a critical role in diabetic wound healing. TLQP-21 is a VGF-derived peptide with promising therapeutic functions on DM. Herein, the protective effects of TLQP-21 on diabetic cutaneous wound and the underlying mechanism will be investigated. Cutaneous wound model was established in T2DM mice, followed by administering 120 nmol/kg and 240 nmol/kg TLQP-21 once a day for 12 days. Decreased wound closure, reduced number of capillaries and EPCs, declined tube formation function of EPCs, and inactivated PI3K/AKT/eNOS signaling in EPCs were observed in T2DM mice, which were sharply alleviated by TLQP-21. Normal EPCs were extracted from mice and stimulated by high glucose (HG), followed by incubated with TLQP-21 in the presence or absence of LY294002, an inhibitor of PI3K. The declined cell viability, increased apoptotic rate, reduced number of migrated cells, declined migration distance, repressed tube formation function, and inactivated PI3K/AKT/eNOS signaling observed in HG-treated EPCs were markedly reversed by TLQP-21, which were dramatically abolished by the co-culture of LY294002. Collectively, TLQP-21 facilitated diabetic wound healing by inducing angiogenesis through alleviating HG-induced injuries on EPCs.
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Affiliation(s)
- Yaqi Fang
- Laboratory Medicine Center, Department of Clinical Laboratory, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Gongshu District, Hangzhou Zhejiang, 310053, China
| | - Yuexia Zhu
- Laboratory Medicine Center, Department of Clinical Laboratory, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Gongshu District, Hangzhou Zhejiang, 310053, China
| | - Minxia Zhang
- Laboratory Medicine Center, Department of Clinical Laboratory, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Gongshu District, Hangzhou Zhejiang, 310053, China
| | - Hua Ying
- Laboratory Medicine Center, Department of Clinical Laboratory, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Gongshu District, Hangzhou Zhejiang, 310053, China
| | - Yubo Xing
- Department of Endocrinology, Affiliated People's Hospital, Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou Medical College, No. 158, Shangtang Road, Gongshu District, Hangzhou Zhejiang, 310053, China.
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Singam A, Bhattacharya C, Park S. Aging-related changes in the mechanical properties of single cells. Heliyon 2024; 10:e32974. [PMID: 38994100 PMCID: PMC11238009 DOI: 10.1016/j.heliyon.2024.e32974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/08/2024] [Accepted: 06/12/2024] [Indexed: 07/13/2024] Open
Abstract
Mechanical properties, along with biochemical and molecular properties, play crucial roles in governing cellular function and homeostasis. Cellular mechanics are influenced by various factors, including physiological and pathological states, making them potential biomarkers for diseases and aging. While several methods such as AFM, particle-tracking microrheology, optical tweezers/stretching, magnetic tweezers/twisting cytometry, microfluidics, and micropipette aspiration have been widely utilized to measure the mechanical properties of single cells, our understanding of how aging affects these properties remains limited. To fill this knowledge gap, we provide a brief overview of the commonly used methods to measure single-cell mechanical properties. We then delve into the effects of aging on the mechanical properties of different cell types. Finally, we discuss the importance of studying cellular viscous and viscoelastic properties as well as aging induced by different stressors to gain a deeper understanding of the aging process and aging-related diseases.
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Affiliation(s)
- Amarnath Singam
- Department of Mechanical Engineering, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA
| | - Chandrabali Bhattacharya
- Department of Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA
- Interdisciplinary Biomedical Engineering Program, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA
| | - Seungman Park
- Department of Mechanical Engineering, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA
- Interdisciplinary Biomedical Engineering Program, University of Nevada, Las Vegas, Las Vegas, NV, 89154, USA
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40
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Bjorgvinsdottir O, Ferguson SJ, Snorradottir BS, Gudjonsson T, Wuertz-Kozak K. The influence of physical and spatial substrate characteristics on endothelial cells. Mater Today Bio 2024; 26:101060. [PMID: 38711934 PMCID: PMC11070711 DOI: 10.1016/j.mtbio.2024.101060] [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: 12/30/2023] [Revised: 03/10/2024] [Accepted: 04/13/2024] [Indexed: 05/08/2024] Open
Abstract
Cardiovascular diseases are a main cause of death worldwide, leading to a growing demand for medical devices to treat this patient group. Central to the engineering of such devices is a good understanding of the biology and physics of cell-surface interactions. In existing blood-contacting devices, such as vascular grafts, the interaction between blood, cells, and material is one of the main limiting factors for their long-term durability. An improved understanding of the material's chemical- and physical properties as well as its structure all play a role in how endothelial cells interact with the material surface. This review provides an overview of how different surface structures influence endothelial cell responses and what is currently known about the underlying mechanisms that guide this behavior. The structures reviewed include decellularized matrices, electrospun fibers, pillars, pits, and grated surfaces.
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Affiliation(s)
- Oddny Bjorgvinsdottir
- Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland
| | - Stephen J. Ferguson
- Institute for Biomechanics, ETH Zurich, Gloriastrasse 37 / 39, 8092, Zurich, Switzerland
| | | | - Thorarinn Gudjonsson
- Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland
| | - Karin Wuertz-Kozak
- Department of Biomedical Engineering, Rochester Institute of Technology (RIT), 160 Lomb Memorial Drive Bldg. 73, Rochester, NY, 14623, USA
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41
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Zhang Y, Feng Y, Zhou S, Gao S, Xiong B, Gao X, Song Y, Liu L, Wang C, Yang Y. Establishment of a model of LPS-induced inflammatory injury in human aortic endothelial cells. Biomed Pharmacother 2024; 174:116576. [PMID: 38593707 DOI: 10.1016/j.biopha.2024.116576] [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: 01/30/2024] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 04/11/2024] Open
Abstract
PURPOSE We aim to establish an LPS-induced human aortic endothelial cells (HAECs) inflammatory injury model and explore the optimal conditions for inducing its injury. We expect to provide modeling references for the related experiments of vascular inflammatory diseases. METHODS HAECs were cultured in vitro and treated with different concentrations of lipopolysaccharide (LPS) (0.1, 1, 10, 50, 100 μg/mL) for 6, 12, and 24 h to establish the HAECs inflammatory injury model. The cell viability was determined by CCK-8 assay; the expression levels of inflammatory cytokines in the cells were detected by RT-PCR;the apoptosis rate of the cells was detected by flow cytometry. RESULTS ① Within 24 h of LPS treatment, the cell viability of the 0.1 and 1 μg/mL groups showed an overall increasing trend with time, while the cell viability of the 10, 50, and 100 μg/mL groups increased first and then decreased with time, and the cell viability of 50 and 100 μg/mL groups was significantly lower than the normal control group at 24 h (P<0.01). ② RT-PCR results showed that after 50 and 100 μg/mL LPS for 24 h, the inflammatory cytokines all showed an apparent upward trend compared with the normal control group (P<0.05), which was more significant in the 100 μg/mL group. ③ After 100 μg/mL LPS for 24 h, the apoptotic necrosis rate of HAECs was higher than the normal control group (P<0.01). CONCLUSIONS This experiment successfully established a HAECs injury model, indicating that the optimal conditions for inducing injury are an LPS concentration of 100 μg/mL and a treatment time of 24 h.
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Affiliation(s)
- Yan Zhang
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Yudi Feng
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Suoni Zhou
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shuochen Gao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Bo Xiong
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xueyan Gao
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yi Song
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Lin Liu
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Chengzeng Wang
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Ying Yang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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Lee JS, Kim G, Lee JH, Ryu JY, Oh EJ, Kim HM, Kwak S, Hur K, Chung HY. MicroRNA-135b-5p Is a Pathologic Biomarker in the Endothelial Cells of Arteriovenous Malformations. Int J Mol Sci 2024; 25:4888. [PMID: 38732107 PMCID: PMC11084653 DOI: 10.3390/ijms25094888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 04/23/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.
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Affiliation(s)
- Joon Seok Lee
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
| | - Gyeonghwa Kim
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41199, Republic of Korea;
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Jong Ho Lee
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
| | - Jeong Yeop Ryu
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
| | - Eun Jung Oh
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Hyun Mi Kim
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Suin Kwak
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Keun Hur
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41199, Republic of Korea;
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ho Yun Chung
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; (J.S.L.); (J.H.L.); (J.Y.R.); (E.J.O.); (H.M.K.); (S.K.)
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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43
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Shi Y, Ji S, Xu Y, Ji J, Yang X, Ye B, Lou J, Tao T. Global trends in research on endothelial cells and sepsis between 2002 and 2022: A systematic bibliometric analysis. Heliyon 2024; 10:e23599. [PMID: 38173483 PMCID: PMC10761786 DOI: 10.1016/j.heliyon.2023.e23599] [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: 04/15/2023] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 01/05/2024] Open
Abstract
Sepsis is a systemic syndrome involving physiological, pathological, and biochemical abnormalities precipitated by infection and is a major global public health problem. Endothelial cells (ECs) dysfunction is a major contributor to sepsis-induced multiple organ failure. This bibliometric analysis aimed to identify and characterize the status, evolution of the field, and new research trends of ECs and sepsis over the past 20 years. For this analysis, the Web of Science Core Collection database was searched to identify relevant publications on ECs in sepsis published between January 1, 2002, and December 31, 2022. Microsoft Excel 2021, VOSviewer software, CiteSpace software, and the online analysis platform of literature metrology (http://bibliometric.com) were used to visualize the trends of publications' countries/regions, institutions, authors, journals, and keywords. In total, 4200 articles were identified and screened, primarily originating from 86 countries/regions and 3489 institutions. The USA was the leading contributor to this research field, providing 1501 articles (35.74 %). Harvard University's scientists were the most prolific, with 129 articles. Overall, 21,944 authors were identified, among whom Bae Jong Sup was the most prolific, contributing 129 publications. Additionally, Levi Marcel was the most frequently co-cited author, appearing 538 times. The journals that published the most articles were SHOCK, CRITICAL CARE MEDICINE, and PLOS ONE, accounting for 10.79 % of the total. The current emerging hotspots are concentrated on "endothelial glycocalyx," "NLRP3 inflammasome," "extracellular vesicle," "biomarkers," and "COVID-19," among others. In conclusion, this study provides a comprehensive overview of the scientific productivity and emerging research trends in the field of ECs in sepsis. The evidence supporting the significant role of ECs in both physiological and pathological responses to sepsis is continuously growing. More in-depth studies of the molecular mechanisms underlying sepsis-induced endothelial dysfunction and EC-targeted therapies are warranted in the future.
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Affiliation(s)
- Yue Shi
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
- Graduate of China Medical University, Shenyang, China
| | - Shunpan Ji
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
- Graduate of China Medical University, Shenyang, China
| | - Yuhai Xu
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
| | - Jun Ji
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
| | - Xiaoming Yang
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
| | - Bo Ye
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
- Graduate of China Medical University, Shenyang, China
| | - Jingsheng Lou
- Department of Anesthesiology, The General Hospital of the People's Liberation Army, Beijing, China
| | - Tianzhu Tao
- Department of Anesthesiology, Air Force Medical Center, Beijing, China
- Graduate of China Medical University, Shenyang, China
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44
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Chandel S, Kumaragurubaran R, Giri H, Dixit M. Isolation and Culture of Human Umbilical Vein Endothelial Cells (HUVECs). Methods Mol Biol 2024; 2711:147-162. [PMID: 37776455 DOI: 10.1007/978-1-0716-3429-5_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2023]
Abstract
This protocol describes a simple and an economical method for isolation of endothelial cells from human umbilical vein. Umbilical cord is easily available postpartum following informed consent, and the method for its collection is noninvasive with few ethical concerns. Thus, umbilical vein is an ideal source for isolation of endothelial cells of human origin. Endothelial cells are isolated from umbilical vein by collagenase digestion. This is followed by their culture on extracellular matrix (ECM) protein coated tissue culture flasks in presence of endothelial cell growth medium. In the last few decades, human umbilical vein endothelial cells (HUVECs) have come to be regarded as a standard model system by vascular biologists to understand general principles of endothelial cell biology and dysfunction. Here, we describe isolation, culture, as well as validation of HUVECs.
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Affiliation(s)
- Shivam Chandel
- Laboratory of Vascular Biology, Centre of Excellence in Molecular Medicine, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras , Chennai, India
| | - Rathnakumar Kumaragurubaran
- Single Cell Genomics, Cincinnati Children's Hospital Medical Centre , University of Cincinnati School of Medicine , Cincinnati, OH, USA
| | - Hemant Giri
- Oklahoma Medical Research Foundation , Oklahoma City, OK, USA
| | - Madhulika Dixit
- Laboratory of Vascular Biology, Centre of Excellence in Molecular Medicine, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras , Chennai, India.
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45
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Katoh K. Effects of Mechanical Stress on Endothelial Cells In Situ and In Vitro. Int J Mol Sci 2023; 24:16518. [PMID: 38003708 PMCID: PMC10671803 DOI: 10.3390/ijms242216518] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Endothelial cells lining blood vessels are essential for maintaining vascular homeostasis and mediate several pathological and physiological processes. Mechanical stresses generated by blood flow and other biomechanical factors significantly affect endothelial cell activity. Here, we review how mechanical stresses, both in situ and in vitro, affect endothelial cells. We review the basic principles underlying the cellular response to mechanical stresses. We also consider the implications of these findings for understanding the mechanisms of mechanotransducer and mechano-signal transduction systems by cytoskeletal components.
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Affiliation(s)
- Kazuo Katoh
- Laboratory of Human Anatomy and Cell Biology, Faculty of Health Sciences, Tsukuba University of Technology, Tsukuba 305-8521, Japan
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46
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Valentini A, Cardillo C, Della Morte D, Tesauro M. The Role of Perivascular Adipose Tissue in the Pathogenesis of Endothelial Dysfunction in Cardiovascular Diseases and Type 2 Diabetes Mellitus. Biomedicines 2023; 11:3006. [PMID: 38002006 PMCID: PMC10669084 DOI: 10.3390/biomedicines11113006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/27/2023] [Accepted: 11/05/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs) representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review, we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.
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Affiliation(s)
- Alessia Valentini
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Carmine Cardillo
- Department of Aging, Policlinico A. Gemelli IRCCS, 00168 Roma, Italy;
- Department of Translational Medicine and Surgery, Catholic University, 00168 Rome, Italy
| | - David Della Morte
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
| | - Manfredi Tesauro
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; (A.V.); (D.D.M.)
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47
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Fanoodi A, Maharati A, Akhlaghipour I, Rahimi HR, Moghbeli M. MicroRNAs as the critical regulators of tumor angiogenesis in liver cancer. Pathol Res Pract 2023; 251:154913. [PMID: 37931431 DOI: 10.1016/j.prp.2023.154913] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/25/2023] [Accepted: 10/26/2023] [Indexed: 11/08/2023]
Abstract
Liver cancer is one of the most common malignancies in human digestive system. Despite the recent therapeutic methods, there is a high rate of mortality among liver cancer patients. Late diagnosis in the advanced tumor stages can be one of the main reasons for the poor prognosis in these patients. Therefore, investigating the molecular mechanisms of liver cancer can be helpful for the early stage tumor detection and treatment. Vascular expansion in liver tumors can be one of the important reasons for poor prognosis and aggressiveness. Therefore, anti-angiogenic drugs are widely used in liver cancer patients. MicroRNAs (miRNAs) have key roles in the regulation of angiogenesis in liver tumors. Due to the high stability of miRNAs in body fluids, these factors are widely used as the non-invasive diagnostic and prognostic markers in cancer patients. Regarding, the importance of angiogenesis during liver tumor growth and invasion, in the present review, we discussed the role of miRNAs in regulation of angiogenesis in these tumors. It has been reported that miRNAs mainly exert an anti-angiogenic function by regulation of tumor microenvironment, transcription factors, and signaling pathways in liver tumors. This review can be an effective step to suggest the miRNAs for the non-invasive early detection of malignant and invasive liver tumors.
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Affiliation(s)
- Ali Fanoodi
- Student Research Committee, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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48
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Luan J, Ji X, Liu L. PPARγ in Atherosclerotic Endothelial Dysfunction: Regulatory Compounds and PTMs. Int J Mol Sci 2023; 24:14494. [PMID: 37833942 PMCID: PMC10572723 DOI: 10.3390/ijms241914494] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
The formation of atherosclerotic plaques is one of the main sources of cardiovascular disease. In addition to known risk factors such as dyslipidemia, diabetes, obesity, and hypertension, endothelial dysfunction has been shown to play a key role in the formation and progression of atherosclerosis. Peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor belonging to the steroid superfamily, is expressed in the aorta and plays a critical role in protecting endothelial function. It thereby serves as a target for treating both diabetes and atherosclerosis. Although many studies have examined endothelial cell disorders in atherosclerosis, the role of PPARγ in endothelial dysfunction is still not well understood. In this review, we summarize the possible mechanisms of action behind PPARγ regulatory compounds and post-translational modifications (PTMs) of PPARγ in the control of endothelial function. We also explore the potential use of endothelial PPARγ-targeted agents in the prevention and treatment of atherosclerosis.
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Affiliation(s)
| | | | - Longhua Liu
- School of Exercise and Health, Shanghai University of Sport, Shanghai 200082, China
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49
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May J, Mitchell JA, Jenkins RG. Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis. J Clin Invest 2023; 133:e172058. [PMID: 37712420 PMCID: PMC10503802 DOI: 10.1172/jci172058] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
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50
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Xue J, Zhang Z, Sun Y, Jin D, Guo L, Li X, Zhao D, Feng X, Qi W, Zhu H. Research Progress and Molecular Mechanisms of Endothelial Cells Inflammation in Vascular-Related Diseases. J Inflamm Res 2023; 16:3593-3617. [PMID: 37641702 PMCID: PMC10460614 DOI: 10.2147/jir.s418166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
Endothelial cells (ECs) are widely distributed inside the vascular network, forming a vital barrier between the bloodstream and the walls of blood vessels. These versatile cells serve myriad functions, including the regulation of vascular tension and the management of hemostasis and thrombosis. Inflammation constitutes a cascade of biological responses incited by biological, chemical, or physical stimuli. While inflammation is inherently a protective mechanism, dysregulated inflammation can precipitate a host of vascular pathologies. ECs play a critical role in the genesis and progression of vascular inflammation, which has been implicated in the etiology of numerous vascular disorders, such as atherosclerosis, cardiovascular diseases, respiratory diseases, diabetes mellitus, and sepsis. Upon activation, ECs secrete potent inflammatory mediators that elicit both innate and adaptive immune reactions, culminating in inflammation. To date, no comprehensive and nuanced account of the research progress concerning ECs and inflammation in vascular-related maladies exists. Consequently, this review endeavors to synthesize the contributions of ECs to inflammatory processes, delineate the molecular signaling pathways involved in regulation, and categorize and consolidate the various models and treatment strategies for vascular-related diseases. It is our aspiration that this review furnishes cogent experimental evidence supporting the established link between endothelial inflammation and vascular-related pathologies, offers a theoretical foundation for clinical investigations, and imparts valuable insights for the development of therapeutic agents targeting these diseases.
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Affiliation(s)
- Jiaojiao Xue
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Ziwei Zhang
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Yuting Sun
- Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China
| | - Di Jin
- Department of Nephrology, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Liming Guo
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Xiaochun Feng
- Department of Nephropathy and Rheumatology in Children, Children’s Medical Center, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Wenxiu Qi
- Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Haoyu Zhu
- Department of Nephropathy and Rheumatology in Children, Children’s Medical Center, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China
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