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Zhu IY, Lloyd A, Critchley WR, Saikia Q, Jade D, Divan A, Zeqiraj E, Harrison MA, Brown CJ, Ponnambalam S. Structure and function of MDM2 and MDM4 in health and disease. Biochem J 2025; 482:BCJ20240757. [PMID: 39960347 DOI: 10.1042/bcj20240757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/28/2025] [Accepted: 01/31/2025] [Indexed: 05/09/2025]
Abstract
Both mouse double-minute 2 (MDM2), an E3 ubiquitin ligase, and its closely related paralog, MDM4, which lacks E3 activity, play central roles in cellular homeostasis. MDM-linked dysfunction is associated with an increased risk of oncogenesis, primarily through targeting the tumor suppressor protein p53 for ubiquitination and degradation. Recent studies have revealed multifaceted roles of MDM proteins that are p53 independent with implications for their oncogenic properties. This review aims to provide an overview of MDM2 and MDM4, by assessing gene and protein structure and implications for protein-protein interactions and functions in cell and animal physiology. We also explore MDM2 and MDM4 role(s) in angiogenesis, a critical feature of solid tumor growth and progression. Finally, we discuss the current landscape in the development of MDM2 and MDM4 inhibitors for cancer therapy.
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Affiliation(s)
- Ivy Yiyi Zhu
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Alec Lloyd
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - William R Critchley
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Queen Saikia
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Dhananjay Jade
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
- School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, U.K
| | - Aysha Divan
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Elton Zeqiraj
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Michael A Harrison
- School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, U.K
| | - Christopher J Brown
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore
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Mani AM, Lamin V, Peach RC, Friesen EH, Wong T, Singh MV, Dokun AO. miRNA-6236 Regulation of Postischemic Skeletal Muscle Angiogenesis. J Am Heart Assoc 2024:e035923. [PMID: 39604034 DOI: 10.1161/jaha.124.035923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Peripheral arterial disease affects >200 million people worldwide and is characterized by impaired blood flow to the lower extremities. There are no effective medical treatments available. Using the mouse hind-limb ischemia model and miRNA sequencing, we identified a novel miRNA, miR-6236, whose expression significantly elevated in ischemic mouse limbs compared with nonischemic limbs. The role of miR-6236 in general or in postischemic angiogenesis is not known. Here we describe its role using in vivo and in vitro models of peripheral arterial disease. METHODS AND RESULTS In primary mouse and human endothelial cells, we studied the effect of simulated ischemia on miR-6236 expression and assessed its role in cell viability, apoptosis, migration, and tube formation during ischemia. Furthermore, we developed miR-6236 null mice and tested its role in postischemic perfusion recovery using the hind-limb ischemia model. Lastly, using bioinformatics and gene expression analysis, we identified putative angiogenic miR-6236 targets. In vitro simulated ischemia-enhanced miR-6236 expression in mouse and human endothelial cells, whereas its inhibition improved viability, migration, tube formation, and reduced apoptosis. In vivo ischemic mouse skeletal muscle tissue showed higher miR-6236 expression compared with nonischemic muscles. Loss of miR-6236 improved impaired postischemic perfusion recovery and poor angiogenesis associated with streptozotocin-induced diabetes in mice. Six of the 8 miR-6236 predicted angiogenic target mRNAs showed expression consistent with regulation by miR-6236 in ischemic skeletal muscle. CONCLUSIONS Our results show for the first time that miR-6236 plays a key role in regulating postischemic perfusion recovery and angiogenesis.
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Affiliation(s)
- Arul M Mani
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Victor Lamin
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Ronan C Peach
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Eli H Friesen
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Thomas Wong
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Madhu V Singh
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
| | - Ayotunde O Dokun
- Division of Endocrinology and Metabolism, Carver College of Medicine University of Iowa Iowa City IA USA
- Fraternal Order of Eagles Diabetes Research Centre, Carver College of Medicine University of Iowa Iowa City IA USA
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Wanionok NE, Colareda GA, Fernandez JM. In vitro effects and mechanisms of Humulus lupulus extract on bone marrow progenitor cells and endothelial cells. Mol Cell Endocrinol 2024; 592:112328. [PMID: 38996835 DOI: 10.1016/j.mce.2024.112328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
Osteoporosis is the most common metabolic bone disorder and is associated with a high incidence of fractures. Angiogenesis and adequate blood flow are important during bone repair and maintenance. Estrogens play a key role in bone formation, in the prevention of bone resorption and vasculature maintenance. Hormone replacement therapy (HRT) has been used with great benefits for bone fracture prevention but has been linked to the development of serious important side effects, including cancer and stroke. Phytoestrogens are an attractive alternative to HRT because their chemical structure is similar to estradiol but, they could behave as selective modulators: acting as antagonists of estrogen receptors in the breast and endometrium and as agonists in the vascular endothelium and bone. Hops contain a wide variety of phytoestrogens that have individually been shown to possess estrogenic activity by either blocking or mimicking. In this study we have to evaluate the in vitro effects and mechanisms of action of hops extracts on the osteogenic and adipogenic capacity of bone marrow progenitor cells (BMPCs), and the angiogenic potential of EA.hy926 endothelial cells. We show that hops extracts increase the proliferative capacity of BMPCs and promote their osteogenic differentiation while decreasing their pro-osteoclastogenic capacity; and that these effects are mediated by the MAPK pathway. Additionally, hops extracts prevent the adipogenic differentiation of BMPCs and promote endothelial cell activity, by mechanisms also partially mediated by MAPK.
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Affiliation(s)
- Nahuel E Wanionok
- Laboratorio de Investigaciones en Osteopatias y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP)-Centro de Investigaciones Científicas (CIC), Calle 47 y 115, La Plata, (1900), Argentina
| | - Germán A Colareda
- Farmacología-GFEYEC, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), Calle 47 y 115, La Plata, (1900), Argentina
| | - Juan M Fernandez
- Laboratorio de Investigaciones en Osteopatias y Metabolismo Mineral (LIOMM), Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP)-Centro de Investigaciones Científicas (CIC), Calle 47 y 115, La Plata, (1900), Argentina.
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Xiong QW, Jiang K, Shen XW, Ma ZR, Yan XM, Xia H, Cao X. The requirement of the mitochondrial protein NDUFS8 for angiogenesis. Cell Death Dis 2024; 15:253. [PMID: 38594244 PMCID: PMC11004167 DOI: 10.1038/s41419-024-06636-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/11/2024]
Abstract
Mitochondria are important for the activation of endothelial cells and the process of angiogenesis. NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8) is a protein that plays a critical role in the function of mitochondrial Complex I. We aimed to investigate the potential involvement of NDUFS8 in angiogenesis. In human umbilical vein endothelial cells (HUVECs) and other endothelial cell types, we employed viral shRNA to silence NDUFS8 or employed the CRISPR/Cas9 method to knockout (KO) it, resulting in impaired mitochondrial functions in the endothelial cells, causing reduction in mitochondrial oxygen consumption and Complex I activity, decreased ATP production, mitochondrial depolarization, increased oxidative stress and reactive oxygen species (ROS) production, and enhanced lipid oxidation. Significantly, NDUFS8 silencing or KO hindered cell proliferation, migration, and capillary tube formation in cultured endothelial cells. In addition, there was a moderate increase in apoptosis within NDUFS8-depleted endothelial cells. Conversely, ectopic overexpression of NDUFS8 demonstrated a pro-angiogenic impact, enhancing cell proliferation, migration, and capillary tube formation in HUVECs and other endothelial cells. NDUFS8 is pivotal for Akt-mTOR cascade activation in endothelial cells. Depleting NDUFS8 inhibited Akt-mTOR activation, reversible with exogenous ATP in HUVECs. Conversely, NDUFS8 overexpression boosted Akt-mTOR activation. Furthermore, the inhibitory effects of NDUFS8 knockdown on cell proliferation, migration, and capillary tube formation were rescued by Akt re-activation via a constitutively-active Akt1. In vivo experiments using an endothelial-specific NDUFS8 shRNA adeno-associated virus (AAV), administered via intravitreous injection, revealed that endothelial knockdown of NDUFS8 inhibited retinal angiogenesis. ATP reduction, oxidative stress, and enhanced lipid oxidation were detected in mouse retinal tissues with endothelial knockdown of NDUFS8. Lastly, we observed an increase in NDUFS8 expression in retinal proliferative membrane tissues obtained from human patients with proliferative diabetic retinopathy. Our findings underscore the essential role of the mitochondrial protein NDUFS8 in regulating endothelial cell activation and angiogenesis.
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Affiliation(s)
- Qian-Wei Xiong
- Department of Urology Surgery, Children's Hospital of Soochow University, Suzhou, China
| | - Kun Jiang
- Vascular Surgery Department, Kunshan Traditional Chinese Medicine Hospital, Kunshan, China
| | - Xiao-Wei Shen
- Department of General Surgery, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, QingPu District Central Hospital Shanghai, Shanghai, China
| | - Zhou-Rui Ma
- Department of Burns and Plastic Surgery, Children's Hospital of Soochow University, Suzhou, China
| | - Xiang-Ming Yan
- Department of Urology Surgery, Children's Hospital of Soochow University, Suzhou, China.
| | - Hao Xia
- Department of Pediatric Emergency and Critical Care Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xu Cao
- Department of Urology Surgery, Children's Hospital of Soochow University, Suzhou, China.
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Lisec B, Bozic T, Santek I, Markelc B, Vrecl M, Frangez R, Cemazar M. Characterization of two distinct immortalized endothelial cell lines, EA.hy926 and HMEC-1, for in vitro studies: exploring the impact of calcium electroporation, Ca 2+ signaling and transcriptomic profiles. Cell Commun Signal 2024; 22:118. [PMID: 38347539 PMCID: PMC10863159 DOI: 10.1186/s12964-024-01503-2] [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: 11/08/2023] [Accepted: 01/28/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Disruption of Ca2+ homeostasis after calcium electroporation (CaEP) in tumors has been shown to elicit an enhanced antitumor effect with varying impacts on healthy tissue, such as endothelium. Therefore, our study aimed to determine differences in Ca2+ kinetics and gene expression involved in the regulation of Ca2+ signaling and homeostasis, as well as effects of CaEP on cytoskeleton and adherens junctions of the established endothelial cell lines EA.hy926 and HMEC-1. METHODS CaEP was performed on EA.hy926 and HMEC-1 cells with increasing Ca2+ concentrations. Viability after CaEP was assessed using Presto Blue, while the effect on cytoskeleton and adherens junctions was evaluated via immunofluorescence staining (F-actin, α-tubulin, VE-cadherin). Differences in intracellular Ca2+ regulation ([Ca2+]i) were determined with spectrofluorometric measurements using Fura-2-AM, exposing cells to DPBS, ionomycin, thapsigargin, ATP, bradykinin, angiotensin II, acetylcholine, LaCl3, and GdCl3. Molecular distinctions were identified by analyzing differentially expressed genes and pathways related to the cytoskeleton and Ca2+ signaling through RNA sequencing. RESULTS EA.hy926 cells, at increasing Ca2+ concentrations, displayed higher CaEP susceptibility and lower survival than HMEC-1. Immunofluorescence confirmed CaEP-induced, time- and Ca2+-dependent morphological changes in EA.hy926's actin filaments, microtubules, and cell-cell junctions. Spectrofluorometric Ca2+ kinetics showed higher amplitudes in Ca2+ responses in EA.hy926 exposed to buffer, G protein coupled receptor agonists, bradykinin, and angiotensin II compared to HMEC-1. HMEC-1 exhibited significantly higher [Ca2+]i changes after ionomycin exposure, while responses to thapsigargin, ATP, and acetylcholine were similar in both cell lines. ATP without extracellular Ca2+ ions induced a significantly higher [Ca2+]i rise in EA.hy926, suggesting purinergic ionotropic P2X and metabotropic P2Y receptor activation. RNA-sequencing analysis showed significant differences in cytoskeleton- and Ca2+-related gene expression, highlighting upregulation of ORAI2, TRPC1, TRPM2, CNGA3, TRPM6, and downregulation of TRPV4 and TRPC4 in EA.hy926 versus HMEC-1. Moreover, KEGG analysis showed upregulated Ca2+ import and downregulated export genes in EA.hy926. CONCLUSIONS Our finding show that significant differences in CaEP response and [Ca2+]i regulation exist between EA.hy926 and HMEC-1, which may be attributed to distinct transcriptomic profiles. EA.hy926, compared to HMEC-1, displayed higher susceptibility and sensitivity to [Ca2+]i changes, which may be linked to overexpression of Ca2+-related genes and an inability to mitigate changes in [Ca2+]i. The study offers a bioinformatic basis for selecting EC models based on research objectives.
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Affiliation(s)
- Barbara Lisec
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000, Ljubljana, Slovenia
| | - Tim Bozic
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000, Ljubljana, Slovenia
| | - Iva Santek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000, Ljubljana, Slovenia
| | - Bostjan Markelc
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000, Ljubljana, Slovenia
| | - Milka Vrecl
- Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, SI-1000, Ljubljana, Slovenia
| | - Robert Frangez
- Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, SI-1000, Ljubljana, Slovenia
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000, Ljubljana, Slovenia.
- Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310, Izola, Slovenia.
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Wu Z, Liu Q, Zhao Y, Fang C, Zheng W, Zhao Z, Zhang N, Yang X. Rhogef17: A novel target for endothelial barrier function. Biomed Pharmacother 2024; 170:115983. [PMID: 38134633 DOI: 10.1016/j.biopha.2023.115983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
ARHGEF17 encodes the protein RhoGEF17, which is highly expressed in vascular endothelial cells. It is a guanine nucleotide exchange factor (GEF) that accelerates the exchange of GDP with GTP on many small GTPases through its Dbl homology (DH) domain, enabling the activation of Rho-GTPases such as RhoA, RhoB, and RhoC. Rho GTPase-regulated changes in the actin cytoskeleton and cell adhesion kinetics are the main mechanisms mediating many endothelial cell (EC) alterations, including cell morphology, migration, and division changes, which profoundly affect EC barrier function. This review focuses on ARHGEF17 expression, activation and biological functions in ECs, linking its regulation of cellular morphology, migration, mitosis and other cellular behaviors to disease onset and progression. Understanding ARHGEF17 mechanisms of action will contribute to the design of therapeutic approaches targeting RhoGEF17, a potential drug target for the treatment of various endothelium-related diseases, Such as vascular inflammation, carcinogenesis and transendothelial metastasis of tumors.
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Affiliation(s)
- Zhuolin Wu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Quanlei Liu
- Department of Neurosurgery, Capital Medical University, Xuanwu Hospital, Beijing, China
| | - Yan Zhao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | | | - Wen Zheng
- Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Zilin Zhao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China
| | - Nai Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xinyu Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, China.
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Moradi M, Mousavi A, Emamgholipour Z, Giovannini J, Moghimi S, Peytam F, Honarmand A, Bach S, Foroumadi A. Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies. Eur J Med Chem 2023; 259:115626. [PMID: 37453330 DOI: 10.1016/j.ejmech.2023.115626] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/14/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023]
Abstract
Angiogenesis, the formation of new blood vessels from the existing vasculature, is pivotal in the migration, growth, and differentiation of endothelial cells in normal physiological conditions. In various types of tumour microenvironments, dysregulated angiogenesis plays a crucial role in supplying oxygen and nutrients to cancerous cells, leading to tumour size growth. VEGFR-2 tyrosine kinase has been extensively studied as a critical regulator of angiogenesis; thus, inhibition of VEGFR-2 has been widely used for cancer treatments in recent years. Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity, especially in the field of tyrosine kinase inhibitors with more than twenty small molecule inhibitors approved by the US Food and Drug Administration in the last two decades. As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer. Despite of prosperous discovery and development of VEGFR-2 down regulator drugs, there still exists limitations in clinical efficacy, adverse effects, a high rate of clinical discontinuation and drug resistance. Therefore, there is an urgent need for the design and synthesis of more selective and effective inhibitors to tackle these challenges. Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes.
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Affiliation(s)
- Mahfam Moradi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Mousavi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Emamgholipour
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Johanna Giovannini
- Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France
| | - Setareh Moghimi
- Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Fariba Peytam
- Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Honarmand
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Stéphane Bach
- Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
| | - Alireza Foroumadi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
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Pohl L, Schiessl IM. Endothelial cell plasticity in kidney fibrosis and disease. Acta Physiol (Oxf) 2023; 239:e14038. [PMID: 37661749 DOI: 10.1111/apha.14038] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/29/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023]
Abstract
Renal endothelial cells demonstrate an impressive remodeling potential during angiogenic sprouting, vessel repair or while transitioning into mesenchymal cells. These different processes may play important roles in both renal disease progression or regeneration while underlying signaling pathways of different endothelial cell plasticity routes partly overlap. Angiogenesis contributes to wound healing after kidney injury and pharmaceutical modulation of angiogenesis may home a great therapeutic potential. Yet, it is not clear whether any differentiated endothelial cell can proliferate or whether regenerative processes are largely controlled by resident or circulating endothelial progenitor cells. In the glomerular compartment for example, a distinct endothelial progenitor cell population may remodel the glomerular endothelium after injury. Endothelial-to-mesenchymal transition (EndoMT) in the kidney is vastly documented and often associated with endothelial dysfunction, fibrosis, and kidney disease progression. Especially the role of EndoMT in renal fibrosis is controversial. Studies on EndoMT in vivo determined possible conclusions on the pathophysiological role of EndoMT in the kidney, but whether endothelial cells really contribute to kidney fibrosis and if not what other cellular and functional outcomes derive from EndoMT in kidney disease is unclear. Sequencing data, however, suggest no participation of endothelial cells in extracellular matrix deposition. Thus, more in-depth classification of cellular markers and the fate of EndoMT cells in the kidney is needed. In this review, we describe different signaling pathways of endothelial plasticity, outline methodological approaches and evidence for functional and structural implications of angiogenesis and EndoMT in the kidney, and eventually discuss controversial aspects in the literature.
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Affiliation(s)
- Layla Pohl
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Paul M, Chakraborty S, Islam S, Ain R. Trans-differentiation of trophoblast stem cells: implications in placental biology. Life Sci Alliance 2023; 6:6/3/e202201583. [PMID: 36574992 PMCID: PMC9797987 DOI: 10.26508/lsa.202201583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/28/2022] Open
Abstract
Trophoblast invasion is a hallmark of hemochorial placentation. Invasive trophoblast cells replace the endothelial cells of uterine spiral arteries. The mechanism by which the invasive trophoblast cells acquire this phenotype is unknown. Here, we demonstrate that, during differentiation, a small population of trophoblast stem (TS) cells trans-differentiate into a hybrid cell type expressing markers of both trophoblast (TC) and endothelial (EC) cells. In addition, a compendium of EC-specific genes was found to be associated with TS cell differentiation. Using functional annotation, these genes were categorized into angiogenesis, cell adhesion molecules, and apoptosis-related genes. HES1 repressed transcription of EC genes in TS cells. Interestingly, differentiated TCs secrete TRAIL, but its receptor DR4 is expressed only in ECs and not in TCs. TRAIL induced apoptosis in EC but not in TC. Co-culture of ECs with TC induced apoptosis in ECs via extrinsic apoptotic pathway. These results highlight that (a) TS cells possess the potential to trans-differentiate into "trophendothelial" phenotype, regulated by HES1 and (b) trophoblast differentiation-induced TRAIL secretion directs preferential demise of ECs located in their vicinity.
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Affiliation(s)
- Madhurima Paul
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Shreeta Chakraborty
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,National Institutes of Health, Bethesda, MD, USA
| | - Safirul Islam
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India.,School of Biotechnology, Presidency University, Kolkata, India
| | - Rupasri Ain
- Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, Kolkata, India
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Yao T, Chen H, Wang R, Rivero R, Wang F, Kessels L, Agten SM, Hackeng TM, Wolfs TG, Fan D, Baker MB, Moroni L. Thiol-ene conjugation of a VEGF peptide to electrospun scaffolds for potential applications in angiogenesis. Bioact Mater 2023; 20:306-317. [PMID: 35755423 PMCID: PMC9192696 DOI: 10.1016/j.bioactmat.2022.05.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 05/07/2022] [Accepted: 05/23/2022] [Indexed: 01/17/2023] Open
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11
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Lin D, Chen Z, Zeng Y, Ding Y, Zhao L, Xu Q, Yu F, Song X, Zhu X. A pyroptosis-related gene signature provides an alternative for predicting the prognosis of patients with hepatocellular carcinoma. BMC Med Genomics 2023; 16:2. [PMID: 36611208 PMCID: PMC9826587 DOI: 10.1186/s12920-023-01431-z] [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: 09/24/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) is a common malignant neoplasm with limited treatment options and poor outcomes. Thus, there is an urgent need to find sensitive biomarkers for HCC. METHODS Gene expression and clinicopathological information were obtained from public databases, based on which a pyroptosis-related gene signature was constructed by the least absolute shrinkage and selection operator Cox regression. The applicability of the signature was evaluated via Kaplan-Meier curve and time-dependent ROC curve. TIMER, QUANTISEQ, MCPCOUNTER, EPIC, CIBERSORT, ssGSEA, and ESTIMATE were employed to assess the immune status. Comparisons between groups were analyzed with Wilcoxon test. Pearson and Spearman correlation analyses were adopted for linear correlation analysis. Genetic knockdown was conducted using siRNA transfection and the mRNA expression levels of interest genes were measured using quantitative reverse transcription PCR. Finally, protein levels in 10 paired tumor tissues and adjacent non-tumor tissues from HCC patients were measured using immunohistochemistry. RESULTS A pyroptosis-related gene signature was established successfully to calculate independent prognostic risk scores. It was found that survival outcomes varied significantly between different risk groups. In addition, an attenuated antitumor immune response was found in the high-risk group. Meanwhile, multiple immune checkpoints were up-regulated in high-risk score patients. Cell cycle-related genes, angiogenesis-related genes and tumor drug resistance genes were also markedly elevated. Knockdown of prognostic genes in the signature significantly inhibited the expression of immune checkpoint genes and angiogenesis-related genes. Besides, each prognostic gene was expressed at a higher level in HCC tissues than in adjacent normal tissues. CONCLUSIONS We successfully established a novel pyroptosis-related gene signature which could help predict the overall survival and assess the immune status of HCC patients.
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Affiliation(s)
- Dezhao Lin
- grid.478150.f0000 0004 1771 6371Department of Surgical Oncology, Wenzhou Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang People’s Republic of China
| | - Zhuoyan Chen
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Yuan Zeng
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Yinrong Ding
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Luying Zhao
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Qian Xu
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Fujun Yu
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Xian Song
- grid.414906.e0000 0004 1808 0918Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
| | - Xiaohong Zhu
- grid.414906.e0000 0004 1808 0918Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang People’s Republic of China
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12
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Wang Q, Zeng A, Zhu M, Song L. Dual inhibition of EGFR‑VEGF: An effective approach to the treatment of advanced non‑small cell lung cancer with EGFR mutation (Review). Int J Oncol 2023; 62:26. [PMID: 36601768 PMCID: PMC9851127 DOI: 10.3892/ijo.2023.5474] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/01/2022] [Indexed: 01/04/2023] Open
Abstract
On a global scale, the incidence and mortality rates of lung cancer are gradually increasing year by year. A number of bad habits and environmental factors are associated with lung cancer, including smoking, second‑hand smoke exposure, occupational exposure, respiratory diseases and genetics. At present, low‑dose spiral computed tomography is routinely the first choice in the diagnosis of lung cancer. However, pathological examination is still the gold standard for the diagnosis of lung cancer. Based on the classification and stage of the cancer, treatment options such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy are available. The activation of the EGFR pathway can promote the survival and proliferation of tumor cells, and the VEGF pathway can promote the formation of blood vessels, thereby promoting tumor growth. In non‑small cell lung cancer (NSCLC) with EGFR mutation, EGFR activation can promote tumor growth by promoting VEGF upregulation through a hypoxia‑independent mechanism. The upregulation of VEGF can make tumor cells resistant to EGFR inhibitors. In addition, the expression of the VEGF signal is also affected by other factors. Therefore, the use of a single EGFR inhibitor cannot completely inhibit the expression of the VEGF signal. In order to overcome this problem, the combination of VEGF inhibitors and EGFR inhibitors has become the method of choice. Dual inhibition can not only overcome the resistance of tumor cells to EGFR inhibitors, but also significantly increase the progression‑free survival time of patients with NSCLC. The present review discusses the associations between the EGFR and VEGF pathways, and the characteristics of dual inhibition of the EGFR‑VEGF pathway.
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Affiliation(s)
- Qian Wang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, P.R. China
| | - Min Zhu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
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13
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Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne) 2023; 10:1140979. [PMID: 37020673 PMCID: PMC10067680 DOI: 10.3389/fmed.2023.1140979] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.
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Affiliation(s)
- Bailey D. Lyttle
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Bailey D. Lyttle,
| | - Alyssa E. Vaughn
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - James R. Bardill
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Anisha Apte
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Lauren T. Gallagher
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
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Riesgo A, Santodomingo N, Koutsouveli V, Kumala L, Leger MM, Leys SP, Funch P. Molecular machineries of ciliogenesis, cell survival, and vasculogenesis are differentially expressed during regeneration in explants of the demosponge Halichondria panicea. BMC Genomics 2022; 23:858. [PMID: 36581804 PMCID: PMC9798719 DOI: 10.1186/s12864-022-09035-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 11/21/2022] [Indexed: 12/30/2022] Open
Abstract
Sponges are interesting animal models for regeneration studies, since even from dissociated cells, they are able to regenerate completely. In particular, explants are model systems that can be applied to many sponge species, since small fragments of sponges can regenerate all elements of the adult, including the oscula and the ability to pump water. The morphological aspects of regeneration in sponges are relatively well known, but the molecular machinery is only now starting to be elucidated for some sponge species. Here, we have used an explant system of the demosponge Halichondria panicea to understand the molecular machinery deployed during regeneration of the aquiferous system. We sequenced the transcriptomes of four replicates of the 5-day explant without an osculum (NOE), four replicates of the 17-18-day explant with a single osculum and pumping activity (PE) and also four replicates of field-collected individuals with regular pumping activity (PA), and performed differential gene expression analysis. We also described the morphology of NOE and PE samples using light and electron microscopy. Our results showed a highly disorganised mesohyl and disarranged aquiferous system in NOE that is coupled with upregulated pathways of ciliogenesis, organisation of the ECM, and cell proliferation and survival. Once the osculum is formed, genes involved in "response to stimulus in other organisms" were upregulated. Interestingly, the main molecular machinery of vasculogenesis described in vertebrates was activated during the regeneration of the aquiferous system. Notably, vasculogenesis markers were upregulated when the tissue was disorganised and about to start forming canals (NOE) and angiogenic stimulators and ECM remodelling machineries were differentially expressed once the aquiferous system was in place (PE and PA). Our results are fundamental to better understanding the molecular mechanisms involved in the formation of the aquiferous system in sponges, and its similarities with the early onset of blood-vessel formation in animal evolution.
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Affiliation(s)
- Ana Riesgo
- Department of Biodiversity and Evolutionary Biology, Museo Nacional de Ciencias Naturales (CSIC), Calle José Gutiérrez Abascal 2, 28006, Madrid, Spain.
- Department of Life Sciences, Natural History Museum, Cromwell Road, London, SW5 7BD, UK.
| | - Nadia Santodomingo
- Department of Life Sciences, Natural History Museum, Cromwell Road, London, SW5 7BD, UK
- Department of Earth Sciences, Oxford University, South Parks Road, Oxford, OX1 3AN, UK
| | - Vasiliki Koutsouveli
- Marine Symbioses Research Unit, GEOMAR Helmholtz Centre for Ocean Research Kiel, Düsternbrooker Weg 20, D-24105, Kiel, Germany
| | - Lars Kumala
- Nordcee, Department of Biology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark
- Marine Biological Research Center, University of Southern Denmark, Hindsholmvej 11, 5300, Kerteminde, Denmark
| | - Michelle M Leger
- Institute of Evolutionary Biology (CSIC-UPF), Paseo Marítimo de la Barceloneta 37-49, 08003, Barcelona, Spain
| | - Sally P Leys
- Department of Biological Sciences, University of Alberta, 11455 Saskatchewan Drive, Edmonton, Alberta, T6G 2R3, Canada
| | - Peter Funch
- Department of Biology, Aarhus University, Ny Munkegade, 114-116, Aarhus C, Denmark
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Li R, Zhou C, Chen J, Luo H, Li R, Chen D, Zou X, Wang W. Synergistic osteogenic and angiogenic effects of KP and QK peptides incorporated with an injectable and self-healing hydrogel for efficient bone regeneration. Bioact Mater 2022; 18:267-283. [PMID: 35387156 PMCID: PMC8961307 DOI: 10.1016/j.bioactmat.2022.02.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/26/2022] [Accepted: 02/10/2022] [Indexed: 12/11/2022] Open
Abstract
Irregular defects generated by trauma or surgery in orthopaedics practice were usually difficult to be fitted by the preformed traditional bone graft substitute. Therefore, the injectable hydrogels have attracted an increasing interest for bone repair because of their fittability and mini-invasivity. However, the uncontrollable spreading or mechanical failures during its manipulation remain a problem to be solved. Moreover, in order to achieve vascularized bone regeneration, alternatives of osteogenic and angiogenic growth factors should be adopted to avoid the problem of immunogenicity and high cost. In this study, a novel injectable self-healing hydrogel system (GMO hydrogel) loaded with KP and QK peptides had been developed for enhancing vascularized regeneration of small irregular bone defect. The dynamic imine bonds between gelatin methacryloyl and oxidized dextran provided the GMO hydrogel with self-healing and shear-thinning abilities, which led to an excellent injectability and fittability. By photopolymerization of the enclosed GelMA, GMO hydrogel was further strengthened and thus more suitable for bone regeneration. Besides, the osteogenic peptide KP and angiogenic peptide QK were tethered to GMO hydrogel by Schiff base reaction, leading to desired releasing profiles. In vitro, this composite hydrogel could significantly improve the osteogenic differentiation of BMSCs and angiogenesis ability of HUVECs. In vivo, KP and QK in the GMO hydrogel demonstrated a significant synergistic effect in promoting new bone formation in rat calvaria. Overall, the KP and QK loaded GMO hydrogel was injectable and self-healing, which can be served as an efficient approach for vascularized bone regeneration via a minimally invasive approach.
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Affiliation(s)
- Runze Li
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
| | - Chen Zhou
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
| | - Jun Chen
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
- The Key Laboratory of Imflammation and Autoimmune Diseases, Guangzhou, 510280, China
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Haotian Luo
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
| | - Ruoyu Li
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
| | - Danying Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
| | - Xuenong Zou
- Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Weicai Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou, 510055, China
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16
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Torres-Vargas JA, Cheng-Sánchez I, Martínez-Poveda B, Medina MÁ, Sarabia F, García-Caballero M, Quesada AR. Characterization of the activity and the mechanism of action of a new toluquinol derivative with improved potential as an antiangiogenic drug. Biomed Pharmacother 2022; 155:113759. [DOI: 10.1016/j.biopha.2022.113759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/12/2022] [Accepted: 09/26/2022] [Indexed: 11/02/2022] Open
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Anti-PTK7 Monoclonal Antibodies Inhibit Angiogenesis by Suppressing PTK7 Function. Cancers (Basel) 2022; 14:cancers14184463. [PMID: 36139622 PMCID: PMC9496920 DOI: 10.3390/cancers14184463] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary PTK7 is a catalytically defective receptor protein tyrosine kinase. We previously demonstrated that PTK7 enhances angiogenesis by interacting with KDR, a vascular endothelial growth factor (VEGF) receptor important for angiogenesis, and activating it through oligomerization. To control angiogenesis by inhibiting PTK7 function, we developed anti-PTK7 monoclonal antibodies (mAbs). The selected PTK7 mAbs reduced VEGF-induced angiogenic phenotypes of endothelial cells and angiogenesis ex vivo and in vivo. The PTK7 mAbs also inhibited VEGF-induced KDR activation in endothelial cells and its downstream signaling and PTK7–KDR interaction. Our results show that the PTK7 mAbs inhibit angiogenesis by blocking PTK7 function. Therefore, PTK7 mAbs could be applied as therapeutics to control angiogenesis-associated diseases such as metastatic cancers. Abstract PTK7, a catalytically defective receptor protein tyrosine kinase, promotes angiogenesis by activating KDR through direct interaction and induction of KDR oligomerization. This study developed anti-PTK7 monoclonal antibodies (mAbs) to regulate angiogenesis by inhibiting PTK7 function. The effect of anti-PTK7 mAbs on vascular endothelial growth factor (VEGF)-induced angiogenic phenotypes in human umbilical vascular endothelial cells (HUVECs) was examined. Analysis of mAb binding with PTK7 deletion mutants revealed that mAb-43 and mAb-52 recognize immunoglobulin (Ig) domain 2 of PTK7, whereas mAb-32 and mAb-50 recognize Ig domains 6–7. Anti-PTK7 mAbs inhibited VEGF-induced adhesion and wound healing in HUVECs. mAb-32, mAb-43, and mAb-52 dose-dependently mitigated VEGF-induced migration and invasion in HUVECs without exerting cytotoxic effects. Additionally, mAb-32, mAb-43, and mAb-52 inhibited capillary-like tube formation in HUVECs, and mAb-32 and mAb-43 suppressed angiogenesis ex vivo (aortic ring assay) and in vivo (Matrigel plug assay). Furthermore, mAb-32 and mAb-43 downregulated VEGF-induced KDR activation and downstream signaling and inhibited PTK7–KDR interaction in PTK7-overexpressing and KDR-overexpressing HEK293 cells. Thus, anti-PTK7 mAbs inhibit angiogenic phenotypes by blocking PTK7–KDR interaction. These findings indicate that anti-PTK7 mAbs that neutralize PTK7 function can alleviate impaired angiogenesis-associated pathological conditions, such as cancer metastasis.
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Lin H, Wang X, Li Z, Huang M, Feng J, Chen H, Gao J, Feng Y, Wu J, Tang S, Zhou R, Ren Y, Huang F, Jiang Z. Total flavonoids of Rhizoma drynariae promote angiogenesis and osteogenesis in bone defects. Phytother Res 2022; 36:3584-3600. [PMID: 35960140 DOI: 10.1002/ptr.7525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 05/22/2022] [Accepted: 05/30/2022] [Indexed: 11/09/2022]
Abstract
Bone defects are difficult to heal, which conveys a heavy burden to patients' lives and their economy. The total flavonoids of Rhizoma drynariae (TFRD) can promote the osteogenesis of distraction osteogenesis. However, the dose effect is not clear, the treatment period is short, and the quality of bone formation is poor. In our study, we observed the long-term effects and dose effects of TFRD on bone defects, verified the main ingredients of TFRD in combination with network pharmacology for the first time, explored its potential mechanism, and verified these findings. We found that TFRD management for 12 weeks regulated osteogenesis and angiogenesis in rats with 4-mm tibial bone defects through the PI3K/AKT/HIF-1α/VEGF signaling pathway, especially at high doses (135 mg kg-1 d-1 ). The vascularization effect of TFRD in promoting human umbilical vein endothelial cells was inhibited by PI3K inhibitors. These results provide a reference for the clinical application of TFRD.
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Affiliation(s)
- Haixiong Lin
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Orthopaedics, Ningxia Hui Autonomous Region Hospital and Research Institute of Traditional Chinese Medicine, Yinchuan, China
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Xiaotong Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Zige Li
- The 2nd Department of Arthrosis, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beiijing, China
| | - Minling Huang
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Junjie Feng
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huamei Chen
- Knee Surgery, The Fifth People's Hospital of Nanhai District, Foshan, China
| | - Junyan Gao
- Department of Orthopaedics & Traumatology, Shantou Hospital of Traditional Chinese Medicine, Shantou, China
| | - Yuanlan Feng
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Wu
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengyao Tang
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruoyu Zhou
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yueyi Ren
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Feng Huang
- The First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziwei Jiang
- Department of Orthopaedics & Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Hu M, Li J, Liu CG, Goh RMWJ, Yu F, Ma Z, Wang L. Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance. Cells 2022; 11:cells11060947. [PMID: 35326397 PMCID: PMC8946542 DOI: 10.3390/cells11060947] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 12/17/2022] Open
Abstract
Extracellular vesicles (EVs) act as multifunctional regulators of intercellular communication and are involved in diverse tumor phenotypes, including tumor angiogenesis, which is a highly regulated multi-step process for the formation of new blood vessels that contribute to tumor proliferation. EVs induce malignant transformation of distinct cells by transferring DNAs, proteins, lipids, and RNAs, including noncoding RNAs (ncRNAs). However, the functional relevance of EV-derived ncRNAs in tumor angiogenesis remains to be elucidated. In this review, we summarized current research progress on the biological functions and underlying mechanisms of EV-derived ncRNAs in tumor angiogenesis in various cancers. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as cancer biomarkers and novel therapeutic targets to tailor anti-angiogenic therapy.
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Affiliation(s)
- Miao Hu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.H.); (C.-G.L.)
| | - Juan Li
- Department of Epidemiology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China;
| | - Chen-Guang Liu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.H.); (C.-G.L.)
| | | | - Fenggang Yu
- Institute of Life Science, Yinfeng Biological Group, Jinan 250000, China;
| | - Zhaowu Ma
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (M.H.); (C.-G.L.)
- Correspondence: (Z.M.); (L.W.); Tel.: +86-15972188216 (Z.M.); +65-65168925 (L.W.)
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
- Correspondence: (Z.M.); (L.W.); Tel.: +86-15972188216 (Z.M.); +65-65168925 (L.W.)
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Chen D, Wu Z, Wu LN, Jiang J, Hu GN. Theaflavin Attenuates TBHP-Induced Endothelial Cells Oxidative Stress by Activating PI3K/AKT/Nrf2 and Accelerates Wound Healing in Rats. Front Bioeng Biotechnol 2022; 10:830574. [PMID: 35309982 PMCID: PMC8924520 DOI: 10.3389/fbioe.2022.830574] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/02/2022] [Indexed: 01/26/2023] Open
Abstract
The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients’ need for functional and aesthetically pleasing scars. Previous reports have shown that Theaflavin can induce angiogenesis and terminate the progression of ischemic cardiovascular disease, but limited therapy is available for the management of cutaneous wounds. In this study, our in vitro work discovered that human umbilical vein endothelial cells (HUVECs) exposed to Theaflavin can alleviate apoptosis and cell dysfunction induced by tert-butyl hydroperoxide (TBHP). The cellular activity of HUVECs were assessed by cell tube formation, migration and adhesion. Mechanistically, Theaflavin protected HUVECs from TBHP-stimulated cell apoptosis through the activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) axis, so Nrf2 silencing can partly eliminate the cytoprotective effect of Theaflavin treatment. In in vivo experiments, administering Theaflavin orally can enhance vascularization in regenerated tissues and accelerate wound healing. In summary, our data served as a novel evidence for the wound healing treatment with Theaflavin, and certified the potential mechanism of Theaflavin, which can be used as a potential agent for cutaneous wound therapy.
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Affiliation(s)
- Dalei Chen
- Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China
| | - Zhijian Wu
- Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China
| | - Lu-Ning Wu
- Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China
| | - Jingtao Jiang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gui-Nv Hu
- Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China
- *Correspondence: Gui-Nv Hu,
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21
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Chen J, Liu J, Xu B, Cao Y, Liang X, Wu F, Shen X, Ma X, Liu J. Ethoxy-erianin phosphate and afatinib synergistically inhibit liver tumor growth and angiogenesis via regulating VEGF and EGFR signaling pathways. Toxicol Appl Pharmacol 2022; 438:115911. [PMID: 35143806 DOI: 10.1016/j.taap.2022.115911] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/26/2022] [Accepted: 02/02/2022] [Indexed: 12/27/2022]
Abstract
The therapeutic efficacy of tyrosine kinase inhibitors (TKIs) on solid tumors is limited by drug resistance and side effects. Currently, the combination therapy comprises of TKIs and angiogenesis inhibitors have been corroborated as an effective approach in cancer therapy. Ethoxy-erianin phosphate (EBTP) is an anti-angiogenic compound with low toxicity obtained by structural modification of the natural product erianin. Here, we aimed to evaluate whether EBTP can cooperate with TKIs to inhibit the proliferation and angiogenesis of tumor cells and reduce toxic effects. First, CCK-8 results showed that EBTP can effectively inhibit the proliferation of liver cancer cell line HepG2. We combined EBTP with four TKIs (Bosutinib, Apatinib, Afatinib and Erlotinib) to treat HepG2 cells and CompuSyn software analysis suggested that EBTP/Afatinib(Afa)shows the best synergistic inhibitory effect. Meanwhile, EBTP/Afa can significantly suppress the proliferation, invasion, migration and angiogenesis of HepG2 and HUVECs. ELISA results revealed that EBTP/Afa inhibits the secretion of VEGF in HepG2. EBTP/Afa down-regulates the expression of VEGF, p-VEGFR1, p-VEGFR2 and p-EGFR in both HepG2 and HUVECs. Further, the supernatant of HepG2 cells treated with EBTP/Afa blocks the intracellular downstream signal transduction shared by VEGF and EGFR in HUVECs. Finally, EBTP/Afa significantly inhibits tumor growth and angiogenesis in vivo. To conclude, EBTP/Afa targets VEGF and EGFR signaling pathways in liver cancer cells and tumor vasculature, thereby inhibiting the proliferation, motion and angiogenesis of liver cancer cells. Overall, this study provides a new combined strategy for the clinical treatment of hepatocellular carcinoma.
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Affiliation(s)
- Jingyun Chen
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Jiajun Liu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Baixue Xu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Yiou Cao
- Department of Surgery, Minhang Hospital, Fudan University, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China
| | - Fanhong Wu
- School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai Engineering Research Center of Green Fluoropharmaceutical Technology, Shanghai 201418, China
| | - Xiaodong Shen
- Department of Surgery, Minhang Hospital, Fudan University, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China.
| | - Xiaoying Ma
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China.
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, People's Republic of China.
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22
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Valanti EK, Dalakoura-Karagkouni K, Fotakis P, Vafiadaki E, Mantzoros CS, Chroni A, Zannis V, Kardassis D, Sanoudou D. Reconstituted HDL-apoE3 promotes endothelial cell migration through ID1 and its downstream kinases ERK1/2, AKT and p38 MAPK. Metabolism 2022; 127:154954. [PMID: 34875308 DOI: 10.1016/j.metabol.2021.154954] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/15/2021] [Accepted: 11/30/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Atherosclerotic Coronary Artery Disease (ASCAD) is the leading cause of mortality worldwide. Novel therapeutic approaches aiming to improve the atheroprotective functions of High Density Lipoprotein (HDL) include the use of reconstituted HDL forms containing human apolipoprotein A-I (rHDL-apoA-I). Given the strong atheroprotective properties of apolipoprotein E3 (apoE3), rHDL-apoE3 may represent an attractive yet largely unexplored therapeutic agent. OBJECTIVE To evaluate the atheroprotective potential of rHDL-apoE3 starting with the unbiased assessment of global transcriptome effects and focusing on endothelial cell (EC) migration as a critical process in re-endothelialization and atherosclerosis prevention. The cellular, molecular and functional effects of rHDL-apoE3 on EC migration-associated pathways were assessed, as well as the potential translatability of these findings in vivo. METHODS Human Aortic ECs (HAEC) were treated with rHDL-apoE3 and total RNA was analyzed by whole genome microarrays. Expression and phosphorylation changes of key EC migration-associated molecules were validated by qRT-PCR and Western blot analysis in primary HAEC, Human Coronary Artery ECs (HCAEC) and the human EA.hy926 EC line. The capacity of rHDL-apoE3 to stimulate EC migration was assessed by wound healing and transwell migration assays. The contribution of MEK1/2, PI3K and the transcription factor ID1 in rHDL-apoE3-induced EC migration and activation of EC migration-related effectors was assessed using specific inhibitors (PD98059: MEK1/2, LY294002: PI3K) and siRNA-mediated gene silencing, respectively. The capacity of rHDL-apoE3 to improve vascular permeability and hypercholesterolemia in vivo was tested in a mouse model of hypercholesterolemia (apoE KO mice) using Evans Blue assays and lipid/lipoprotein analysis in the serum, respectively. RESULTS rHDL-apoE3 induced significant expression changes in 198 genes of HAEC mainly involved in re-endothelialization and atherosclerosis-associated functions. The most pronounced effect was observed for EC migration, with 42/198 genes being involved in the following EC migration-related pathways: 1) MEK/ERK, 2) PI3K/AKT/eNOS-MMP2/9, 3) RHO-GTPases, 4) integrin. rHDL-apoE3 induced changes in 24 representative transcripts of these pathways in HAEC, increasing the expression of their key proteins PIK3CG, EFNB2, ID1 and FLT1 in HCAEC and EA.hy926 cells. In addition, rHDL-apoE3 stimulated migration of HCAEC and EA.hy926 cells, and the migration was markedly attenuated in the presence of PD98059 or LY294002. rHDL-apoE3 also increased the phosphorylation of ERK1/2, AKT, eNOS and p38 MAPK in these cells, while PD98059 and LY294002 inhibited rHDL-apoE3-induced phosphorylation of ERK1/2, AKT and p38 MAPK, respectively. LY had no effect on rHDL-apoE3-mediated eNOS phosphorylation. ID1 siRNA markedly decreased EA.hy926 cell migration by inhibiting rHDL-apoE3-triggered ERK1/2 and AKT phosphorylation. Finally, administration of a single dose of rHDL-apoE3 in apoE KO mice markedly improved vascular permeability as demonstrated by the reduced concentration of Evans Blue dye in tissues such as the stomach, the tongue and the urinary bladder and ameliorated hypercholesterolemia. CONCLUSIONS rHDL-apoE3 significantly enhanced EC migration in vitro, predominantly via overexpression of ID1 and subsequent activation of MEK1/2 and PI3K, and their downstream targets ERK1/2, AKT and p38 MAPK, respectively, and improved vascular permeability in vivo. These novel insights into the rHDL-apoE3 functions suggest a potential clinical use to promote re-endothelialization and retard development of atherosclerosis.
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Affiliation(s)
- Eftaxia-Konstantina Valanti
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Katerina Dalakoura-Karagkouni
- Laboratory of Biochemistry, University of Crete Medical School, Heraklion, Greece; Division of Gene Regulation and Genomics, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | | | - Elizabeth Vafiadaki
- Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | | | - Angeliki Chroni
- Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Athens, Greece
| | - Vassilis Zannis
- Molecular Genetics, Boston University Medical School, Boston, USA
| | - Dimitris Kardassis
- Laboratory of Biochemistry, University of Crete Medical School, Heraklion, Greece; Division of Gene Regulation and Genomics, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Despina Sanoudou
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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23
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García-Caballero M, Torres-Vargas JA, Marrero AD, Martínez-Poveda B, Medina MÁ, Quesada AR. Angioprevention of Urologic Cancers by Plant-Derived Foods. Pharmaceutics 2022; 14:pharmaceutics14020256. [PMID: 35213989 PMCID: PMC8875200 DOI: 10.3390/pharmaceutics14020256] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
The number of cancer cases worldwide keeps growing unstoppably, despite the undeniable advances achieved by basic research and clinical practice. Urologic tumors, including some as prevalent as prostate, bladder or kidney tumors, are no exceptions to this rule. Moreover, the fact that many of these tumors are detected in early stages lengthens the duration of their treatment, with a significant increase in health care costs. In this scenario, prevention offers the most cost-effective long-term strategy for the global control of these diseases. Although specialized diets are not the only way to decrease the chances to develop cancer, epidemiological evidence support the role of certain plant-derived foods in the prevention of urologic cancer. In many cases, these plants are rich in antiangiogenic phytochemicals, which could be responsible for their protective or angiopreventive properties. Angiogenesis inhibition may contribute to slow down the progression of the tumor at very different stages and, for this reason, angiopreventive strategies could be implemented at different levels of chemoprevention, depending on the targeted population. In this review, epidemiological evidence supporting the role of certain plant-derived foods in urologic cancer prevention are presented, with particular emphasis on their content in bioactive phytochemicals that could be used in the angioprevention of cancer.
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Affiliation(s)
- Melissa García-Caballero
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
| | - José Antonio Torres-Vargas
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
| | - Ana Dácil Marrero
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
| | - Beatriz Martínez-Poveda
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), E-28019 Madrid, Spain
| | - Miguel Ángel Medina
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
- CIBER de Enfermedades Raras (CIBERER), E-29071 Malaga, Spain
| | - Ana R. Quesada
- Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Andalucía Tech, E-29071 Malaga, Spain; (M.G.-C.); (J.A.T.-V.); (A.D.M.); (B.M.-P.); (M.Á.M.)
- IBIMA (Biomedical Research Institute of Malaga), E-29071 Malaga, Spain
- CIBER de Enfermedades Raras (CIBERER), E-29071 Malaga, Spain
- Correspondence:
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24
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Mendez EF, Wei H, Hu R, Stertz L, Fries GR, Wu X, Najera KE, Monterey MD, Lincoln CM, Kim JW, Moriel K, Meyer TD, Selvaraj S, Teixeira AL, Zhao Z, Xu J, Wu J, Walss-Bass C. Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain. Mol Psychiatry 2021; 26:7803-7812. [PMID: 34385598 PMCID: PMC8837724 DOI: 10.1038/s41380-021-01259-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 07/19/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
Opioid use disorder (OUD) is a public health crisis in the U.S. that causes over 50 thousand deaths annually due to overdose. Using next-generation RNA sequencing and proteomics techniques, we identified 394 differentially expressed (DE) coding and long noncoding (lnc) RNAs as well as 213 DE proteins in Brodmann Area 9 of OUD subjects. The RNA and protein changes converged on pro-angiogenic gene networks and cytokine signaling pathways. Four genes (LGALS3, SLC2A1, PCLD1, and VAMP1) were dysregulated in both RNA and protein. Dissecting these DE genes and networks, we found cell type-specific effects with enrichment in astrocyte, endothelial, and microglia correlated genes. Weighted-genome correlation network analysis (WGCNA) revealed cell-type correlated networks including an astrocytic/endothelial/microglia network involved in angiogenic cytokine signaling as well as a neuronal network involved in synaptic vesicle formation. In addition, using ex vivo magnetic resonance imaging, we identified increased vascularization in postmortem brains from a subset of subjects with OUD. This is the first study integrating dysregulation of angiogenic gene networks in OUD with qualitative imaging evidence of hypervascularization in postmortem brain. Understanding the neurovascular effects of OUD is critical in this time of widespread opioid use.
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Affiliation(s)
- Emily F Mendez
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Haichao Wei
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX, USA
| | - Ruifeng Hu
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Laura Stertz
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Gabriel R Fries
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Xizi Wu
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX, USA
| | - Katherine E Najera
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Michael D Monterey
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | | | - Joo-Won Kim
- Department of Radiology, Baylor College of Medicine, Houston, TX, USA
- Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA
| | - Karla Moriel
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Thomas D Meyer
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sudhakar Selvaraj
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Antonio L Teixeira
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zhongming Zhao
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Junqian Xu
- Department of Radiology, Baylor College of Medicine, Houston, TX, USA
- Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA
| | - Jiaqian Wu
- The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Stem Cell and Regenerative Medicine, UT Brown Foundation Institute of Molecular Medicine, Houston, TX, USA
- MD Anderson Cancer Center University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Consuelo Walss-Bass
- Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
- MD Anderson Cancer Center University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
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25
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Morbidelli L, Genah S, Cialdai F. Effect of Microgravity on Endothelial Cell Function, Angiogenesis, and Vessel Remodeling During Wound Healing. Front Bioeng Biotechnol 2021; 9:720091. [PMID: 34631676 PMCID: PMC8493071 DOI: 10.3389/fbioe.2021.720091] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Wound healing is a complex phenomenon that involves different cell types with various functions, i.e., keratinocytes, fibroblasts, and endothelial cells, all influenced by the action of soluble mediators and rearrangement of the extracellular matrix (ECM). Physiological angiogenesis occurs in the granulation tissue during wound healing to allow oxygen and nutrient supply and waste product removal. Angiogenesis output comes from a balance between pro- and antiangiogenic factors, which is finely regulated in a spatial and time-dependent manner, in order to avoid insufficient or excessive nonreparative neovascularization. The understanding of the factors and mechanisms that control angiogenesis and their change following unloading conditions (in a real or simulated space environment) will allow to optimize the tissue response in case of traumatic injury or medical intervention. The potential countermeasures under development to optimize the reparative angiogenesis that contributes to tissue healing on Earth will be discussed in relation to their exploitability in space.
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Affiliation(s)
| | - Shirley Genah
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Francesca Cialdai
- ASA Campus Joint Laboratory, ASA Research Division & Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
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26
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Moreira HR, Marques AP. Vascularization in skin wound healing: where do we stand and where do we go? Curr Opin Biotechnol 2021; 73:253-262. [PMID: 34555561 DOI: 10.1016/j.copbio.2021.08.019] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/23/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022]
Abstract
Cutaneous healing is a highly complex process that, if altered due to, for example, impaired vascularization, results in chronic wounds or repaired neotissue of poor quality. Significant progress has been achieved in promoting neotissue vascularization during tissue repair/regeneration. In this review, we discuss the strategies that have been explored and how each one of them contributes to regulate vascularization in the context of cutaneous wound healing from two different perspectives - biomaterial-based and a cell-based approaches. Finally, we discuss the implications of these findings on the development of the 'next generation' approaches to target vascularization in wound healing highlighting the importance of going beyond its contribution to regulate vascularization and take into consideration the temporal features of the healing process and of different types of wounds.
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Affiliation(s)
- Helena R Moreira
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Guimarães 4805-017, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal
| | - Alexandra P Marques
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Avepark - Zona Industrial da Gandra, Guimarães 4805-017, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães 4805-017, Portugal.
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27
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Multi-functional silica-based mesoporous materials for simultaneous delivery of biologically active ions and therapeutic biomolecules. Acta Biomater 2021; 129:1-17. [PMID: 34010692 DOI: 10.1016/j.actbio.2021.05.007] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022]
Abstract
Mesoporous silica-based materials, especially mesoporous bioactive glasses (MBGs), are being highly considered for biomedical applications, including drug delivery and tissue engineering, not only because of their bioactivity and biocompatibility but also due to their tunable composition and potential use as drug delivery carriers owing to their controllable nanoporous structure. Numerous researches have reported that MBGs can be doped with various therapeutic ions (strontium, copper, magnesium, zinc, lithium, silver, etc.) and loaded with specific biomolecules (e.g., therapeutic drugs, antibiotics, growth factors) achieving controllable loading and release kinetics. Therefore, co-delivery of ions and biomolecules using a single MBG carrier is highly interesting as this approach provides synergistic effects toward improved therapeutic outcomes in comparison to the strategy of sole drug or ion delivery. In this review, we discuss the state-of-the-art in the field of mesoporous silica-based materials used for co-delivery of ions and therapeutic drugs with osteogenesis/cementogenesis, angiogenesis, antibacterial and anticancer properties. The analysis of the literature reveals that specially designed mesoporous nanocarriers can release multiple ions and drugs at therapeutically safe and relevant levels, achieving the desired biological effects (in vivo, in vitro) for specific biomedical applications. It is expected that this review on the ion/drug co-delivery concept using MBG carriers will shed light on the advantages of such co-delivery systems for clinical use. Areas for future research directions are identified and discussed. STATEMENT OF SIGNIFICANCE: Many studies in literature focus on the potential of single drug or ion delivery by mesoporous silica-based materials, exploiting the bioactivity, biocompatibility, tunable composition and controllable nanoporosity of these materials. Recenlty, studies have adopted the "dual-delivery" concept, by designing multi-functional mesoporous silica-based systems which are capable to deliver both biologically active ions and biomolecules (growth factors, drugs) simultaneously in order to achieve synergy of their complementary therapeutic activities. This review summarizes the state of the art in the field, with focus on osteogenesis/cementogenesis, angiogenesis, antibacterial and anticancer properties, and discusses the challenges and prospects for further progress in this area, expecting to generate broader interest in the technology for applications in disease treatment and regenerative medicine.
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28
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Zeng Y, Zheng Z, Liu F, Yi G. Circular RNAs in metabolism and metabolic disorders. Obes Rev 2021; 22:e13220. [PMID: 33580638 DOI: 10.1111/obr.13220] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 12/21/2022]
Abstract
Metabolic syndrome (MetS) is a serious health condition triggered by hyperglycemia, dyslipidemia, and abnormal adipose deposition. Recently, circular RNAs (circRNAs) have been proposed as key molecular players in metabolic homeostasis due to their regulatory effects on genes linked to the modulation of multiple aspects of metabolism, including glucose and lipid homeostasis. Dysregulation of circRNAs can lead to metabolic disorders, indicating that circRNAs represent plausible potential targets to alleviate metabolic abnormalities. More recently, a series of circulating circRNAs have been identified to act as both essential regulatory molecules and biomarkers for the progression of metabolism-related disorders, including type 2 diabetes mellitus (T2DM or T2D) and cardiovascular disease (CVD). The findings of this study highlight the function of circRNAs in signaling pathways implicated in metabolic diseases and their potential as future therapeutics and disease biomarkers.
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Affiliation(s)
- Yongzhi Zeng
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, China
| | - Zhi Zheng
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, China
| | - Fengtao Liu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, China
| | - Guanghui Yi
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, China
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29
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Abstract
In diabetic patients, diabetic retinopathy (DR) is the leading cause of blindness and seriously affects the quality of life. However, current treatment methods of DR are not satisfactory. Advances have been made in understanding abnormal protein interactions and signaling pathways in DR pathology, but little is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs (circRNAs), have been shown to be associated with DR. In this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment.
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Affiliation(s)
- Huan-Ran Zhou
- Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong-Yu Kuang
- Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
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30
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Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque. Acta Neurochir (Wien) 2021; 163:1777-1785. [PMID: 32995934 DOI: 10.1007/s00701-020-04595-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 09/22/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND The purpose of the present study was to clarify the characteristics of endothelial cell (EC) proliferation in intraplaque microvessels in vulnerable plaques and impact on clinical results. METHODS The present study included 76 patients who underwent carotid endarterectomy. Patients were classified into three groups based on their symptoms: asymptomatic, symptomatic without recurrent ischemic event, and symptomatic with recurrent ischemic event. MR plaque imaging was performed and surgical specimens underwent immunohistochemical analysis. The number of CD31+ microvessels, and Ki67+ and CD105+ ECs in the carotid plaques was quantified, as measurements of maximum CD31+ microvessel diameter. RESULTS MR plaque imaging yielded 41 subjects (54.0%) diagnosed with plaque with intraplaque hemorrhage (IPH), 14 subjects (18.4%) diagnosed with fibrous plaques, and 21 (27.6%) subjects diagnosed with lipid-rich plaques. The average largest diameter of microvessel in fibrous plaques, lipid-rich plaques, and plaque with IPH was 12.7 ± 4.1 μm, 31.3 ± 9.3 μm, and 56.4 ± 10.0 μm, respectively (p < 0.01). Dilated microvessels (>40 μm) were observed in 9.6% of plaques with IPH but only in 2.8% of lipid-rich plaques and 0% of fibrous plaques (p < 0.01). Ki67+/CD31+ ECs were identified in 2.8 ± 1.2% of fibrous plaques, 9.6 ± 6.9% of lipid-rich plaques, and in 19.5 ± 5.9% of plaques with IPH (p < 0.01). The average largest diameter of microvessels in the asymptomatic group was 17.1 ± 8.7 μm, 32.3 ± 10.8 μm in the symptomatic without recurrence group, and 55.2 ± 13.2 μm in the symptomatic with recurrence group (p < 0.01). CONCLUSION Dilated microvessels with proliferative ECs may play a key role in IPH pathogenesis. Furthermore, dilated microvessels are likely related to clinical onset and the recurrence of ischemic events. The purpose of the present study was to clarify the characteristics of EC proliferation in intraplaque microvessels in vulnerable plaques and their impact on clinical results, focusing on dilated intraplaque microvessels.
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Yoodee S, Peerapen P, Plumworasawat S, Thongboonkerd V. ARID1A knockdown in human endothelial cells directly induces angiogenesis by regulating angiopoietin-2 secretion and endothelial cell activity. Int J Biol Macromol 2021; 180:1-13. [PMID: 33675830 DOI: 10.1016/j.ijbiomac.2021.02.218] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 02/10/2021] [Accepted: 02/24/2021] [Indexed: 12/29/2022]
Abstract
AT-rich interactive domain 1A (ARID1A) is a novel tumor suppressor gene found in several human cells and its loss/defect is commonly observed in many cancers. However, its roles in angiogenesis, which is one of the hallmarks for tumor progression, remained unclear. Herein, we demonstrated the direct effects of ARID1A knockdown in human endothelial cells by lentivirus-based short-hairpin RNA (shRNA) (shARID1A) on angiogenesis. Functional assays revealed that shARID1A significantly enhanced cell proliferation and migration/invasion and endothelial tube formation compared with the control cells transfected with scramble shRNA (shControl). Additionally, the shARID1A-transfected cells had significantly increased podosome formation and secretion of angiopoietin-2 (ANG2), a key angiogenic factor. Moreover, neutralization of ANG2 with monoclonal anti-ANG2 antibody strongly reduced cell proliferation and migration/invasion and endothelial tube formation in the shARID1A-transfected cells. These findings indicate that down-regulation of ARID1A in human endothelial cells directly induces angiogenesis by regulating angiopoietin-2 secretion and endothelial cell activity.
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Affiliation(s)
- Sunisa Yoodee
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Paleerath Peerapen
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Sirikanya Plumworasawat
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
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Choi RJ, Mohamad Zobir SZ, Alexander-Dann B, Sharma N, Ma MK, Lam BY, Yeo GS, Zhang W, Fan TP, Bender A. Combination of Ginsenosides Rb2 and Rg3 Promotes Angiogenic Phenotype of Human Endothelial Cells via PI3K/Akt and MAPK/ERK Pathways. Front Pharmacol 2021; 12:618773. [PMID: 33643049 PMCID: PMC7902932 DOI: 10.3389/fphar.2021.618773] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/11/2021] [Indexed: 11/26/2022] Open
Abstract
Shexiang Baoxin Pill (SBP) is an oral formulation of Chinese materia medica for the treatment of angina pectoris. It displays pleiotropic roles in protecting the cardiovascular system. However, the mode of action of SBP in promoting angiogenesis, and in particular the synergy between its constituents is currently not fully understood. The combination of ginsenosides Rb2 and Rg3 were studied in human umbilical vein endothelial cells (HUVECs) for their proangiogenic effects. To understand the mode of action of the combination in more mechanistic detail, RNA-Seq analysis was conducted, and differentially expressed genes (DEGs), pathway analysis and Weighted Gene Correlation Network Analysis (WGCNA) were applied to further identify important genes that a play pivotal role in the combination treatment. The effects of pathway-specific inhibitors were observed to provide further support for the hypothesized mode of action of the combination. Ginsenosides Rb2 and Rg3 synergistically promoted HUVEC proliferation and tube formation under defined culture conditions. Also, the combination of Rb2/Rg3 rescued cells from homocysteine-induced damage. mRNA expression of CXCL8, CYR61, FGF16 and FGFRL1 was significantly elevated by the Rb2/Rg3 treatment, and representative signaling pathways induced by these genes were found. The increase of protein levels of phosphorylated-Akt and ERK42/44 by the Rb2/Rg3 combination supports the notion that it promotes endothelial cell proliferation via the PI3K/Akt and MAPK/ERK signaling pathways. The present study provides the hypothesis that SBP, via ginsenosides Rb2 and Rg3, involves the CXCR1/2 CXCL8 (IL8)-mediated PI3K/Akt and MAPK/ERK signaling pathways in achieving its proangiogenic effects.
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Affiliation(s)
- Ran Joo Choi
- Department of Chemistry, Center for Molecular Science Informatics, University of Cambridge, Cambridge, United Kingdom
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Siti Zuraidah Mohamad Zobir
- Department of Chemistry, Center for Molecular Science Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Ben Alexander-Dann
- Department of Chemistry, Center for Molecular Science Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Nitin Sharma
- Department of Chemistry, Center for Molecular Science Informatics, University of Cambridge, Cambridge, United Kingdom
| | - Marcella K.L. Ma
- Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome–MRC Institute of Metabolic Science, Genomics and Transcriptomics Core, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Brian Y.H. Lam
- Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome–MRC Institute of Metabolic Science, Genomics and Transcriptomics Core, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Giles S.H. Yeo
- Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome–MRC Institute of Metabolic Science, Genomics and Transcriptomics Core, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Weidong Zhang
- Department of Pharmacy, Second Military Medical University, Shanghai, China
| | - Tai-Ping Fan
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
| | - Andreas Bender
- Department of Chemistry, Center for Molecular Science Informatics, University of Cambridge, Cambridge, United Kingdom
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Impaired capillary tube formation induced by elevated secretion of IL8 involves altered signaling via the CXCR1/PI3K/MMP2 pathway. Mol Biol Rep 2021; 48:601-610. [PMID: 33411234 DOI: 10.1007/s11033-020-06104-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/18/2020] [Indexed: 10/22/2022]
Abstract
Angiogenesis is a multistep process requiring endothelial cell activation, migration, proliferation and tube formation. We recently reported that elevated secretion of interlukin 8 (IL8) by myotubes (MT) from subjects with Type-2 Diabetes (T2D) reduced angiogenesis by human umbilical vein endothelial cells (HUVEC) and human skeletal muscle explants. This lower vascularization was mediated through impaired activation of the phosphatidylinositol 3-kinase (PI3K)-pathway. We sought to investigate additional signaling elements that might mediate reduced angiogenesis. HUVEC were exposed to levels of IL8 equal to those secreted by MT from non-diabetic (ND) and T2D subjects and the involvement of components in the angiogenic response pathway examined. Cellular content of reactive oxygen species and Nitrate secretion were similar after treatment with [ND-IL8] and [T2D-IL8]. CXCR1 protein was down-regulated after treatment with [T2D-IL8] (p < 0.01 vs [ND-IL8] treatment); CXCR2 expression was unaltered. Addition of neutralizing antibodies against CXCR1 and CXCR2 to HUVEC treated with IL8 confirmed that CXCR1 alone mediated the angiogenic response to IL8. A key modulator of angiogenesis is matrix metalloproteinase-2 (MMP2). MMP2 secretion was higher after treatment with [ND-IL8] vs [T2D-IL8] (p < 0.01). MMP2 inhibition reduced tube formation to greater extent with [ND-IL8] than with [T2D-IL8] (p < 0.005). The PI3K-pathway inhibitor LY294002 reduced IL8-induced MMP2 release. IL8 regulation of MMP2 release was CXCR1 dependent, as anti-CXCR1 significantly reduced MMP2 release (p < 0.05). These results suggest that high levels of IL8 secreted by T2D MT trigger reduced capillarization via lower activation of a CXCR1-PI3K pathway, followed by impaired release and activity of MMP2.
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da Silva SM, Campos GD, Gomes FCA, Stipursky J. Radial Glia-endothelial Cells' Bidirectional Interactions Control Vascular Maturation and Astrocyte Differentiation: Impact for Blood-brain Barrier Formation. Curr Neurovasc Res 2020; 16:291-300. [PMID: 31633476 DOI: 10.2174/1567202616666191014120156] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 08/01/2019] [Accepted: 08/05/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND In the developing cerebral cortex, Radial Glia (RG) multipotent neural stem cell, among other functions, differentiate into astrocytes and serve as a scaffold for blood vessel development. After some time, blood vessel Endothelial Cells (ECs) become associated with astrocytes to form the neurovascular Blood-Brain Barrier (BBB) unit. OBJECTIVE Since little is known about the mechanisms underlying bidirectional RG-ECs interactions in both vascular development and astrocyte differentiation, this study investigated the impact of interactions between RG and ECs mediated by secreted factors on EC maturation and gliogenesis control. METHODS First, we demonstrated that immature vasculature in the murine embryonic cerebral cortex physically interacts with Nestin positive RG neural stem cells in vivo. Isolated Microcapillary Brain Endothelial Cells (MBEC) treated with the conditioned medium from RG cultures (RG-CM) displayed decreased proliferation, reduction in the protein levels of the endothelial tip cell marker Delta-like 4 (Dll4), and decreased expression levels of the vascular permeability associated gene, plasmalemma vesicle-associated protein-1 (PLVAP1). These events were also accompanied by increased levels of the tight junction protein expression, zonula occludens-1 (ZO-1). RESULTS Finally, we demonstrated that isolated RG cells cultures treated with MBEC conditioned medium promoted the differentiation of astrocytes in a Vascular Endothelial Growth Factor-A (VEGF-A) dependent manner. CONCLUSION These results suggest that the bidirectional interaction between RG and ECs is essential to induce vascular maturation and astrocyte generation, which may be an essential cell-cell communication mechanism to promote BBB establishment.
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Affiliation(s)
- Siqueira M da Silva
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ, 21941-901, Brazil
| | - Gisbert D Campos
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ, 21941-901, Brazil
| | - Flávia C A Gomes
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ, 21941-901, Brazil
| | - Joice Stipursky
- Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro - RJ, 21941-901, Brazil
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Jayasuriya R, Dhamodharan U, Karan AN, Anandharaj A, Rajesh K, Ramkumar KM. Role of Nrf2 in MALAT1/ HIF-1α loop on the regulation of angiogenesis in diabetic foot ulcer. Free Radic Biol Med 2020; 156:168-175. [PMID: 32473205 DOI: 10.1016/j.freeradbiomed.2020.05.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/24/2020] [Indexed: 12/17/2022]
Abstract
Diabetic non healing wounds often result in significant morbidity and mortality. The number of effective targets to detect these wounds are meagre. Slow lymphangiogenesis is one of the complex processes involved in impaired healing of wounds. Long non coding RNAs (lncRNAs) have been importantly recognized for their role in pathological conditions. Multiple studies highlighting the role of lncRNAs in the regulation of several biological processes and complex diseases. Herein, we investigated the role of lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the progression of diabetic foot ulcer (DFU). We report a significant reduction in the expression of lncRNA MALAT1 in the infected DFU subjects which was positively correlated with the expression of angiogenic factors such as Nrf2, HIF-1α and VEGF. Further, expression of pro-inflammatory markers TNF-α and IL-6 were found to be increased while, the expression of anti-inflammatory marker IL-10 was decreased in infected DFU tissues. Involvement of lncRNA MALAT1 in angiogenesis in EA.hy926 cells was demonstrated by silencing the expression of Nrf2, HIF-1α, and VEGF through interference mediated by MALAT1. In addition, its inflammatory role was demonstrated by decreased expression of TNF-α, IL-6 and not affecting the expression of IL-10. Further, CRISPR-Cas9 knock out of Nrf2 decreased the expression of lncRNA MALAT1, HIF-1α and VEGF which revealed the association of Nrf2 in regulating MALAT1/HIF-1α loop through positive feedback mechanism. Collectively, our results suggested the role of Nrf2 on MALAT1/HIF-1α loop in the regulation of angiogenesis, which could act as a novel target in the treatment of diabetic wounds.
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Affiliation(s)
- Ravichandran Jayasuriya
- Department of Biotechnology and SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Umapathy Dhamodharan
- Department of Biotechnology and SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Amin Naresh Karan
- Department of Biotechnology and SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Arunkumar Anandharaj
- Indian Institute of Food Processing Technology, Pudukkottai Road, Thanjavur, 613005, Tamil Nadu, India
| | - Kesavan Rajesh
- Department of Podiatry, Hycare Super Speciality Hospital, MMDA Colony, Arumbakkam, Chennai, 600 106, Tamil Nadu, India.
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology and SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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Dong X, He Z, Xiang G, Cai L, Xu Z, Mao C, Feng Y. Paeoniflorin promotes angiogenesis and tissue regeneration in a full-thickness cutaneous wound model through the PI3K/AKT pathway. J Cell Physiol 2020; 235:9933-9945. [PMID: 32542807 DOI: 10.1002/jcp.29808] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/16/2020] [Accepted: 05/08/2020] [Indexed: 12/19/2022]
Abstract
The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients' need for functional and aesthetically pleasing scars. For the wound healing process, new blood vessels which can deliver nutrients and oxygen to the wound area are necessary. In this study, we investigated the pro-angiogenesis ability and mechanism in wound healing of paeoniflorin (PF), which is a traditional Chinese medicine. In our in vitro results, the ability for proliferation, migration and in vitro angiogenesis in human umbilical vein endothelial cells was promoted by coculturing with PF (1.25-5 μM). Meanwhile, molecular docking studies revealed that PF has excellent binding abilities to phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT), and consistent with our western blot results, that PF suppressed PI3K and AKT phosphorylation. Furthermore, to investigate the healing effect of PF in vivo, we constructed a full-thickness cutaneous wound model in rats. PF stimulated the cellular proliferation status, collagen matrix deposition and remodeling processes in vitro and new blood vessel formation at the wound bed resulting in efficient wound healing after intragastric administration of 10 mg·kg-1 ·day-1 in vivo. Overall, PF performed the pro-angiogenetic effect in vitro and accelerating wound healing in vivo. In summary, the capacity for angiogenesis in endothelial cells could be enhanced by PF treatment via the PI3K/AKT pathway in vitro and could accelerate the wound healing process in vivo through collagen deposition and angiogenesis in regenerated tissue. This study provides evidence that application of PF represents a novel therapeutic approach for the treatment of cutaneous wounds.
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Affiliation(s)
- Xiaoyu Dong
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zili He
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangheng Xiang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Leyi Cai
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhenjiang Xu
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Cong Mao
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongzeng Feng
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopedics of Zhejiang Province, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Venturini E, Iannuzzo G, D’Andrea A, Pacileo M, Tarantini L, Canale M, Gentile M, Vitale G, Sarullo F, Vastarella R, Di Lorenzo A, Testa C, Parlato A, Vigorito C, Giallauria F. Oncology and Cardiac Rehabilitation: An Underrated Relationship. J Clin Med 2020; 9:1810. [PMID: 32532011 PMCID: PMC7356735 DOI: 10.3390/jcm9061810] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer and cardiovascular diseases are globally the leading causes of mortality and morbidity. These conditions are closely related, beyond that of sharing many risk factors. The term bidirectional relationship indicates that cardiovascular diseases increase the likelihood of getting cancer and vice versa. The biological and biochemical pathways underlying this close relationship will be analyzed. In this new overlapping scenario, physical activity and exercise are proven protective behaviors against both cardiovascular diseases and cancer. Many observational studies link an increase in physical activity to a reduction in either the development or progression of cancer, as well as to a reduction in risk in cardiovascular diseases, a non-negligible cause of death for long-term cancer survivors. Exercise is an effective tool for improving cardio-respiratory fitness, quality of life, psychological wellbeing, reducing fatigue, anxiety and depression. Finally, it can counteract the toxic effects of cancer therapy. The protection obtained from physical activity and exercise will be discussed in the various stages of the cancer continuum, from diagnosis, to adjuvant therapy, and from the metastatic phase to long-term effects. Particular attention will be paid to the shelter against chemotherapy, radiotherapy, cardiovascular risk factors or new onset cardiovascular diseases. Cardio-Oncology Rehabilitation is an exercise-based multi-component intervention, starting from the model of Cardiac Rehabilitation, with few modifications, to improve care and the prognosis of a patient's cancer. The network of professionals dedicated to Cardiac Rehabilitation is a ready-to-use resource, for implementing Cardio-Oncology Rehabilitation.
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Affiliation(s)
- E. Venturini
- Cardiac Rehabilitation Unit, Azienda USL Toscana Nord-Ovest, Cecina Civil Hospital, 57023 LI Cecina, Italy
| | - G. Iannuzzo
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy; (G.I.); (M.G.)
| | - A. D’Andrea
- Unit of Cardiology and Intensive Care, “Umberto I” Hospital, Viale San Francesco, Nocera Inferiore, 84014 SA, Italy; (A.D.); (M.P.)
| | - M. Pacileo
- Unit of Cardiology and Intensive Care, “Umberto I” Hospital, Viale San Francesco, Nocera Inferiore, 84014 SA, Italy; (A.D.); (M.P.)
| | - L. Tarantini
- Division of Cardiology, Ospedale San Martino ULSS1 Dolomiti, 32100 Belluno, Italy;
| | - M.L. Canale
- Department of Cardiology, Azienda USL Toscana Nord-Ovest, Ospedale Versilia, Lido di Camaiore, 55041 LU, Italy;
| | - M. Gentile
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy; (G.I.); (M.G.)
| | - G. Vitale
- Cardiovascular Rehabilitation Unit, Buccheri La Ferla Fatebenefratelli Hospital, 90123 Palermo, Italy; (G.V.); (F.M.S.)
| | - F.M. Sarullo
- Cardiovascular Rehabilitation Unit, Buccheri La Ferla Fatebenefratelli Hospital, 90123 Palermo, Italy; (G.V.); (F.M.S.)
| | - R. Vastarella
- UOSD Scompenso Cardiaco e Cardiologia Riabilitativa, AORN Ospedale dei Colli-Monaldi, 80131 Naples, Italy;
| | - A. Di Lorenzo
- Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (A.D.L.); (C.T.); (A.P.); (C.V.); (F.G.)
| | - C. Testa
- Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (A.D.L.); (C.T.); (A.P.); (C.V.); (F.G.)
| | - A. Parlato
- Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (A.D.L.); (C.T.); (A.P.); (C.V.); (F.G.)
| | - C. Vigorito
- Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (A.D.L.); (C.T.); (A.P.); (C.V.); (F.G.)
| | - F. Giallauria
- Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (A.D.L.); (C.T.); (A.P.); (C.V.); (F.G.)
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Dos Santos PK, Altei WF, Danilucci TM, Lino RLB, Pachane BC, Nunes ACC, Selistre-de-Araujo HS. Alternagin-C (ALT-C), a disintegrin-like protein, attenuates alpha2beta1 integrin and VEGF receptor 2 signaling resulting in angiogenesis inhibition. Biochimie 2020; 174:144-158. [PMID: 32360415 DOI: 10.1016/j.biochi.2020.04.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/03/2020] [Accepted: 04/21/2020] [Indexed: 01/01/2023]
Abstract
Angiogenesis, a crucial process in tumor progression, is mainly regulated by vascular endothelial growth factor (VEGF) and its receptor, VEGFR2. Studies have shown the interaction between α2β1 integrin, a collagen receptor, and VEGFR2 in VEGF-driven angiogenesis in vitro and in vivo. Alternagin-C (ALT-C), an ECD-disintegrin-like protein from Bothrops alternatus snake venom, has high affinity for α2β1 integrin and shows antiangiogenic activity in concentrations higher than 100 nM. Despite previous results, its mechanism of action on angiogenic signaling pathways has not been addressed. Here we evaluate the antiangiogenic activity of ALT-C in human umbilical vein endothelial cells (HUVECs) associated or not with VEGF, as well as its interference in the α2β1/VEGFR2 crosstalk. ALT-C (1000 nM) affected actin cytoskeleton, decreased the number of cell filopodia, and strongly inhibited HUVEC tube formation, adhesion to type I collagen and cell migration. Down-regulation of α2β1/VEGFR2 crosstalk by ALT-C decreased the protein content and phosphorylation of VEGFR2 and β1 integrin subunit, inhibited ERK 1/2 and PI3K signaling and regulated FAK/Src and paxillin pathways. Furthermore, ALT-C increased the content of the autophagic markers LC3B and Beclin-1 in the presence of VEGF, which is associated with decreased angiogenesis. In conclusion, we suggest that ALT-C, after binding to α2β1 integrin, inhibits VEGF/VEGFR2 signaling, which results in impaired angiogenesis. These results demonstrate that ALT-C may be a potential candidate for the development of antiangiogenic therapies for tumor and metastasis treatment and help to understand the complexity and fundamental role of integrin inhibition in the tumor microenvironment.
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Affiliation(s)
- Patty K Dos Santos
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil.
| | - Wanessa F Altei
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Taís M Danilucci
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Rafael L B Lino
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Bianca C Pachane
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Ana C C Nunes
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
| | - Heloisa S Selistre-de-Araujo
- Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of São Carlos, Rod. Washington Luís, km 235 - SP-310 - São Carlos, São Paulo, CEP 13565-905, Brazil
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Ocaña MC, Martínez-Poveda B, Marí-Beffa M, Quesada AR, Medina MÁ. Fasentin diminishes endothelial cell proliferation, differentiation and invasion in a glucose metabolism-independent manner. Sci Rep 2020; 10:6132. [PMID: 32273578 PMCID: PMC7145862 DOI: 10.1038/s41598-020-63232-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 03/27/2020] [Indexed: 12/19/2022] Open
Abstract
The synthetic compound fasentin has been described as a modulator of GLUT-1 and GLUT-4 transporters, thus inhibiting glucose uptake in some cancer cells. Endothelial glucose metabolism has been recently connected to angiogenesis and it is now an emerging topic in scientific research. Indeed, certain compounds with a known effect on glucose metabolism have also been shown to inhibit angiogenesis. In this work we tested the capability of fasentin to modulate angiogenesis in vitro and in vivo. We show that fasentin inhibited tube formation in endothelial cells by a mechanism that involves a negative effect on endothelial cell proliferation and invasion, without affecting other steps related to the angiogenic process. However, fasentin barely decreased glucose uptake in human dermal microvascular endothelial cells and the GLUT-1 inhibitor STF-31 failed to inhibit tube formation in these cells. Therefore, this modulatory capacity on endothelial cells function exerted by fasentin is most likely independent of a modulation of glucose metabolism. Taken together, our results show a novel biological activity of fasentin, which could be evaluated for its utility in cancer and other angiogenesis-dependent diseases.
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Affiliation(s)
- Mª Carmen Ocaña
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain
| | - Beatriz Martínez-Poveda
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain
| | - Manuel Marí-Beffa
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, E-29071, Málaga, Spain
| | - Ana R Quesada
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain
- IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain
- CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain
| | - Miguel Ángel Medina
- Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, E-29071, Málaga, Spain.
- IBIMA (Biomedical Research Institute of Málaga), E-29071, Málaga, Spain.
- CIBER de Enfermedades Raras (CIBERER), E-29071, Málaga, Spain.
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Cho KH, Choi JI, Kim JO, Jung JE, Kim DW, Kim M. Therapeutic mechanism of cord blood mononuclear cells via the IL-8-mediated angiogenic pathway in neonatal hypoxic-ischaemic brain injury. Sci Rep 2020; 10:4446. [PMID: 32157146 PMCID: PMC7064601 DOI: 10.1038/s41598-020-61441-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/25/2020] [Indexed: 01/08/2023] Open
Abstract
In a clinical trial of cerebral palsy, the level of plasma interleukin-8 (IL-8) was increased, correlated with motor improvement, after human umbilical cord blood mononuclear cell (hUCBC) infusion. This study aimed to elucidate the role of IL-8 in the therapeutic effects of hUCBCs in a mouse model of hypoxic-ischaemic brain injury (HI). In P7 HI mouse brains, hUCBC administration at day 7 after HI upregulated the gene expression of Cxcl2, the mouse IL-8 homologue and increased the expression of its receptor, CXCR2. hUCBC administration restored the sequential downstream signalling axis of p-p38/p-MAPKAPK2, NFκB, and angiogenic factors, which were downregulated by HI. An in vitro assay revealed the downregulation of the angiogenic pathway by CXCR2 knockdown and p38 inhibition. In vivo p38 inhibition prior to hUCBC administration in HI mouse brains produced identical results. Behavioural outcomes revealed a therapeutic effect (ps < 0.01) of hUCBC or IL-8 administration, which was correlated with decreases in infarct size and angiogenic findings in the striatum. In conclusion, the response of the host to hUCBC administration in mice upregulated Cxcl2, which led to the activation of the IL-8-mediated p-p38 signalling pathway. The upregulation of the downstream pathway and angiogenic growth factors via NFκB can be inferred to be the potential therapeutic mechanism of hUCBCs.
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Affiliation(s)
- Kye Hee Cho
- Department of Rehabilitation Medicine, CHA Gumi Medical Center, CHA University College of Medicine, Gumi, Gyeongsangbukdo, Republic of Korea
| | - Jee In Choi
- Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea
| | - Jin-Ock Kim
- College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea
| | - Joo Eun Jung
- Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas, USA
| | - Dong-Wook Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - MinYoung Kim
- Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea. .,Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University College of Medicine, Seongnam, Gyeonggi-do, Republic of Korea.
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Sabbatinelli J, Prattichizzo F, Olivieri F, Procopio AD, Rippo MR, Giuliani A. Where Metabolism Meets Senescence: Focus on Endothelial Cells. Front Physiol 2019; 10:1523. [PMID: 31920721 PMCID: PMC6930181 DOI: 10.3389/fphys.2019.01523] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD+-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.
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Affiliation(s)
- Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | | | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
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Dual Action of Sulfated Hyaluronan on Angiogenic Processes in Relation to Vascular Endothelial Growth Factor-A. Sci Rep 2019; 9:18143. [PMID: 31792253 PMCID: PMC6889296 DOI: 10.1038/s41598-019-54211-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 11/05/2019] [Indexed: 01/13/2023] Open
Abstract
Pathological healing characterized by abnormal angiogenesis presents a serious burden to patients’ quality of life requiring innovative treatment strategies. Glycosaminoglycans (GAG) are important regulators of angiogenic processes. This experimental and computational study revealed how sulfated GAG derivatives (sGAG) influence the interplay of vascular endothelial growth factor (VEGF)165 and its heparin-binding domain (HBD) with the signaling receptor VEGFR-2 up to atomic detail. There was profound evidence for a HBD-GAG-HBD stacking configuration. Here, the sGAG act as a “molecular glue” leading to recognition modes in which sGAG interact with two VEGF165-HBDs. A 3D angiogenesis model demonstrated the dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells. While GAG alone promote sprouting, they downregulate VEGF165-mediated signaling and, thereby, elicit VEGF165-independent and -dependent effects. These findings provide novel insights into the modulatory potential of sGAG derivatives on angiogenic processes and point towards their prospective application in treating abnormal angiogenesis.
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Yang CY, Chen C, Lin CY, Chen YH, Lin CY, Chi CW, Chen YJ, Liu SC, Chang TK, Tang CH, Lai YW, Tsai HJ, Chen JJ, Wang SW. Garcimultiflorone K inhibits angiogenesis through Akt/eNOS- and mTOR-dependent pathways in human endothelial progenitor cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 64:152911. [PMID: 31454653 DOI: 10.1016/j.phymed.2019.152911] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/13/2019] [Accepted: 04/01/2019] [Indexed: 06/10/2023]
Abstract
Background Garcimultiflorone K is a novel polyprenylated polycyclic acylphloroglucinol isolated from the stems of Garcinia multiflora that exhibits promising anti-angiogenic activity in human endothelial progenitor cells (EPCs). Purpose This study sought to determine the underlying anti-angiogenic mechanisms and pharmacological properties of garcimultiflorone K. Methods We examined the anti-angiogenic effects of garcimultiflorone K and its mechanisms of action using in vitro EPC models and in vivo zebrafish embryos. Results EPCs proliferation, migration, differentiation and capillary-like tube formation were effectively and concentration-dependently inhibited by garcimultiflorone K without any signs of cytotoxicity. Our investigations revealed that garcimultiflorone K suppressed EPCs angiogenesis through Akt, mTOR, p70S6K, and eNOS signaling cascades. Notably, garcimultiflorone K dose-dependently impeded angiogenesis in zebrafish embryos. Conclusion Our data demonstrate the anti-angiogneic effects of garcimultiflorone K in both in vitro and in vivo models. Garcimultiflorone K appears to have potential in the treatment of angiogenesis-related diseases.
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Affiliation(s)
- Chen-Yu Yang
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chi Chen
- Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan
| | - Cheng-Yung Lin
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan
| | - Yi-Hsuan Chen
- Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan
| | - Chih-Yang Lin
- Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan
| | - Chih-Wen Chi
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan
| | - Yu-Jen Chen
- Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan; Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan
| | - Shih-Chia Liu
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan
| | - Ting-Kuo Chang
- Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan
| | - Chih-Hsin Tang
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Yu-Wei Lai
- Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan; Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Huai-Jen Tsai
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan
| | - Jih-Jung Chen
- Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
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The strigolactone analog GR-24 inhibits angiogenesis in vivo and in vitro by a mechanism involving cytoskeletal reorganization and VEGFR2 signalling. Biochem Pharmacol 2019; 168:366-383. [DOI: 10.1016/j.bcp.2019.07.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 07/22/2019] [Indexed: 12/27/2022]
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45
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Wang X, Tian W, Banh BT, Statler BM, Liang J, Stone DE. Mating yeast cells use an intrinsic polarity site to assemble a pheromone-gradient tracking machine. J Cell Biol 2019; 218:3730-3752. [PMID: 31570500 PMCID: PMC6829655 DOI: 10.1083/jcb.201901155] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/06/2019] [Accepted: 08/08/2019] [Indexed: 12/12/2022] Open
Abstract
The mating of budding yeast depends on chemotropism, a fundamental cellular process. The two yeast mating types secrete peptide pheromones that bind to GPCRs on cells of the opposite type. Cells find and contact a partner by determining the direction of the pheromone source and polarizing their growth toward it. Actin-directed secretion to the chemotropic growth site (CS) generates a mating projection. When pheromone-stimulated cells are unable to sense a gradient, they form mating projections where they would have budded in the next cell cycle, at a position called the default polarity site (DS). Numerous models have been proposed to explain yeast gradient sensing, but none address how cells reliably switch from the intrinsically determined DS to the gradient-aligned CS, despite a weak spatial signal. Here we demonstrate that, in mating cells, the initially uniform receptor and G protein first polarize to the DS, then redistribute along the plasma membrane until they reach the CS. Our data indicate that signaling, polarity, and trafficking proteins localize to the DS during assembly of what we call the gradient tracking machine (GTM). Differential activation of the receptor triggers feedback mechanisms that bias exocytosis upgradient and endocytosis downgradient, thus enabling redistribution of the GTM toward the pheromone source. The GTM stabilizes when the receptor peak centers at the CS and the endocytic machinery surrounds it. A computational model simulates GTM tracking and stabilization and correctly predicts that its assembly at a single site contributes to mating fidelity.
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Affiliation(s)
- Xin Wang
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
| | - Wei Tian
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL
| | - Bryan T Banh
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
| | | | - Jie Liang
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL
| | - David E Stone
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
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Tsui KH, Wu MY, Lin LT, Wen ZH, Li YH, Chu PY, Li CJ. Disruption of mitochondrial homeostasis with artemisinin unravels anti-angiogenesis effects via auto-paracrine mechanisms. Theranostics 2019; 9:6631-6645. [PMID: 31588240 PMCID: PMC6771251 DOI: 10.7150/thno.33353] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 07/30/2019] [Indexed: 12/19/2022] Open
Abstract
Rationale: Tumor angiogenesis promotes tumor development, progression, growth, and metastasis. Metronomic chemotherapy involves the frequent administration of low-dose chemotherapeutic agents to block angiogenic activity and reduce side effects. Methods: MDA-MB-231 cells were treated with various concentrations of artemisinin (ART) and vinorelbine (NVB) and the cytotoxic effects of ART/NVB were determined using the CCK-8 assay. Mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) and mass were assessed using MitoSOX, TMRE and MitoTracker green staining. Western blot analysis was used to quantify the expression of autophagy-related proteins. Herein, by using bioinformatics analysis and experimental verification, we identified CREB as a master in MDA-MB-231 cells. Results: We found that artemisinin (ART), which exhibits anti-angiogenic and anti-cancer effects via mitochondrial regulation, synergized with vinorelbine (NVB) to inhibit MDA-MB-231 cell proliferation. ART and NVB cooperated to regulate mitochondrial biogenesis. CREB acted as a crucial regulator of PGC1α and VEGF, which played critical roles in NVB-dependent growth factor depletion. Moreover, CREB suppression significantly reversed mitochondrial dysfunction following ART/NVB co-treatment. In addition, combination treatment with ART and NVB significantly suppressed tumor growth in a nude mouse xenograft model, with downregulated CREB and PGC1α expression levels observed in tumor biopsies, in agreement with our in vitro and ex vivo data. Conclusions: These findings support the hypothesis that ART affects cancer and endothelial cells by targeting the auto-paracrine effects of VEGF to suppress mitochondrial biogenesis, angiogenesis, and migration between cancer cells and endothelial cells.
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Affiliation(s)
- Kuan-Hao Tsui
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung County, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
| | - Meng-Yu Wu
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Li-Te Lin
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
- Marine Biomedical Laboratory and Center for Translational Biopharmaceuticals, Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiun, Taiwan
| | - Yi-Han Li
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA
| | - Pei-Yi Chu
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei city, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan
- Department of Health Food, Chung Chou University of Science and Technology, Changhua, Taiwan
| | - Chia-Jung Li
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
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Da Silva AC, Jammal MP, Crispim PCA, Murta EFC, Nomelini RS. The Role of Stroma in Ovarian Cancer. Immunol Invest 2019; 49:406-424. [PMID: 32264761 DOI: 10.1080/08820139.2019.1658770] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background: Ovarian cancer is one of the gynecological malignancies responsible for thousands of deaths in women worldwide. Malignant solid tumors are formed by malignant cells and stroma that influence each other, where different types of cells in the stromal environment can be recruited by malignant cells to promote tumor growth and facilitate metastasis. The chronic inflammatory response is increasingly accepted in its relation to the pathophysiology of the onset and development of tumors, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma and DNA damage agents may increase the risk to develop a neoplasm.Methods: A search for the following keywords was performed in the PubMed database; "Ovarian cancer", "stroma", "tumor-associated macrophages", "cancer-associated fibroblasts", "cytokines", "angiogenesis", "epithelial-mesenchymal transition", and "extracellular matrix".Results: The articles identified were published in English between 1971 and 2018. A total of 154 articles were selected for further analysis. Conclusion: We consider ovarian cancer as a heterogeneous disease, not only in the sense that different histological or molecular subtypes may be behind the same clinical result, but also that multiple cell types besides cancer cells, like other non-cellular components, need to be mobilized and coordinated to support tumor survival, growth, invasion and progression.
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Affiliation(s)
- Ana Carolinne Da Silva
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Millena Prata Jammal
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Paula Carolina Arvelos Crispim
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Eddie Fernando Candido Murta
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
| | - Rosekeila Simões Nomelini
- Research Institute of Oncology (IPON)/Department of Gynecology and Obstetrics, Federal University of Triângulo Mineiro, Uberaba, Minas Gerais, Brazil
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The Mediterranean Diet, a Rich Source of Angiopreventive Compounds in Cancer. Nutrients 2019; 11:nu11092036. [PMID: 31480406 PMCID: PMC6769787 DOI: 10.3390/nu11092036] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 08/19/2019] [Accepted: 08/25/2019] [Indexed: 12/12/2022] Open
Abstract
Diet-based chemoprevention of cancer has emerged as an interesting approach to evade the disease or even target its early phases, reducing its incidence or slowing down tumor progression. In its basis in the essential role of angiogenesis for tumor growth and metastasis, angioprevention proposes the use of inhibitors of angiogenesis in cancer prevention. The anti-angiogenic potential exhibited by many natural compounds contained in many Mediterranean diet constituents makes this dietary pattern especially interesting as a source of chemopreventive agents, defined within the angioprevention strategy. In this review, we focus on natural bioactive compounds derived from the main foods included in the Mediterranean diet that display anti-angiogenic activity, as well as their possible use as angiopreventive agents.
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49
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Ghasemi H, Sabati Z, Ghaedi H, Salehi Z, Alipoor B. Circular RNAs in β-cell function and type 2 diabetes-related complications: a potential diagnostic and therapeutic approach. Mol Biol Rep 2019; 46:5631-5643. [PMID: 31302804 DOI: 10.1007/s11033-019-04937-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 06/20/2019] [Indexed: 12/14/2022]
Abstract
Recent investigations have indicated that altered expression of non-coding RNAs (ncRNAs) could be associated with human diseases such as type 2 diabetes (T2D). Circular RNAs (circRNAs) are a new discovered class of ncRNAs with unique structural characteristics that involved in several molecular and cellular functions. Exploring of the circulating circRNAs as a reliable non-invasive biomarker for monitoring and diagnosing of human diseases has grown significantly. However, the molecular functions and clinical relevance of circRNAs are not yet well clarified in T2D. Accordingly, in this review, the involvement of circRNAs in the β-cell function and T2D-related complications is highlighted. The study also shed light on the possibility of using circRNAs as a biomarker for T2D diagnosis.
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Affiliation(s)
- Hassan Ghasemi
- Department of Clinical Biochemistry, Abadan Faculty of Medical Sciences, Abadan, Iran
| | - Zolfaghar Sabati
- Student Research Committee, Abadan Faculty of Medical Sciences, Abadan, Iran
| | - Hamid Ghaedi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zaker Salehi
- Department of Radiation Sciences, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Behnam Alipoor
- Department of Laboratory Sciences, Faculty of Paramedicine, Yasuj University of Medical Sciences, Yasuj, Iran.
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50
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Mg–Zn–Mn alloy extract induces the angiogenesis of human umbilical vein endothelial cells via FGF/FGFR signaling pathway. Biochem Biophys Res Commun 2019; 514:618-624. [DOI: 10.1016/j.bbrc.2019.04.198] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 04/29/2019] [Indexed: 11/21/2022]
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