|
1
|
Schlosser A, Pilecki B, Allen C, Benest AV, Lynch AP, Hua J, Ved N, Blackley Z, Andersen TL, Hennig D, Graversen JH, Möller S, Skallerup S, Ormhøj M, Lange C, Agostini HT, Grauslund J, Heegaard S, Dacheva I, Koss M, Hu W, Iglesias B, Lawrence MS, Beck HC, Steffensen LB, Laursen NS, Andersen GR, Holmskov U, Bates DO, Sorensen GL. Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage. Mol Ther 2025; 33:1048-1072. [PMID: 39863929 PMCID: PMC11897753 DOI: 10.1016/j.ymthe.2025.01.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/13/2024] [Accepted: 01/22/2025] [Indexed: 01/27/2025] Open
Abstract
Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial cells, including choroidal vascular mural cells, retinal astrocytes, and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction, and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy, and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326 treatment significantly enriched Gene Ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases.
Collapse
Affiliation(s)
- Anders Schlosser
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Bartosz Pilecki
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Claire Allen
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Andrew V Benest
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Amy P Lynch
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Jing Hua
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Nikita Ved
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Zoe Blackley
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Thomas L Andersen
- Molecular Bone Histology Laboratory, Department of Pathology, Odense University Hospital, 5000 Odense, Denmark; Molecular Bone Histology Laboratory, Research Unit of Pathology, Department of Clinical Research, University of Southern Denmark, 5230 Odense, Denmark; Danish Spatial Imaging Consortium (DanSIC), University of Southern Denmark, 5230 Odense, Denmark
| | - Dorle Hennig
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Jonas H Graversen
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Sören Möller
- OPEN - Open Patient Data Explorative Network, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Sofie Skallerup
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Maria Ormhøj
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Clemens Lange
- Ophtha-Lab, Department of Ophthalmology, St. Franziskus Hospital, 48145 Münster, Germany; Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Hansjürgen T Agostini
- Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Jakob Grauslund
- Department of Ophthalmology, Odense University Hospital, 5000 Odense, Denmark
| | - Steffen Heegaard
- Department of Pathology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet-Glostrup, University of Copenhagen, 2600 Glostrup, Denmark
| | - Ivanka Dacheva
- Department of Ophthalmology, University of Heidelberg, 69047 Heidelberg, Germany
| | - Michael Koss
- Department of Ophthalmology, University of Heidelberg, 69047 Heidelberg, Germany
| | - Wenzheng Hu
- Virscio, Inc., 5 Science Park, New Haven, CT 06511, USA
| | | | | | - Hans Christian Beck
- Department of Clinical Biochemistry, Odense University Hospital, 5000 Odense, Denmark
| | - Lasse Bach Steffensen
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Nick S Laursen
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
| | - Gregers R Andersen
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
| | - Uffe Holmskov
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - David O Bates
- Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2UH, UK
| | - Grith L Sorensen
- Department of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark.
| |
Collapse
|
|
2
|
Ong JYS, Tan SML, Koh AS, Kong W, Sia CH, Yeo TC, Quek SC, Poh KK. Novel Circulating Biomarkers in Aortic Valve Stenosis. Int J Mol Sci 2025; 26:1902. [PMID: 40076529 PMCID: PMC11899762 DOI: 10.3390/ijms26051902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/14/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
The underlying pathophysiology of aortic stenosis and factors affecting its clinical progression remain poorly understood. Apart from B-type natriuretic peptide (BNP), novel and emerging biomarkers have been described in association with aortic stenosis, emphasising the potential for these biomarkers to illuminate on yet unknown mechanisms of its pathogenesis. In this review, we aimed to summarise what is known about aortic stenosis biomarkers, highlight the emerging ones, and provide a roadmap for translating these insights into clinical applications. Among the biomarkers studied, lipoprotein(a) [Lp(a)] has emerged as the most promising for risk stratification. Elevated Lp(a) levels are often associated with more rapid aortic stenosis progression. This detrimental effect is attributed to its role in promoting valve calcification. While other emerging biomarkers such as matrix metalloproteinases, monocytes, and metabolites show promises, their specific roles in aortic stenosis pathophysiology remain less clear. This may be due to their relatively recent discovery. Ongoing research aims to elucidate their mechanisms of action.
Collapse
Affiliation(s)
- Joy Yi-Shan Ong
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
| | - Sarah Ming Li Tan
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
| | - Angela S. Koh
- National Heart Centre Singapore, Singapore 169609, Singapore
- DUKE-NUS Medical School, Singapore 169857, Singapore
| | - William Kong
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ching Hui Sia
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Tiong Cheng Yeo
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Swee Chye Quek
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Kian Keong Poh
- Department of Cardiology, National University Heart Centre Singapore, Singapore 119074, Singapore; (J.Y.-S.O.); (S.M.L.T.)
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| |
Collapse
|
|
3
|
Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
Collapse
Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| |
Collapse
|
|
4
|
Saravanan V, Gopalakrishnan V, Mahendran MIMS, Vaithianathan R, Srinivasan S, Boopathy V, Krishnamurthy S. Biofilm mediated integrin activation and directing acceleration of colorectal cancer. APMIS 2024; 132:688-705. [PMID: 39246244 DOI: 10.1111/apm.13466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/15/2024] [Indexed: 09/10/2024]
Abstract
Bacterial biofilm plays a vital role in influencing several diseases, infections, metabolic pathways and communication channels. Biofilm influence over colorectal cancer (CRC) has been a booming area of research interest. The virulence factors of bacterial pathogen have a high tendency to induce metabolic pathway to accelerate CRC. The bacterial species biofilm may induce cancer through regulating the major signalling pathways responsible for cell proliferation, differentiation, survival and growth. Activation of cancer signals may get initiated from the chronic infections through bacterial biofilm species. Integrin mediates in the activation of major pathway promoting cancer. Integrin-mediated signals are expected to be greatly influenced by biofilm. Integrins are identified as an important dimer, whose dysfunction may alter the signalling cascade specially focusing on TGF-β, PI3K/Akt/mToR, MAPK and Wnt pathway. Along with biofilm shield, the tumour gains greater resistance from radiation, chemotherapy and also from other antibiotics. The biofilm barrier is known to cause challenges for CRC patients undergoing treatment.
Collapse
Affiliation(s)
- Vaijayanthi Saravanan
- MGM Advanced Research Institute, Sri Balaji Vidhyapeeth (Deemed to be University), Pondicherry, Tamil Nadu, India
| | - Vinoj Gopalakrishnan
- MGM Advanced Research Institute, Sri Balaji Vidhyapeeth (Deemed to be University), Pondicherry, Tamil Nadu, India
| | | | - Rajan Vaithianathan
- Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidhyapeeth (Deemed to be University), Pondicherry, Tamil Nadu, India
| | - Sowmya Srinivasan
- Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidhyapeeth (Deemed to be University), Pondicherry, Tamil Nadu, India
| | | | | |
Collapse
|
|
5
|
Jung S, Cheong S, Lee Y, Lee J, Lee J, Kwon MS, Oh YS, Kim T, Ha S, Kim SJ, Jo DH, Ko J, Jeon NL. Integrating Vascular Phenotypic and Proteomic Analysis in an Open Microfluidic Platform. ACS NANO 2024; 18:24909-24928. [PMID: 39208278 PMCID: PMC11394367 DOI: 10.1021/acsnano.4c05537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
This research introduces a vascular phenotypic and proteomic analysis (VPT) platform designed to perform high-throughput experiments on vascular development. The VPT platform utilizes an open-channel configuration that facilitates angiogenesis by precise alignment of endothelial cells, allowing for a 3D morphological examination and protein analysis. We study the effects of antiangiogenic agents─bevacizumab, ramucirumab, cabozantinib, regorafenib, wortmannin, chloroquine, and paclitaxel─on cytoskeletal integrity and angiogenic sprouting, observing an approximately 50% reduction in sprouting at higher drug concentrations. Precise LC-MS/MS analyses reveal global protein expression changes in response to four of these drugs, providing insights into the signaling pathways related to the cell cycle, cytoskeleton, cellular senescence, and angiogenesis. Our findings emphasize the intricate relationship between cytoskeletal alterations and angiogenic responses, underlining the significance of integrating morphological and proteomic data for a comprehensive understanding of angiogenesis. The VPT platform not only advances our understanding of drug impacts on vascular biology but also offers a versatile tool for analyzing proteome and morphological features across various models beyond blood vessels.
Collapse
Affiliation(s)
- Sangmin Jung
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Sunghun Cheong
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Yoonho Lee
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Jungseub Lee
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Jihye Lee
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
| | - Min-Seok Kwon
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
- Department
of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Sun Oh
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
| | - Taewan Kim
- Department
of Electrical and Computer Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Sungjae Ha
- ProvaLabs,
Inc., Seoul 08826, Republic of Korea
| | - Sung Jae Kim
- Department
of Electrical and Computer Engineering, Seoul National University, Seoul 08826, Republic of Korea
- SOFT
Foundry, Seoul National University, Seoul 08826, Republic of Korea
- Inter-university
Semiconductor Research Center, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Dong Hyun Jo
- Department
of Anatomy and Cell Biology, Seoul National
University College of Medicine, Seoul 03080, Republic of Korea
| | - Jihoon Ko
- Department
of BioNano Technology, Gachon University, Seongnam-si, Gyeonggi-do 13120, Republic
of Korea
| | - Noo Li Jeon
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Institute
of Advanced Machines and Design, Seoul National
University, Seoul 08826, Republic
of Korea
- Qureator, Inc., San
Diego, California 92121, United States
| |
Collapse
|
|
6
|
Takada YK, Wu X, Wei D, Hwang S, Takada Y. FGF1 Suppresses Allosteric Activation of β3 Integrins by FGF2: A Potential Mechanism of Anti-Inflammatory and Anti-Thrombotic Action of FGF1. Biomolecules 2024; 14:888. [PMID: 39199276 PMCID: PMC11351609 DOI: 10.3390/biom14080888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/09/2024] [Accepted: 07/19/2024] [Indexed: 09/01/2024] Open
Abstract
Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. FGF2 is pro-inflammatory and pro-thrombotic, and FGF1, homologous to FGF2, has anti-inflammatory and anti-thrombotic actions, but the mechanism of these actions is unknown. We hypothesized that FGF2 and FGF1 bind to site 2 of integrins and regulate inflammatory signaling. Here, we describe that FGF2 is bound to site 2 and allosterically activated β3 integrins, suggesting that the pro-inflammatory action of FGF2 is mediated by binding to site 2. In contrast, FGF1 bound to site 2 but did not activate these integrins and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2 and that the anti-inflammatory action of FGF1 is mediated by blocking site 2. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvβ3, suppressed β3 integrin activation by FGF2 as effectively as WT FGF1.
Collapse
Affiliation(s)
- Yoko K. Takada
- Department of Dermatology, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA; (Y.K.T.); (X.W.); (D.W.); (S.H.)
| | - Xuesong Wu
- Department of Dermatology, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA; (Y.K.T.); (X.W.); (D.W.); (S.H.)
| | - David Wei
- Department of Dermatology, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA; (Y.K.T.); (X.W.); (D.W.); (S.H.)
| | - Samuel Hwang
- Department of Dermatology, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA; (Y.K.T.); (X.W.); (D.W.); (S.H.)
| | - Yoshikazu Takada
- Department of Dermatology, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA; (Y.K.T.); (X.W.); (D.W.); (S.H.)
- Department of Biochemistry and Molecular Medicine, Research III Suite 3300, UC Davis School of Medicine, Sacramento, CA 95817, USA
| |
Collapse
|
|
7
|
Tai L, Saffery NS, Chin SP, Cheong SK. Secretome profile of TNF-α-induced human umbilical cord mesenchymal stem cells unveils biological processes relevant to skin wound healing. Regen Med 2023; 18:839-856. [PMID: 37671699 DOI: 10.2217/rme-2023-0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023] Open
Abstract
Aim: To profile and study the proteins responsible for the beneficial effect of the TNF-α-induced human umbilical cord mesenchymal stem cells (hUCMSCs) secretome in wound healing. Methods: The hUCMSCs secretome was generated with (induced) or without (uninduced) TNF-α and was subsequently analyzed by liquid chromatography-mass spectrometry, immunoassay and in vitro scratch assay. Results: Proteomic analysis revealed approximately 260 proteins, including 51 and 55 unique proteins in the induced and uninduced secretomes, respectively. Gene ontology analysis disclosed that differential proteins in the induced secretome mainly involved inflammation-related terms. The induced secretome, consisting of higher levels of FGFb, VEGF, PDGF and IL-6, significantly accelerated wound closure and enhanced MMP-13 secretion in HaCaT keratinocytes. Conclusion: The secretome from induced hUCMSCs includes factors that promote wound closure.
Collapse
Affiliation(s)
- Lihui Tai
- Cytopeutics Sdn Bhd, Suite 2-3 2nd floor, Bio-X Centre, Persiaran Cyberpoint Selatan, Cyber 8, 63000, Cyberjaya, Selangor, Malaysia
| | - Nik Syazana Saffery
- Cytopeutics Sdn Bhd, Suite 2-3 2nd floor, Bio-X Centre, Persiaran Cyberpoint Selatan, Cyber 8, 63000, Cyberjaya, Selangor, Malaysia
| | - Sze Piaw Chin
- Cytopeutics Sdn Bhd, Suite 2-3 2nd floor, Bio-X Centre, Persiaran Cyberpoint Selatan, Cyber 8, 63000, Cyberjaya, Selangor, Malaysia
| | - Soon Keng Cheong
- Cytopeutics Sdn Bhd, Suite 2-3 2nd floor, Bio-X Centre, Persiaran Cyberpoint Selatan, Cyber 8, 63000, Cyberjaya, Selangor, Malaysia
- M. Kandiah Faculty of Medicine & Health Sciences (MK FMHS), Universiti Tunku Abdul Rahman Sungai Long City Campus, Jalan Sungai Long, Bandar Sungai Long, Cheras, 43000, Kajang, Selangor, Malaysia
| |
Collapse
|
|
8
|
Fisher GJ, Wang B, Cui Y, Shi M, Zhao Y, Quan T, Voorhees JJ. Skin aging from the perspective of dermal fibroblasts: the interplay between the adaptation to the extracellular matrix microenvironment and cell autonomous processes. J Cell Commun Signal 2023; 17:523-529. [PMID: 37067763 PMCID: PMC10409944 DOI: 10.1007/s12079-023-00743-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/10/2023] [Indexed: 04/18/2023] Open
Abstract
This article summarizes important molecular mechanisms that drive aging in human skin from the perspective of dermal fibroblasts. The dermis comprises the bulk of the skin and is largely composed of a collagen-rich extracellular matrix (ECM). The dermal ECM provides mechanical strength, resiliency, and an environment that supports the functions of ibroblasts and other types of dermal cells. Fibroblasts produce the dermal ECM and maintain its homeostasis. Fibroblasts attach to the ECM and this attachment controls their morphology and function. During aging, the ECM undergoes gradual degradation that is nitiated by matrix metalloproteinases (MMPs). This degradation alters mechanical forces within the dermal ECM and disrupts he interactions between fibroblasts and the ECM thereby generating an aged fibroblast phenotype. This aged fibroblast phenotype is characterized by collapsed morphology, altered mechanosignaling, induction of CCN1, and activation of transcription factor AP-1, with consequent upregulation of target genes including MMPs and pro-inflammatory mediators. The TGF-beta pathway coordinately regulates ECM production and turnover. Altered mechanical forces, due to ECM fragmentation, down-regulate the type II TGF-beta receptor, thereby reducing ECM production and further increasing ECM breakdown. Thus, dermal aging involves a feed-forward process that reinforces the aged dermal fibroblast phenotype and promotes age-related dermal ECM deterioration. As discussed in the article, the expression of the aged dermal fibroblast phenotype involves both adaptive and cell-autonomous mechanisms.
Collapse
Affiliation(s)
- Gary J Fisher
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
| | - Bo Wang
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yilei Cui
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Mai Shi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yi Zhao
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Taihao Quan
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - John J Voorhees
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| |
Collapse
|
|
9
|
Zhu J, Li W, Jing J. Design, Synthesis and Anti-Melanoma Activity of Novel Annexin V Derivative with β 3-Integrin Affinity. Int J Mol Sci 2023; 24:11107. [PMID: 37446286 DOI: 10.3390/ijms241311107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Tumor tissues often exhibit unique integrin receptor presentation during development, such as high exposures of αvβ3 and αIIbβ3 integrins. These features are not present in normal tissues. The induction of selective thrombosis and infarction in the tumor-feeding vessels, as well as specific antagonism of αvβ3 integrin on the surface of tumor endothelial cells, is a potential novel antitumor strategy. The Echistatin-Annexin V (EAV) fusion protein is a novel Annexin V (ANV) derivative that possesses a high degree of αvβ3 and αIIbβ3 integrin receptor recognition and binding characteristics while retaining the specific binding ability of the natural ANV molecule for phosphatidylserine (PS). We systematically investigated the biological effects of this novel molecule with superimposed functions on mouse melanoma. We found that EAV inhibited the viability and migration of B16F10 murine melanoma cells in a dose-dependent manner, exhibited good tumor suppressive effects in a xenograft mouse melanoma model, strongly induced tumor tissue necrosis in mice, and targeted the inhibition of angiogenesis in mouse melanoma tumor tissue. EAV exhibited stronger biological effects than natural ANV molecules in inhibiting melanoma in mice. The unique biological effects of EAV are based on its high β3-type integrin receptor-specific recognition and binding ability, as well as its highly selective binding to PS molecules. Based on these findings, we propose that EAV-mediated tumor suppression is a novel and promising antitumor strategy that targets both PS- and integrin β3-positive tumor neovascularization and the tumor cells themselves, thus providing a possible mechanism for the treatment of melanoma.
Collapse
Affiliation(s)
- Jingyi Zhu
- Beijing Key Lab of Biotechnology and Genetic Engineering, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Wenjuan Li
- Beijing Key Lab of Biotechnology and Genetic Engineering, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Jian Jing
- Beijing Key Lab of Biotechnology and Genetic Engineering, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| |
Collapse
|
|
10
|
Wang J, Song Y, Xie W, Zhao J, Wang Y, Yu W. Therapeutic angiogenesis based on injectable hydrogel for protein delivery in ischemic heart disease. iScience 2023; 26:106577. [PMID: 37192972 PMCID: PMC10182303 DOI: 10.1016/j.isci.2023.106577] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2023] Open
Abstract
Ischemic heart disease (IHD) remains the leading cause of death and disability worldwide and leads to myocardial necrosis and negative myocardial remodeling, ultimately leading to heart failure. Current treatments include drug therapy, interventional therapy, and surgery. However, some patients with severe diffuse coronary artery disease, complex coronary artery anatomy, and other reasons are unsuitable for these treatments. Therapeutic angiogenesis stimulates the growth of the original blood vessels by using exogenous growth factors to generate more new blood vessels, which provides a new treatment for IHD. However, direct injection of these growth factors can cause a short half-life and serious side effects owing to systemic spread. Therefore, to overcome this problem, hydrogels have been developed for temporally and spatially controlled delivery of single or multiple growth factors to mimic the process of angiogenesis in vivo. This paper reviews the mechanism of angiogenesis, some important bioactive molecules, and natural and synthetic hydrogels currently being applied for bioactive molecule delivery to treat IHD. Furthermore, the current challenges of therapeutic angiogenesis in IHD and its potential solutions are discussed to facilitate real translation into clinical applications in the future.
Collapse
Affiliation(s)
- Junke Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 26000, China
- Qingdao Medical College, Qingdao University, Qingdao, Shandong 266071, China
| | - Yancheng Song
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 26000, China
| | - Wenjie Xie
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Shandong, Qingdao, Shandong 26000, China
| | - Jiang Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Ying Wang
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, Shandong 26000, China
- Corresponding author
| | - Wenzhou Yu
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 26003, China
- Corresponding author
| |
Collapse
|
|
11
|
Wang M, Shen S, Hou F, Yan Y. Pathophysiological roles of integrins in gliomas from the perspective of glioma stem cells. Front Cell Dev Biol 2022; 10:962481. [PMID: 36187469 PMCID: PMC9523240 DOI: 10.3389/fcell.2022.962481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma is the most common primary intracranial tumor and is also one of the most malignant central nervous system tumors. Its characteristics, such as high malignancy, abundant tumor vasculature, drug resistance, and recurrence-prone nature, cause great suffering to glioma patients. Furthermore, glioma stem cells are the primordial cells of the glioma and play a central role in the development of glioma. Integrins—heterodimers composed of noncovalently bound a and ß subunits—are highly expressed in glioma stem cells and play an essential role in the self-renewal, differentiation, high drug resistance, and chemo-radiotherapy resistance of glioma stem cells through cell adhesion and signaling. However, there are various types of integrins, and their mechanisms of function on glioma stem cells are complex. Therefore, this article reviews the feasibility of treating gliomas by targeting integrins on glioma stem cells.
Collapse
|
|
12
|
Zheng G, Bouamar H, Cserhati M, Zeballos CR, Mehta I, Zare H, Broome L, Hu R, Lai Z, Chen Y, Sharkey FE, Rani M, Halff GA, Cigarroa FG, Sun LZ. Integrin alpha 6 is upregulated and drives hepatocellular carcinoma progression through integrin α6β4 complex. Int J Cancer 2022; 151:930-943. [PMID: 35657344 PMCID: PMC9329238 DOI: 10.1002/ijc.34146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/24/2022]
Abstract
Integrin α6 (ITGA6) forms integrin receptors with either integrin β1 (ITGB1) or integrin β4 (ITGB4). How it functions to regulate hepatocellular carcinoma (HCC) progression is not well-elucidated. We found that ITGA6 RNA and protein expression levels are significantly elevated in human HCC tissues in comparison with paired adjacent nontumor tissues by RNA sequencing, RT-qPCR, Western blotting and immunofluorescence staining. Stable knockdown of ITGA6 with different ITGA6 shRNA expression lentivectors significantly inhibited proliferation, migration and anchorage-independent growth of HCC cell lines in vitro, and xenograft tumor growth in vivo. The inhibition of anchorage-dependent and -independent growth of HCC cell lines was also confirmed with anti-ITGA6 antibody. ITGA6 knockdown was shown to induce cell-cycle arrest at G0/G1 phase. Immunoprecipitation assay revealed apparent interaction of ITGA6 with ITGB4, but not ITGB1. Expression studies showed that ITGA6 positively regulates the expression of ITGB4 with no or negative regulation of ITGB1 expression. Finally, while high levels of ITGA6 and ITGB4 together were associated with significantly worse survival of HCC patients in TCGA data set, the association was not significant for high levels of ITGA6 and ITGB1. In conclusion, ITGA6 is upregulated in HCC tumors and has a malignant promoting role in HCC cells through integrin α6β4 complex. Thus, integrin α6β4 may be a therapeutic target for treating patients with HCC.
Collapse
Affiliation(s)
- Guixi Zheng
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, China
| | - Hakim Bouamar
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Matyas Cserhati
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Carla R. Zeballos
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Isha Mehta
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Habil Zare
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Larry Broome
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Ruolei Hu
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, TX
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX
- Department of Population Health Sciences, University of Texas Health Science Center at San Antonio, TX
| | - Francis E. Sharkey
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, TX
| | - Meenakshi Rani
- Transplant Center, University of Texas Health Science Center at San Antonio, TX
| | - Glenn A. Halff
- Transplant Center, University of Texas Health Science Center at San Antonio, TX
| | | | - Lu-Zhe Sun
- Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, TX
| |
Collapse
|
|
13
|
Flournoy J, Ashkanani S, Chen Y. Mechanical regulation of signal transduction in angiogenesis. Front Cell Dev Biol 2022; 10:933474. [PMID: 36081909 PMCID: PMC9447863 DOI: 10.3389/fcell.2022.933474] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/28/2022] [Indexed: 11/21/2022] Open
Abstract
Biophysical and biochemical cues work in concert to regulate angiogenesis. These cues guide angiogenesis during development and wound healing. Abnormal cues contribute to pathological angiogenesis during tumor progression. In this review, we summarize the known signaling pathways involved in mechanotransduction important to angiogenesis. We discuss how variation in the mechanical microenvironment, in terms of stiffness, ligand availability, and topography, can modulate the angiogenesis process. We also present an integrated view on how mechanical perturbations, such as stretching and fluid shearing, alter angiogenesis-related signal transduction acutely, leading to downstream gene expression. Tissue engineering-based approaches to study angiogenesis are reviewed too. Future directions to aid the efforts in unveiling the comprehensive picture of angiogenesis are proposed.
Collapse
Affiliation(s)
- Jennifer Flournoy
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
| | - Shahad Ashkanani
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Yun Chen
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
- Center for Cell Dynamics, Johns Hopkins University, Baltimore, MD, United States
- Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD, United States
| |
Collapse
|
|
14
|
Jang JH, Kim JG, Lee YH, Bae JG, Park JH. The association between amniotic fluid-derived inflammatory mediators and the risk of retinopathy of prematurity. Medicine (Baltimore) 2022; 101:e29368. [PMID: 35801764 PMCID: PMC9259150 DOI: 10.1097/md.0000000000029368] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Prenatal and perinatal infections and inflammation appear to associated with the development of retinopathy of prematurity (ROP). In this study, we evaluated whether inflammatory mediators in amniotic fluid (AF) retrieved during cesarean delivery influence the development of ROP in very low birth weight (VLBW) infants. This retrospective study included 16 and 32 VLBW infants who did and did not develop any stage of ROP, respectively. Each infant with ROP was matched with 2 infants without ROP based on days of ventilation care, gestational age, and birth weight. AF was obtained during cesarean delivery, and the levels of intra-amniotic inflammatory mediators such as interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and tumor necrosis factor (TNF)-α were measured using a Human Magnetic Luminex assay (R&D Systems, Minneapolis, MN). The differences in the levels of inflammatory mediators according to the presence or absence of ROP were compared. In patients who developed ROP, the level of MMP-2 in the AF was significantly increased (P = .011), whereas the levels of IL-10 and TNF-α were significantly decreased (P = .028 and .046, respectively) compared with those in infants who did not develop ROP. The levels of the other mediators were not significantly different between the 2 groups. Multivariate regression analysis showed that MMP-2 was a risk factor for the development of ROP (odds ratio, 2.445; 95% confidence interval, 1.170-5.106; P = .017). The concentration of MMP-2 in AF is an independent factor in the development of ROP. Further studies are needed to determine whether the levels of inflammatory mediators in AF affect the ROP severity.
Collapse
Affiliation(s)
- Ji Hye Jang
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Jae-Gon Kim
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Yu Hyun Lee
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Jin Gon Bae
- Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Jae Hyun Park
- Department of Pediatrics, Keimyung University School of Medicine, Daegu, Republic of Korea
- * Correspondence: Jae Hyun Park, MD, Department of Pediatrics, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea (e-mail: )
| |
Collapse
|
|
15
|
Spinelli FM, Rosales P, Pluda S, Vitale DL, Icardi A, Guarise C, Reszegi A, Kovalszky I, García M, Sevic I, Galesso D, Alaniz L. The effects of sulfated hyaluronan in breast, lung and colorectal carcinoma and monocytes/macrophages cells: Its role in angiogenesis and tumor progression. IUBMB Life 2022; 74:927-942. [PMID: 35218610 DOI: 10.1002/iub.2604] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 11/11/2022]
Abstract
Hyaluronan (HA) is a component of the extracellular matrix (ECM) it is the main non-sulfated glycosaminoglycan able to modulate cell behavior in the healthy and tumor context. Sulfated hyaluronan (sHA) is a biomaterial derived from chemical modifications of HA, since this molecule is not naturally sulfated. The HA sulfation modifies several properties of the native molecule, acquiring antitumor properties in different cancers. In this study, we evaluated the action of sHA of ~30-60 kDa with different degrees of sulfation (0.7 sHA1 and 2.5 sHA3) on tumor cells of a breast, lung, and colorectal cancer model and its action on other cells of the tumor microenvironment, such as endothelial and monocytes/macrophage cells. Our data showed that in breast and lung tumor cells, sHA3 is able to modulate cell viability, cytotoxicity, and proliferation, but no effects were observed on colorectal cancer cells. In 3D cultures of breast and lung cancer cells, sHA3 diminished the size of the tumorsphere and modulated total HA levels. In these tumor models, treatment of monocytes/macrophages with sHA3 showed a downregulation of the expression of angiogenic factors. We also observed a decrease in endothelial cell migration and modulation of the hyaluronan-binding protein TSG-6. In the breast in vivo xenograft model, monocytes/macrophages preincubated with sHA1 or sHA3 decreased tumor vasculature, TSG-6 and HA levels. Besides, in silico analysis showed an association of TSG-6, HAS2, and IL-8 with biological processes implicated in the progression of the tumor. Taken together, our data indicate that sHA in a breast and lung tumor context is able to induce an antiangiogenic action on tumor cells as well as in monocytes/macrophages (Mo/MØ) by modulation of endothelial migration, angiogenic factors, and vessel formation.
Collapse
Affiliation(s)
- Fiorella M Spinelli
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| | - Paolo Rosales
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| | | | - Daiana L Vitale
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| | - Antonella Icardi
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| | | | - Andrea Reszegi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Mariana García
- Laboratorio de Terapia Génica, IIMT - CONICET, Universidad Austral, Derqui-Pilar, Argentina
| | - Ina Sevic
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| | | | - Laura Alaniz
- Laboratorio de Microambiente Tumoral, CIBA, UNNOBA/CIT NOBA (UNNOBA-UNSADA-CONICET), Jorge Newbery 261, Junín, Argentina
| |
Collapse
|
|
16
|
Marei I, Chidiac O, Thomas B, Pasquier J, Dargham S, Robay A, Vakayil M, Jameesh M, Triggle C, Rafii A, Jayyousi A, Al Suwaidi J, Abi Khalil C. Angiogenic content of microparticles in patients with diabetes and coronary artery disease predicts networks of endothelial dysfunction. Cardiovasc Diabetol 2022; 21:17. [PMID: 35109843 PMCID: PMC8812242 DOI: 10.1186/s12933-022-01449-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/20/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Elevated endothelial microparticles (EMPs) levels are surrogate markers of vascular dysfunction. We analyzed EMPs with apoptotic characteristics and assessed the angiogenic contents of microparticles in the blood of patients with type 2 diabetes (T2D) according to the presence of coronary artery disease (CAD). METHODS A total of 80 participants were recruited and equally classified as (1) healthy without T2D, (2) T2D without cardiovascular complications, (3) T2D and chronic coronary artery disease (CAD), and (4) T2D and acute coronary syndrome (ACS). MPs were isolated from the peripheral circulation, and EMPs were characterized using flow cytometry of CD42 and CD31. CD62E was used to determine EMPs' apoptotic/activation state. MPs content was extracted and profiled using an angiogenesis array. RESULTS Levels of CD42- CD31 + EMPs were significantly increased in T2D with ACS (257.5 ± 35.58) when compared to healthy subjects (105.7 ± 12.96, p < 0.01). There was no significant difference when comparing T2D with and without chronic CAD. The ratio of CD42-CD62 +/CD42-CD31 + EMPs was reduced in all T2D patients, with further reduction in ACS when compared to chronic CAD, reflecting a release by apoptotic endothelial cells. The angiogenic content of the full population of MPs was analyzed. It revealed a significant differential expression of 5 factors in patients with ACS and diabetes, including TGF-β1, PD-ECGF, platelet factor 4, serpin E1, and thrombospondin 1. Ingenuity Pathway Analysis revealed that those five differentially expressed molecules, mainly TGF-β1, inhibit key pathways involved in normal endothelial function. Further comparison of the three diabetes groups to healthy controls and diabetes without cardiovascular disease to diabetes with CAD identified networks that inhibit normal endothelial cell function. Interestingly, DDP-IV was the only differentially expressed protein between chronic CAD and ACS in patients with diabetes. CONCLUSION Our data showed that the release of apoptosis-induced EMPs is increased in diabetes, irrespective of CAD, ACS patients having the highest levels. The protein contents of MPs interact in networks that indicate vascular dysfunction.
Collapse
Affiliation(s)
- Isra Marei
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
- National Heart and Lung Institute, Imperial College London, London, UK
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Omar Chidiac
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Binitha Thomas
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Jennifer Pasquier
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Soha Dargham
- Biostatistics Core, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Amal Robay
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Muneera Vakayil
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | | | - Arash Rafii
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Amin Jayyousi
- Department of Endocrinology, Hamad Medical Corporation, Doha, Qatar
| | | | - Charbel Abi Khalil
- Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
- Heart Hospital, Hamad Medical Corporation, Doha, Qatar.
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, USA.
| |
Collapse
|
|
17
|
Silva AL, Babo PS, Rodrigues MT, Gonçalves AI, Novoa-Carballal R, Pires RA, Rouwkema J, Reis RL, Gomes ME. Hyaluronic Acid Oligomer Immobilization as an Angiogenic Trigger for the Neovascularization of TE Constructs. ACS APPLIED BIO MATERIALS 2021; 4:6023-6035. [DOI: 10.1021/acsabm.1c00291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Ana L. Silva
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Pedro S. Babo
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Márcia T. Rodrigues
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Ana I. Gonçalves
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Ramon Novoa-Carballal
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Ricardo A. Pires
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Jeroen Rouwkema
- Department of Biomechanical Engineering, Faculty of Engineering Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands
| | - Rui L. Reis
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| | - Manuela E. Gomes
- 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, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal
- ICVS/3B’s−PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
| |
Collapse
|
|
18
|
Sun S, Huang C, Leng D, Chen C, Zhang T, Lei KC, Zhang XD. Gene fusion of IL7 involved in the regulation of idiopathic pulmonary fibrosis. Ther Adv Respir Dis 2021; 15:1753466621995045. [PMID: 33878985 PMCID: PMC8064517 DOI: 10.1177/1753466621995045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development. Methods: In this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects. Results: We identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress. Conclusion: Based on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF via enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF. The reviews of this paper are available via the supplemental material section.
Collapse
Affiliation(s)
- Shixue Sun
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Chen Huang
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Dongliang Leng
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Chang Chen
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Teng Zhang
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Kuan Cheok Lei
- CRDA, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Xiaohua Douglas Zhang
- CRDA, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China
| |
Collapse
|
|
19
|
Sakharkar MK, Dhillon SK, Mazumder M, Yang J. Key drug-targeting genes in pancreatic ductal adenocarcinoma. Genes Cancer 2021; 12:12-24. [PMID: 33884102 PMCID: PMC8045979 DOI: 10.18632/genesandcancer.210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/21/2021] [Indexed: 01/03/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer. In this study,
we undertook a pairwise comparison of gene expression pattern between tumor tissue and its
matching adjacent normal tissue for 45 PDAC patients and identified 22 upregulated and 32
downregulated genes. PPI network revealed that fibronectin 1 and serpin peptidase
inhibitor B5 were the most interconnected upregulated-nodes. Virtual screening identified
bleomycin exhibited reasonably strong binding to both proteins. Effect of bleomycin on
cell viability was examined against two PDAC cell lines, AsPC-1 and MIA PaCa-2. AsPC-1 did
not respond to bleomycin, however, MIA PaCa-2 responded to bleomycin with an
IC50 of 2.6 μM. This implicates that bleomycin could be repurposed for the
treatment of PDAC, especially in combination with other chemotherapy agents. In
vivo mouse xenograft studies and patient clinical trials are warranted to
understand the functional mechanism of bleomycin towards PDAC and optimize its therapeutic
efficacy. Furthermore, we will evaluate the antitumor activity of the other identified
drugs in our future studies.
Collapse
Affiliation(s)
- Meena Kishore Sakharkar
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Sarinder Kaur Dhillon
- Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
| | - Mohit Mazumder
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Jian Yang
- Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
20
|
Dolinschek R, Hingerl J, Benge A, Zafiu C, Schüren E, Ehmoser EK, Lössner D, Reuning U. Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells. Mol Oncol 2020; 15:503-522. [PMID: 33155399 PMCID: PMC7858284 DOI: 10.1002/1878-0261.12845] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/30/2020] [Accepted: 10/21/2020] [Indexed: 02/01/2023] Open
Abstract
Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage-dependent epithelial-type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high-affinity and constitutively signaling-competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D-hydrogels, involving p27kip upregulation. Moreover, it promoted EGF-R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti-apoptotic factors Bcl-2 and survivin suppressing caspase activation, compared to a signaling-incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3-dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3-triggered prosurvival signaling.
Collapse
Affiliation(s)
- Romana Dolinschek
- Department for Obstetrics & Gynecology, Clinical Research Unit, Technische Universität München, Germany
| | - Julia Hingerl
- Department for Obstetrics & Gynecology, Clinical Research Unit, Technische Universität München, Germany
| | - Anke Benge
- Department for Obstetrics & Gynecology, Clinical Research Unit, Technische Universität München, Germany
| | - Christian Zafiu
- Department of Water, Atmosphere, and Environment, University for Natural Resources and Applied Life Sciences (BOKU), Vienna, Austria
| | - Elisabeth Schüren
- Department for Obstetrics & Gynecology, Clinical Research Unit, Technische Universität München, Germany
| | - Eva-Kathrin Ehmoser
- Department for Nanobiotechnology, Institute for Synthetic Bioarchitectures, University for Natural Resources and Applied Life Sciences (BOKU), Vienna, Austria
| | - Daniela Lössner
- Faculties of Engineering and Medicine, Nursing & Health Sciences, Monash University, Melbourne, Vic., Australia
| | - Ute Reuning
- Department for Obstetrics & Gynecology, Clinical Research Unit, Technische Universität München, Germany
| |
Collapse
|
|
21
|
Gong J, Jie Y, Xiao C, Zhou W, Li X, Chen Y, Wu Y, Cao J, Zhang Q, Gao Z, Hu B, Chong Y. Increased Expression of Fibulin-1 Is Associated With Hepatocellular Carcinoma Progression by Regulating the Notch Signaling Pathway. Front Cell Dev Biol 2020; 8:478. [PMID: 32612994 PMCID: PMC7308487 DOI: 10.3389/fcell.2020.00478] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/21/2020] [Indexed: 02/05/2023] Open
Abstract
Fibulin-1, a component of the extracellular matrix (ECM), its prognostic, pathophysiologic and diagnostic role in hepatocellular carcinoma (HCC) is still unexplored. We first found that either Fibulin-1 messenger RNA (mRNA) or protein level was highly elevated in HCC tissues compared with normal tissues. Fibulin-1 correlated with poor overall survival, and it was an independent prognostic predictor (p = 0.001). Furthermore, Overexpression or inhibition of Fibulin-1 reduced or sensitized HCC cells to apoptotic signals, and Fibulin-1 silencing suppressed the ability of HCC cells to form tumors in vivo. Moreover, Fibulin-1 inhibited apoptosis via the Notch pathway while Fibulin-1 silencing had no obvious effect on p-MAPK, p-c-jun and p-stat3 expression, and both Mcl-1 and Bcl-xL are targets of Fibulin-1. Furthermore, the stromal and immune score was elevated in high Fibulin-1 tissues, and FBLN1 expression was associated with increased infiltrating macrophages using xCell, TIMER and TISDIB tool based on TCGA HCC database. Importantly, the circulating cell-free RNA (cfRNA) level of Fibulin-1 in the serum were significantly increased in patients with HCC compared with those in healthy controls, individuals with chronic hepatitis B and patients with HBV-induced liver cirrhosis. The area under receiver operating characteristic curves (AUC) was 0.791 for Fibulin-1, 0.640 for α-fetoprotein and 0.868 for the combination of the two tumor markers. Our findings indicate that Fibulin-1 may be a potential prognostic indicator, a promising serum biomarker and a therapeutic target in patients with HCC.
Collapse
Affiliation(s)
- Jiao Gong
- Department of Laboratory Medicine, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yusheng Jie
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Cuicui Xiao
- Cell-gene Therapy Translational Medicine Research Center, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenying Zhou
- Department of Laboratory Medicine, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xinhua Li
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yaqiong Chen
- Department of Laboratory Medicine, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuankai Wu
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jing Cao
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qi Zhang
- Cell-gene Therapy Translational Medicine Research Center, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhiliang Gao
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bo Hu
- Department of Laboratory Medicine, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yutian Chong
- Department of Infectious Diseases, Key Laboratory of Liver Disease of Guangdong Province, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
22
|
Dual functionality of the amyloid protein TasA in Bacillus physiology and fitness on the phylloplane. Nat Commun 2020; 11:1859. [PMID: 32313019 PMCID: PMC7171179 DOI: 10.1038/s41467-020-15758-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 03/27/2020] [Indexed: 02/07/2023] Open
Abstract
Bacteria can form biofilms that consist of multicellular communities embedded in an extracellular matrix (ECM). In Bacillus subtilis, the main protein component of the ECM is the functional amyloid TasA. Here, we study further the roles played by TasA in B. subtilis physiology and biofilm formation on plant leaves and in vitro. We show that ΔtasA cells exhibit a range of cytological symptoms indicative of excessive cellular stress leading to increased cell death. TasA associates to the detergent-resistant fraction of the cell membrane, and the distribution of the flotillin-like protein FloT is altered in ΔtasA cells. We propose that, in addition to a structural function during ECM assembly and interactions with plants, TasA contributes to the stabilization of membrane dynamics as cells enter stationary phase. The amyloid protein TasA is a main component of the extracellular matrix in Bacillus subtilis biofilms. Here the authors show that, in addition to a structural function during biofilm assembly and interactions with plants, TasA contributes to the stabilization of membrane dynamics during stationary phase.
Collapse
|
|
23
|
Dong Q, Wang Z, Jiang M, Sun H, Wang X, Li Y, Zhang Y, Cheng H, Chai Y, Shao T, Shi L, Wang Z. Transcriptome analysis of the response provided by Lasiopodomys mandarinus to severe hypoxia includes enhancing DNA repair and damage prevention. Front Zool 2020; 17:9. [PMID: 32256671 PMCID: PMC7106638 DOI: 10.1186/s12983-020-00356-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/16/2020] [Indexed: 02/08/2023] Open
Abstract
Background Severe hypoxia induces a series of stress responses in mammals; however, subterranean rodents have evolved several adaptation mechanisms of energy metabolisms and O2 utilization for hypoxia. Mammalian brains show extreme aerobic metabolism. Following hypoxia exposure, mammals usually experience irreversible brain damage and can even develop serious diseases, such as hypoxic ischemic encephalopathy and brain edema. To investigate mechanisms underlying the responses of subterranean rodents to severe hypoxia, we performed a cross-species brain transcriptomic analysis using RNA sequencing and identified differentially expressed genes (DEGs) between the subterranean rodent Lasiopodomys mandarinus and its closely related aboveground species L. brandtii under severe hypoxia (5.0% O2, 6 h) and normoxia (20.9% O2, 6 h). Results We obtained 361 million clean reads, including 69,611 unigenes in L. mandarinus and 69,360 in L. brandtii. We identified 359 and 515 DEGs by comparing the hypoxic and normoxia groups of L. mandarinus and L. brandtii, respectively. Gene Ontology (GO) analysis showed that upregulated DEGs in both species displayed similar terms in response to severe hypoxia; the main difference is that GO terms of L. brandtii were enriched in the immune system. However, in the downregulated DEGs, GO terms of L. mandarinus were enriched in cell proliferation and protein transport and those of L. brandtii were enriched in nuclease and hydrolase activities, particularly in terms of developmental functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that upregulated DEGs in L. mandarinus were associated with DNA repair and damage prevention as well as angiogenesis and metastasis inhibition, whereas downregulated DEGs were associated with neuronal synaptic transmission and tumor-associated metabolic pathways. In L. brandtii, upregulated KEGG pathways were enriched in the immune, endocrine, and cardiovascular systems and particularly in cancer-related pathways, whereas downregulated DEGs were associated with environmental information processing and misregulation in cancers. Conclusions L. mandarinus has evolved hypoxia adaptation by enhancing DNA repair, damage prevention, and augmenting sensing, whereas L. brandtii showed a higher risk of tumorigenesis and promoted innate immunity toward severe hypoxia. These results reveal the hypoxic mechanisms of L. mandarinus to severe hypoxia, which may provide research clues for hypoxic diseases.
Collapse
Affiliation(s)
- Qianqian Dong
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Zishi Wang
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Mengwan Jiang
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Hong Sun
- 2College of Physical Education (main campus), Zhengzhou University, Zhengzhou, Henan Province China
| | - Xuqin Wang
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Yangwei Li
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China.,3Central Laboratory, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008 Henan Province China
| | - Yifeng Zhang
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Han Cheng
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Yurong Chai
- 4School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Tian Shao
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Luye Shi
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| | - Zhenlong Wang
- 1School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan Province China
| |
Collapse
|
|
24
|
Wei Z, Volkova E, Blatchley MR, Gerecht S. Hydrogel vehicles for sequential delivery of protein drugs to promote vascular regeneration. Adv Drug Deliv Rev 2019; 149-150:95-106. [PMID: 31421149 PMCID: PMC6889011 DOI: 10.1016/j.addr.2019.08.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/04/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022]
Abstract
In recent years, as the mechanisms of vasculogenesis and angiogenesis have been uncovered, the functions of various pro-angiogenic growth factors (GFs) and cytokines have been identified. Therefore, therapeutic angiogenesis, by delivery of GFs, has been sought as a treatment for many vascular diseases. However, direct injection of these protein drugs has proven to have limited clinical success due to their short half-lives and systemic off-target effects. To overcome this, hydrogel carriers have been developed to conjugate single or multiple GFs with controllable, sustained, and localized delivery. However, these attempts have failed to account for the temporal complexity of natural angiogenic pathways, resulting in limited therapeutic effects. Recently, the emerging ideas of optimal sequential delivery of multiple GFs have been suggested to better mimic the biological processes and to enhance therapeutic angiogenesis. Incorporating sequential release into drug delivery platforms will likely promote the formation of neovasculature and generate vast therapeutic potential.
Collapse
Affiliation(s)
- Zhao Wei
- Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology Physical-Sciences Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Eugenia Volkova
- Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology Physical-Sciences Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Michael R Blatchley
- Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology Physical-Sciences Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sharon Gerecht
- Department of Chemical and Biomolecular Engineering, The Institute for NanoBioTechnology Physical-Sciences Oncology Center, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| |
Collapse
|
|
25
|
Microfluidic Collective Cell Migration Assay for Study of Endothelial Cell Proliferation and Migration under Combinations of Oxygen Gradients, Tensions, and Drug Treatments. Sci Rep 2019; 9:8234. [PMID: 31160651 PMCID: PMC6546762 DOI: 10.1038/s41598-019-44594-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/20/2019] [Indexed: 01/28/2023] Open
Abstract
Proliferation and migration of endothelial cells play an important role in many biological activities, and they can be regulated by various microenvironmental factors. In this paper, a novel microfluidic collective cell migration assay is developed to study endothelial cell migration and proliferation under combinations of three oxygen conditions: normoxia, oxygen gradient, and hypoxia and three medium compositions: normal growth medium, the medium with cytochalasin-D for actin polymerization inhibition, and with YC-1 for hypoxia-inducible factor (HIF) inhibition. The microfluidic device designed in the paper allows cell patterns formed with consistent dimensions using laminar flow patterning. In addition, stable oxygen gradients can be generated within the device by a spatially confined chemical reaction method. The device can be operated in conventional cell incubators with minimal chemical reagents and instrumentation for practical applications. The results show directional collective cell migration of the endothelial cells under the oxygen gradients for all the medium compositions. The directional behavior has never been discussed before, and indicates critical roles of oxygen gradients in guiding endothelial cell migration during various biological activities. The developed assay provides a practical yet powerful tool for further in vitro study of endothelial cell behaviors under various physiological microenvironments.
Collapse
|
|
26
|
Sun Z, Xue S, Xu H, Hu X, Chen S, Yang Z, Yang Y, Ouyang J, Cui H. Expression profiles of long noncoding RNAs associated with the NSUN2 gene in HepG2 cells. Mol Med Rep 2019; 19:2999-3008. [PMID: 30816500 PMCID: PMC6423554 DOI: 10.3892/mmr.2019.9984] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 01/25/2019] [Indexed: 12/19/2022] Open
Abstract
NOP2/Sun domain family member 2 (NSUN2) is upregulated in numerous types of tumors and may be implicated in multiple biological processes, including cell proliferation, migration and human tumorigenesis. However, little is known about how NSUN2 serves a role in these processes. In the present study, expression profiles of long noncoding RNAs (lncRNAs) and mRNAs were developed in NSUN2‑deficient HepG2 cells by RNA‑sequencing analysis. A total of 757 lncRNAs were differentially expressed, 392 of which were upregulated, and 365 were downregulated compared with wild‑type HepG2 cells. Moreover, 212 lncRNAs were co‑expressed with 368 target mRNAs. It was also observed that 253 pairs of lncRNAs and mRNAs exhibited negative correlations and that 290 pairs had positive correlations. Bioinformatics analysis indicated that these lncRNAs regulated by NSUN2 were associated with 'signal transduction', 'extracellular exosome' and 'calcium ion binding', and were enriched in 'pathways in cancer', 'PI3K‑Akt signaling pathway' and 'ECM‑receptor interaction pathway'. These results illustrate the landscape and co‑expression network of lncRNAs regulated by NSUN2 and provide invaluable information for studying the molecular function of NSUN2.
Collapse
Affiliation(s)
- Zhen Sun
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Shonglei Xue
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Hui Xu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Xuming Hu
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Shihao Chen
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Zhe Yang
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Yu Yang
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Juan Ouyang
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Hengmi Cui
- Institute of Epigenetics and Epigenomics and College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
- Institute of Comparative Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
- Joint International Research Laboratory of Agricultural and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
- Ministry of Education Key Lab for Avian Preventive Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| |
Collapse
|
|
27
|
Saberianpour S, Heidarzadeh M, Geranmayeh MH, Hosseinkhani H, Rahbarghazi R, Nouri M. Tissue engineering strategies for the induction of angiogenesis using biomaterials. J Biol Eng 2018; 12:36. [PMID: 30603044 PMCID: PMC6307144 DOI: 10.1186/s13036-018-0133-4] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 12/13/2018] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is touted as a fundamental procedure in the regeneration and restoration of different tissues. The induction of de novo blood vessels seems to be vital to yield a successful cell transplantation rate loaded on various scaffolds. Scaffolds are natural or artificial substances that are considered as one of the means for delivering, aligning, maintaining cell connection in a favor of angiogenesis. In addition to the potential role of distinct scaffold type on vascularization, the application of some strategies such as genetic manipulation, and conjugation of pro-angiogenic factors could intensify angiogenesis potential. In the current review, we focused on the status of numerous scaffolds applicable in the field of vascular biology. Also, different strategies and priming approaches useful for the induction of pro-angiogenic signaling pathways were highlighted.
Collapse
Affiliation(s)
- Shirin Saberianpour
- 1Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, 5166614756 Iran
- 2Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Heidarzadeh
- 1Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, 5166614756 Iran
| | - Mohammad Hossein Geranmayeh
- 3Neuroscience Research Center, Imam Reza Medical Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Reza Rahbarghazi
- 1Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, 5166614756 Iran
- 5Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- 2Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- 1Stem Cell Research Center, Tabriz University of Medical Sciences, Imam Reza St., Golgasht St, Tabriz, 5166614756 Iran
- 5Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
28
|
Burgett ME, Lathia JD, Roth P, Nowacki AS, Galileo DS, Pugacheva E, Huang P, Vasanji A, Li M, Byzova T, Mikkelsen T, Bao S, Rich JN, Weller M, Gladson CL. Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells. Oncotarget 2018; 7:43852-43867. [PMID: 27270311 PMCID: PMC5190064 DOI: 10.18632/oncotarget.9700] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 05/13/2016] [Indexed: 12/15/2022] Open
Abstract
The secretion of soluble pro-angiogenic factors by tumor cells and stromal cells in the perivascular niche promotes the aggressive angiogenesis that is typical of glioblastoma (GBM). Here, we show that angiogenesis also can be promoted by a direct interaction between brain tumor cells, including tumor cells with cancer stem-like properties (CSCs), and endothelial cells (ECs). As shown in vitro, this direct interaction is mediated by binding of integrin αvβ3 expressed on ECs to the RGD-peptide in L1CAM expressed on CSCs. It promotes both EC network formation and enhances directed migration toward basic fibroblast growth factor. Activation of αvβ3 and bone marrow tyrosine kinase on chromosome X (BMX) is required for migration stimulated by direct binding but not for migration stimulated by soluble factors. RGD-peptide treatment of mice with established intracerebral GBM xenografts significantly reduced the percentage of Sox2-positive tumor cells and CSCs in close proximity to ECs, decreased integrin αvβ3 and BMX activation and p130CAS phosphorylation in the ECs, and reduced the vessel surface area. These results reveal a previously unrecognized aspect of the regulation of angiogenesis in GBM that can impact therapeutic anti-angiogenic targeting.
Collapse
Affiliation(s)
- Monica E Burgett
- Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA.,School of Biomedical Sciences, Kent State University, Kent, OH, USA
| | - Justin D Lathia
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Patrick Roth
- Department of Neurology, Laboratory of Molecular Neuro-Oncology, University Hospital, Zurich, Switzerland
| | - Amy S Nowacki
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Deni S Galileo
- Department of Biological Sciences, University of Delaware and Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA
| | - Elena Pugacheva
- Department of Biochemistry, West Virginia University, Morgantown, VA, USA
| | - Ping Huang
- Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA
| | | | - Meizhang Li
- Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Tatiana Byzova
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA
| | - Tom Mikkelsen
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA
| | - Shideng Bao
- Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Jeremy N Rich
- Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Michael Weller
- Department of Neurology, Laboratory of Molecular Neuro-Oncology, University Hospital, Zurich, Switzerland
| | | |
Collapse
|
|
29
|
Pseudolaric acid B induces endometrial cancer Ishikawa cell apoptosis and inhibits metastasis through AKT-GSK-3β and ERK1/2 signaling pathways. Anticancer Drugs 2017; 28:603-612. [PMID: 28422767 DOI: 10.1097/cad.0000000000000500] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Pseudolaric acid B (PAB) is the most active constituent extracted from the bark of Pseudolarix kaempferi, which has been used as an antifungal remedy in traditional Chinese medicine. It is reported to have cytotoxicity to many tumor cell lines. In this study, we investigated the effects of PAB against human endometrial cancer Ishikawa cells. We found that PAB inhibited Ishikawa cell proliferation, and induced cell apoptosis and G2/M phase arrest through a mechanism involving AKT-GSK-3β and ERK1/2 signaling pathways. PAB also suppressed the Ishikawa cell adhesion, invasion, migration, and colony formation ability by increasing the expression of E-cadherin, Ezrin, and Kiss-1, and decreasing the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. Taken together, these data indicated that PAB can be expected to be a novel treatment agent for endometrial cancer therapy.
Collapse
|
|
30
|
Lee J, Lee J, Yun JH, Choi C, Cho S, Kim SJ, Kim JH. Autocrine DUSP28 signaling mediates pancreatic cancer malignancy via regulation of PDGF-A. Sci Rep 2017; 7:12760. [PMID: 28986588 PMCID: PMC5630619 DOI: 10.1038/s41598-017-13023-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/15/2017] [Indexed: 01/17/2023] Open
Abstract
Pancreatic cancer remains one of the most deadly cancers with a grave prognosis. Despite continuous efforts to improve remedial values, limited progress has been made. We have reported that dual specificity phosphatase 28 (DUSP28) has a critical role of chemo-resistance and migration in pancreatic cancers. However, its mechanism remains unclear. Here, we further clarify the function of DUSP28 in pancreatic cancers. Analysis using a public microarray database and in vitro assay indicated a critical role of platelet derived growth factor A (PDGF-A) in pancreatic cancer malignancy. PDGF-A was positively regulated by DUSP28 expression at the mRNA and protein levels. Enhanced DUSP28 sensitized pancreatic cancer cells to exogenous PDGF-A treatment in migration, invasion, and proliferation. Transfection with siRNA targeting DUSP28 blunted the influence of administered PDGF-A by inhibition of phosphorylation of FAK, ERK1/2, and p38 signalling pathways. In addition, DUSP28 and PDGF-A formed an acquired autonomous autocrine-signaling pathway. Furthermore, targeting DUSP28 inhibited the tumor growth and migratory features through the blockade of PDGF-A expression and intracellular signaling in vivo. Our results establish novel insight into DUSP28 and PDGF-A related autonomous signaling pathway in pancreatic cancer.
Collapse
Affiliation(s)
- Jungwhoi Lee
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea.
| | - Jungsul Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Jeong Hun Yun
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea
| | - Chulhee Choi
- Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea
| | - Sayeon Cho
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Seung Jun Kim
- Division of Strategic Research Planning and Assessment, Korea Research Institute of Bioscience & Biotechnology, Daejeon, 34141, Republic of Korea
| | - Jae Hoon Kim
- Department of biotechnology, College of Applied Life Science, SARI, Jeju National University, Jeju-do, 63243, Republic of Korea.
| |
Collapse
|
|
31
|
Falero-Perez J, Park S, Sorenson CM, Sheibani N. PEDF expression affects retinal endothelial cell proangiogenic properties through alterations in cell adhesive mechanisms. Am J Physiol Cell Physiol 2017; 313:C405-C420. [PMID: 28747334 PMCID: PMC5668572 DOI: 10.1152/ajpcell.00004.2017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 07/20/2017] [Accepted: 07/20/2017] [Indexed: 12/17/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis. Although various ocular cell types including retinal endothelial cells (EC) produce PEDF, we know very little about cell autonomous effects of PEDF in these cell types. Here we determined how PEDF expression affects retinal EC proangiogenic properties. Retinal EC were prepared from wild-type (PEDF+/+) and PEDF-deficient (PEDF-/-) mice. The identity of EC was confirmed by staining for specific markers including vascular endothelial cadherin, CD31, and B4-lectin. Retinal EC also expressed VEGF receptor 1 and endoglin, as well as ICAM-1, ICAM-2, and VCAM-1. PEDF-/- retinal EC were more proliferative, less apoptotic when challenged with H2O2, less migratory, and less adherent compared with PEDF+/+ EC. These changes could be associated, at least in part, with increased levels of tenascin-C, fibronectin, thrombospondin-1 and collagen IV, and lower amounts of osteopontin. PEDF-/- EC also exhibited alterations in expression of a number of integrins including α2, αv, β1, β8, and αvβ3, and cell-cell adhesion molecules including CD31, zonula occluden-1, and occludin. These observations correlated with attenuation of capillary morphogenesis and increased levels of oxidative stress in PEDF-/- EC. PEDF-/- EC also produced lower levels of VEGF compared with PEDF+/+ cells. Thus, PEDF deficiency has a significant impact on retinal EC adhesion and migration, perhaps through altered production of extracellular matrix and junctional proteins in response to increased oxidative stress affecting their proangiogenic activity.
Collapse
Affiliation(s)
- Juliana Falero-Perez
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - SunYoung Park
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Christine M Sorenson
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin;
- McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; and
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| |
Collapse
|
|
32
|
Nemati S, Rezabakhsh A, Khoshfetrat AB, Nourazarian A, Biray Avci Ç, Goker Bagca B, Alizadeh Sardroud H, Khaksar M, Ahmadi M, Delkhosh A, Sokullu E, Rahbarghazi R. Alginate-gelatin encapsulation of human endothelial cells promoted angiogenesis in in vivo and in vitro milieu. Biotechnol Bioeng 2017; 114:2920-2930. [DOI: 10.1002/bit.26395] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 07/31/2017] [Accepted: 08/01/2017] [Indexed: 01/04/2023]
Affiliation(s)
- Sorour Nemati
- Chemical Engineering Faculty; Sahand University of Technology; Tabriz Iran
- Stem Cell Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Aysa Rezabakhsh
- Department of Pharmacology and Toxicology; Faculty of Pharmacy; Tabriz University of Medical Sciences; Tabriz Iran
| | | | - Alireza Nourazarian
- Department of Biochemistry and Clinical Laboratories; Faculty of Medicine; Tabriz University of Medical Sciences; Tabriz Iran
| | - Çığır Biray Avci
- Department of Medical Biology; Faculty of Medicine; Ege University; Izmir Turkey
| | - Bakiye Goker Bagca
- Department of Medical Biology; Faculty of Medicine; Ege University; Izmir Turkey
| | | | - Majid Khaksar
- Stem Cell Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Mahdi Ahmadi
- Department of Physiology; Faculty of Medicine; Tabriz University of Medical Sciences; Tabriz Iran
| | - Aref Delkhosh
- Stem Cell Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Emel Sokullu
- Izmir Katip Celebi University; Bioengineering Department; Izmir Turkey
- Harvard Medical School; Division of Biomedical Engineering at Brigham and Women's Hospital, Harvard-MIT Health Sciences and Technology; Cambridge MA
| | - Reza Rahbarghazi
- Stem Cell Research Center; Tabriz University of Medical Sciences; Tabriz Iran
- Department of Applied Cell Sciences; Faculty of Advanced Medical Sciences; Tabriz University of Medical Sciences; Tabriz Iran
| |
Collapse
|
|
33
|
Spanggaard I, Dahlstroem K, Laessoee L, Hansen RH, Johannesen HH, Hendel HW, Bouquet C, Attali P, Gehl J. Gene therapy for patients with advanced solid tumors: a phase I study using gene electrotransfer to muscle with the integrin inhibitor plasmid AMEP. Acta Oncol 2017; 56:909-916. [PMID: 28438067 DOI: 10.1080/0284186x.2017.1315171] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gene electrotrotransfer describes the use of electric pulses to transfer DNA to cells. Particularly skeletal muscle has potential for systemic secretion of therapeutic proteins. Gene electrotransfer to muscle using the integrin inhibitor plasmid AMEP (Antiangiogenic MEtargidin Peptide) was investigated in a phase I dose escalation study. Primary objective was safety. MATERIAL AND METHODS Patients with metastatic or locally advanced solid tumors, without further standard treatments available, were treated with once-only gene electrotransfer of plasmid AMEP to the femoral muscle. Safety was monitored by adverse events registration, visual analog scale (VAS) after procedure and magnetic resonance imaging (MRI) of treated muscles. Pharmacokinetics of plasmid AMEP in plasma and urine was determined by quantitative polymerase chain reaction. Response was evaluated by positron emission tomography-computed tomography (PET-CT) scans. RESULTS Seven patients were enrolled and treated at dose levels from 50 to 250 μg of plasmid AMEP, the study was terminated early due to cessation of plasmid production. Minimal systemic toxicity was observed and only transient mild pain was associated with the delivery of the electric pulses. MRI of the treated muscles revealed discrete intramuscular edema 24 h after treatment. The changes in the muscle tissue resolved within 2 weeks after treatment. Peak concentrations of plasmid AMEP was detected only in plasma within the first 24 hours after injection. Protein AMEP could not be detected, which could be due to the limit of detection. No objective responses were seen. CONCLUSIONS Gene electrotransfer of plasmid AMEP was found to be safe and tolerable. No objective responses were observed but other DNA drugs may be tested in the future using this procedure.
Collapse
Affiliation(s)
- Iben Spanggaard
- Center for Experimental Drug and Gene Electrotransfer, Department of Oncology, Copenhagen University Hospitals Herlev, Herlev, Denmark
| | - Karin Dahlstroem
- Department of Plastic Surgery, Copenhagen University Hospitals Herlev, Herlev, Denmark
| | - Line Laessoee
- Department of Plastic Surgery, Copenhagen University Hospitals Herlev, Herlev, Denmark
| | - Rasmus Hvass Hansen
- Department of Radiology, Copenhagen University Hospitals Herlev, Herlev, Denmark
| | | | - Helle Westergren Hendel
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospitals Herlev, Herlev, Denmark
| | | | | | - Julie Gehl
- Center for Experimental Drug and Gene Electrotransfer, Department of Oncology, Copenhagen University Hospitals Herlev, Herlev, Denmark
| |
Collapse
|
|
34
|
Li Y, Chen YM, Sun MM, Guo XD, Wang YC, Zhang ZZ. Inhibition on Apoptosis Induced by Elevated Hydrostatic Pressure in Retinal Ganglion Cell-5 via Laminin Upregulating β1-integrin/Focal Adhesion Kinase/Protein Kinase B Signaling Pathway. Chin Med J (Engl) 2017; 129:976-83. [PMID: 27064044 PMCID: PMC4831534 DOI: 10.4103/0366-6999.179785] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: Glaucoma is a progressive optic neuropathy characterized by degeneration of neurons due to loss of retinal ganglion cells (RGCs). High intraocular pressure (HIOP), the main risk factor, causes the optic nerve damage. However, the precise mechanism of HIOP-induced RGC death is not yet completely understood. This study was conducted to determine apoptosis of RGC-5 cells induced by elevated hydrostatic pressures, explore whether laminin is associated with apoptosis under pressure, whether laminin can protect RGCs from apoptosis and affirm the mechanism that regulates the process of RGCs survival. Methods: RGC-5 cells were exposed to 0, 20, 40, and 60 mmHg in a pressurized incubator for 6, 12, and 24 h, respectively. The effect of elevated hydrostatic pressure on RGC-5 cells was measured by Annexin V-fluorescein isothiocyanate/propidium iodide staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and Western blotting of cleaved caspase-3 protein. Location and expression of laminin were detected by immunofluorescence. The expression of β1-integrin, phosphorylation of focal adhesion kinase (FAK) and protein kinase B (PKB, or AKT) were investigated with real-time polymerase chain reaction and Western blotting analysis. Results: Elevated hydrostatic pressure induced apoptosis in cultured RGC-5 cells. Pressure with 40 mmHg for 24 h induced a maximum apoptosis. Laminin was declined in RGC-5 cells after exposing to 40 mmHg for 24 h. After pretreating with laminin, RGC-5 cells survived from elevated pressure. Furthermore, β1-integrin and phosphorylation of FAK and AKT were increased compared to 40 mmHg group. Conclusions: The data show apoptosis tendency of RGC-5 cells with elevated hydrostatic pressure. Laminin can protect RGC-5 cells against high pressure via β1-integrin/FAK/AKT signaling pathway. These results suggest that the decreased laminin of RGC-5 cells might be responsible for apoptosis induced by elevated hydrostatic pressure, and laminin or activating β1-integrin/FAK/AKT pathway might be potential treatments to prevent RGC loss in glaucomatous optic neuropathy.
Collapse
Affiliation(s)
| | | | | | | | | | - Zhong-Zhi Zhang
- Department of Ophthalmology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China
| |
Collapse
|
|
35
|
Wang D, Xin Y, Tian Y, Li W, Sun D, Yang Y. Pseudolaric acid B inhibits gastric cancer cell metastasis in vitro and in haematogenous dissemination model through PI3K/AKT, ERK1/2 and mitochondria-mediated apoptosis pathways. Exp Cell Res 2017; 352:34-44. [PMID: 28132880 DOI: 10.1016/j.yexcr.2017.01.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 01/15/2017] [Accepted: 01/25/2017] [Indexed: 12/30/2022]
Abstract
Pseudolaric acid B (PAB) is the major bioactive constituent in the root bark of Pseudolarix kaempferi and has been reported to have cytotoxicity against tumor cells. Our in vivo experiments showed that PAB could inhibit gastric cancer cell lung metastasis in a nude mouse haematogenous dissemination model. To evaluate the anti-metastasis mechanism of PAB in gastric cancer cells, cytological experiments were performed. The results showed that PAB could inhibit the adhesion ability to matrigel, migration, invasion and colony formation ability of BGC-823 and MKN-45 cells. Western blot further confirmed that the inhibitory effects of PAB on anti-metastasis may involve regulating the expression of the metastasis-related proteins MMP-9, HIF-1α, VEGF, VEGFR2, E-Cadherin and Ezrin. We obtained further proof that PAB which could be used as a multi-targeted agent to inhibit the PI3K/AKT, ERK1/2 and mitochondria-mediated apoptosis pathways and consequently suppress tumor growth and metastasis. Our experiments suggest that PAB-induced effects may have novel therapeutic applications for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Dan Wang
- Department of Gastrointestinal Tumor Pathology of Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China; Colledge of Pharmacy, Liaoning University, Shenyang, China.
| | - Yan Xin
- Department of Gastrointestinal Tumor Pathology of Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yanqiu Tian
- Colledge of Life Science, Liaoning University, Shenyang, China
| | - Wenhui Li
- Department of Gastrointestinal Tumor Pathology of Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China
| | - Dan Sun
- Department of Gastrointestinal Tumor Pathology of Cancer Institute and General Surgery Institute, The First Hospital of China Medical University, Shenyang, China
| | - Yi Yang
- Laboratory Animal Center, China Medical University, Shenyang, China
| |
Collapse
|
|
36
|
Colladel R, Pellicani R, Andreuzzi E, Paulitti A, Tarticchio G, Todaro F, Colombatti A, Mongiat M. MULTIMERIN2 binds VEGF-A primarily via the carbohydrate chains exerting an angiostatic function and impairing tumor growth. Oncotarget 2016; 7:2022-37. [PMID: 26655500 PMCID: PMC4811514 DOI: 10.18632/oncotarget.6515] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 11/21/2015] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis is a key process occurring under both physiological and pathological conditions and is a hallmark of cancer. We have recently demonstrated that the extracellular matrix (ECM) molecule MULTIMERIN2 exerts an angiostatic function through the binding to VEGF-A. In this study we identify the region of the molecule responsible for the binding and demonstrate that the interaction involves the carbohydrate chains. MULTIMERIN2 interacts with other VEGF-A isoforms and VEGF family members such as VEGF-B, -C, -D and PlGF-1 suggesting that the molecule may function as a reservoir for different cytokines. In response to VEGF-A165, we show that MULTIMERIN2 impairs the phosphorylation of VEGFR2 at both Y1175 and Y1214 residues, halts SAPK2/p38 activation and negatively affects endothelial cell motility. In addition, MULTIMERIN2 and its active deletion mutant decrease the availability of the VEGFR2 receptor at the EC plasma membrane. The ectopic expression of MULTIMERIN2 or its active deletion mutant led to a striking reduction of tumor-associated angiogenesis and tumor growth. In conclusion, these data pinpoint MULTIMERIN2 as a key angiostatic molecule and disclose the possibility to develop new prognostic tools and improve the management of cancer patients.
Collapse
Affiliation(s)
- Roberta Colladel
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Rosanna Pellicani
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Eva Andreuzzi
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Alice Paulitti
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Giulia Tarticchio
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Federico Todaro
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Alfonso Colombatti
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| | - Maurizio Mongiat
- Department of Translational Research, Experimental Oncology Division 2, CRO, Aviano, Italy
| |
Collapse
|
|
37
|
Gál B, Dulic S, Kiss M, Groma G, Kovács L, Kemény L, Bata-Csörgő Z. Increased circulating anti-α6-integrin autoantibodies in psoriasis and psoriatic arthritis but not in rheumatoid arthritis. J Dermatol 2016; 44:370-374. [DOI: 10.1111/1346-8138.13667] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 09/22/2016] [Indexed: 01/13/2023]
Affiliation(s)
- Brigitta Gál
- Department of Dermatology and Allergology; University of Szeged; Szeged Hungary
| | - Sonja Dulic
- Department of Rheumatology; University of Szeged; Szeged Hungary
| | - Mária Kiss
- Department of Dermatology and Allergology; University of Szeged; Szeged Hungary
| | - Gergely Groma
- MTA-SZTE, Dermatological Research Group; Szeged Hungary
| | - László Kovács
- Department of Rheumatology; University of Szeged; Szeged Hungary
| | - Lajos Kemény
- Department of Dermatology and Allergology; University of Szeged; Szeged Hungary
- MTA-SZTE, Dermatological Research Group; Szeged Hungary
| | | |
Collapse
|
|
38
|
|
|
39
|
Chee CS, Chang KM, Loke MF, Angela Loo VP, Subrayan V. Association of potential salivary biomarkers with diabetic retinopathy and its severity in type-2 diabetes mellitus: a proteomic analysis by mass spectrometry. PeerJ 2016; 4:e2022. [PMID: 27280065 PMCID: PMC4893325 DOI: 10.7717/peerj.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 04/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM/HYPOTHESIS The aim of our study was to characterize the human salivary proteome and determine the changes in protein expression in two different stages of diabetic retinopathy with type-2 diabetes mellitus: (1) with non-proliferative diabetic retinopathy (NPDR) and (2) with proliferative diabetic retinopathy (PDR). Type-2 diabetes mellitus without diabetic retinopathy (XDR) was designated as control. METHOD In this study, 45 saliva samples were collected (15 samples from XDR control group, 15 samples from NPDR disease group and 15 samples from PDR disease group). Salivary proteins were extracted, reduced, alkylated, trypsin digested and labeled with an isobaric tag for relative and absolute quantitation (iTRAQ) before being analyzed by an Orbitrap fusion tribrid mass spectrometer. Protein annotation, fold change calculation and statistical analysis were interrogated by Proteome Discoverer. Biological pathway analysis was performed by Ingenuity Pathway Analysis. Data are available via ProteomeXchange with identifiers PXD003723-PX003725. RESULTS A total of 315 proteins were identified from the salivary proteome and 119 proteins were found to be differentially expressed. The differentially expressed proteins from the NPDR disease group and the PDR disease group were assigned to respective canonical pathways indicating increased Liver X receptor/Retinoid X receptor (LXR/RXR) activation, Farnesoid X receptor/Retinoid X receptor (FXR/RXR) activation, acute phase response signaling, sucrose degradation V and regulation of actin-based motility by Rho in the PDR disease group compared to the NPDR disease group. CONCLUSIONS/INTERPRETATION Progression from non-proliferative to proliferative retinopathy in type-2 diabetic patients is a complex multi-mechanism and systemic process. Furthermore, saliva was shown to be a feasible alternative sample source for diabetic retinopathy biomarkers.
Collapse
Affiliation(s)
- Chin Soon Chee
- Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
| | - Khai Meng Chang
- Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
| | - Mun Fai Loke
- Department of Medical Microbiology/Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Visvaraja Subrayan
- Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
| |
Collapse
|
|
40
|
Almqvist S, Kleinman HK, Werthén M, Thomsen P, Agren MS. Effects of amelogenins on angiogenesis-associated processes of endothelial cells. J Wound Care 2016; 20:68, 70-5. [PMID: 21378680 DOI: 10.12968/jowc.2011.20.2.68] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To study the effects of an amelogenin mixture on integrin-dependent adhesion, DNA synthesis and apoptosis of cultured human dermal microvascular endothelial cells and angiogenesis in an organotypic assay. METHOD Immobilised antibodies against specific integrins (alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-v, ß1, ß2, ß3, ß4, ß6, alpha-vß3, alpha-vß5 and alpha-5ß1) were used to capture treated human dermal microvascular endothelial cells, which were detected colourimetrically. DNA synthesis of the cells was monitored by 5-bromo-2'- deoxyuridine incorporation and apoptosis by a TdT-mediated dUTP nick-end labelling technique. Tubule formation from aortic arches of 13-d-old chick embryos were followed over 48h. RESULTS The amelogenin mixture increased microvessel outgrowth by 76% (p < 0.01, n=12) from the aortic explants. Also, amelogenins increased the adhesion (p < 0.01, n = 5) by multiple angiogenesis associated integrin subunits and alpha-vß3, alpha-vß5 and alpha-5ß1 heterodimers on human dermal microvascular endothelial cells at a non-mitogenic concentration (100 µg/ml). Conversely, amelogenins at 1,000 µg/ml decreased microvessel formation possibly due to attenuation of corresponding integrins despite increasing (p < 0.001, n = 8) DNA synthesis. No significant apoptosis was detected in human dermal microvascular endothelial cells cultured on Matrigel with and without amelogenins. CONCLUSION Increased surface expression of integrins on endothelial cells may contribute to the proangiogenic property of amelogenins.
Collapse
Affiliation(s)
- S Almqvist
- Department of Biomaterials, Sahlgrenska Academy at the University of Gotheburg, Göteborg, Sweden
| | | | | | | | | |
Collapse
|
|
41
|
Abstract
Templates inserted into surgical wounds strongly influence the healing responses in humans. The science of these templates, in the form of extracellular matrix biomaterials, is rapidly evolving and improving as the natural interactions with the body become better understood.
Collapse
Affiliation(s)
- Jason Hodde
- Director of Medical Sciences, Cook Biotech, Incorporated, West Lafayette, Indiana, USA
| | - Michael Hiles
- Vice President for Research and Development, Cook Biotech, Incorporated, 1425 Innovation Place, West Lafayette, Indiana 47906, USA and Adjunct Professor of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
| |
Collapse
|
|
42
|
Qin Z, Robichaud P, Quan T. Oxidative stress and CCN1 protein in human skin connective tissue aging. AIMS MOLECULAR SCIENCE 2016. [DOI: 10.3934/molsci.2016.2.269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
|
|
43
|
Wang S, Cao W, Xing H, Chen YL, Li Q, Shen T, Jiang C, Zhu D. Activation of ERK pathway is required for 15-HETE-induced angiogenesis in human umbilical vascular endothelial cells. J Recept Signal Transduct Res 2015; 36:225-32. [PMID: 26460784 DOI: 10.3109/10799893.2015.1077865] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis plays a critical role in the progression of cardiovascular disease, retinal ischemia, or tumorigenesis. The imbalance of endothelial cell proliferation and apoptosis disturbs the establishment of the vasculogenesis, which is affected by several arachidonic acid metabolites. 15-Hydroxyeicosatetraenoic acid (15-HETE) is one of the metabolites. However, the underlying mechanisms of angiogenesis induced by 15-HETE in human umbilical vascular endothelial cells (HUVECs) are still poorly understood. Since extracellular signal-regulated kinase (ERK) is a critical regulator of cell proliferation, there may be a crosstalk between 15-HETE-regulating angiogenic process and ERK-proliferative effect in HUVECs. To test this hypothesis, we study the effect of 15-HETE on cell proliferation, angiogenesis, and apoptosis using cell viability measurement, cell cycle analysis, western blot, scratch-wound, tube formation assay, and nuclear morphology determination. We found that 15-HETE promoted HUVEC angiogenesis, which were mediated by ERK. Moreover, 15-HETE-induced proliferation and cell cycle transition from the G(0)/G(1) phase to the G(2)/M + S phase. All these effects were reversed after blocking ERK with PD98059 (an ERK inhibitor). In addition, HUVEC apoptosis was relieved by 15-HETE through the ERK pathway. Thus, ERK is necessary for the effects of 15-HETE in the regulation of HUVEC angiogenesis, which may be a novel potential target for the treatment of angiogenesis-related diseases.
Collapse
Affiliation(s)
- Shuang Wang
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China
| | - Weiwei Cao
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China
| | - Hao Xing
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China
| | - Ying Li Chen
- b Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University - Daqing , Daqing, Heilongjiang Province , People's Republic of China , and
| | - Qian Li
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China
| | - Tingting Shen
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China
| | - Chun Jiang
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China .,c Department of Biology , Georgia State University , Atlanta , GA , USA
| | - Daling Zhu
- a Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University , Nangang District , Harbin, Heilongjiang , People's Republic of China .,b Department of Biopharmaceutical Sciences , College of Pharmacy, Harbin Medical University - Daqing , Daqing, Heilongjiang Province , People's Republic of China , and
| |
Collapse
|
|
44
|
Yanagi T, Shi R, Aza-Blanc P, Reed JC, Matsuzawa SI. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines. PLoS One 2015; 10:e0119404. [PMID: 25790448 PMCID: PMC4366397 DOI: 10.1371/journal.pone.0119404] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 01/12/2015] [Indexed: 12/11/2022] Open
Abstract
While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL). Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.
Collapse
Affiliation(s)
- Teruki Yanagi
- Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America
| | - Ranxin Shi
- Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America
| | - Pedro Aza-Blanc
- Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America
| | - John C. Reed
- Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America
- * E-mail: (JR); (SM)
| | - Shu-ichi Matsuzawa
- Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California, United States of America
- * E-mail: (JR); (SM)
| |
Collapse
|
|
45
|
El-Refaei MF, Abduljawad SH, Alghamdi AH. Alternative Medicine in Diabetes - Role of Angiogenesis, Oxidative Stress, and Chronic Inflammation. Rev Diabet Stud 2015; 11:231-44. [PMID: 26177484 PMCID: PMC5397289 DOI: 10.1900/rds.2014.11.231] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 01/12/2015] [Accepted: 02/06/2015] [Indexed: 12/11/2022] Open
Abstract
Diabetes is a chronic metabolic disorder that is characterized by hyperglycemia due to lack of or resistance to insulin. Patients with diabetes are frequently afflicted with ischemic vascular disease and impaired wound healing. Type 2 diabetes is known to accelerate atherosclerotic processes, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. Herbal medicines and naturally occurring substances may positively affect diabetes management, and could thus be utilized as cost-effective means of supporting treatment in developing countries. Natural treatments have been used in these countries for a long time to treat diabetes. The present review analyses the features of aberrant angiogenesis, abnormalities in growth factors, oxidative stress, and metabolic derangements relevant to diabetes, and how herbal substances and their active chemical constituents may counteract these events. Evidence for possible biochemical effectiveness and limitations of herbal medicines are given, as well as details regarding the role of cytokines and nitric oxide.
Collapse
|
|
46
|
Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 2015; 15:786-801. [PMID: 25415508 DOI: 10.1038/nrm3904] [Citation(s) in RCA: 2968] [Impact Index Per Article: 296.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.
Collapse
Affiliation(s)
- Caroline Bonnans
- 1] Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0452, USA. [2] Oncology Department, INSERM U661, Functional Genomic Institute, 141 rue de la Cardonille, 34094 Montpellier, France
| | - Jonathan Chou
- 1] Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0452, USA. [2] Department of Medicine, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0452, USA
| | - Zena Werb
- Department of Anatomy, University of California, 513 Parnassus Avenue, San Francisco, California 94143-0452, USA
| |
Collapse
|
|
47
|
Spanggaard I, Gehl J. Antiangiogenic Metargidin Peptide (AMEP) Gene Therapy in Disseminated Melanoma. Methods Mol Biol 2015; 1317:359-64. [PMID: 26072417 DOI: 10.1007/978-1-4939-2727-2_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Gene delivery by electroporation is an efficient method for transfecting genes into various tissues including tumors. Here we present the treatment protocol used in a phase 1 study on gene electrotransfer of plasmid DNA encoding an antiangiogenic peptide into cutaneous melanoma.
Collapse
Affiliation(s)
- Iben Spanggaard
- Department of Oncology, Center for Experimental Drug and Gene Electrotransfer, Copenhagen University Hospital Herlev, Herlev Ringvej 75, 2730, Herlev, Denmark
| | | |
Collapse
|
|
48
|
Irvin MW, Zijlstra A, Wikswo JP, Pozzi A. Techniques and assays for the study of angiogenesis. Exp Biol Med (Maywood) 2014; 239:1476-88. [PMID: 24872440 PMCID: PMC4216737 DOI: 10.1177/1535370214529386] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The importance of studying angiogenesis, the formation of new blood vessels from pre-existing vessels, is underscored by its involvement in both normal physiology, such as embryonic growth and wound healing, and pathologies, such as diabetes and cancer. Treatments targeting the molecular drive of angiogenesis have been developed, but many of the molecular mechanisms that mediate vascularization, as well as how these mechanisms can be targeted in therapy, remain poorly understood. The limited capacity to quantify angiogenesis properly curtails our molecular understanding and development of new drugs and therapies. Although there are a number of assays for angiogenesis, many of them strip away its important components and/or limit control of the variables that direct this highly cooperative and complex process. Here we review assays commonly used in endothelial cell biology and describe the progress toward development of a physiologically realistic platform that will enable a better understanding of the molecular and physical mechanisms that govern angiogenesis.
Collapse
Affiliation(s)
- Michael W. Irvin
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
| | - Andries Zijlstra
- Vanderbilt Institute for Integrative Biosystems Research and Education, Nashville, TN 37235
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232
| | - John P. Wikswo
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235
- Vanderbilt Institute for Integrative Biosystems Research and Education, Nashville, TN 37235
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37235
| | - Ambra Pozzi
- Vanderbilt Institute for Integrative Biosystems Research and Education, Nashville, TN 37235
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232
- Department of Medicine, Veterans Affairs Hospitals, Nashville, TN, 37232
| |
Collapse
|
|
49
|
Abstract
Targeting prostate cancer metastasis has very high therapeutic potential. Prostate cancer is the second most common cause of cancer death among men in the USA, and death results from the development of metastatic disease. In order to metastasize, cancer cells must complete a series of steps that together constitute the metastatic cascade. Each step therefore offers the opportunity for therapeutic targeting. However, practical limitations have served as limiting roadblocks to successfully targeting the metastatic cascade. They include our still-emerging understanding of the underlying biology, as well as the fact that many of the dysregulated processes have critical functionality in otherwise normal cells. We provide a discussion of the underlying biology, as it relates to therapeutic targeting. Therapeutic inroads are rapidly being made, and we present a series of case studies to highlight key points. Finally, future perspectives related to drug discovery for antimetastatic agents are discussed.
Collapse
|
|
50
|
Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014; 25:719-734. [PMID: 24856586 PMCID: PMC4180632 DOI: 10.1016/j.ccr.2014.04.005] [Citation(s) in RCA: 1870] [Impact Index Per Article: 170.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/08/2014] [Accepted: 04/10/2014] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
Collapse
Affiliation(s)
- Berna C Özdemir
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | | | - Julienne L Carstens
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Xiaofeng Zheng
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Chia-Chin Wu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Tyler R Simpson
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Hanane Laklai
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hikaru Sugimoto
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Kahlert
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Sergey V Novitskiy
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Ana De Jesus-Acosta
- Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
| | - Padmanee Sharma
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Pedram Heidari
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Umar Mahmood
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lynda Chin
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Harold L Moses
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Valerie M Weaver
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - James P Allison
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Valerie S LeBleu
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|