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Li Y, Zhang R, Dang Y, Liang Y, Wang L, Chen N, Zhuang L, Liu W, Gong T. Sieging tumor cells using an amorphous ferric coordination polymer. MATERIALS HORIZONS 2025; 12:3388-3398. [PMID: 40025991 DOI: 10.1039/d4mh01558d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Metastasis is one of the main reasons for cancer treatment failure. Unfortunately, most treatment approaches inevitably damage the extracellular matrix (ECM) during tumor cell elimination, thereby augmenting the risk of metastasis. Herein, we proposed a "sieging tumor cells" strategy based on ferric coordination polymers (FeCPs), which involved anchoring tumor cells through ECM consolidation and selectively eliminating them in the tumor regions. Due to the weak coordination interactions and amorphous structure of FeCPs, the acidic tumor microenvironment facilitated their disintegration, releasing salicylic acid (SA), 2,5-dihydroxyterephthalic acid (DHTA) and Fe3+ ions. The released SA inhibited heparinase activity to consolidate the ECM, while Fe-mediated chemodynamic therapy (CDT) was enhanced by DHTA due to its fast electron transport behavior, ultimately inhibiting tumor growth and metastasis. The results from the orthotopic 4T1 breast tumor model indicated that lung metastasis was reduced by about 90%, and the survival rate improved by 70% after FeCP treatment. Overall, this "sieging tumor cells" strategy provides an emerging approach for the treatment of malignant tumors by consolidating the ECM in combination with self-enhanced CDT.
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Affiliation(s)
- Yanli Li
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Ruoqi Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Yuanye Dang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Yongyu Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Lulu Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
| | - Na Chen
- Soochow University Library, Soochow University, Suzhou 215006, China
| | - Luwen Zhuang
- Center for Water Resources and Environment, and Guangdong Key Laboratory of Marine Civil Engineering, School of Civil Engineering, Sun Yat-sen University, Guangzhou 510275, China.
| | - Wen Liu
- School of Public Health, Guangzhou Medical University, Guangzhou 511436, China.
| | - Teng Gong
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
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Dombrowsky CS, Geyer FK, Zakharchuk D, Kolmar H. Tumor-specific cytosol-penetrating antibodies for antigen- and TME-dependent intracellular cargo delivery. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200931. [PMID: 39895690 PMCID: PMC11786873 DOI: 10.1016/j.omton.2024.200931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/13/2024] [Accepted: 12/30/2024] [Indexed: 02/04/2025]
Abstract
Although a considerable number of disease-related biomolecular interactions occur in the cytosol, therapeutic and diagnostic application of target-specific binding proteins is largely confined to surface-exposed or extracellular targets. Therefore, protein-cargo delivery approaches, including cell-penetrating peptides and cytosol-penetrating antibodies, are being explored to overcome this limitation. In this context, we have developed a modular approach for cytosolic penetration of tumor cells based on bispecific antibodies containing a masked cytosol-penetrating Fab on one arm and a tumor-targeting scFv linked via an endosomal cleavable linker on the other arm. The relevance of the antigen-specific binding, internalization, and cytosolic cargo delivery was demonstrated in several in vitro assays using different cell lines with anti-B7-H3 scFv, the well-characterized trastuzumab (HER2), and inotuzumab (CD22) as examples. In addition, presence of the masking moiety to prevent non-specific surface binding, as well as the activation of cytosol-penetrating capabilities in the tumor microenvironment upon release by tumor-specific proteases was confirmed using the catalytic domain of Pseudomonas exotoxin as model cargo for cytosol delivery. Tumor microenvironment-dependent as well as tumor-associated antigen-specific cytosol-penetrating antibodies of the type developed here have the potential to serve as a modular platform to deliver macromolecular cargoes for addressing intracellular targets in tumor cells.
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Affiliation(s)
- Carolin Sophie Dombrowsky
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, 64287 Darmstadt, Germany
| | - Felix Klaus Geyer
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, 64287 Darmstadt, Germany
| | - Diana Zakharchuk
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, 64287 Darmstadt, Germany
| | - Harald Kolmar
- Institute for Organic Chemistry and Biochemistry, Technical University of Darmstadt, Peter-Grünberg-Strasse 4, 64287 Darmstadt, Germany
- Centre for Synthetic Biology, Technical University of Darmstadt, 64287 Darmstadt, Germany
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Ouidja MO, Biard DSF, Huynh MB, Laffray X, Gomez-Henao W, Chantepie S, Le Douaron G, Rebergue N, Maïza A, Merrick H, De Lichy A, Dady A, González-Velasco O, Rubio K, Barreto G, Baranger K, Cormier-Daire V, De Las Rivas J, Fernig DG, Papy-Garcia D. Genetic variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfate diversity. Essays Biochem 2024; 68:555-578. [PMID: 39630030 PMCID: PMC11625870 DOI: 10.1042/ebc20240106] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/14/2024] [Accepted: 10/25/2024] [Indexed: 12/11/2024]
Abstract
Heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans (PG) consist of a core protein to which the glycosaminoglycan (GAG) chains, HS or CS, are attached through a common linker tetrasaccharide. In the extracellular space, they are involved in the regulation of cell communication, assuring development and homeostasis. The HSPG biosynthetic pathway has documented 51 genes, with many diseases associated to defects in some of them. The phenotypic consequences of this genetic variation in humans, and of genetic ablation in mice, and their expression patterns, led to a phenotypically centered HSPG biosynthetic pathway model. In this model, HS sequences produced by ubiquitous NDST1, HS2ST and HS6ST enzymes are essential for normal development and homeostasis, whereas tissue restricted HS sequences produced by the non-ubiquitous NDST2-4, HS6ST2-3, and HS3ST1-6 enzymes are involved in adaptative behaviors, cognition, tissue responsiveness to stimuli, and vulnerability to disease. The model indicates that the flux through the HSPG/CSPG pathways and its diverse branches is regulated by substrate preferences and protein-protein-interactions. This results in a privileged biosynthesis of HSPG over that of CSPGs, explaining the phenotypes of linkeropathies, disease caused by defects in genes involved in the biosynthesis of the common tetrasaccharide linker. Documented feedback loops whereby cells regulate HS sulfation, and hence the interactions of HS with protein partners, may be similarly implemented, e.g., protein tyrosine sulfation and other posttranslational modifications in enzymes of the HSPG pathway. Together, ubiquitous HS, specialized HS, and their biosynthesis model can facilitate research for a better understanding of HSPG roles in physiology and pathology.
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Affiliation(s)
- Mohand Ouidir Ouidja
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Denis S F Biard
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
- CEA, Institut de Biologie François Jacob (IBFJ), SEPIA, Université Paris-Saclay, Fontenay-aux-Roses, France
| | - Minh Bao Huynh
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Xavier Laffray
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Wilton Gomez-Henao
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
- Departamento de Bioquímica, Laboratorio Internacional Gly-CRRET-UNAM, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Sandrine Chantepie
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Gael Le Douaron
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Nicolas Rebergue
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Auriane Maïza
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Heloise Merrick
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Aubert De Lichy
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Alwyn Dady
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
| | - Oscar González-Velasco
- Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IMBCC, CSIC/USAL/IBSAL), University of Salamanca (USAL), Salamanca, Spain
| | - Karla Rubio
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Instituto de Ciencias, Ecocampus, Benemérita Universidad Autónoma de Puebla (BUAP), Puebla 72570, Mexico
- Université De Lorraine, CNRS, Laboratoire IMoPA, UMR 7365; F-54000 Nancy, France
| | - Guillermo Barreto
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
- Université De Lorraine, CNRS, Laboratoire IMoPA, UMR 7365; F-54000 Nancy, France
| | | | - Valerie Cormier-Daire
- Department of Genomic Medicine for Rare Diseases, French Reference Center for Constitutional Bone Diseases, Necker-Enfants Malades Hospital, Paris, France
| | - Javier De Las Rivas
- Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IMBCC, CSIC/USAL/IBSAL), University of Salamanca (USAL), Salamanca, Spain
| | - David G Fernig
- Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrated Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, U.K
| | - Dulce Papy-Garcia
- Univ Paris Est Creteil, Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Creteil, France
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Song Y, Zhou D, Zhang P, Zhu N, Guo R, Wang T, Zhuang F, Sun D. Heparanase accelerates the angiogenesis and inhibits the ferroptosis of p53-mutant non-small cell cancers in VEGF-dependent manner. Cytotechnology 2024; 76:503-517. [PMID: 39188651 PMCID: PMC11344742 DOI: 10.1007/s10616-024-00632-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 04/17/2024] [Indexed: 08/28/2024] Open
Abstract
The aim of this study is to explore the effects and specific mechanisms of heparanase on angiogenesis and iron deficiency anemia in TP53 mutant cancer. For this purpose, we conducted in vitro cell experiments and in vivo animal experiments respectively. In this study, we first analyzed the differential expression of heparanase in TP53 wild-type and mutant cells, and analyzed its effects on iron removal and angiogenesis in two types of CALU-1 and NCI-H358 cells. Secondly, we validated whether the mechanism of action of heparanase on TP53 mutant cells for iron removal and angiogenesis is related to VEGF. We applied the iron removal agonist erastin and VEGF inhibitor bevacizumab in both in vitro and in vivo experiments to validate the relationship between heparanase and VEGF in the mechanisms of iron removal and angiogenesis. The experimental results show that heparanase is highly expressed in TP53 mutated cancer cells, and has anti-ferroptosis and pro-angiogenic effects. Our experiment also confirmed that the effect of heparanase on TP53 mutant cancer's iron removal and angiogenesis is related to VEGF. In short, heparanase is highly expressed in p53 mutated lung cancer, and the mechanism of ferroptosis tolerance to TP53 mutated cancer is related to VEGF.
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Affiliation(s)
- Yaobo Song
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Dongmei Zhou
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Ping Zhang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Na Zhu
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Ruijuan Guo
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Tian Wang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Feifei Zhuang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, China
| | - Dengjun Sun
- Department of Medical Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, 264000 Shandong Province China
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Smirnova O, Efremov Y, Klyucherev T, Peshkova M, Senkovenko A, Svistunov A, Timashev P. Direct and cell-mediated EV-ECM interplay. Acta Biomater 2024; 186:63-84. [PMID: 39043290 DOI: 10.1016/j.actbio.2024.07.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 07/07/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
Extracellular vesicles (EV) are a heterogeneous group of lipid particles excreted by cells. They play an important role in regeneration, development, inflammation, and cancer progression, together with the extracellular matrix (ECM), which they constantly interact with. In this review, we discuss direct and indirect interactions of EVs and the ECM and their impact on different physiological processes. The ECM affects the secretion of EVs, and the properties of the ECM and EVs modulate EVs' diffusion and adhesion. On the other hand, EVs can affect the ECM both directly through enzymes and indirectly through the modulation of the ECM synthesis and remodeling by cells. This review emphasizes recently discovered types of EVs bound to the ECM and isolated by enzymatic digestion, including matrix-bound nanovesicles (MBV) and tissue-derived EV (TiEV). In addition to the experimental studies, computer models of the EV-ECM-cell interactions, from all-atom models to quantitative pharmacology models aiming to improve our understanding of the interaction mechanisms, are also considered. STATEMENT OF SIGNIFICANCE: Application of extracellular vesicles in tissue engineering is an actively developing area. Vesicles not only affect cells themselves but also interact with the matrix and change it. The matrix also influences both cells and vesicles. In this review, different possible types of interactions between vesicles, matrix, and cells are discussed. Furthermore, the united EV-ECM system and its regulation through the cellular activity are presented.
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Affiliation(s)
- Olga Smirnova
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Yuri Efremov
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Timofey Klyucherev
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | - Maria Peshkova
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia; World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, 119991 Moscow, Russia
| | - Alexey Senkovenko
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia
| | | | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, 119991 Moscow, Russia; World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, 119991 Moscow, Russia; Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia.
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Chen D, Wang LJ, Li HL, Feng F, Li JC, Liu L. Progress of heparanase in septic cardiomyopathy: A review. Medicine (Baltimore) 2024; 103:e38901. [PMID: 39151539 PMCID: PMC11332786 DOI: 10.1097/md.0000000000038901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 08/19/2024] Open
Abstract
Septic cardiomyopathy (SCM) is a severe complication caused by sepsis, resulting in a high mortality rate. The current understanding of the pathogenic mechanism of SCM primarily involves endocardial injury, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Heparanase (HPA), an endo-β-D-glucuronidase, has been implicated in inflammation, immune response, coagulation promotion, microcirculation disturbance, mitochondrial dysfunction and fibrosis. Therefore, it was hypothesized that HPA may play an important role in the pathogenesis of SCM. The present study provides a summary of various pathophysiological changes and mechanisms behind the involvement of HPA in SCM. It also presents a novel perspective on the pathogenic mechanism, diagnosis and treatment of SCM.
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Affiliation(s)
- Di Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
| | - Lin-Jun Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
| | - Hong-Lei Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
| | - Fei Feng
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
| | - Jian-Chun Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
| | - Liping Liu
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu, P. R. China
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, P. R. China
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Ricard-Blum S, Vivès RR, Schaefer L, Götte M, Merline R, Passi A, Heldin P, Magalhães A, Reis CA, Skandalis SS, Karamanos NK, Perez S, Nikitovic D. A biological guide to glycosaminoglycans: current perspectives and pending questions. FEBS J 2024; 291:3331-3366. [PMID: 38500384 DOI: 10.1111/febs.17107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/08/2024] [Accepted: 02/20/2024] [Indexed: 03/20/2024]
Abstract
Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that are covalently attached to core proteins to form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan sulfate (KS), and heparan sulfate (HS). It focuses on the major processes that remain to be deciphered to get a comprehensive view of the mechanisms mediating GAG biological functions. They include the regulation of GAG biosynthesis and postsynthetic modifications in heparin (HP) and HS, the composition, heterogeneity, and function of the tetrasaccharide linkage region and its role in disease, the functional characterization of the new PGs recently identified by glycoproteomics, the selectivity of interactions mediated by GAG chains, the display of GAG chains and PGs at the cell surface and their impact on the availability and activity of soluble ligands, and on their move through the glycocalyx layer to reach their receptors, the human GAG profile in health and disease, the roles of GAGs and particular PGs (syndecans, decorin, and biglycan) involved in cancer, inflammation, and fibrosis, the possible use of GAGs and PGs as disease biomarkers, and the design of inhibitors targeting GAG biosynthetic enzymes and GAG-protein interactions to develop novel therapeutic approaches.
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Affiliation(s)
- Sylvie Ricard-Blum
- Univ Lyon 1, ICBMS, UMR 5246 University Lyon 1 - CNRS, Villeurbanne cedex, France
| | | | - Liliana Schaefer
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Germany
| | - Rosetta Merline
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany
| | | | - Paraskevi Heldin
- Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden
| | - Ana Magalhães
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal
| | - Celso A Reis
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Serge Perez
- Centre de Recherche sur les Macromolécules Végétales, University of Grenoble-Alpes, CNRS, France
| | - Dragana Nikitovic
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, Heraklion, Greece
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Masenga SK, Liweleya S, Kirabo A. High salt intake and HIV infection on endothelial glycocalyx shedding in salt-sensitive hypertension. Front Cell Dev Biol 2024; 12:1395885. [PMID: 39081863 PMCID: PMC11286502 DOI: 10.3389/fcell.2024.1395885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 06/28/2024] [Indexed: 08/02/2024] Open
Abstract
The endothelial glycocalyx is closely associated with various physiological and pathophysiological events. Significant modification of the endothelial glycocalyx is an early process in the pathogenesis of cardiovascular disease. High dietary salt and HIV infection damages the endothelial glycocalyx causing endothelial dysfunction and increasing the risk for salt-sensitive hypertension and cardiovascular disease. The two factors, HIV infection and dietary salt are critical independent predictors of hypertension and cardiovascular disease and often synergize to exacerbate and accelerate disease pathogenesis. Salt-sensitive hypertension is more common among people living with HIV and is associated with risk for cardiovascular disease, stroke, heart attack and even death. However, the underlying mechanisms linking endothelial glycocalyx damage to dietary salt and HIV infection are lacking. Yet, both HIV infection/treatment and dietary salt are closely linked to endothelial glycocalyx damage and development of salt-sensitive hypertension. Moreover, the majority of individuals globally, consume more salt than is recommended and the burden of HIV especially in sub-Sahara Africa is disproportionately high. In this review, we have discussed the missing link between high salt and endothelial glycocalyx shedding in the pathogenesis of salt-sensitive hypertension. We have further elaborated the role played by HIV infection and treatment in modifying endothelial glycocalyx integrity to contribute to the development of hypertension and cardiovascular disease.
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Affiliation(s)
- Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone, Zambia
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Situmbeko Liweleya
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone, Zambia
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt Center for Immunobiology, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, United States
- Vanderbilt Institute for Global Health, Nashville, TN, United States
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Meem SS, Proma AY, Bhuiyan MA, Dewan SMR. The pressing need for study on the effects of Mpox on the progression of vascular inflammation: A well-timed call. Health Sci Rep 2024; 7:e2223. [PMID: 38946778 PMCID: PMC11211998 DOI: 10.1002/hsr2.2223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 06/12/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024] Open
Abstract
Background This article explored the possibility that the Mpox virus (MPXV) may initiate or stimulate the consequences of vascular inflammation. In 1970, it was discovered that Macaca cynomolgus primates infected with MPXV also infected humans in the Democratic Republic of the Congo. Discussion The study demonstrates that MPXV invades host cells via viral proteins and surface receptors, initiating the release of diverse inflammatory mediators such as IL-1, IL-6, TNF-α, CCL2, CXCL2, CXCL8, CXCL10, and so forth probably through endothelial dysfunction by reactive oxygen species production. In general, these mediators have been found to contribute to vascular inflammation and the formation of atherosclerotic plaque at a later stage, which may contribute to the onset of vascular inflammation. Conclusion The discussed association between vascular inflammation and Mpox has the potential to be an important finding in the field of vascular biology research.
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Affiliation(s)
- Sara Shahid Meem
- Department of Pharmacy, School of MedicineUniversity of Asia PacificDhakaBangladesh
| | - Amrin Yeasin Proma
- Department of Pharmacy, School of MedicineUniversity of Asia PacificDhakaBangladesh
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10
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Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions. Int J Mol Sci 2024; 25:7209. [PMID: 39000315 PMCID: PMC11241800 DOI: 10.3390/ijms25137209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024] Open
Abstract
Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.
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Affiliation(s)
- Juan-Fernando Padín
- Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain
| | - José Manuel Pérez-Ortiz
- Facultad HM de Ciencias de la Salud, Universidad Camilo José Cela, 28692 Madrid, Spain
- Instituto de Investigación Sanitaria HM Hospitales, 28015 Madrid, Spain
| | - Francisco Javier Redondo-Calvo
- Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain
- Department of Anaesthesiology and Critical Care Medicine, University General Hospital, 13005 Ciudad Real, Spain
- Translational Research Unit, University General Hospital and Research Institute of Castilla-La Mancha (IDISCAM), 13005 Ciudad Real, Spain
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11
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Dehghani S, Aghaee Z, Soleymani S, Tafazoli M, Ghabool Y, Tavassoli A. An overview of the production of tissue extracellular matrix and decellularization process. Cell Tissue Bank 2024; 25:369-387. [PMID: 37812368 DOI: 10.1007/s10561-023-10112-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/09/2023] [Indexed: 10/10/2023]
Abstract
Thousands of patients need an organ transplant yearly, while only a tiny percentage have this chance to receive a tissue/organ transplant. Nowadays, decellularized animal tissue is one of the most widely used methods to produce engineered scaffolds for transplantation. Decellularization is defined as physically or chemically removing cellular components from tissues while retaining structural and functional extracellular matrix (ECM) components and creating an ECM-derived scaffold. Then, decellularized scaffolds could be reseeded with different cells to fabricate an autologous graft. Effective decellularization methods preserve ECM structure and bioactivity through the application of the agents and techniques used throughout the process. The most valuable agents for the decellularization process depend on biological properties, cellular density, and the thickness of the desired tissue. ECM-derived scaffolds from various mammalian tissues have been recently used in research and preclinical applications in tissue engineering. Many studies have shown that decellularized ECM-derived scaffolds could be obtained from tissues and organs such as the liver, cartilage, bone, kidney, lung, and skin. This review addresses the significance of ECM in organisms and various decellularization agents utilized to prepare the ECM. Also, we describe the current knowledge of the decellularization of different tissues and their applications.
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Affiliation(s)
- Shima Dehghani
- Department of Biology, Kavian Institute of Higher Education, Mashhad, Iran
| | - Zahra Aghaee
- Department of Biology, Kavian Institute of Higher Education, Mashhad, Iran
| | - Safoura Soleymani
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 9177948974, Iran
| | - Maryam Tafazoli
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 9177948974, Iran
| | - Yasin Ghabool
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Amin Tavassoli
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 9177948974, Iran.
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12
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Rabinowitz ZM, Wang Z, Liu J, Zhang Y, Ybargollin AJ, Saketkhou M, Cui L. A Fluorogenic Green Merocyanine-Based Probe to Detect Heparanase-1 Activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.25.581963. [PMID: 38464176 PMCID: PMC10925095 DOI: 10.1101/2024.02.25.581963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Heparanase-1 (HPSE-1), an endo-β-D-glucuronidase, is an extracellular matrix (ECM) remodeling enzyme that degrades heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs). HPSE-1 functions to remodel the ECM and thereby disseminate cells, liberate HS-bound bioactive molecules, and release biologically active HS fragments. Being the only known enzyme for the cleavage of HS, HPSE-1 regulates a number of fundamental cellular processes including cell migration, cytokine regulation, angiogenesis, and wound healing. Overexpression of HPSE-1 has been discovered in most cancers, inflammatory diseases, viral infections, among others. As an emerging therapeutic target, the biological role of HPSE-1 remains to be explored but is hampered by a lack of research tools. To expand the chemical tool-kit of fluorogenic probes to interrogate HPSE-1 activity, we design and synthesized a fluorogenic green disaccharide-based HPSE-1 probe using our design strategy of tuning the electronic effect of the aryl aglycon. The novel probe exhibits a highly sensitive 278-fold fluorescence turn-on response in the presence of recombinant human HPSE-1, while emitting green light at 560 nm, enabling the fluorescence imaging of HPSE-1 activity in cells.
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13
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Veider F, Zöller K, Saleh A, Bernkop-Schnürch A. Overcoming intestinal barriers by heparanase-responsive charge-converting nanocarriers. Int J Pharm 2024; 651:123817. [PMID: 38237708 DOI: 10.1016/j.ijpharm.2024.123817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 01/22/2024]
Abstract
In this study, we present a novel approach for overcoming intestinal barriers by utilizing heparanase-responsive charge-converting nanocarriers (NCs). These NCs are designed to undergo charge conversion in response to the activity of heparanase (HPSE), an enzyme commonly overexpressed in cancer cells. Nanostructured lipid carriers (NLCs) and solid lipid nanocarriers (SLNs) with a positively charged core were coated with heparin (Hep), resulting in a negative surface charge and a size between 195 and 220 nm. However, upon encountering heparanase, heparin undergoes enzymatic cleavage, resulting in zeta potential shift from -22.1 to +8.3 mV for NLC-Hep and from -19.8 to +5.1 mV for SLN-Hep. Heparin-coated NCs showed more than 6-fold higher mucus permeating properties compared to the uncoated NCs. In vitro experiments using the heparanase-expressing cancer cell line HT29 demonstrated an up to 4-fold improved cellular uptake of the heparin coated NCs compared to co-incubation with the HPSE inhibitor suramin. Furthermore, cellular uptake was investigated on Caco-2 cells and on a Caco-2/HT29-MTX co-culture. Overall, this study highlights the potential of heparanase-responsive charge-converting NCs as a promising strategy for overcoming intestinal barriers and enhancing cellular uptake.
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Affiliation(s)
- Florina Veider
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Katrin Zöller
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Ahmad Saleh
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; Department of Pharmacy, Universitas Mandala Waluya, A.H. Nasution, Kendari 93231, Southeast Sulawesi, Indonesia
| | - Andreas Bernkop-Schnürch
- Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
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14
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Belvedere R, Novizio N, Palazzo M, Pessolano E, Petrella A. The pro-healing effects of heparan sulfate and growth factors are enhanced by the heparinase enzyme: New association for skin wound healing treatment. Eur J Pharmacol 2023; 960:176138. [PMID: 37923158 DOI: 10.1016/j.ejphar.2023.176138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/02/2023] [Accepted: 10/18/2023] [Indexed: 11/07/2023]
Abstract
Effective treatment strategies for skin wound repair are the focus of numerous studies. New pharmacological approaches appear necessary to guarantee a correct and healthy tissue regeneration. For these reasons, we purposed to investigate the effects of the combination between heparan sulfate and growth factors further adding the heparinase enzyme. Interestingly, for the first time, we have found that this whole association retains a marked pro-healing activity when topically administered to the wound. In detail, this combination significantly enhances the motility and activation of the main cell populations involved in tissue regeneration (keratinocytes, fibroblasts and endothelial cells), compared with single agents administered without heparinase. Notably, using an experimental C57BL/6 mouse model of skin wounding, we observed that the topical treatment of skin lesions with heparan sulfate + growth factors + heparinase promotes the highest closure of wounds compared to each substance mixed with the other ones in all the possible combinations. Eosin/hematoxylin staining of skin biopsies revealed that treatment with the whole combination allows the formation of a well-structured matrix with numerous new vessels. Confocal analyses for vimentin, FAP1α, CK10 and CD31 have highlighted the presence of activated fibroblasts, differentiated keratinocytes and endothelial cells at the closed region of wounds. Our results encourage defining this combined treatment as a new and appealing therapy expedient in skin wound healing, as it is able to activate cell components and promote a dynamic lesions closure.
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Affiliation(s)
| | - Nunzia Novizio
- Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
| | | | - Emanuela Pessolano
- Department of Pharmacological Sciences, University of Piemonte Orientale, Novara, Italy
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15
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Abstract
In this comprehensive review, we will dissect the impact of research on proteoglycans focusing on recent developments involved in their synthesis, degradation, and interactions, while critically assessing their usefulness in various biological processes. The emerging roles of proteoglycans in global infections, specifically the SARS-CoV-2 pandemic, and their rising functions in regenerative medicine and biomaterial science have significantly affected our current view of proteoglycans and related compounds. The roles of proteoglycans in cancer biology and their potential use as a next-generation protein-based adjuvant therapy to combat cancer is also emerging as a constructive and potentially beneficial therapeutic strategy. We will discuss the role of proteoglycans in selected and emerging areas of proteoglycan science, such as neurodegenerative diseases, autophagy, angiogenesis, cancer, infections and their impact on mammalian diseases.
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Affiliation(s)
- Christopher Xie
- Department of Pathology and Genomic Medicine, the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Liliana Schaefer
- Institute of Pharmacology and Toxicology, Goethe University, Frankfurt, Germany
| | - Renato V. Iozzo
- Department of Pathology and Genomic Medicine, the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
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16
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Chen TT, Lv JJ, Chen L, Li M, Liu LP. Heparanase inhibition leads to improvement in patients with acute gastrointestinal injuries induced by sepsis. World J Gastroenterol 2023; 29:5154-5165. [PMID: 37744293 PMCID: PMC10514756 DOI: 10.3748/wjg.v29.i35.5154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/23/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA) plays an important role in septic AGI (S-AGI), but its specific mechanism is not completely understood, and few clinical reports are available. AIM To explore the effect and mechanism of HPA inhibition in S-AGI patients. METHODS In our prospective clinical trial, 48 patients with S-AGI were randomly assigned to a control group to receive conventional treatment, whereas 47 patients were randomly assigned to an intervention group to receive conventional treatment combined with low molecular weight heparin. AGI grade, sequential organ failure assessment score, acute physiology and chronic health evaluation II score, D-dimer, activated partial thromboplastin time (APTT), anti-Xa factor, interleukin-6, tumour necrosis factor-α, HPA, syndecan-1 (SDC-1), LC3B (autophagy marker), intestinal fatty acid binding protein, D-lactate, motilin, gastrin, CD4/CD8, length of intensive care unit (ICU) stay, length of hospital stay and 28-d survival on the 1st, 3rd and 7th d after treatment were compared. Correlations between HPA and AGI grading as well as LC3B were compared. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic value of HPA, intestinal fatty acid binding protein and D-lactate in S-AGI. RESULTS Serum HPA and SCD-1 levels were significantly reduced in the intervention group compared with the control group (P < 0.05). In addition, intestinal fatty acid-binding protein, D-lactate, AGI grade, motilin, and gastrin levels and sequential organ failure assessment score were significantly decreased (P < 0.05) in the intervention group. However, LC3B, APTT, anti-Xa factor, and CD4/CD8 were significantly increased (P < 0.05) in the intervention group. No significant differences in interleukin-6, tumour necrosis factor-α, d-dimer, acute physiology and chronic health evaluation II score, length of ICU stay, length of hospital stay, or 28-d survival were noted between the two groups (P > 0.05). Correlation analysis revealed a significant negative correlation between HPA and LC3B and a significant positive correlation between HPA and AGI grade. ROC curve analysis showed that HPA had higher specificity and sensitivity in diagnosis of S-AGI. CONCLUSION HPA has great potential as a diagnostic marker for S-AGI. Inhibition of HPA activity reduces SDC-1 shedding and alleviates S-AGI symptoms. The inhibitory effect of HPA in gastrointestinal protection may be achieved by enhanced autophagy.
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Affiliation(s)
- Ting-Ting Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jia-Jun Lv
- The First Clinical Medical School of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ling Chen
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Min Li
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Li-Ping Liu
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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17
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Li JC, Wang LJ, Feng F, Chen TT, Shi WG, Liu LP. Role of heparanase in sepsis‑related acute kidney injury (Review). Exp Ther Med 2023; 26:379. [PMID: 37456170 PMCID: PMC10347300 DOI: 10.3892/etm.2023.12078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/08/2023] [Indexed: 07/18/2023] Open
Abstract
Sepsis-related acute kidney injury (S-AKI) is a common and significant complication of sepsis in critically ill patients, which can often only be treated with antibiotics and medications that reduce S-AKI symptoms. The precise mechanism underlying the onset of S-AKI is still unclear, thus hindering the development of new strategies for its treatment. Therefore, it is necessary to explore the pathogenesis of S-AKI to identify biomarkers and therapeutic targets for its early diagnosis and treatment. Heparanase (HPA), the only known enzyme that cleaves the side chain of heparan sulfate, has been widely studied in relation to tumor metabolism, procoagulant activity, angiogenesis, inflammation and sepsis. It has been reported that HPA plays an important role in the progression of S-AKI. The aim of the present review was to provide an overview of the function of HPA in S-AKI and to summarize its underlying molecular mechanisms, including mediating inflammatory response, immune response, autophagy and exosome biogenesis. It is anticipated that emerging discoveries about HPA in S-AKI will support HPA as a potential biomarker and therapeutic target to combat S-AKI.
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Affiliation(s)
- Jian-Chun Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Lin-Jun Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Fei Feng
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ting-Ting Chen
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Wen-Gui Shi
- Cuiying Biomedical Research Center, The Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li-Ping Liu
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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18
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Zhang Y, Cui L. Discovery and development of small-molecule heparanase inhibitors. Bioorg Med Chem 2023; 90:117335. [PMID: 37257254 PMCID: PMC10884955 DOI: 10.1016/j.bmc.2023.117335] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/08/2023] [Accepted: 05/12/2023] [Indexed: 06/02/2023]
Abstract
Heparanase-1 (HPSE) is a promising yet challenging therapeutic target. It is the only known enzyme that is responsible for cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs), and is the key enzyme involved in the remodeling and degradation of the extracellular matrix (ECM). Overexpression of HPSE is found in various types of diseases, including cancers, inflammations, diabetes, and viral infections. Inhibiting HPSE can restore ECM functions and integrity, making the development of HPSE inhibitors a highly sought-after topic. So far, all HPSE inhibitors that have entered clinical trials belong to the category of HS mimetics, and no small-molecule or drug-like HPSE inhibitors have made similar progress. None of the HS mimetics have been approved as drugs, with some clinical trials discontinued due to poor bioavailability, side effects, and unfavorable pharmacokinetics characteristics. Small-molecule HPSE inhibitors are, therefore, particularly appealing due to their drug-like characteristics. Advances in the chemical spaces and drug design technologies, including the increasing use of in vitro and in silico screening methods, have provided new opportunities in drug discovery. This article aims to review the discovery and development of small-molecule HPSE inhibitors via screening strategies to shed light on the future endeavors in the development of novel HPSE inhibitors.
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Affiliation(s)
- Yuzhao Zhang
- Department of Medicinal Chemistry, College of Pharmacy, UF Health Science Center, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
| | - Lina Cui
- Department of Medicinal Chemistry, College of Pharmacy, UF Health Science Center, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
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19
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Abstract
Cancer is still a serious health problem globally. Conventional therapies have adverse effects, which affect human life quality. Tumor microenvironment (TME), also known as surrounding stroma, has a contributory role in cancer development. Understanding the interaction between TME and cancer progression is a challenge and helps to develop new therapeutic strategies that neutralize the tracks taken by cancer cells to grow, spread, and resist therapy. Therefore, targeting TME components may be effective in improving tumor therapy. Using nanotechnology for drug delivery is of great interest, where it overcomes some obstacles such as solubility and absorption of drugs and delivering them to the appropriate place of action. The main target of nanotechnology for drug delivery is the ability to differentiate between normal and cancer cells. It can be concluded that TME is an important complementary strategy for the development of anticancer drugs. Multitargeted therapy has better efficient potential than individual therapy against cancer.
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Yang Y, Yuan F, Zhou H, Quan J, Liu C, Wang Y, Xiao F, Liu Q, Liu J, Zhang Y, Yu X. Potential roles of heparanase in cancer therapy: Current trends and future direction. J Cell Physiol 2023; 238:896-917. [PMID: 36924082 DOI: 10.1002/jcp.30995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/17/2023]
Abstract
Heparanase (HPSE; heparanase-1) is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase-2 (HPSE-2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro- and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.
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Affiliation(s)
- Yiyuan Yang
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Fengyan Yuan
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Huiqin Zhou
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Jing Quan
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Chongyang Liu
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Yi Wang
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Fen Xiao
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Qiao Liu
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Jie Liu
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Yujing Zhang
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
| | - Xing Yu
- Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China
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Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria. EBioMedicine 2023; 90:104506. [PMID: 36889064 PMCID: PMC10043778 DOI: 10.1016/j.ebiom.2023.104506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the development of proteinuria, whereas peroxisome proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by inhibiting glomerular HPSE expression. METHODS Regulation of HPSE by PPARɣ was assessed in the adriamycin nephropathy rat model, and cultured glomerular endothelial cells and podocytes. Analyses included immunofluorescence staining, real-time PCR, heparanase activity assay and transendothelial albumin passage assay. Direct binding of PPARɣ to the HPSE promoter was evaluated by the luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before and after 16/24 weeks treatment with the PPARɣ agonist pioglitazone. FINDINGS Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and decreased heparan sulfate (HS) expression, which was ameliorated by treatment with pioglitazone. In line, the PPARɣ antagonist GW9662 increased cortical HPSE and decreased HS expression, accompanied with proteinuria in healthy rats, as previously shown. In vitro, GW9662 induced HPSE expression in both endothelial cells and podocytes, and increased transendothelial albumin passage in a HPSE-dependent manner. Pioglitazone normalized HPSE expression in adriamycin-injured human endothelial cells and mouse podocytes, and adriamycin-induced transendothelial albumin passage was reduced as well. Importantly, we demonstrated a regulatory effect of PPARɣ on HPSE promoter activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE activity of T2DM patients treated with pioglitazone for 16/24 weeks was related to their hemoglobin A1c and showed a moderate, near significant correlation with plasma creatinine levels. INTERPRETATION PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice. FUNDING This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
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22
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Al-Kuraishy HM, Al-Gareeb AI, Hetta HF, Alexiou A, Papadakis M, Batiha GES. Heparanase is the possible link between monkeypox and Covid-19: robust candidature in the mystic and present perspective. AMB Express 2023; 13:13. [PMID: 36705773 PMCID: PMC9880376 DOI: 10.1186/s13568-023-01517-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 01/18/2023] [Indexed: 01/28/2023] Open
Abstract
Heparanase (HPSE) is an endoglycosidase cleaves heparan sulfate (HS) and this contributes to the degradation and remodeling of the extracellular matrix. HS cleaved by HPSE induces activation of autophagy and formation of autophagosommes which facilitate binding of HPSE to the HS and subsequent release of growth factors. The interaction between HPSE and HS triggers releases of chemokines and cytokines which affect inflammatory response and cell signaling pathways with development of hyperinflammation, cytokine storm (CS) and coagulopathy. HPSE expression is induced by both SARS-CoV-2 and monkeypox virus (MPXV) leading to induction release of pro-inflammatory cytokines, endothelial dysfunction and thrombotic events. Co-infection of MPX with SARS-CoV-2 may occur as we facing many outbreaks of MPX cases during Covid-19 pandemic. Therefore, targeting of HPSE by specific inhibitors may reduce the risk of complications in both SARS-CoV-2 and MPXV infections. Taken together, HPSE could be a potential link between MPX with SARS-CoV-2 in Covid-19 era.
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Affiliation(s)
- Hayder M. Al-Kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - Helal F. Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515 Egypt
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770 Australia
- AFNP Med, 1030 Vienna, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Heusnerstrasse 40, 42283 Wuppertal, Germany
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, AlBeheira, Damanhour, 22511 Egypt
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23
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Chai H, Gu Q, Robertson DL, Hughes J. Defining the characteristics of interferon-alpha-stimulated human genes: insight from expression data and machine learning. Gigascience 2022; 11:giac103. [PMID: 36399061 PMCID: PMC9673497 DOI: 10.1093/gigascience/giac103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 09/07/2022] [Accepted: 10/02/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND A virus-infected cell triggers a signalling cascade, resulting in the secretion of interferons (IFNs), which in turn induces the upregulation of the IFN-stimulated genes (ISGs) that play a role in antipathogen host defence. Here, we conducted analyses on large-scale data relating to evolutionary gene expression, sequence composition, and network properties to elucidate factors associated with the stimulation of human genes in response to IFN-α. RESULTS We find that ISGs are less evolutionary conserved than genes that are not significantly stimulated in IFN experiments (non-ISGs). ISGs show obvious depletion of GC content in the coding region. This influences the representation of some compositions following the translation process. IFN-repressed human genes (IRGs), downregulated genes in IFN experiments, can have similar properties to the ISGs. Additionally, we design a machine learning framework integrating the support vector machine and novel feature selection algorithm that achieves an area under the receiver operating characteristic curve (AUC) of 0.7455 for ISG prediction. Its application in other IFN systems suggests the similarity between the ISGs triggered by type I and III IFNs. CONCLUSIONS ISGs have some unique properties that make them different from the non-ISGs. The representation of some properties has a strong correlation with gene expression following IFN-α stimulation, which can be used as a predictive feature in machine learning. Our model predicts several genes as putative ISGs that so far have shown no significant differential expression when stimulated with IFN-α in the cell/tissue types in the available databases. A web server implementing our method is accessible at http://isgpre.cvr.gla.ac.uk/. The docker image at https://hub.docker.com/r/hchai01/isgpre can be downloaded to reproduce the prediction.
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Affiliation(s)
- Haiting Chai
- MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Campus, 464 Bearsden Road, Glasgow, G61 1QH, Scotland, UK
| | - Quan Gu
- MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Campus, 464 Bearsden Road, Glasgow, G61 1QH, Scotland, UK
| | - David L Robertson
- MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Campus, 464 Bearsden Road, Glasgow, G61 1QH, Scotland, UK
| | - Joseph Hughes
- MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, Garscube Campus, Campus, 464 Bearsden Road, Glasgow, G61 1QH, Scotland, UK
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24
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Zappe A, Miller RL, Struwe WB, Pagel K. State-of-the-art glycosaminoglycan characterization. MASS SPECTROMETRY REVIEWS 2022; 41:1040-1071. [PMID: 34608657 DOI: 10.1002/mas.21737] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/02/2021] [Accepted: 09/22/2021] [Indexed: 06/13/2023]
Abstract
Glycosaminoglycans (GAGs) are heterogeneous acidic polysaccharides involved in a range of biological functions. They have a significant influence on the regulation of cellular processes and the development of various diseases and infections. To fully understand the functional roles that GAGs play in mammalian systems, including disease processes, it is essential to understand their structural features. Despite having a linear structure and a repetitive disaccharide backbone, their structural analysis is challenging and requires elaborate preparative and analytical techniques. In particular, the extent to which GAGs are sulfated, as well as variation in sulfate position across the entire oligosaccharide or on individual monosaccharides, represents a major obstacle. Here, we summarize the current state-of-the-art methodologies used for GAG sample preparation and analysis, discussing in detail liquid chromatograpy and mass spectrometry-based approaches, including advanced ion activation methods, ion mobility separations and infrared action spectroscopy of mass-selected species.
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Affiliation(s)
- Andreas Zappe
- Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Rebecca L Miller
- Department of Cellular and Molecular Medicine, Copenhagen Centre for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | | | - Kevin Pagel
- Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
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25
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Liu M, Xu X, Peng K, Hou P, Yuan Y, Li S, Sun X, Shi Z, Zhang J, Dong Y, Liu Q, Ai L, Liang L, Gan L, Huang Q, Yu Y, Liu T. Heparanase modulates the prognosis and development of BRAF V600E-mutant colorectal cancer by regulating AKT/p27Kip1/Cyclin E2 pathway. Oncogenesis 2022; 11:58. [PMID: 36130926 PMCID: PMC9492760 DOI: 10.1038/s41389-022-00428-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/09/2022] Open
Abstract
BRAF V600E-mutant colorectal cancer (CRC) is a rare subtype of colorectal cancer with poor prognosis. Compelling evidence indicates that the heparanase (HPSE) gene has multiple functions in cancer, however, its role in BRAF V600E-mutant CRC remains elusive. Differentially expressed genes between BRAF V600E-mutant and wild-type patients were explored by analyzing public data from The Cancer Genome Atlas and the Gene Expression Omnibus. Clinical samples of 172 patients with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University were collected. Overall survival was analyzed using Kaplan-Meier curves and Cox regression models. Cell models and xenografts were utilized to investigate the effect of HPSE on tumor proliferation. HPSE was significantly highly expressed in the BRAF V600E-mutant group. High HPSE expression level was independently associated with inferior survival in the BRAF V600E-mutant cohort. HPSE knockdown impeded tumor proliferation of BRAF V600E-mutant CRC cells in vitro and in vivo. Mechanistically, HPSE silencing arrested cell cycle in G0/G1 phase by downregulating Cyclin E2 expression via the AKT/p27Kip1 pathway. These findings support a role for HPSE in promoting BRAF V600E-mutant CRC progression, which suggests it holds great promise as a prognostic biomarker and a potential therapeutic target for the aggressive CRC subtype.
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Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaojing Xu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ke Peng
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Pengcong Hou
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yitao Yuan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Suyao Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhongyi Shi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiayu Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Luoyan Ai
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Li Liang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lu Gan
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qihong Huang
- Department of Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Center of Evidence-based Medicine, Fudan University, Shanghai, 200032, China.
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26
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Yuan F, Yang Y, Zhou H, Quan J, Liu C, Wang Y, Zhang Y, Yu X. Heparanase in cancer progression: Structure, substrate recognition and therapeutic potential. Front Chem 2022; 10:926353. [PMID: 36157032 PMCID: PMC9500389 DOI: 10.3389/fchem.2022.926353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/22/2022] [Indexed: 12/03/2022] Open
Abstract
Heparanase, a member of the carbohydrate-active enzyme (CAZy) GH79 family, is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulphate proteoglycans, thus modulating and facilitating remodeling of the extracellular matrix. Heparanase activity is strongly associated with major human pathological complications, including but not limited to tumour progress, angiogenesis and inflammation, which make heparanase a valuable therapeutic target. Long-due crystallographic structures of human and bacterial heparanases have been recently determined. Though the overall architecture of human heparanase is generally comparable to that of bacterial glucuronidases, remarkable differences exist in their substrate recognition mode. Better understanding of regulatory mechanisms of heparanase in substrate recognition would provide novel insight into the anti-heparanase inhibitor development as well as potential clinical applications.
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Affiliation(s)
| | | | | | | | | | | | | | - Xing Yu
- *Correspondence: Yujing Zhang, ; Xing Yu,
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27
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Masola V, Franchi M, Zaza G, Atsina FM, Gambaro G, Onisto M. Heparanase regulates EMT and cancer stem cell properties in prostate tumors. Front Oncol 2022; 12:918419. [PMID: 35965510 PMCID: PMC9363836 DOI: 10.3389/fonc.2022.918419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Prostate cancer displays a certain phenotypic plasticity that allows for the transition of cells from the epithelial to the mesenchymal state. This process, known as epithelial–mesenchymal transition (EMT), is one of the factors that give the tumor cells greater invasive and migratory capacity with subsequent formation of metastases. In addition, many cancers, including prostate cancer, are derived from a cell population that shows the properties of stem cells. These cells, called cancer stem cells (CSCs) or tumor-initiating cells, not only initiate the tumor process and growth but are also able to mediate metastasis and drug resistance. However, the impact of EMT and CSCs in prostate cancer progression and patient survival is still far from fully understood. Heparanase (HPSE), the sole mammalian endoglycosidase capable of degrading heparan sulfate (HS), is also involved in prostate cancer progression. We had previously proved that HPSE regulates EMT in non-cancerous pathologies. Two prostate cancer cell lines (DU145 and PC3) were silenced and overexpressed for HPSE. Expression of EMT and stemness markers was evaluated. Results showed that the expression of several EMT markers are modified by HPSE expression in both the prostate cancer cell lines analyzed. In the same way, the stemness markers and features are also modulated by HPSE expression. Taken together, the present findings seem to prove a new mechanism of action of HPSE in sustaining prostate cancer growth and diffusion. As for other tumors, these results highlight the importance of HPSE as a potential pharmacological target in prostate cancer treatment.
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Affiliation(s)
- Valentina Masola
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- *Correspondence: Maurizio Onisto, ; Valentina Masola,
| | - Marco Franchi
- Department of Life Quality Sciences, University of Bologna, Rimini, Italy
| | - Gianluigi Zaza
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Giovanni Gambaro
- Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- *Correspondence: Maurizio Onisto, ; Valentina Masola,
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28
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Xu H, Yang B, Ren Z, Wu D, Hu A, Hu J. miR-429 negatively regulates the progression of hypoxia-induced retinal neovascularization by the HPSE-VEGF pathway. Exp Eye Res 2022; 223:109196. [PMID: 35872179 DOI: 10.1016/j.exer.2022.109196] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 11/26/2022]
Abstract
Heparanase (HPSE) and vascular endothelial growth factor (VEGF) are believed to play a vital role in hypoxia-induced retinal neovascularization (RNV). HPSE is a target gene of miR-429. Our study aimed to investigate the effect of the miR-429-HPSE-VEGF pathway on hypoxia-induced RNV. The gene and protein expression of miR-429, HPSE and VEGF in human retinal endothelial cells and retinas was determined by real-time PCR and Western blot assays. The effects of miR-429 on human retinal endothelial cells and retinal neovascularization under hypoxia condition were verified by in vitro and in vivo experiments. First, we studied the effect of the miR-429-HPSE-VEGF pathway in HRECs under hypoxic conditions. HREC functions such as migration and tube formation were enhanced under hypoxic conditions. Overexpression of miR-429 in HRECs reversed these changes. Then, we investigated the effect of miR-429 on hypoxia-induced RNV in vivo. When miR-429 agomirs were injected into the vitreous cavity of mice with oxygen-induced retinopathy to overexpress miR-429, the mRNA and protein expression of VEGF was significantly reduced. In addition, indicators of retinal neovascularization, such as the retinal avascular area, and morphology of vessels, were reduced significantly in the miR-429 overexpression group. In this study, our data showed that miR-429 plays an important role by inhibiting the HPSE-VEGF pathway in hypoxia-induced retinopathy.
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Affiliation(s)
- Haiyan Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Bing Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Zewen Ren
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Dongjing Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Andina Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Jie Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
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Gallard C, Lebsir N, Khursheed H, Reungoat E, Plissonnier ML, Bré J, Michelet M, Chouik Y, Zoulim F, Pécheur EI, Bartosch B, Grigorov B. Heparanase-1 is upregulated by hepatitis C virus and favors its replication. J Hepatol 2022; 77:29-41. [PMID: 35085593 DOI: 10.1016/j.jhep.2022.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 01/03/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE). METHODS HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection. RESULTS HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation. CONCLUSIONS We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM. LAY SUMMARY Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM.
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Affiliation(s)
- Christophe Gallard
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Nadjet Lebsir
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Hira Khursheed
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Emma Reungoat
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Marie-Laure Plissonnier
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Jennifer Bré
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Maud Michelet
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Yasmina Chouik
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Fabien Zoulim
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Eve-Isabelle Pécheur
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
| | - Birke Bartosch
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Boyan Grigorov
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
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30
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Zha D, Fu M, Qian Y. Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19. Cells 2022; 11:cells11121972. [PMID: 35741101 PMCID: PMC9221624 DOI: 10.3390/cells11121972] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/10/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2. COVID-19 is characterized by progressive respiratory failure resulting from diffuse alveolar damage, inflammatory infiltrates, endotheliitis, and pulmonary and systemic coagulopathy forming obstructive microthrombi with multi-organ dysfunction, indicating that endothelial cells (ECs) play a central role in the pathogenesis of COVID-19. The glycocalyx is defined as a complex gel-like layer of glycosylated lipid–protein mixtures, which surrounds all living cells and acts as a buffer between the cell and the extracellular matrix. The endothelial glycocalyx layer (EGL) plays an important role in vascular homeostasis via regulating vascular permeability, cell adhesion, mechanosensing for hemodynamic shear stresses, and antithrombotic and anti-inflammatory functions. Here, we review the new findings that described EGL damage in ARDS, coagulopathy, and the multisystem inflammatory disease associated with COVID-19. Mechanistically, the inflammatory mediators, reactive oxygen species (ROS), matrix metalloproteases (MMPs), the glycocalyx fragments, and the viral proteins may contribute to endothelial glycocalyx damage in COVID-19. In addition, the potential therapeutic strategies targeting the EGL for the treatment of severe COVID-19 are summarized and discussed.
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Affiliation(s)
- Duoduo Zha
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
| | - Mingui Fu
- Shock/Trauma Research Center, Department of Biomedical Sciences, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA;
| | - Yisong Qian
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
- Correspondence:
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31
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Loka RS, Song Z, Sletten ET, Kayal Y, Vlodavsky I, Zhang K, Nguyen HM. Heparan Sulfate Mimicking Glycopolymer Prevents Pancreatic β Cell Destruction and Suppresses Inflammatory Cytokine Expression in Islets under the Challenge of Upregulated Heparanase. ACS Chem Biol 2022; 17:1387-1400. [PMID: 35658404 PMCID: PMC9251817 DOI: 10.1021/acschembio.1c00908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Diabetes is a chronic disease in which the levels of blood glucose are too high because the body does not effectively produce insulin to meet its needs or is resistant to insulin. β Cells in human pancreatic islets produce insulin, which signals glucogen production by the liver and causes muscles and fat to uptake glucose. Progressive loss of insulin-producing β cells is the main cause of both type 1 and type 2 diabetes. Heparan sulfate (HS) is a ubiquitous polysaccharide found at the cell surface and in the extracellular matrix (ECM) of a variety of tissues. HS binds to and assembles proteins in ECM, thus playing important roles in the integrity of ECM (particularly basement membrane), barrier function, and ECM-cell interactions. Islet HS is highly expressed by the pancreatic β cells and critical for the survival of β cells. Heparanase is an endoglycosidase and cleaves islet HS in the pancreas, resulting in β-cell death and oxidative stress. Heparanase could also accelerate β-cell death by promoting cytokine release from ECM and secretion by activated inflammatory and endothelial cells. We demonstrate that HS-mimicking glycopolymer, a potent heparanase inhibitor, improves the survival of cultured mouse pancreatic β cells and protects HS contents under the challenge of heparanase in human pancreatic islets. Moreover, this HS-mimicking glycopolymer reduces the expression levels of cytokines (IL8, IL1β, and TNFα) and the gene encoding Toll-like Receptor 2 (TLR2) in human pancreatic islets.
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Affiliation(s)
- Ravi S Loka
- Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
| | - Zhenfeng Song
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201, United States
| | - Eric T Sletten
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
| | - Yasmin Kayal
- Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525422, Israel
| | - Israel Vlodavsky
- Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 3525422, Israel
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201, United States
| | - Hien M Nguyen
- Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
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Rodrigues AAN, Lopes-Santos L, Lacerda PA, Juste MF, Mariz BA, Cajazeiro DC, Giacobbe V, Borges R, Casarim A, Callegari GDS, Claret Arcadipane FAM, Aprahamian I, Salo TA, De Oliveira CE, Coletta RD, Augusto TM, Cervigne NK. Heparanase 1 Upregulation Promotes Tumor Progression and Is a Predictor of Low Survival for Oral Cancer. Front Cell Dev Biol 2022; 10:742213. [DOI: 10.3389/fcell.2022.742213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Oral cavity cancer is still an important public health problem throughout the world. Oral squamous cell carcinomas (OSCCs) can be quite aggressive and metastatic, with a low survival rate and poor prognosis. However, this is usually related to the clinical stage and histological grade, and molecular prognostic markers for clinical practice are yet to be defined. Heparanase (HPSE1) is an endoglycosidase associated with extracellular matrix remodeling, and although involved in several malignancies, the clinical implications of HPSE1 expression in OSCCs are still unknown.Methods: We sought to investigate HPSE1 expression in a series of primary OSCCs and further explore whether its overexpression plays a relevant role in OSCC tumorigenesis. mRNA and protein expression analyses were performed in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function strategy using an ORF vector targeting HPSE1 were employed to investigate the endogenous modulation of HPSE1 and its effects on proliferation, apoptosis, adhesion, epithelial–mesenchymal transition (EMT), angiogenesis, migration, and invasion of oral cancer in vitro.Results: We demonstrated that HPSE1 is frequently upregulated in OSCC samples and cell lines and is an unfavorable prognostic indicator of disease-specific survival when combined with advanced pT stages. Moreover, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis and inhibited proliferation, migration, invasion, and epithelial–mesenchymal transition by significantly decreasing the expression of N-cadherin and vimentin. Furthermore, a conditioned medium of HPSE1-downregulated cells resulted in reduced vascular endothelial growth.Conclusion: Our results confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression as it is associated with several important biological processes for oral tumorigenesis, and can be managed as a prognostic marker for patients with OSCC.
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33
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Identification of Novel Potential Heparanase Inhibitors Using Virtual Screening. Catalysts 2022. [DOI: 10.3390/catal12050503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Heparanase (HPSE) is a mammalian endo-β-D-glucuronidase that cleaves heparan sulphate (HS) side chains of heparin sulphate proteoglycans (HSPG), a class of molecules composed of repeating polysulfated disaccharide units of glucosamine and hexuronic acid residues. HPSE controls the availability of growth factors, chemokines, lipoproteins and other bioactive molecules by degrading HS into smaller fractions, allowing the release of saccharide fragments that activate a plethora of signaling processes. HPSE overexpression has been correlated with tumor survival and metastasis as well as several diseases associated with chronic inflammation, including the ongoing COVID-19 pandemic caused by SARS-CoV-2. Thus, the search for molecules that could potentially inhibit HPSE has become increasingly relevant in the clinic. In this study, we have integrated a strategy that combines virtual screening and molecular docking of publicly available chemical databases to identify small compounds that can be developed into novel HPSE inhibitors. Structural rationalization of the interactions previously reported compounds led us to identify promising unexplored chemotypes. Here we show that these novel potential HPSE inhibitors present optimized in silico druggability and docking properties and may serve as pharmacological tools for the treatment of chronic and infectious diseases associated with chronic inflammation.
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Molecular Mechanism of Gleditsiae Spina for the Treatment of High-Grade Serous Ovarian Cancer Based on Network Pharmacology and Pharmacological Experiments. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5988310. [PMID: 35299895 PMCID: PMC8923798 DOI: 10.1155/2022/5988310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 02/13/2022] [Accepted: 02/22/2022] [Indexed: 11/17/2022]
Abstract
Background Gleditsiae Spina, widely used in traditional Chinese medicine, has a good curative effect on malignant tumors such as ovarian cancer, but the mechanism is not clear. So, we aimed to analyze the pharmacological mechanism of Gleditsiae Spina in the treatment of high-grade serous ovarian cancer (HGSC) based on network pharmacology and biological experiments. Methods The main active ingredients of Gleditsiae Spina were identified by high performance liquid chromatography (HPLC) and mass spectrometry (MS), and the active ingredients were performed by ADME screening. The component targets of Gleditsiae Spina were screened using the PharmMapper platform, and differentially expressed genes in normal and HGSC tissues were identified through the GEO database. Thereafter, the network of “active ingredient-targets” was constructed by cytoscape 3.7.2 software. The protein-protein interaction network was established by the BioGenet database to mine the potential protein function. Biological processes and pathways were analyzed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The binding ability of the core components of the Gleditsiae Spina and the core target of HGSC was verified by molecular docking and molecular dynamics simulation, and the therapeutic effect of Gleditsiae Spina was proved in vitro through cytotoxicity experiments. The effect of Gleditsiae Spina on the core pathway is obtained by western blotting. Results Gleditsiae Spina had cytotoxicity on HGSC based on network pharmacology and biological experiments. Luteolin, genistein, D-(+)-tryptophan, ursolic acid, and berberine are the identified core active ingredients of Gleditsiae Spina for regulating HGSC, with HPSE, PI3KCA, AKT1, and CTNNB1as the ideal targets. The prediction results were verified by molecular docking, molecular dynamic simulation, cell viability, and western blot analysis. Conclusion Gleditsiae Spina mainly downregulates the expression of heparanase and β-catenin to affect the composition of tumor cytoplasmic matrix and can regulate the PI3K-AKT pathway, integrating multiple targets and multiple pathways to play a therapeutic role. It also provides a theoretical basis for the prevention of ovarian cancer and its treatment using traditional Chinese medicine in the future.
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Masola V, Greco N, Gambaro G, Franchi M, Onisto M. Heparanase as active player in endothelial glycocalyx remodeling. Matrix Biol Plus 2022; 13:100097. [PMID: 35036899 PMCID: PMC8749438 DOI: 10.1016/j.mbplus.2021.100097] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
The surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection. In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy.,Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Nicola Greco
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Giovanni Gambaro
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy
| | - Marco Franchi
- Dept. of Life Quality Sciences, University of Bologna, Rimini, Italy
| | - Maurizio Onisto
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
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Karamanos NK, Theocharis AD, Piperigkou Z, Manou D, Passi A, Skandalis SS, Vynios DH, Orian-Rousseau V, Ricard-Blum S, Schmelzer CEH, Duca L, Durbeej M, Afratis NA, Troeberg L, Franchi M, Masola V, Onisto M. A guide to the composition and functions of the extracellular matrix. FEBS J 2021; 288:6850-6912. [PMID: 33605520 DOI: 10.1111/febs.15776] [Citation(s) in RCA: 482] [Impact Index Per Article: 120.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/13/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022]
Abstract
Extracellular matrix (ECM) is a dynamic 3-dimensional network of macromolecules that provides structural support for the cells and tissues. Accumulated knowledge clearly demonstrated over the last decade that ECM plays key regulatory roles since it orchestrates cell signaling, functions, properties and morphology. Extracellularly secreted as well as cell-bound factors are among the major members of the ECM family. Proteins/glycoproteins, such as collagens, elastin, laminins and tenascins, proteoglycans and glycosaminoglycans, hyaluronan, and their cell receptors such as CD44 and integrins, responsible for cell adhesion, comprise a well-organized functional network with significant roles in health and disease. On the other hand, enzymes such as matrix metalloproteinases and specific glycosidases including heparanase and hyaluronidases contribute to matrix remodeling and affect human health. Several cell processes and functions, among them cell proliferation and survival, migration, differentiation, autophagy, angiogenesis, and immunity regulation are affected by certain matrix components. Structural alterations have been also well associated with disease progression. This guide on the composition and functions of the ECM gives a broad overview of the matrisome, the major ECM macromolecules, and their interaction networks within the ECM and with the cell surface, summarizes their main structural features and their roles in tissue organization and cell functions, and emphasizes the importance of specific ECM constituents in disease development and progression as well as the advances in molecular targeting of ECM to design new therapeutic strategies.
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Affiliation(s)
- Nikos K Karamanos
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Achilleas D Theocharis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Zoi Piperigkou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Dimitra Manou
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Alberto Passi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Spyros S Skandalis
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Demitrios H Vynios
- Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Greece
| | - Véronique Orian-Rousseau
- Karlsruhe Institute of Technology, Institute of Biological and Chemical Systems- Functional Molecular Systems, Eggenstein-Leopoldshafen, Germany
| | - Sylvie Ricard-Blum
- University of Lyon, UMR 5246, ICBMS, Université Lyon 1, CNRS, Villeurbanne Cedex, France
| | - Christian E H Schmelzer
- Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany
- Institute of Pharmacy, Faculty of Natural Sciences I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Laurent Duca
- UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2: Matrix Aging and Vascular Remodelling, Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France
| | - Madeleine Durbeej
- Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, Sweden
| | - Nikolaos A Afratis
- Department Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Linda Troeberg
- Norwich Medical School, University of East Anglia, Bob Champion Research and Education Building, Norwich, UK
| | - Marco Franchi
- Department for Life Quality Study, University of Bologna, Rimini, Italy
| | | | - Maurizio Onisto
- Department of Biomedical Sciences, University of Padova, Italy
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Heparanase-Induced Activation of AKT Stabilizes β-Catenin and Modulates Wnt/β-Catenin Signaling during Herpes Simplex Virus 1 Infection. mBio 2021; 12:e0279221. [PMID: 34749529 PMCID: PMC8576534 DOI: 10.1128/mbio.02792-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Under pathological conditions like herpes simplex virus 1 (HSV-1) infection, host-pathogen interactions lead to major reconstruction of the host protein network, which contributes to the dysregulation of signaling pathways and disease onset. Of note is the upregulation of a multifunctional host protein, heparanase (HPSE), following infection, which serves as a mediator in HSV-1 replication. In this study, we identify a novel function of HPSE and highlight it as a key regulator of β-catenin signal transduction. The regulatory role of HPSE on the activation, nuclear translocation, and signal transduction of β-catenin disrupts cellular homeostasis and establishes a pathogenic environment that promotes viral replication. Under normal physiological conditions, β-catenin is bound to a group of proteins, referred to as the destruction complex, and targeted for ubiquitination and, ultimately, degradation. We show that virus-induced upregulation of HPSE leads to the activation of Akt and subsequent stabilization and activation of β-catenin through (i) the release of β-catenin from the destruction complex, and (ii) direct phosphorylation of β-catenin at Ser552. This study also provides an in-depth characterization of the proviral role of β-catenin signaling during HSV-1 replication using physiologically relevant cell lines and in vivo models of ocular infection. Furthermore, pharmacological inhibitors of this pathway generated a robust antiviral state against multiple laboratory and clinical strains of HSV-1. Collectively, our findings assign a novel regulatory role to HPSE as a driver of β-catenin signaling in HSV-1 infection. IMPORTANCE Heparanase (HPSE) and β-catenin have independently been implicated in regulating key pathophysiological processes, including neovascularization, angiogenesis, and inflammation; however, the relationship between the two proteins has remained elusive thus far. For that reason, characterizing this relationship is crucial and can lead to the development of novel therapeutics. For HSV-1 specifically, current antivirals are not able to abolish the virus from the host, leaving patients susceptible to episodes of viral reactivation. Identifying a host-based intervention can provide a better alternative with enhanced efficacy and sustained relief.
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Schultheis N, Jiang M, Selleck SB. Putting the brakes on autophagy: The role of heparan sulfate modified proteins in the balance of anabolic and catabolic pathways and intracellular quality control. Matrix Biol 2021; 100-101:173-181. [PMID: 33548399 DOI: 10.1016/j.matbio.2021.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/29/2021] [Accepted: 01/30/2021] [Indexed: 12/11/2022]
Abstract
Autophagy is a fundamental cellular process discovered as a response to nutrient deprivation. It provides the cellular and molecular machinery for catabolism of cellular constituents, generating energy and providing building blocks for continued survival. However, autophagy does much more than provide an entry into catabolic pathways, it provides a mechanism for intracellular quality control, removing damaged organelles and misfolded proteins, processes critical for cellular health. Autophagy serves as a counterpoint to cell growth and anabolic events, activated when growth is not possible or is suppressed. Hence, there is an inherent antagonism between autophagy and growth. Heparan sulfate modified proteins are important co-receptors that generally promote growth factor activity and are therefore positioned within signaling networks that inhibit, or negatively regulate autophagy levels. This review summarizes evidence that heparan sulfate modified proteins provide an evolutionarily conserved inhibitory modulation of autophagy that can have profound effects on cell physiology and organismal responses to stress.
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Affiliation(s)
- Nicholas Schultheis
- Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802, United States
| | - Mei Jiang
- Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802, United States
| | - Scott B Selleck
- Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA 16802, United States.
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Eustes AS, Campbell RA, Middleton EA, Tolley ND, Manne BK, Montenont E, Rowley JW, Krauel K, Blair A, Guo L, Kosaka Y, Medeiros-de-Moraes IM, Lacerda M, Hottz ED, Neto HCF, Zimmerman GA, Weyrich AS, Petrey A, Rondina MT. Heparanase expression and activity are increased in platelets during clinical sepsis. J Thromb Haemost 2021; 19:1319-1330. [PMID: 33587773 PMCID: PMC8218538 DOI: 10.1111/jth.15266] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 01/22/2021] [Accepted: 02/08/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Heparanase (HPSE) is the only known mammalian enzyme that can degrade heparan sulfate. Heparan sulfate proteoglycans are essential components of the glycocalyx, and maintain physiological barriers between the blood and endothelial cells. HPSE increases during sepsis, which contributes to injurious glyocalyx degradation, loss of endothelial barrier function, and mortality. OBJECTIVES As platelets are one of the most abundant cellular sources of HPSE, we sought to determine whether HPSE expression and activity increases in human platelets during clinical sepsis. We also examined associations between platelet HPSE expression and clinical outcomes. PATIENTS/METHODS Expression and activity of HPSE was determined in platelets isolated from septic patients (n = 59) and, for comparison, sex-matched healthy donors (n = 46) using complementary transcriptomic, proteomic, and functional enzymatic assays. Septic patients were followed for the primary outcome of mortality, and clinical data were captured prospectively for septic patients. RESULTS The mRNA expression of HPSE was significantly increased in platelets isolated from septic patients. Ribosomal footprint profiling, followed by [S35] methionine labeling assays, demonstrated that HPSE mRNA translation and HPSE protein synthesis were significantly upregulated in platelets during sepsis. While both the pro- and active forms of HPSE protein increased in platelets during sepsis, only the active form of HPSE protein significantly correlated with sepsis-associated mortality. Consistent with transcriptomic and proteomic upregulation, HPSE enzymatic activity was also increased in platelets during sepsis. CONCLUSIONS During clinical sepsis HPSE, translation, and enzymatic activity are increased in platelets. Increased expression of the active form of HPSE protein is associated with sepsis-associated mortality.
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Affiliation(s)
- Alicia S Eustes
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
- Hospitals and Clinics Pathology, Internal Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Robert A Campbell
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Elizabeth A Middleton
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Neal D Tolley
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Bhanu K Manne
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Emilie Montenont
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Jesse W Rowley
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Krystin Krauel
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Antoinette Blair
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Li Guo
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Yasuhiro Kosaka
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Isabel M Medeiros-de-Moraes
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz, Rio de Janeiro and Manaus, Brazil
| | - Marcus Lacerda
- Fundacao de Medicina Tropical - Dr. Heitor Vieira Dourado (FMT-HVD) and Fiocruz Manaus, Manaus, Brazil
| | - Eugenio D Hottz
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz, Rio de Janeiro and Manaus, Brazil
- Immunothrombosis Laboratory, Department of Biochemistry, Federal University of Juiz de Fora, Juiz de Fora, Brazil
- Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, Brazil
| | - Hugo Castro Faria Neto
- Fundacao de Medicina Tropical - Dr. Heitor Vieira Dourado (FMT-HVD) and Fiocruz Manaus, Manaus, Brazil
| | - Guy A Zimmerman
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
| | - Andrew S Weyrich
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Aaron Petrey
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Matthew T Rondina
- Department of Internal Medicine and Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
- Department of Internal Medicine and GRECC, George E. Wahlen VAMC, Salt Lake City, Utah, USA
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Kaur R, Deb PK, Diwan V, Saini B. Heparanase Inhibitors in Cancer Progression: Recent Advances. Curr Pharm Des 2021; 27:43-68. [PMID: 33185156 DOI: 10.2174/1381612826666201113105250] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 08/25/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND An endo-β-glucuronidase enzyme, Heparanase (HPSE), degrades the side chains of polymeric heparan sulfate (HS), a glycosaminoglycan formed by alternate repetitive units of D-glucosamine and D-glucuronic acid/L-iduronic acid. HS is a major component of the extracellular matrix and basement membranes and has been implicated in processes of the tissue's integrity and functional state. The degradation of HS by HPSE enzyme leads to conditions like inflammation, angiogenesis, and metastasis. An elevated HPSE expression with a poor prognosis and its multiple roles in tumor growth and metastasis has attracted significant interest for its inhibition as a potential anti-neoplastic target. METHODS We reviewed the literature from journal publication websites and electronic databases such as Bentham, Science Direct, PubMed, Scopus, USFDA, etc., about HPSE, its structure, functions, and role in cancer. RESULTS The present review is focused on Heparanase inhibitors (HPIns) that have been isolated from natural resources or chemically synthesized as new therapeutics for metastatic tumors and chronic inflammatory diseases in recent years. The recent developments made in the HPSE structure and function are also discussed, which can lead to the future design of HPIns with more potency and specificity for the target. CONCLUSION HPIns can be a better target to be explored against various cancers.
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Affiliation(s)
- Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pran Kishore Deb
- Faculty of Pharmacy, Philadelphia University, Philadelphia, Jordan
| | - Vishal Diwan
- Faculty of Medicine, The University of Queensland, Queensland, Australia
| | - Balraj Saini
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Abstract
The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.
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Affiliation(s)
- Thomas R Cox
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
- St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.
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Piperigkou Z, Kyriakopoulou K, Koutsakis C, Mastronikolis S, Karamanos NK. Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer. Cancers (Basel) 2021; 13:1441. [PMID: 33809973 PMCID: PMC8005147 DOI: 10.3390/cancers13061441] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Tissue functionality and integrity demand continuous changes in distribution of major components in the extracellular matrices (ECMs) under normal conditions aiming tissue homeostasis. Major matrix degrading proteolytic enzymes are matrix metalloproteinases (MMPs), plasminogen activators, atypical proteases such as intracellular cathepsins and glycolytic enzymes including heparanase and hyaluronidases. Matrix proteases evoke epithelial-to-mesenchymal transition (EMT) and regulate ECM turnover under normal procedures as well as cancer cell phenotype, motility, invasion, autophagy, angiogenesis and exosome formation through vital signaling cascades. ECM remodeling is also achieved by glycolytic enzymes that are essential for cancer cell survival, proliferation and tumor progression. In this article, the types of major matrix remodeling enzymes, their effects in cancer initiation, propagation and progression as well as their pharmacological targeting and ongoing clinical trials are presented and critically discussed.
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Affiliation(s)
- Zoi Piperigkou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), 265 04 Patras, Greece
| | - Konstantina Kyriakopoulou
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
| | - Christos Koutsakis
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
| | | | - Nikos K. Karamanos
- Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 265 04 Patras, Greece; (K.K.); (C.K.)
- Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), 265 04 Patras, Greece
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Endothelial Glycocalyx as a Regulator of Fibrotic Processes. Int J Mol Sci 2021; 22:ijms22062996. [PMID: 33804258 PMCID: PMC7999025 DOI: 10.3390/ijms22062996] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 12/31/2022] Open
Abstract
The endothelial glycocalyx, the gel layer covering the endothelium, is composed of glycosaminoglycans, proteoglycans, and adsorbed plasma proteins. This structure modulates vessels’ mechanotransduction, vascular permeability, and leukocyte adhesion. Thus, it regulates several physiological and pathological events. In the present review, we described the mechanisms that disturb glycocalyx stability such as reactive oxygen species, matrix metalloproteinases, and heparanase. We then focused our attention on the role of glycocalyx degradation in the induction of profibrotic events and on the possible pharmacological strategies to preserve this delicate structure.
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Madavaraju K, Koganti R, Volety I, Yadavalli T, Shukla D. Herpes Simplex Virus Cell Entry Mechanisms: An Update. Front Cell Infect Microbiol 2021; 10:617578. [PMID: 33537244 PMCID: PMC7848091 DOI: 10.3389/fcimb.2020.617578] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/02/2020] [Indexed: 12/17/2022] Open
Abstract
Herpes simplex virus (HSV) can infect a broad host range and cause mild to life threating infections in humans. The surface glycoproteins of HSV are evolutionarily conserved and show an extraordinary ability to bind more than one receptor on the host cell surface. Following attachment, the virus fuses its lipid envelope with the host cell membrane and releases its nucleocapsid along with tegument proteins into the cytosol. With the help of tegument proteins and host cell factors, the nucleocapsid is then docked into the nuclear pore. The viral double stranded DNA is then released into the host cell’s nucleus. Released viral DNA either replicates rapidly (more commonly in non-neuronal cells) or stays latent inside the nucleus (in sensory neurons). The fusion of the viral envelope with host cell membrane is a key step. Blocking this step can prevent entry of HSV into the host cell and the subsequent interactions that ultimately lead to production of viral progeny and cell death or latency. In this review, we have discussed viral entry mechanisms including the pH-independent as well as pH-dependent endocytic entry, cell to cell spread of HSV and use of viral glycoproteins as an antiviral target.
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Affiliation(s)
- Krishnaraju Madavaraju
- Shukla Lab, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States
| | - Raghuram Koganti
- Shukla Lab, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States
| | - Ipsita Volety
- Shukla Lab, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States
| | - Tejabhiram Yadavalli
- Shukla Lab, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States
| | - Deepak Shukla
- Shukla Lab, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States.,Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States
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Van Bergen T, Etienne I, Jia J, Li JP, Vlodavsky I, Stitt A, Vermassen E, Feyen JHM. Heparanase Deficiency Is Associated with Disruption, Detachment, and Folding of the Retinal Pigment Epithelium. Curr Eye Res 2020; 46:1166-1170. [PMID: 33372561 DOI: 10.1080/02713683.2020.1862239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE Pentosan polysulfate sodium (PPS; Elmiron) is a FDA-approved heparanase inhibitor for the treatment of bladder pain and interstitial cystitis. The chronic use of PPS has been associated with a novel pigmentary maculopathy, associated with discrete vitelliform deposits that exhibit hyperfluorescence, macular hyper-pigmentary spots, and foci of nodular RPE enlargement. Therefore, this study aimed to investigate the retinal morphology of heparanase knockout mice. MATERIAL AND METHODS The retinal morphology of heparanase knock-out and age-matched control wild type mice of 3-, 9- and 15-weeks old was characterized by means of histological evaluation. Immuno-histological stains for RPE65, F4/80 and Ki67 were performed for investigating the RPE, inflammatory and proliferating cells, respectively. RESULTS Histological analysis showed no changes in age-matched wild-type controls, whereas the eyes of heparanase null mice were characterized by alterations in RPE and neural retina, as manifest by RPE folds and choroidal thickening, detached RPE cells, thickening of the photoreceptor layer and retinal disorganization. The presence of discrete hyperfluorescent foci, however, was absent. The prevalence of the RPE/choroidal changes or protrusions seemed to progress over time and were correlated with more RPE65 signal rather than influx of F4/80- or Ki67-positive cells. These results indicate that the subretinal alterations were mostly RPE driven, without influx of inflammatory or proliferating cells. CONCLUSIONS Our results indicate that heparanase deficiency in the mice leads to RPE folds, choroidal thickening, and retinal disorganization. The presence of discrete hyperfluorescent foci, a key characteristic of the human disease, was not observed. However, it can be concluded that some of the observations in mice are similar to those seen after chronic use of PPS in humans. These findings indicate that the toxicity observed in the presence of heparanase inhibitors is target-related and will preclude the clinical use of heparanase inhibition as a therapeutic intervention.
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Affiliation(s)
| | | | - Juan Jia
- Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden
| | - Jin-Ping Li
- Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden
| | - Israël Vlodavsky
- The Bruce Rappaport Faculty of Medicine, Technion Integrated Cancer Center, Technion, Haifa, Israel
| | - Alan Stitt
- Oxurion NV, Gaston Geenslaan 1, Heverlee, Belgium.,Centre for Experimental Medicine, The Wellcome-Wolfson Building, Queen's University of Belfast, Belfast, Northern Ireland, UK
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46
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Transcriptome profiling of different developmental stages of corpus luteum during the estrous cycle in pigs. Genomics 2020; 113:366-379. [PMID: 33309770 DOI: 10.1016/j.ygeno.2020.12.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/17/2020] [Accepted: 12/06/2020] [Indexed: 12/22/2022]
Abstract
To better understand the molecular basis of corpus luteum (CL) development and function RNA-Seq was utilized to identify differentially expressed genes (DEGs) in porcine CL during different physiological stages of the estrous cycle viz. early (EL), mid (ML), late (LL) and regressed (R) luteal. Stage wise comparisons obtained 717 (EL vs. ML), 568 (EL vs. LL), 527 (EL vs. R), 786 (ML vs. LL), 474 (ML vs. R) and 534 (LL vs. R) DEGs with log2(FC) ≥1 and p < 0.05. The process of angiogenesis, steroidogenesis, signal transduction, translation, cell proliferation and tissue remodelling were significantly (p < 0.05) enriched in EL, ML and LL stages, where as apoptosis was most active in regressed stage. Pathway analysis revealed that most annotated genes were associated with lipid metabolism, translation, immune and endocrine system pathways depicting intra-luteal control of diverse CL function. The network analysis identified genes AR, FOS, CDKN1A, which were likely the novel hub genes regulating CL physiology.
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47
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Koganti R, Suryawanshi R, Shukla D. Heparanase, cell signaling, and viral infections. Cell Mol Life Sci 2020; 77:5059-5077. [PMID: 32462405 PMCID: PMC7252873 DOI: 10.1007/s00018-020-03559-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/17/2020] [Accepted: 05/22/2020] [Indexed: 12/13/2022]
Abstract
Heparanase (HPSE) is a multifunctional protein endowed with many non-enzymatic functions and a unique enzymatic activity as an endo-β-D-glucuronidase. The latter allows it to serve as a key modulator of extracellular matrix (ECM) via a well-regulated cleavage of heparan sulfate side chains of proteoglycans at cell surfaces. The cleavage and associated changes at the ECM cause release of multiple signaling molecules with important cellular and pathological functions. New and emerging data suggest that both enzymatic as well as non-enzymatic functions of HPSE are important for health and illnesses including viral infections and virally induced cancers. This review summarizes recent findings on the roles of HPSE in activation, inhibition, or bioavailability of key signaling molecules such as AKT, VEGF, MAPK-ERK, and EGFR, which are known regulators of common viral infections in immune and non-immune cell types. Altogether, our review provides a unique overview of HPSE in cell-survival signaling pathways and how they relate to viral infections.
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Affiliation(s)
- Raghuram Koganti
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor St, Chicago, IL, 60612, USA
| | - Rahul Suryawanshi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor St, Chicago, IL, 60612, USA
| | - Deepak Shukla
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor St, Chicago, IL, 60612, USA.
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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48
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Sugiura M, Sato H, Kanesaka M, Imamura Y, Sakamoto S, Ichikawa T, Kaneda A. Epigenetic modifications in prostate cancer. Int J Urol 2020; 28:140-149. [PMID: 33111429 DOI: 10.1111/iju.14406] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/27/2020] [Indexed: 12/18/2022]
Abstract
Prostate cancer is a major cause of cancer-related deaths among men worldwide. In addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. While aberrant deoxyribonucleic acid hypermethylation in promoter CpG islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. Acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. Deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone H3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. In this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.
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Affiliation(s)
- Masahiro Sugiura
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan.,Department of, Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hiroaki Sato
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan.,Department of, Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Manato Kanesaka
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan.,Department of, Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yusuke Imamura
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinichi Sakamoto
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomohiko Ichikawa
- Departments of, Department of, Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Atsushi Kaneda
- Department of, Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
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49
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Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity. Molecules 2020; 25:molecules25184215. [PMID: 32937952 PMCID: PMC7570499 DOI: 10.3390/molecules25184215] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/08/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Glycosylation is a common and widespread post-translational modification that affects a large majority of proteins. Of these, a small minority, about 20, are specifically modified by the addition of heparan sulfate, a linear polysaccharide from the glycosaminoglycan family. The resulting molecules, heparan sulfate proteoglycans, nevertheless play a fundamental role in most biological functions by interacting with a myriad of proteins. This large functional repertoire stems from the ubiquitous presence of these molecules within the tissue and a tremendous structural variety of the heparan sulfate chains, generated through both biosynthesis and post synthesis mechanisms. The present review focusses on how proteoglycans are “gagosylated” and acquire structural complexity through the concerted action of Golgi-localized biosynthesis enzymes and extracellular modifying enzymes. It examines, in particular, the possibility that these enzymes form complexes of different modes of organization, leading to the synthesis of various oligosaccharide sequences.
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50
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Ahrens TD, Bang-Christensen SR, Jørgensen AM, Løppke C, Spliid CB, Sand NT, Clausen TM, Salanti A, Agerbæk MØ. The Role of Proteoglycans in Cancer Metastasis and Circulating Tumor Cell Analysis. Front Cell Dev Biol 2020; 8:749. [PMID: 32984308 PMCID: PMC7479181 DOI: 10.3389/fcell.2020.00749] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 07/17/2020] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) are accessible by liquid biopsies via an easy blood draw. They represent not only the primary tumor site, but also potential metastatic lesions, and could thus be an attractive supplement for cancer diagnostics. However, the analysis of rare CTCs in billions of normal blood cells is still technically challenging and novel specific CTC markers are needed. The formation of metastasis is a complex process supported by numerous molecular alterations, and thus novel CTC markers might be found by focusing on this process. One example of this is specific changes in the cancer cell glycocalyx, which is a network on the cell surface composed of carbohydrate structures. Proteoglycans are important glycocalyx components and consist of a protein core and covalently attached long glycosaminoglycan chains. A few CTC assays have already utilized proteoglycans for both enrichment and analysis of CTCs. Nonetheless, the biological function of proteoglycans on clinical CTCs has not been studied in detail so far. Therefore, the present review describes proteoglycan functions during the metastatic cascade to highlight their importance to CTCs. We also outline current approaches for CTC assays based on targeting proteoglycans by their protein cores or their glycosaminoglycan chains. Lastly, we briefly discuss important technical aspects, which should be considered for studying proteoglycans.
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Affiliation(s)
- Theresa D. Ahrens
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sara R. Bang-Christensen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
| | | | - Caroline Løppke
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte B. Spliid
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Nicolai T. Sand
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Thomas M. Clausen
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Ali Salanti
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mette Ø. Agerbæk
- Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark
- VarCT Diagnostics, Copenhagen, Denmark
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