Article
Biochemistry & Molecular Biology
Zuopeng Wu, Rebecca A. Sweet, Gerard F. Hoyne, Charmaine J. Simeonovic, Christopher R. Parish
Summary: It has been accepted for decades that T lymphocytes and metastasising tumour cells traverse basement membranes (BM) by deploying a battery of degradative enzymes, particularly proteases. However, recent studies suggest that there are other mechanisms that allow cell migration through basement membranes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Miriam Gross-Cohen, Sari Feld, Gil Arvatz, Neta Ilan, Israel Vlodavsky
Summary: Hpa2, a close homolog of heparanase, plays a role in a rare genetic disease called urofacial syndrome, indicating its importance in protein coding; despite lacking HS-degrading activity, it shows a high affinity to HS; experimental evidence shows that Hpa2 affects cell adhesion, migration, and colony morphology.
FRONTIERS IN ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Casper de Boer, Zachary Armstrong, Vincent A. J. Lit, Uri Barash, Gijs Ruijgrok, Ilanit Boyango, Merle M. Weitzenberg, Sybrin P. Schroder, Alexi J. C. Sarris, Nico J. Meeuwenoord, Pedro Bule, Yasmine Kayal, Neta Ilan, Jeroen D. C. Codee, Israel Vlodavsky, Herman S. Overkleeft, Gideon J. Davies, Liang Wu
Summary: Research has shown that by developing effective HPSE inhibitors, extracellular HPSE activity can be reduced, thereby reducing the aggressiveness of cancer and potentially controlling pathological HPSE-driven malignancies.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Hematology
Raghuram Koganti, Abdullah Memon, Deepak Shukla
Summary: Heparan sulfate is a glycosaminoglycan found in mammalian tissues that contributes to the structural integrity of the extracellular matrix and cell signaling, but is also exploited by viruses during infection. Loss or inhibition of heparan sulfate proteoglycans during infection can lead to significant decreases in viral entry and infectivity, affecting multiple viruses such as herpesviruses, HIV, dengue virus, HPV, and coronaviruses.
SEMINARS IN THROMBOSIS AND HEMOSTASIS
(2021)
Article
Cell Biology
Alyce J. Mayfosh, Katharine J. Goodall, Tien Nguyen, Nikola Baschuk, Mark D. Hulett
Summary: Heparanase is an important enzyme in NK cell cytotoxicity and activation, and its inhibition in clinical trials for metastatic cancer may impact NK cell immunsurveillance.
JOURNAL OF LEUKOCYTE BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Joseph Wakpal, Vishaka Pathiranage, Alice R. Walker, Hien M. Nguyen
Summary: This article describes a method for synthesizing a library of HS mimetics from natural aminoglycosides, reducing the number of steps compared to traditional methods. Computational modeling was used to identify a new class of trisaccharide compounds derived from tobramycin that mimic natural HS and have a strong binding to heparanase but a low affinity for off-target platelet factor-4 protein.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Medicine, Research & Experimental
Sarah K. Popp, Federica Vecchio, Debra J. Brown, Riho Fukuda, Yuri Suzuki, Yuma Takeda, Rikako Wakamatsu, Mahalakshmi A. Sarma, Jessica Garrett, Anna Giovenzana, Emanuele Bosi, Antony R. A. Lafferty, Karen J. Brown, Elizabeth E. Gardiner, Lucy A. Coupland, Helen E. Thomas, Beng H. Chong, Christopher R. Parish, Manuela Battaglia, Alessandra Petrelli, Charmaine J. Simeonovic
Summary: Platelet-neutrophil aggregates (PNAs) play a role in facilitating neutrophil activation and migration during the pathogenesis of type 1 diabetes (T1D). Elevated PNAs were observed in T1D patients and mice, as well as in isolated islets/insulitis, accompanied by increased islet-associated neutrophil extracellular trap (NET) products. Histones and NETs induced islet cell damage, which was prevented by the drug mCBS. PNAs could therefore serve as a biomarker for T1D autoimmunity and potentially be used for early diagnosis.
Article
Chemistry, Multidisciplinary
Mohit Chhabra, Gareth G. Doherty, Nicholas W. See, Neha S. Gandhi, Vito Ferro
Summary: Heparan sulfate is a complex polysaccharide widely expressed on cell surfaces and in the extracellular matrix, interacting with numerous proteins to mediate various biological and pathological processes. Developing synthetically tractable HS mimetics with fewer side effects has become an attractive approach for treating cancer and infectious diseases.
Article
Biochemistry & Molecular Biology
Carina Mucciolo Melo, Helena Bonciani Nader, Giselle Zenker Justo, Maria Aparecida Silva Pinhal
Summary: Heparanase is an enzyme in mammals that cleaves heparan sulfate/heparin chains from proteoglycans. Experiments showed that exogenous heparin can increase Heparanase expression through the Wnt/beta-catenin pathway.
MOLECULAR BIOLOGY REPORTS
(2021)
Article
Medicine, General & Internal
Elisabeth Zechendorf, Katharina Schroeder, Lara Stiehler, Nadine Frank, Christian Beckers, Sandra Kraemer, Michael Dreher, Alexander Kersten, Christoph Thiemermann, Gernot Marx, Tim-Philipp Simon, Lukas Martin
Summary: Heparanase activity and heparan sulfate levels correlate with the severity and outcomes of COVID-19, and may be helpful in predicting clinical progression and outcomes in patients.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Alyce J. Mayfosh, Tien K. Nguyen, Mark D. Hulett
Summary: The extracellular matrix plays crucial roles in maintaining tissue structure, immune defense, and acting as a reservoir for bioactive molecules, with heparan sulfate proteoglycans (HSPGs) and their component heparan sulfate being essential in these processes. Understanding the regulation of heparanase and its downstream targets is important for potential therapeutic strategies in inflammatory diseases, atherosclerosis, fibrosis, and cancer metastasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Mohit Chhabra, Jennifer C. Wilson, Liang Wu, Gideon J. Davies, Neha S. Gandhi, Vito Ferro
Summary: This study investigates the interaction between Pixatimod and heparanase using a combination of NMR experiments and molecular modeling. The results show that Pixatimod can bind to the active site of heparanase in different conformations, effectively blocking the binding of its natural substrate. This study provides insights for the design of next-generation heparanase inhibitors and substrates.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Review
Cell Biology
Amrita Basu, Neil G. Patel, Elijah D. Nicholson, Ryan J. Weiss
Summary: Glycosaminoglycans (GAGs) are long polysaccharides found on the cell surface and extracellular matrix of animal cells, and play important roles in cellular processes and diseases. GAGs are complex molecules with extensive structural and functional heterogeneity, and their biosynthesis is a non-template driven process involving a group of enzymes. Due to their key roles in cell homeostasis and disease, targeting the assembly and function of GAGs is of great interest as a therapeutic approach.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Cell Biology
Tien K. Nguyen, Stephanie Paone, Enoch Chan, Ivan K. H. Poon, Amy A. Baxter, Shane R. Thomas, Mark D. Hulett
Summary: Cardiovascular disease is the leading cause of death and disability worldwide, and atherosclerosis plays a crucial role in its development. Heparanase, as the only mammalian enzyme known to cleave heparan sulfate, has been found to be involved in various physiological and pathological processes, including inflammation and plaque formation. This review focuses on the emerging role of heparanase in atherosclerosis and provides an up-to-date overview of its functions.
Article
Biochemistry & Molecular Biology
Vaishali N. Patel, Dallas L. Pineda, Elsa Berenstein, Belinda R. Hauser, Sophie Choi, Michaela Prochazkova, Changyu Zheng, Corinne M. Goldsmith, Toin H. van Kuppevelt, Ashok Kulkarni, Yuefan Song, Robert J. Linhardt, Alejandro M. Chibly, Matthew P. Hoffman
Summary: Heparan sulfate 3-O-sulfotransferases generate highly sulfated rare heparan sulfate epitopes, and their knockout affects epithelial morphogenesis and salivary gland function.
Review
Immunology
Isabella McGoverne, Jenny Dunn, Jacob Batham, Wen Juan Tu, Jeremy Chrisp, Sudha Rao
Article
Cell Biology
Jinsoo Yoon, Christopher R. Parish, Anneke C. Blackburn, Lucy A. Coupland
Summary: This study revealed a significantly different effect of platelets on mesenchymal and epithelial cancers, with platelets inhibiting invasion of some sarcomas while promoting mammary carcinoma metastasis. Gene expression analysis showed upregulation of oncogenes and EMT-associated genes in breast carcinoma cells exposed to platelets, while a tumor-suppressor gene was upregulated in fibrosarcoma cells. Further investigation is warranted to fully understand the underlying mechanisms.
Article
Multidisciplinary Sciences
Connor H. O'Meara, Lucy A. Coupland, Farzaneh Kordbacheh, Benjamin J. C. Quah, Chih-Wei Chang, David A. Simon Davis, Anna Bezos, Anna M. Browne, Craig Freeman, Dillon J. Hammill, Pradeep Chopra, Gergely Pipa, Paul D. Madge, Esther Gallant, Courtney Segovis, Angela F. Dulhunty, Leonard F. Arnolda, Imogen Mitchell, Levon M. Khachigian, Ross W. Stephens, Mark von Itzstein, Christopher R. Parish
NATURE COMMUNICATIONS
(2020)
Article
Oncology
Gregory M. Kelly, Fares Al-Ejeh, Robert McCuaig, Francesco Casciello, Nabilah Ahmad Kamal, Blake Ferguson, Antonia L. Pritchard, Sayed Ali, Ines P. Silva, James S. Wilmott, Georgina Long, Richard A. Scolyer, Sudha Rao, Nicholas K. Hayward, Frank Gannon, Jason S. Lee
Summary: The study suggests that LC3B may serve as a biomarker for checkpoint inhibitor blockade to guide patient selection. Additionally, G9a inhibition shows potential in enhancing the efficacy of checkpoint inhibitor blockade and increasing response rates in melanoma patients undergoing immunotherapy.
CLINICAL CANCER RESEARCH
(2021)
Article
Cardiac & Cardiovascular Systems
Mohammed Shah, Zhenhe He, Ali Rauf, Siavash B. Kalkhoran, Christina Mathisen Heiestad, Kare-Olav Stenslokken, Christopher R. Parish, Oliver Soehnlein, Sapna Arjun, Sean M. Davidson, Derek Yellon
Summary: This study found that histones released during myocardial infarction are toxic to cardiomyocytes, and this toxicity is independent of TLR4. Inhibiting the release of histones can reduce cardiomyocyte death, providing a new therapeutic opportunity for ischemia-reperfusion injury.
CARDIOVASCULAR RESEARCH
(2022)
Article
Cell Biology
Jasmine Li, Kristine Hardy, Moshe Olshansky, Adele Barugahare, Linden J. Gearing, Julia E. Prier, Xavier Y. X. Sng, Michelle Ly Thai Nguyen, Dana Piovesan, Brendan E. Russ, Nicole L. La Gruta, Paul J. Hertzog, Sudha Rao, Stephen J. Turner
Summary: New research has revealed that rapid upregulation of the histone demethylase KDM6B is crucial for initiating H3K27me3 removal and promoting T cell differentiation and proliferation after CD8(+) T cell activation. Inhibiting KDM6B-dependent H3K27me3 demethylation limits the effectiveness of primary virus-specific CD8(+) T cell response and the formation of memory CD8(+) T cell populations. The study defines early spatial and temporal events necessary for chromatin reprogramming in CD8(+) T cells for autonomous proliferation and differentiation.
Article
Multidisciplinary Sciences
Sarita Dhounchak, Sarah K. Popp, Debra J. Brown, D. Ross Laybutt, Trevor J. Biden, Stefan R. Bornstein, Christopher R. Parish, Charmaine J. Simeonovic
Summary: This study found that ER stress may contribute to oxidative stress and type 2 diabetes by depleting beta cell HSPGs/HS. Furthermore, it revealed that TUDCA may improve glycemic control by increasing intra-islet HSPG/HS.
Article
Cell Biology
Wen Juan Tu, Robert D. McCuaig, Michelle Melino, Daniel J. Rawle, Thuy T. Le, Kexin Yan, Andreas Suhrbier, Rebecca L. Johnston, Lambros T. Koufariotis, Nicola Waddell, Emily M. Cross, Sofiya Tsimbalyuk, Amanda Bain, Elizabeth Ahern, Natasha Collinson, Simon Phipps, Jade K. Forwood, Nabila Seddiki, Sudha Rao
Summary: A novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and LSD1 has been discovered, and two new peptide inhibitors can competitively inhibit virus-ACE2 interactions to significantly inhibit viral replication. ACE2, in addition to being expressed on the cell membrane, also has a nuclear shuttling domain that can be blocked by a nuclear-specific ACE2 inhibitor, effectively inhibiting viral replication in cells.
Article
Multidisciplinary Sciences
Alicia S. Wilson, Katrina L. Randall, Jessica A. Pettitt, Julia Ellyard, Antje Blumenthal, Anselm Enders, Benjamin J. Quah, Tobias Bopp, Christopher R. Parish, Anne Bruestle
Summary: This study reveals the mechanism by which neutrophil extracellular traps (NETs) directly activate T cells and specifically enhance Th17 cell differentiation. This suggests a direct link between neutrophils, NETs, and T cell autoimmunity.
NATURE COMMUNICATIONS
(2022)
Article
Medicine, Research & Experimental
Sarah K. Popp, Federica Vecchio, Debra J. Brown, Riho Fukuda, Yuri Suzuki, Yuma Takeda, Rikako Wakamatsu, Mahalakshmi A. Sarma, Jessica Garrett, Anna Giovenzana, Emanuele Bosi, Antony R. A. Lafferty, Karen J. Brown, Elizabeth E. Gardiner, Lucy A. Coupland, Helen E. Thomas, Beng H. Chong, Christopher R. Parish, Manuela Battaglia, Alessandra Petrelli, Charmaine J. Simeonovic
Summary: Platelet-neutrophil aggregates (PNAs) play a role in facilitating neutrophil activation and migration during the pathogenesis of type 1 diabetes (T1D). Elevated PNAs were observed in T1D patients and mice, as well as in isolated islets/insulitis, accompanied by increased islet-associated neutrophil extracellular trap (NET) products. Histones and NETs induced islet cell damage, which was prevented by the drug mCBS. PNAs could therefore serve as a biomarker for T1D autoimmunity and potentially be used for early diagnosis.
Article
Biochemistry & Molecular Biology
Zuopeng Wu, Rebecca A. Sweet, Gerard F. Hoyne, Charmaine J. Simeonovic, Christopher R. Parish
Summary: It has been accepted for decades that T lymphocytes and metastasising tumour cells traverse basement membranes (BM) by deploying a battery of degradative enzymes, particularly proteases. However, recent studies suggest that there are other mechanisms that allow cell migration through basement membranes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Immunology
Alessandra Petrelli, Sarah K. Popp, Riho Fukuda, Christopher R. Parish, Emanuele Bosi, Charmaine J. Simeonovic
Summary: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells, with neutrophils playing a significant role in the disease development. Neutrophils release NETs in the pancreas and form PNAs with platelets, facilitating activation and recruitment to the pancreas.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Canete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen-Hua Huang, Jonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu
Summary: In antibody responses, mutated germinal center B (BGc) cells are positively selected for reentry or differentiation, with the support of TFH cell-derived signals including CD40 and IL-21. The binding and signaling of IL-21 in BGc cells is reduced compared to non-BGc cells, due to low cellular heparan sulfate (HS) sulfation. Ndst1-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength, and selective desensitization to IL-21 occurs in BGc cells. Therefore, the biochemical regulation of IL-21 availability and signal strength plays a crucial role in GC selection.
SCIENCE IMMUNOLOGY
(2023)
Article
Immunology
James H. O'Connor, Hayley A. McNamara, Yeping Cai, Lucy A. Coupland, Elizabeth E. Gardiner, Brendan J. McMorran, Christopher R. Parish, Brendan J. McMorran, Vitaly V. Ganusov, Ian A. Cockburn
Summary: Liver-resident CD8(+) T cells have critical roles in pathogen control, but it is also proposed that the liver may be the main site for eliminating these cells. This study suggests that the expression of asialo-glycoproteins (ASGPs) drives the accumulation of effector CD8(+) T cells in the spleen rather than the liver. Platelet interactions do not strongly influence the function of CD8(+) T cells in the liver.
JOURNAL OF IMMUNOLOGY
(2022)
Article
Biochemical Research Methods
Jinsoo Yoon, Christopher R. Parish, Lucy A. Coupland
METHODS AND PROTOCOLS
(2020)