Heparanase and Type 1 Diabetes

Simeonovic, Charmaine J.; Popp, Sarah; Brown, Debra J.; Li, Fei-Ju; Lafferty, Antony; Freeman, Craig; Parish, Christopher R.

doi:10.1007/978-3-030-34521-1_24

Cited by 13 publications

(10 citation statements)

References 123 publications

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“…Over time, published scientific evidence has proved the involvement of HPSE in multiple other pathological conditions such as diabetes [615,616], dysfunction of the coagulation system [617,618], amyloid disease [619][620][621][622], renal disease [615][616][617][618][619][620][621][622][623][624][625][626][627][628], fibrosis [629][630][631][632], pancreatitis and viral infections [633][634][635][636] (Table 6).…”

Section: Hpse In Physiology and Diseasementioning

confidence: 99%

A guide to the composition and functions of the extracellular matrix

et al. 2021

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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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Section: Hpse In Physiology and Diseasementioning

confidence: 99%

A guide to the composition and functions of the extracellular matrix

et al. 2021

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“…In contrast, HSPG core proteins (COL18, SDC1, CD44)/HS are highly expressed intracellularly in normal mouse and human beta cells [ 15 , 16 , 27 ]. HS in beta cells functions as a non-enzymatic antioxidant [ 15 , 16 , 28 ], influences postnatal islet maturation and regulates insulin secretion [ 29 , 30 ]. In addition, studies in beta cell lines have also demonstrated that desulfation of HS impairs protection from hydrogen peroxide-induced death [ 31 ] and that the HSPG core protein syndecan (SDC4) plays an important role in insulin secretion [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…We also found that beta cell HSPG core proteins were decreased in human pancreases from donors with T1D [ 16 ], potentially due to protease(s) produced by invading leukocytes and/or ER stress [ 33 – 35 ]. We reason that the substantial loss of beta cell HS following islet/beta cell isolation in vitro and in T1D increases the sensitivity of beta cells to oxidative (ROS-mediated) damage [ 15 , 16 , 28 ]. Against this background we have explored whether beta cell HSPGs and HS are altered in T2D and impact cell viability.…”

Section: Introductionmentioning

confidence: 99%

Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes

et al. 2021

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Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.

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“…Selected molecules exerting little or no side effects will then be examined for oral availability and anti-cancer effects in combination with currently available treatments. We will also study the effect of our lead compounds on other pathological indications involving heparanase, such as chronic inflammation (i.e., colitis, pancreatitis) [51,52], tissue fibrosis [53], kidney dysfunction (i.e., AKI, diabetic nephropathy) [54][55][56][57], and diabetes [58]. Of particular relevance are recent studies on the presumed involvement of heparanase and heparan sulfate in the pathogenesis of COVID-19 [59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

Barash

Rangappa²,

Mohan

et al. 2021

Cancers

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Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.

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Heparanase and Type 1 Diabetes

Cited by 13 publications

References 123 publications

A guide to the composition and functions of the extracellular matrix

A guide to the composition and functions of the extracellular matrix

Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes

New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis

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