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Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice.
Br J Pharmacol
December 2024
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.
Background And Purpose: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA.
View Article and Find Full Text PDFReal-time analysis of osteoclast resorption and fusion dynamics in response to bone resorption inhibitors.
Sci Rep
March 2024
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
Cathepsin K (CatK), an essential collagenase in osteoclasts (OCs), is a potential therapeutic target for the treatment of osteoporosis. Using live-cell imaging, we monitored the bone resorptive behaviour of OCs during dose-dependent inhibition of CatK by an ectosteric (Tanshinone IIA sulfonate) and an active site inhibitor (odanacatib). CatK inhibition caused drastic reductions in the overall resorption speed of OCs.
View Article and Find Full Text PDFExpression of elastolytic cathepsins in human skin and their involvement in age-dependent elastin degradation.
Biochim Biophys Acta Gen Subj
May 2020
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T1Z3, Canada; Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T1Z3. Electronic address:
Background: Skin ageing is associated with structure-functional changes in the extracellular matrix, which is in part caused by proteolytic degradation. Since cysteine cathepsins are major matrix protein-degrading proteases, we investigated the age-dependent expression of elastolytic cathepsins K, S, and V in human skin, their in vitro impact on the integrity of the elastic fibre network, their cleavage specificities, and the release of bioactive peptides.
Methods: Cathepsin-mediated degradation of human skin elastin samples was assessed from young to very old human donors using immunohistochemical and biochemical assays, scanning electron microscopy, and mass spectrometry.
Characterization of cathepsin S exosites that govern its elastolytic activity.
Biochem J
January 2020
Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
Article Synopsis
- The study identifies two crucial regions (exosites) on cathepsins K and V that are required for their elastolytic activities, but the specific structural features for cathepsin S (CatS) remain unclear.
- Mutating different exosites on CatS revealed that only changes to exosite 2 significantly reduced its ability to cleave elastin, while other substrate degradations remained unaffected.
- An ectosteric inhibitor, T06, was shown to greatly decrease elastin cleavage by CatS by binding to a site outside the active site, and structural differences between CatS and CatL highlighted key regions that also influenced elastin degradation.
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