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Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato\u2010protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato\u2010protective effect better than each drug alone. Thus, the current study examines the pancreato\u2010protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild\u2010type (WT) and Hpa over\u2010expressing (Hpa\u2010Tg) mice. Cerulein\u2010induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa\u2010Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti\u2010Hpa drug combinations constitute a novel therapy for this common orphan disease.<\/jats:p>","DOI":"10.1111\/jcmm.18512","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T12:47:51Z","timestamp":1725886071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches"],"prefix":"10.1111","volume":"28","author":[{"given":"Dalit B.","family":"Hamo\u2010Giladi","sequence":"first","affiliation":[{"name":"Department of Physiology The Ruth &amp; Bruce Rappaport Faculty of Medicine  Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Fokra","sequence":"additional","affiliation":[{"name":"Department of Physiology The Ruth &amp; Bruce Rappaport Faculty of Medicine  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