pg-545 and Disease-Models--Animal

Topics: Animals; Anti-Inflammatory Agents; Antiviral Agents; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Glucuronidase; Mice; Ross River virus; Saponins; Viral Load

Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E. Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545.. Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Blood Pressure; Disease Models, Animal; Disease Progression; Fatty Liver; Glucuronidase; Glycoside Hydrolase Inhibitors; Lipids; Liver; Male; Mice, Knockout, ApoE; Oxidative Stress; Plaque, Atherosclerotic; Saponins

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.

Topics: Acute Kidney Injury; Animals; Biomarkers; Disease Models, Animal; Epithelial-Mesenchymal Transition; Glucuronidase; Humans; Kidney; Male; Mice; Mice, Transgenic; Reperfusion Injury; Saponins; Up-Regulation

Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by heparanase is still incompletely understood. Here, we provide evidence that heparanase down regulates the expression of p21 (WAF1/CIP1), a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Colonic Neoplasms; Colonic Polyps; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Mice; Mice, Knockout; NF-kappa B; Saponins; Signal Transduction; Toll-Like Receptors; Xenograft Model Antitumor Assays

Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo- and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo- and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle-disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses.

Topics: Administration, Intravaginal; Animals; Antiviral Agents; Disease Models, Animal; Female; Herpes Genitalis; Herpesvirus 2, Human; Lipids; Mice, Inbred C57BL; Oligosaccharides; Saponins; Virion

Aggressive tumor progression, metastasis, and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types, including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in experimental PDAC. PG545 inhibited the proliferation, migration, and colony formation of pancreatic cancer cells in vitro at pharmacologically relevant concentrations. Heparanase inhibition also reduced the proliferation of fibroblasts but had only modest effects on endothelial cells in vitro. Furthermore, PG545 significantly prolonged animal survival in intraperitoneal and genetic models (mPDAC: LSL-Kras(G12D); Cdkn2a(lox/lox); p48(Cre)) of PDAC. PG545 also inhibited primary tumor growth and metastasis in orthotopic and genetic endpoint studies. Analysis of tumor tissue revealed that PG545 significantly decreased cell proliferation, increased apoptosis, reduced microvessel density, disrupted vascular function, and elevated intratumoral hypoxia. Elevated hypoxia is a known driver of collagen deposition and tumor progression; however, tumors from PG545-treated animals displayed reduced collagen deposition and a greater degree of differentiation compared with control or gemcitabine-treated tumors. These results highlight the potent antitumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Glucuronidase; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Metastasis; Pancreatic Neoplasms; Random Allocation; Saponins