ABSTRACT
Alzheimer's disease (AD) is a chronic neurodegenerative disease which contributes to memory loss and cognitive decline in the elderly. Fucoidan, extracted from brown algae, is a complex sulfated polysaccharide and potential bioactive compound. In this study, we investigated whether fucoidan protects PC12 cells from apoptosis induced by a combination of beta-amyloid 25-35 (Aß25-35) and d-galactose (d-Gal), and improves learning and memory impairment in AD model mice. The results indicated that fucoidan could inhibit the release of cytochrome c from the mitochondria to cytosol and activation of caspases, and increase the expression of apoptosis inhibitor proteins (IAPs), including livin and X-linked IAP (XIAP) in PC12 cells damaged by Aß25-35 and d-Gal-induction. Fucoidan reversed the decreased activity of acetylcholine (ACh) and choline acetyl transferase (ChAT), as well as the increased activity of acetylcholine esterase (AChE), in AD model mice induced by infusion of d-Gal. Furthermore, fucoidan improved antioxidant activity in vitro and in vivo by activation of superoxide dismutase (SOD) and glutathione (GSH). These results suggested that fucoidan could protect PC12 cells from apoptosis and ameliorate the learning and memory impairment in AD model mice, which appeared to be due to regulating the cholinergic system, reducing oxidative stress, and inhibiting the caspase-dependent apoptosis pathway.
Subject(s)
Amyloid beta-Peptides/pharmacology , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Galactose/pharmacology , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/drug therapy , Peptide Fragments/pharmacology , Polysaccharides/pharmacology , Acetylcholine/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Antioxidants/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Choline O-Acetyltransferase/metabolism , Cognitive Dysfunction/metabolism , Disease Models, Animal , Glutathione/metabolism , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Neurotoxicity Syndromes/metabolism , Oxidative Stress/drug effects , PC12 Cells , Rats , Superoxide Dismutase/metabolismABSTRACT
Lymphangiogenesis is one of the promoters of tumor lymphatic metastasis. Fucoidan which is a fucose-enriched sulfated polysaccharide has effect on various pharmacological activities including anti-metastasis activity. However, the inhibitory effect of fucoidan on lymphangiogenesis remains unclear. Here, fucoidan extracted from U. pinnatifida sporophylls suppressed HLECs proliferation, migration and tube-like structure formation, and had inhibitory effect of tumor-induced lymphangiogenesis in vitro. Additionally, we found that fucoidan had a dose-dependent depressive effect on the expressions of PROX1, vascular endothelial growth factor receptor 3 (VEGFR3), NF-κB, phospho-PI3K and phospho-Akt in HLECs. Moreover, anti-lymphangiogenesis effect of fucoidan was assessed by using mouse tumor model. In summary, fucoidan inhibit tumor lymphangiogenesis and lymphatic metastasis by suppressing the NF-κB/PI3K/Akt signaling pathway through reduced levels of PROX1 and VEGFR3.
Subject(s)
Antineoplastic Agents/pharmacology , Endothelial Cells/drug effects , Homeodomain Proteins/biosynthesis , Lymphangiogenesis/drug effects , Polysaccharides/pharmacology , Tumor Suppressor Proteins/biosynthesis , Vascular Endothelial Growth Factor Receptor-3/biosynthesis , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Lymphatic Metastasis , Male , Mice , Polysaccharides/administration & dosage , Random Allocation , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.
