ABSTRACT
Parkinson's disease is a neurodegenerative disease that is characterized by the loss of dopaminergic neurons. Fucoidan, which has emerged as a neuroprotective agent, is a marine-origin sulfated polysaccharide enriched in brown algae and sea cucumbers. However, variations in structural characteristics exist among fucoidans derived from different sources, resulting in a wide spectrum of biological effects. It is urgent to find the fucoidan with the strongest neuroprotective effect, and the mechanism needs to be further explored. We isolated and purified four different fucoidan species with different chemical structures and found that Type II fucoidan from Fucus vesiculosus (FvF) significantly improved mitochondrial dysfunction, prevented neuronal apoptosis, reduced dopaminergic neuron loss, and improved motor deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Further mechanistic investigation revealed that the ATP5F1a protein is a key target responsible for alleviating mitochondrial dysfunction of FvF to exert neuroprotective effects. This study highlights the favorable properties of FvF for neuroprotection, making FvF a promising candidate for the treatment of PD.
Subject(s)
Fucus , Neurodegenerative Diseases , Neuroprotective Agents , Mice , Animals , Dopaminergic Neurons , Fucus/chemistry , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Polysaccharides/chemistry , Mitochondria , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Mice, Inbred C57BL , Disease Models, AnimalABSTRACT
AIMS: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds. METHODS: The lead compounds with neuroprotective effects were screened by H2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes. RESULTS: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways. CONCLUSION: Lead compounds from marine corals exerted significant neuroprotective effectsï¼ which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease.
Subject(s)
Neuroblastoma , Neuroprotective Agents , Animals , Humans , Neuroprotective Agents/therapeutic use , Nuclear Receptor Subfamily 4, Group A, Member 2 , Caenorhabditis elegans/metabolism , Dopaminergic Neurons/metabolism , Cell Line, TumorABSTRACT
Trelagliptin inhibits the enzyme dipeptidyl-4 (DPP-4) to treat type 2 diabetes and it may possess the potential to improve insulin resistance. However, the molecular mechanism is not known. In this study, the effect of trelagliptin succinate in improving insulin resistance was investigated. The differentiation system of 3T3-L1 mouse preadipocytes was used to determine the content of adipokines and the content of GLUT4 in the outer membrane. The expression of AKT, P-AKT, IRS-1 and P-IRS-1 in differentiated 3T3-L1 adipocytes was determined by western blotting. Our results demonstrated that trelagliptin succinate increased the expression of AKT, P-AKT, IRS-1 and P-IRS-1 in the PI-3K/AKT insulin signaling pathway. These events promote the trans-membrane function of GLUT4 and concomitant glucose intake in adipocytes. In addition, the secretion of free fatty acids and resistin were decreased. In conclusion, our study suggested that trelagliptin succinate improved insulin resistance in adipocytes via regulation of PI-3K/AKT/GLUT4 insulin signaling pathway.
Subject(s)
Adipocytes/drug effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Insulin Resistance , Uracil/analogs & derivatives , 3T3-L1 Cells , Adipokines/genetics , Adipokines/metabolism , Animals , Fatty Acids, Nonesterified , Gene Expression Regulation/drug effects , Glucose/genetics , Glucose/metabolism , Glucose Transporter Type 4/genetics , Glucose Transporter Type 4/metabolism , Mice , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Rats , Resistin/genetics , Resistin/metabolism , Signal Transduction , Uracil/pharmacologyABSTRACT
AIM: Alizarin (AZ), that can be isolated from Rubia cordifolia, has biological activities such as antioxidation and anti-inflammatory. This study aimed to investigate the effect of AZ on glucose and lipid metabolism disorders in alloxan-induced diabetic mice and also explored the effect of AZ on insulin resistance in 3T3-L1 adipocytes. RESULTS: The research showed that AZ could decrease fasting and postprandial blood glucose, TG, TC and MDA, and it could also increase liver glycogen levels and SOD activity in diabetic mice. AZ could significantly improve the glucose uptake of 3T3-L1 adipocytes under insulin resistance, and could also increase GLUT4 protein expression levels, IRS-1 and Akt protein phosphorylation. CONCLUSION: These results showed that AZ has the potential to reduce blood sugar and improve insulin resistance.
Subject(s)
Anthraquinones/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Glucose/metabolism , Hypoglycemic Agents/pharmacology , 3T3-L1 Cells , Adipocytes , Alloxan , Animals , Anthraquinones/administration & dosage , Anthraquinones/therapeutic use , Diabetes Mellitus, Experimental/metabolism , Glucose Transporter Type 4/metabolism , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Insulin Receptor Substrate Proteins/metabolism , Insulin Resistance , Male , Mice , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effectsABSTRACT
Flowers of Malus halliana (M. halliana) Koehne have been used as a Chinese traditional medicine to treat metrorrhagia and in our study, its chemical composition and anticoagulant effect were investigated. Five compounds were isolated and identified from M. halliana flowers, including limocitrin-3-O-glucoside (1), baohuoside â ¡ (2), kaempferol-3-O-α-L-furan arabinoside (3), phloretin-4'-O-glycosidase (4) and afzeloside (5). Compound 1-3 were isolated for the first time from this genus. The anticoagulant effect of the compounds and extracts of M. halliana flowers were evaluated by APTT, PT, TT and FIB on plasma of rabbit in vitro. The results indicated that several fractions of M. halliana flowers and compounds 2-5 exhibited anticoagulant activity in vitro. Subsequently, afzeloside (5), the abundant component in M. halliana flowers, was investigated further for its antithrombotic effect in vivo and its antithrombotic mechanisms were evaluated on rats acute blood-stasis model. The antithrombotic effect was evaluated by WBV, PV, HCT, ESR, APTT, PT, TT, FIB, 6-keto-PGF1α, TXB2, ET-1 and eNOS in vivo. Afzeloside demonstrated inhibitory effect of thrombus formation, and its underlying antithrombotic mechanism was found to be related to the regulation of vascular endothelium active substance, activating blood flow and anticoagulant effect. Hence, we postulate that flavonoids may be the active ingredients of the plant.
