Previously, we screened a proteoglycan for anti-hyperglycemic, named FYGL, from Ganoderma Lucidum. For further research of the antidiabetic mechanisms of FYGL in vivo, the glucose homeostasis, activities of insulin-sensitive enzymes, glucose transporter expression and pancreatic function were analyzed using db/db mice as diabetic models in the present work. FYGL not only lead to a reduction in glycated hemoglobin level, but also an increase in insulin and C-peptide level, whereas a decrease in glucagons level and showed a potential for the remediation of pancreatic islets. FYGL also increased the glucokinase activities, and simultaneously lowered the phosphoenol pyruvate carboxykinase activities, accompanied by a reduction in the expression of hepatic glucose transporter protein 2, while the expression of adipose and skeletal glucose transporter protein 4 was increased. Moreover, the antioxidant enzyme activities were also increased by FYGL treatment. Thus, FYGL was an effective antidiabetic agent by enhancing insulin secretion and decreasing hepatic glucose output along with increase of adipose and skeletal muscle glucose disposal in the late stage of diabetes. Furthermore, FYGL is beneficial against oxidative stress, thereby being helpful in preventing the diabetic complications.
The fibrillation and aggregation of α-synuclein (AS), along with the conformational transition from random coil to β-sheet, are the critical steps in the development of Parkinson's disease (PD). It is acknowledged that iron accumulation in the brain may lead to the fibrillation of AS. However, (-)-epigallocatechin gallate (EGCG) can penetrate the blood-brain barrier, chelate metal ions, and inhibit the fibrillation of amyloid proteins. Therefore, EGCG is warranted to be investigated for its potential to cure amyloid-related diseases. In the present work, we sought to study the effects of EGCG on Fe(III)-induced fibrillation of AS on both molecular and cellular levels. We demonstrate that Fe(III) interacts with the amino residue of Tyr and Ala of AS, then accelerates the fibrillation of AS, and increases intracellular reactive oxygen species (ROS) in the AS transduced-PC12 cells (AS-PC12 cells). However, EGCG significantly inhibits this process by chelating Fe(III) and protects AS-PC12 cells against the toxicity induced by ROS and β-sheet-enriched AS fibrils. These findings yield useful information that EGCG might be a promising drug to prevent and treat the neurodegenerative diseases.
The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) is associated with development of type II diabetes mellitus (T2DM). (-)-Epigallocatechin gallate (EGCG) can bind amyloid proteins to inhibit the fibrillation of these proteins. However, the mechanic detail of EGCG inhibiting amyloid formation is still unclear at the molecular level. In the present work, we sought to investigate the effect of EGCG on amidated hIAPP (hIAPP-NH ) fibrillation and aggregation by using spectroscopic and microscopic techniques, and also sought to gain insights into the interaction of EGCG and hIAPP by using spectroscopic experiments and quantum chemical calculations. ThT fluorescence, real-time NMR, and TEM studies demonstrated that EGCG inhibits the formation of hIAPP-NH fibrils, while promoting the formation of hIAPP-NH amorphous aggregates. Phenylalanine intrinsic fluorescence and NMR studies of the EGCG/hIAPP complex revealed three important binding sites including the A ring of EGCG, residue Phe23, and residue Ile26. DFT calculations identified the dominant binding structures of EGCG/Phe23 and EGCG/Ile26 complexes, named structure I and structure II, respectively. Our study demonstrates the inhibitory mechanism of EGCG on fibrillation and aggregation of hIAPP-NH in which EGCG interacts with hIAPP-NH through hydrogen bonding and π-π interactions between the A ring and residue Phe23 as well as hydrophobic interactions between the A ring and residue Ile26, which can thus inhibit the interpeptide interaction between hIAPP-NH monomers and finally inhibit fibrillation of hIAPP-NH . This study agrees with and reinforces previous studies and offers an intuitive explanation at both the atomic and molecular levels. Our findings may provide an invaluable reference for the future development of new drugs in the management of diabetes.
The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (−)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H2O)2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.