RSC Advances
·
2016
·Vol. 6
·期 107
·105690-105698
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IF 3.289
Qing Sun,Juan Zhao,Yuan Zhang,Hongjie Yang,Ping Zhou
The self-association of human islet amyloid polypeptide (IAPP) into cytotoxic fibrillar assemblies that induce pancreatic β-cell apoptosis has been postulated as one of the major contributors to the development of type 2 diabetes (T2D). Hence, preventing IAPP amyloid fibrillation and β-cell apoptosis is regarded as a promising treatment for T2D. Intrigued by our previous findings that a natural amphiphilic hyperbranched proteoglycan from Ganoderma lucidum, named FYGL, can decrease plasma glucose level in vivo, we demonstrated here that FYGL efficiently inhibits IAPP fibrillation and attenuates β-cell apoptosis, using a combination of biophysical, calculation and cell culture methods, including thioflavin T (ThT) and 8-anilino-1-naphthalene sulfonate (ANS) fluorescence spectroscopy, transmission electron microscopy (TEM), atomic force microscopy (AFM), circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), nuclear magnetic resonance (NMR) spectroscopy, molecular docking, cell viability tests and laser scanning confocal microscopy imaging. Moreover, a universally applicable inhibition mechanism proposed that FYGL blocks the interpeptide interaction and stabilizes IAPP structure in an α-helical conformation by forming multiple hydrogen bonds with IAPP. The findings of this study warrant FYGL to be further investigated as a potential therapeutic treatment and may provide a valuable reference for medicinal chemistry in the development of drugs against T2D as well as other amyloid diseases such as Alzheimer's disease and Huntington's disease.
研究领域:
生物化学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
ACS Omega
·
2021
·
IF 3.512
Fanzhen Yu,Yingxin Wang,Yilong Teng,Shutong Yang,Yanming He,Zeng Zhang,Hongjie Yang,Chuan-Fan Ding,Ping Zhou
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and an effective target for the treatment of type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum, namely, Fudan-Yueyang G. Lucidum (FYGL), was demonstrated capable of inhibiting the activity of PTP1B. Here, to identify the effective active components of FYGL, three different components, the polysaccharide FYGL-1, proteoglycans FYGL-2, and FYGL-3, were isolated from FYGL, and then, the protein moiety of FYGL-3 was further separated, namely, FYGL-3-P. Their abilities to enhance the glucose uptake in cells and inhibit the activity of PTP1B were compared. The inhibitory mechanisms were systematically explored by spectroscopic methods and MD simulations. The results showed that FYGL-3 and FYGL-3-P significantly enhanced the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, detected by the glucose oxidase method. Also, the FYGL-3-P protein moiety in FYGL played an essential role in inhibiting the activity of PTP1B. A strong, enthalpy-driven, and multitargeted interaction by electrostatic forces between PTP1B and FYGL-3-P dramatically inhibited the catalytic activity of PTP1B. These results provided deep insights into the molecular mechanisms of FYGL inhibiting the activity of PTP1B and structurally helped researchers seek natural PTP1B inhibitors.
研究领域:
生物化学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
RSC Advances
·
2017
·Vol. 7
·期 66
·41779-41786
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IF 3.108
Zhou Yang,Fan Wu,Hongjie Yang,Ping Zhou
A novel protein tyrosine phosphatase 1B (PTP1B) inhibitor, FYGL, extracted from Ganoderma lucidum, was first reported to have an efficient hypoglycemic effect and high safety in vivo in our previous study. However, the underlying mechanism of the anti-diabetes activity was still unclear. The dominant effective component of FYGL was demonstrated to be a neutral hyperbranched proteoglycan macromolecule. Therefore, it is necessary to first elucidate how the biomacromolecule works at the cellular level, in order to understand its possible functional mechanism in vivo. Herein, we focused on demonstrating the cell internalization and endocytosis mechanism of FYGL in HepG2 cells. A series of cellular uptake pathways was explored, including clathrin-mediated endocytosis, caveolae/lipid-mediated endocytosis, and macropinocytosis. Confocal laser scanning microscopy and flow cytometry were used to demonstrate the absorption of FYGL by HepG2 cells. Furthermore, pharmacologically selective inhibitors and Western blot methods were used to demonstrate that macropinocytosis mediated by c-Src/PI3K cascades was the preferred route for the uptake of FYGL in cells. Our study provided the basis of uptake of FYGL for an efficient hypoglycemic effect. The functional mechanism of the signaling pathway in vivo will be reported in the future.
研究领域:
药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Food & Function
·
2017
·Vol. 9
·期 1
·397-406
·
IF 3.247
Zhou Yang,Fan Wu,Yanming He,Qiang Zhang,Yuan Zhang,Guangrong Zhou,Hongjie Yang,Ping Zhou
Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body weight and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were observed. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a positive effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theoretical evidence for FYGL to be potentially used in T2D management.
研究领域:
药理学
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内分泌学
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分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 5
·1457
·
IF 4.927
Ying Zhang,Yanna Pan,Jiaqi Li,Zeng Zhang,Yanming He,Hongjie Yang,Ping Zhou
The prevention of postprandial hyperglycemia and diabetic complications is crucial for diabetes management. Inhibition of α-glucosidase to slow carbohydrate metabolism is a strategy to alleviate postprandial hyperglycemia. In addition, suppression of non-enzymatic glycation can diminish the advanced glycation end products and reduce the oxidative stress and inflammation, thereby preventing the diabetic complications. In this study, an anti-oxidative proteoglycan (namedFYGL) extracted fromGanoderma lucidumwas investigated in vitro for its inhibitory effect on α-glucosidase and non-enzymatic glycation using molecular kinetics, intrinsic fluorescence assay, and bovine serum albumin glycation models. The molecular kinetics and fluorescence assay revealed thatFYGLdecreases α-glucosidase activity by forming aFYGL–α-glucosidase complex. To evaluate the anti-glycation effect, fructose-glycated and methylglyoxal-glycated BSA models were analyzed by spectroscopic and SDS-PAGE methods. Results showed thatFYGLinhibited the glycation at every stage and suppressed glycoxidation, possibly due to its anti-oxidative capacity andFYGL–BSA complex formation. Furthermore, we demonstrated in vivo thatFYGLcould alleviate postprandial hyperglycemia indb/dbmice as well as AGE accumulation and vascular injury in diabetic rats. Overall,FYGLpossesses anti-postprandial hyperglycemia and anti-glycation functions and would be potentially used in clinic for diabetes and related complication management.Keywords:Ganoderma lucidum;postprandial hyperglycemia;α-glucosidase;non-enzymatic glycation;advanced glycation end products (AGEs)
研究领域:
药理学
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糖尿病研究
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生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2020
·
IF 3.701
Yilong Teng,Haohui Liang,Zeng Zhang,Yanming He,Yanna Pan,Shilin Yuan,Xiao Wu,Qingjie Zhao,Hongjie Yang,Ping Zhou
A proteoglycan, namely FYGL extracted from Ganoderma lucidum , was proved previously efficient for anti-diabetes in vivo . However, many medicine functions of FYGL have not been revealed, such as immunoregulation, an important function of Ganoderma in the traditional Chinese medicine. In this work, we firstly investigated the distribution of FYGL orally administrated by mice and found that FYGL was available in small intestine and viscera organs and enriched mostly in liver. Consequently, we studied the immunoregulation mechanism of FYGL in RAW 264.7 macrophages. The results showed that FYGL could induce initially ROS and trigger Ca 2+ ions influx into cells, leading to the activation of NF-κB and MAPK signaling to secret NO and cytokines for immune responses, and the promotion of phagocytosis. Meanwhile, FYGL absorbed in cells could reduce ROS, therefore preventing mitochondrial membrane from damage for cells safety. The results provided the immunoregulation basis of FYGL potentially applicable in clinics.
研究领域:
药理学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Yanna Pan,Shilin Yuan,Yilong Teng,Zeng Zhang,Yanming He,Ying Zhang,Haohui Liang,Xiao Wu,Jiaqi Li,Hongjie Yang,Ping Zhou
Oxidative stress is one of the major factors in induction of pancreatic β-cell apoptosis and diabetes. Here, we investigated systematically the roles of a proteoglycan (namely, FYGL ) from Ganoderma lucidum in protection and repair of pancreatic β-cells against oxidative stress-induced injury and apoptosis on molecular, cellular and animal basis. FYGL in vitro had antioxidant activity in terms of scavenging of free radicals and reduction power. FYGL improved cells viability, insulin secretion, redox indicator expressions, and mitochondrial membrane potential in H 2 O 2 -induced INS-1 cell via regulating the activations of apoptosis-related mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB) pathways as well as the insulin secretion-related pathway. Thrillingly in vivo , FYGL repaired the injured pancreas, reduced the pancreatic β-cells apoptosis, and improved insulin secretion because of regulating the balance of oxidation-reduction, therefore well managed blood glucose in db/db diabetic mice. These results demonstrated that FYGL is promising to be used as a novel natural remedy for protection of pancreatic β-cells against oxidative stress in diabetes treatment.
研究领域:
药理学
·
糖尿病
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2020
·Vol. 84
·期 12
·2491-2498
·
IF 1.516
Liang Haohui,Pan Yanna,Teng Yilong,Yuan Shilin,Wu Xiao,Yang Hongjie,Zhou Ping
The pancreatic β-cell death or dysfunction induced by oxidative stress plays an important effect on the development and progression of diabetes mellitus. Based on our previous findings, a natural proteoglycan extracted from Ganoderma Lucidum, named FYGL, could treat T2DM in vivo. In this study, we investigated the effects of FYGL on STZ‐induced apoptosis of INS-1 cells and its underlying mechanisms. The results showed that FYGL significantly improved the cell viability and alleviated the apoptosis in STZ‐treated INS‐1 cells. Moreover, FYGL markedly decreased the intracellular ROS accumulation and NO release, and deactivated NF-κB, JNK, and p38 MAPK signaling pathways in STZ-induced INS-1 cells. Furthermore, FYGL improved the insulin secretion through inhibiting the activation of JNK and improving the expression of Pdx-1 in INS-1 cells damaged by STZ. These results indicated that FYGL could protect pancreatic β-cells against apoptosis and dysfunction, and be used as a promising pharmacological medicine for diabetes management.Abbreviations: T2DM: type 2 diabetes mellitus; FYGL: Fudan-Yueyang G. lucidum; ROS: reactive oxygen species; NO: reactive oxygen species; NF-κB: nuclear factor kappa beta; JNK: c-jun N-terminal kinase; MAPK: mitogen-activated protein kinase; Pdx-1: Pancreatic duodenal homeobox 1
研究领域:
药理学
·
糖尿病
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）