Journal of Diabetes Research
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2016
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IF 2.431
Zhi-Xue Xu,Qiang Zhang,Gong-Li Ma,Cong-Heng Chen,Yan-Ming He,Li-Hui Xu,Yuan Zhang,Guang-Rong Zhou,Zhen-Hua Li,Hong-Jie Yang,Ping Zhou
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.
研究领域:
生物化学
·
医学
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DOI
PubMed
高影响因子
Nanoscale
·
2018
·Vol. 10
·期 42
·19995-20006
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IF 7.233
Miaoyi Wang,Yunxiang Sun,Xueying Cao,Guotao Peng,Ibrahim Javed,Aleksandr Kakinen,Thomas P. Davis,Sijie Lin,Jingquan Liu,Feng Ding,Pu Chun Ke
The development of biocompatible nanomaterials has become a new frontier in the detection, treatment and prevention of human amyloid diseases. Here we demonstrated the use of graphene quantum dots (GQDs) as a potent inhibitor against the in vivo aggregation and toxicity of human islet amyloid polypeptide (IAPP), a hallmark of type 2 diabetes. GQDs initiated contact with IAPP through electrostatic and hydrophobic interactions as well as hydrogen bonding, which subsequently drove the peptide fibrillization off-pathway to eliminate the toxic intermediates. Such interactions, probed in vitro by a thioflavin T kinetic assay, fluorescence quenching, circular dichroism spectroscopy, a cell viability assay and in silico by discrete molecular dynamics simulations, translated to a significant recovery of embryonic zebrafish from the damage elicited by IAPP in vivo, as indicated by improved hatching as well as alleviated reactive oxygen species production, abnormality and mortality of the organism. This study points to the potential of using zero-dimensional nanomaterials for in vivo mitigation of a range of amyloidosis.
研究领域:
生物医学
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纳米材料科学
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分子生物学
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DOI
PubMed
高影响因子
TALANTA
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2015
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IF 3.545
Yexuan Mao,Lanlan Yu,Ran Yang,Chuanguo Ma,Ling-bo Qu,Peter de B. Harrington
The formation of highly ordered fibrils for the human islet amyloid polypeptide (hIAPP) is considered as one of the precipitating factors of type 2 diabetes mellitus. In this study, an emerging new approach microscale thermophoresis and conventional ThT fluorescence assay were utilized to investigate the aggregation behavior of hIAPP 11–20 , giving a new insight of the solvent effect on the aggregation of hIAPP 11–20 . hIAPP 11–20 displayed different aggregation behaviors in various buffers, revealing that hIAPP 11–20 not only self-aggregates but also binds to solvent components. hIAPP 11–20 had a higher binding affinity for Tris than other selected buffers because multiple hydrogen bonds form, resulting in weaker self-aggregation of hIAPP 11–20 at the early stage of aggregation and prolonging the fibril formation process. hIAPP 11–20 displayed similar self-aggregation in both HEPES and pure water. Negatively charged phosphate ions in the PBS solution ‘neutralize’ the charges carried by hIAPP 11–20 itself to some extent, causing rapid aggregation of hIAPP 11–20 , and leading to a shorter fibrillation process of hIAPP 11–20 . These results revealed that solvents contribute to the aggregation of hIAPP 11–20 and demonstrated the affect of solvents on the activity of biomolecules. Additionally, as a new technique, microscale thermophoresis offers a powerful and promising approach to study the early stages of aggregation of peptides or proteins.
研究领域:
生物化学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
JOURNAL OF PEPTIDE SCIENCE
·
2017
·Vol. 24
·期 1
·e3058
·
IF 1.972
Yexuan Mao,Lanlan Yu,Mengfan Mao,Chuanguo Ma,Lingbo Qu
Type 2 diabetes mellitus, a kind of conformational disease, has become an epidemic disease, which seriously endangers the quality of life and health of human beings. The deposition of human islet amyloid polypeptide (hIAPP) has been considered as one of the major pathological features of type 2 diabetes mellitus. As lipopeptides have some hydrophobic groups, which are similar to the reported aggregation inhibitors, and some lipopeptides could prevent cells from depositing of amyloid fibrils, several potential lipopeptide inhibitors have been engineered and synthesized, which have been assessed for their inhibitory effect in preventing amyloid fibrils formation of hIAPP 11-20 by using the conventional thioflavin-T fluorescence assay and new technique microscale thermophoresis (MST). The final amyloid fibrils of hIAPP 11-20 were characterized by transmission electron microscopy. Results suggested that with the increasing length of alkyl chain, the antiaggregation efficiency of lipopeptide inhibitors towards hIAPP 11-20 increased gradually. Meanwhile, the amount of arginines, which represent the head groups of lipopeptides, may also have some influence. The binding events also showed that the inhibitory efficiency of these lipopeptide inhibitors was enhanced with the increase of affinities between lipopeptides and hIAPP 11-20 , which were obtained from MST. This study demonstrated the efficiency of lipopeptides in inhibiting the aggregation of hIAPP 11-20 and proved that MST could be regarded as an appropriate and rapid method to screen potential inhibitors of hIAPP 11-20 or other amyloid proteins. This study also broadens the types of inhibitors on inhibiting amyloid formation of hIAPP.
研究领域:
生物化学
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分子生物学
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药物化学
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DOI
PubMed
高影响因子
JOURNAL OF MASS SPECTROMETRY
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2020
·Vol. 55
·期 10
·e4643
·
IF 1.671
Bo Pang,Xiaoyu Zhuang,Xinyu Bian,Shu Liu,Zhiqiang Liu,Fengrui Song
A wealth of epidemiological evidence indicates a strong link between type 2 diabetes (T2D) and Alzheimer's disease (AD). The fiber deposition with cross-β-sheet structure formed by self-aggregation and misfolding of amyloidogenic peptides is a common hallmark of both diseases. For the patients with T2D, the fibrils are mainly found in the islets of Langerhans that results from the accumulation of human islet amyloid polypeptide (hIAPP). The major component of aggregates located in the brain of AD patients is amyloid-β (Aβ). Many biophysical and physiological properties are shared by hIAPP and Aβ, and both peptides show similar cytotoxic mechanisms. Therefore, it is meaningful to investigate the possible cross-interactions of hIAPP and Aβ in both diseases. In this article, the segment 25–35 of Aβ was selected because Aβ 25–35 was a core region in the process of amyloid formation and showed similar aggregation tendency and toxicity with full-length Aβ. The electrospray ionization-ion mobility-mass spectrometry analysis and thioflavin T fluorescence kinetic analysis combined with transmission electron microscopy were used to explore the effects of the coexistence of Aβ 25–35 and hIAPP on the self-aggregation of both peptides and whether there was co-assembly in fibrillation. The results indicated that the aggregation of hIAPP and Aβ 25–35 had two nucleation stages in the binary mixtures. hIAPP and Aβ 25–35 had a high binding affinity and a series of hetero-oligomers formed in the mixtures of hIAPP and Aβ 25–35 in the early stage. The cross-reaction between hIAPP monomers and Aβ 25–35 monomers as well as a little of oligomers during primary nucleation stage could accelerate the aggregation of Aβ 25–35 . However, owing to the obvious difference in aggregation ability between hIAPP and Aβ 25–35 , this cross-interaction had no significant impact on the self-assembly of hIAPP. Our study may offer a better understanding for exploring the molecular mechanism of the association between AD and T2D observed in clinical and epidemiological studies and developing therapeutic strategies against amyloid diseases.
研究领域:
生物化学
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神经科学
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糖尿病研究
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阿尔茨海默病研究
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DOI
高影响因子
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