BIOPHYSICAL CHEMISTRY
·
2021
·
IF 2.352
Fanzhen Yu,Yilong Teng,Shutong Yang,Yanming He,Zeng Zhang,Hongjie Yang,Chuan-Fan Ding,Ping Zhou
Ganoderma lucidum is a valuable medicinal herbal which has been reported to prevent type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum , namely, FYGL , has been demonstrated to inhibit the amyloidosis of human islet amyloid polypeptide (hIAPP) previously by our lab. However, the effective active components and the mechanisms of FYGL in inhibiting hIAPP amyloidosis are unknown. To identify the effective active components, different components from FYGL were isolated: the polysaccharide FYGL-1 , the proteoglycans of FYGL-2 and FYGL-3 . We further separated and sequenced the protein moieties of FYGL-2 and FYGL-3 , namely, FYGL-2-P and FYGL-3-P , respectively, and compared their abilities to inhibit hIAPP amyloidosis, and systematically explored the inhibitory mechanisms by spectroscopy, microscopy and molecular dynamic simulation methods. Results showed that the protein moieties of FYGL played essential roles in inhibiting hIAPP amyloidosis. The strong, specific, and enthalpy-driven interaction by π-π stacking and electrostatic forces between hIAPP and FYGL-3-P dramatically inhibited hIAPP amyloidosis. These results suggested that FYGL-3-P had enormous potential to prevent hIAPP misfolding-induced diabetes and structurally helped researchers to seek or design inhibitors against polypeptide amyloidosis.
研究领域:
生物化学
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分子生物学
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医学
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DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2020
·Vol. 44
·期 22
·9438-9443
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IF 3.288
Yongxiu Song,Ping Li,Zhiming Zhang,Yin Wang,Zhefei Zhang,Lei Liu,Mingdong Dong
Amyloid deposits in pancreatic islets of type 2 diabetes mellitus (T2DM) are mainly comprised of human islet amyloid polypeptide (hIAPP), which is believed to be generated as a paracrine hormone along with insulin secretion. Misfolded hIAPP in islet beta cells is associated with T2DM. To reduce the risk of T2DM, amyloid aggregate degradation to remove insoluble amyloid deposits has been proven to be a preventive strategy against T2DM. However, the development of effective approaches and degradation mechanisms needs to be further addressed. Herein, we introduce tetrasodium-meso-tetra(4-sulfonatophenyl)porphyrin binding to hIAPP37 aggregates by electrostatic interactions, which could enhance the degradability of hIAPP37 fibrils under photo-irradiation. The morphology change of hIAPP fibrils could be easily revealed through the effect of photoexcited porphyrin without any additives under neutral conditions. The photoexcited porphyrin-induced degradation of amyloid fibrils may be attributed to reactive oxygen species destabilizing the β-sheet secondary structure under photo-irradiation. Moreover, the degraded products of hIAPP37 fibrils show low cytotoxicity to INS cells. This work could be beneficial for the molecular design of novel photodegradation agents of amyloid fibrils and also expand the biomedical application of porphyrin for photosensitization.
研究领域:
生物化学
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糖尿病研究
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材料科学
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产品关联
DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
·
2019
·
IF 2.54
Bo Pang,Xinyu Bian,Junpeng Xing,Shu Liu,Zhiqiang Liu,Fengrui Song
The abnormal aggregation of human islet amyloid polypeptide (hIAPP) is a crucial pathogenic factor associated with type 2 diabetes (T2D). The development of effective inhibitors to prevent hIAPP aggregation is a common therapeutic strategy against T2D. Lithospermic acid (LA) is a natural compound with diversified biological activities. In this study, electrospray ionization coupled with ion mobility–mass spectrometry, thioflavin T fluorescence assay , Congo red binding assay, Nile red fluorescence assay, circular dichroism spectroscopy, transmission electron microscopy , cell toxicity, lactate dehydrogenase assay (LDH) assay and molecular docking were combined to explore the influence of LA on hIAPP aggregation. Results showed that LA had favorable binding affinity to hIAPP and formed hIAPP–LA complexes, which could alter the relative abundance of the compact and extended conformers and promoted the transition of extended structures to compact conformers. LA also displayed strong inhibitory actions on fibrillation and potential protective effects against hIAPP-induced cell toxicity. Therefore, the obtained results were useful to understand the possible inhibitory mechanism of LA on hIAPP aggregation and provided valuable reference for the screening of potent amyloid inhibitors.
研究领域:
生物化学
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药物化学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2013
·Vol. 8
·期 1
·e54198
·
IF 3.73
Hao Gong,Xin Zhang,Biao Cheng,Yue Sun,Chuanzhou Li,Ting Li,Ling Zheng,Kun Huang
Bisphenol A (BPA) is a chemical compound widely used in manufacturing plastic products. Recent epidemiological studies suggest BPA exposure is positively associated with the incidence of type 2 diabetes mellitus (T2DM), however the mechanisms underlying this link remain unclear. Human islet amyloid polypeptide (hIAPP) is a hormone synthesized and secreted by the pancreatic β-cells. Misfolding of hIAPP into toxic oligomers and mature fibrils can disrupt cell membrane and lead to β-cell death, which is regarded as one of the causative factors of T2DM. To test whether there are any connections between BPA exposure and hIAPP misfolding, we investigated the effects of BPA on hIAPP aggregation using thioflavin-T based fluorescence, transmission electronic microscopy, circular dichroism, dynamic light scattering, size-exclusion chromatography,fluorescence-dye leakage assay in an artificial micelle system and the generation of reactive oxygen species in INS-1 cells. We demonstrated that BPA not only dose-dependently promotes the aggregation of hIAPP and enhances the membrane disruption effects of hIAPP, but also promotes the extent of hIAPP aggregation related oxidative stress. Taken together, our results suggest that BPA exposure increased T2DM risk may involve the exacerbated toxic aggregation of hIAPP.
研究领域:
毒理学
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内分泌学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
RSC Advances
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2016
·Vol. 6
·期 9
·7239-7248
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IF 3.289
Lizi Huang,Mingyan Liao,Xin Yang,Hao Gong,Liang Ma,Yudan Zhao,Kun Huang
Bisphenols (BPs) are a group of chemicals with two hydroxyphenyl functionalities. BPs analogues including bisphenol A (BPA), bisphenol B (BPB), bisphenol F (BPF), bisphenol S (BPS), bisphenol AF (BPAF), bisphenol AP (BPAP), tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are widely used in the production of plastic materials. There has been a growing concern worldwide about environmental BPs exposure due to their potential adverse effects on human health. Deposition of β-cell toxic misfolded human islet amyloid polypeptide (hIAPP), a hormone biosynthesized and secreted by the pancreatic β-cells, is a cardinal finding in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest BPA exposure is positively associated with the incidence of T2DM, which may be due to the exacerbated toxic aggregation of hIAPP induced by BPA as we previously reported. Here, we demonstrate that bisphenol analogues showed different effects on hIAPP amyloid formation. Unlike the accelerating effects of BPA, four BPs analogues (BPAF, BPAP, TBBPA and TCBPA) showed inhibitory effects on hIAPP aggregation and decreased the membrane disruption capacity of hIAPP. Our results also explained a possible relationship between the spatial structure and the inhibitory capacities of BPs analogues.
研究领域:
环境科学
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毒理学
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分子生物学
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内分泌学
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产品关联
DOI
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2025
·
IF 3.2
Bin Xiao,Junhao Xiao,Xiaoying Xiao,Sisi Liu,Hongmei Chen,Shengping Dai,Yan Sui,Huixian Ye
Amyloid deposition of human islet amyloid polypeptide (hIAPP) is closely linked to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Developing effective inhibitors to suppress hIAPP aggregation holds significant therapeutic potential for the prevention and treatment of T2DM. Recent researches indicate that both heme and lithospermic acid (LPA) can inhibit hIAPP aggregation. However, heme is prone to induce protein damage under oxidative stress, while LPA exhibits limited inhibitory efficacy despite its antioxidant properties. To overcome these limitations, we aimed to develop a dual-component inhibitor comprising heme and LPA. thioflavin T (ThT) fluorescence, transmission electron microscopy (TEM), circular dichroism (CD) and gel electrophoresis were combined to observe the inhibitory efficacy of heme-LPA co-formulation on hIAPP aggregation. The results demonstrate that LPA and heme can synergistically inhibit hIAPP aggregation. The inhibitory effect of heme-LPA co-formulation on hIAPP aggregation is significantly stronger than that of either component alone. The heme-LPA not only prevents the complete conversion of hIAPP into β-sheet fibrillar structures but also maintains its active monomeric conformation for extended periods. Furthermore, peroxidase activity assays revealed that the presence of LPA significantly reduces the peroxidase activity of heme in a concentration-dependent manner and attenuates peptide nitration damage under H₂O₂-NO₂ − oxidative stress. At a heme-to-LPA ratio of 1:4, peptide nitration bands were virtually undetectable. These findings indicate that the dual-component inhibitor heme-LPA represents an efficient and safe strategy for inhibiting hIAPP aggregation. This research provides an important avenue for developing novel anti-hIAPP aggregation inhibitors for the prevention and treatment of T2DM.
研究领域:
分子生物学
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内分泌学
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药理学
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转化医学
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蛋白质化学
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代谢病研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MASS SPECTROMETRY
·
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
·
阿尔茨海默病研究
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DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Ling Qin,Yajing Yang,Jiejie Hao,Xiaoxi He,Shan Liu,Xiao Chu,Wenjun Mao
A water-soluble polysaccharide from the green alga Chaetomorpha linum , designated CHS2, was obtained by water extraction, preparative anion-exchange and size-exclusion chromatography. Results of chemical and spectroscopic analyses showed that CHS2 was a sulfated rhamnogalactoarabinan, and its backbone was mainly constituted by 4-linked and 3,4-linked β- l -arabinopyranose with sulfate groups at C-2/C-3 of 4-linked β- l -arabinopyranose. The branching contained 4-linked, 6-linked β- d -galactopyranose and terminal rhamnose residues. Based on the inhibition of human islet amyloid polypeptide (hIAPP) aggregation and morphology change of hIAPP aggregates in in vitro tests, it was proved that CHS2 effectively inhibited the hIAPP aggregation and possessed strong antidiabetic activity. CHS2 was nearly no toxicity in NIT-1 cells and could attenuate hIAPP-induced cytotoxicity. CHS2 may significantly reduce the generation of intracellular reactive oxygen species and hIAPP aggregation-induced oxidative stress in NIT-1 cells. CHS2 was co-localized with mitochondria, and largely protected mitochondria function from hIAPP aggregation-induced damage through stabilizing mitochondrial membrane potential and enhancing the mitochondrial complex I, II or III activity and ATP level. The data demonstrated that CHS2 could have potential prospect to become an antidiabetic drug for type 2 diabetes mellitus treatment.
研究领域:
药理学
·
生物化学
·
分子生物学
·
糖尿病研究
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2013
·
IF 3.01
Lihua Jiao,Xin Zhang,Lianqi Huang,Hao Gong,Biao Cheng,Yue Sun,Yixuan Li,Qi Liu,Ling Zheng,Kun Huang
Cinnamon consumption has been found to associate with the attenuation of diabetes mellitus. The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as a causative factor of type 2 diabetes mellitus (T2DM). Here, we investigated whether cinnamon has any beneficial effect on the toxic aggregation of hIAPP. We found that cinnamon water extract (CWE) inhibited the amyloid formation of hIAPP in a dose-dependent manner, and identified proanthocyanidins as the major anti-amyloidogenic compounds of CWE. Proanthocyanidins affected the secondary structures of hIAPP and delayed the structural transition from unstructured coils to β-sheet-rich structures. Further studies showed that proanthocyanidins not only inhibited the formation of hIAPP oligomers, but also significantly attenuated the membrane damaging and cytotoxic effects caused by the hIAPP aggregation. Together, these results suggest a possible way by which cinnamon shows beneficial effects on T2DM, and indicate a potential pharmacological usage of proanthocyanidins as an anti-diabetic drug candidate.
研究领域:
药理学
·
糖尿病研究
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
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