EUROPEAN JOURNAL OF PHARMACOLOGY
·
2017
·
IF 2.896
Yexuan Mao,Lanlan Yu,Ran Yang,Chuanguo Ma,Lingbo Qu,Peter de B. Harrington
The structural transition and misfolding of human islet amyloid polypeptide may cause a common metabolic disease Type 2 diabetes mellitus . Seventeen peptides have been synthesized, possessing different lengths, compositions , and peptide conformation. In this study, the mechanism of these peptides on inhibiting the formation of hIAPP 11–20 amyloid fibrils was investigated using a conventional ThT fluorescence assay and microscale thermophoresis. The results showed that short peptides AT, SA, RF, KS, KT and KN, and cyclic peptides cyclic-KS, cyclic-KT and cyclic-KN displayed considerable inhibitory effect on hIAPP 11–20 fibril formation and a strong affinity for hIAPP 11–20 . The detailed investigation indicated that the phenylalanine residue and some special peptide composition significantly inhibit amyloid formation. The peptide conformation of the designed peptide inhibitors may also play an important role. Microscale thermophoresis quantified the binding affinities between hIAPP 11–20 and the peptides; and revealed that high affinity binding more likely leads to inhibiting fibril formation of hIAPP 11–20 and vice versa, which is in accordance with the results from the ThT assays. These findings suggest a feasible model of peptide inhibitor design for inhibiting amyloid formation. In addition, microscale thermophoresis was proven as a promising rapid method for preliminarily screening inhibitors of hIAPP 11–20 .
研究领域:
生物化学
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分子生物学
·
代谢疾病研究
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DOI
高影响因子
ACS Biomaterials Science & Engineering
·
2018
·
IF 4.432
Yanru Xin,Huazhi Zhang,Qigang Hu,Sidan Tian,Chenhui Wang,Liang Luo,Fanling Meng
Misfolding and amyloid formation of human islet amyloid polypeptide (IAPP) are believed to be critical in the pathogenesis of type 2 diabetes. Inhibitors that can effectively prevent protein aggregation and fibrillation are considered as potential therapeutics for the prevention and treatment of type 2 diabetes. Here, we report that oligotyrosines manipulate IAPP amyloid formation in vitro and modulate IAPP-induced cytotoxicity in a manner that is related to the number of tyrosine units. Tyr2 and Tyr3 can effectively inhibit the aggregation of IAPP, either in bulk solution or in the presence of lipid membranes, and alleviate IAPP-mediated cytotoxicity. On the contrary, Tyr, Tyr4, and Tyr6 do not show significant inhibitory effects on the IAPP aggregation at the same conditions. To the best of our knowledge, this is the first report of a residue-number-dependent inhibition of IAPP aggregation by oligotyrosines, and Tyr2 and Tyr3 are proved to be potent inhibitors of IAPP amyloid formation. The interactions between oligotyrosines and IAPP were simulated through molecular docking, which provides us a new insight about the inhibition mechanism of IAPP amyloid formation that will be helpful for developing antidiabetic drug candidates.
研究领域:
生物化学
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分子生物学
·
医学
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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
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DOI
PubMed
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
Scientific Reports
·
2015
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IF 5.578
Caiao Guo,Liang Ma,Yudan Zhao,Anlin Peng,Biao Cheng,Qiaoqiao Zhou,Ling Zheng,Kun Huang
Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives.
研究领域:
药理学
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生物化学
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分子生物学
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中医药
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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
·
2016
·Vol. 6
·期 9
·7239-7248
·
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
·
分子生物学
·
内分泌学
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产品关联
DOI
高影响因子
JACS Au
·
2025
·
IF 8.7
Zhuo Zhang,Mingchen Lv,Jiaxi Xu,Yaping Liu,Jinlong Qin,Zhen Fan,Jianzhong Du
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by abnormal performance in memory, cognition, and language, and it imposes a heavy economic burden worldwide. Amyloidosis and oxidative stress are highly associated with AD progression, yet limited clinical drugs are available at present. Nanozymes exhibit diverse enzyme-mimetic activities and have attracted widespread attention as a promising alternative candidate for scavenging reactive oxygen species to maintain the oxidation–antioxidation balance in cells. Neurotoxic amyloid-β (Aβ) aggregation is also a critical event in AD pathology. The development of dual-targeting nanomaterials with antiamyloidosis ability and enzyme-mimicking activity is expected to be a promising strategy for the treatment of amyloidosis and reactive oxygen species-mediated AD progression. Here, bimetallic-peptide framework nanozymes (CuZn-PEP NZs) with amyloid-β (Aβ) attenuating ability, multiple enzyme-mimicking properties, and broad-spectrum reactive oxygen species scavenging capacity were endowed to inhibit Aβ fibrillization, disaggregate Aβ fibrils, and scavenge Aβ fibril-induced reactive oxygen species. An obvious inhibitory effect on Aβ fibrillization and a disaggregation effect on Aβ fibrils were observed after treatment with CuZn-PEP NZs. Meanwhile, the cytotoxicity of Aβ fibrils toward PC12 cells was significantly reduced by CuZn-PEP NZs. Meanwhile, CuZn-PEP NZs with multiple redox pairs exhibit superoxide dismutase, catalase, and glutathione peroxidase-mimicking enzyme properties simultaneously, which further display cytoprotective effects against Aβ fibril-induced reactive oxygen species and mitochondrial damage. Besides, cellular studies verified that CuZn-PEP NZs possess excellent biocompatibility and blood–brain barrier penetration capacity. Overall, these bimetallic-peptide framework nanozymes represent a promising perspective for attenuation of amyloid-β aggregation and reactive oxygen species simultaneously, which highlights the potential of nanozymes for the treatment of amyloidosis and reactive oxygen species-mediated AD progression.
研究领域:
纳米技术
·
神经科学
·
生物化学
·
材料科学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 7
·2802-2815
·
IF 8.307
Liyuan Zhao,Sheng Wang,Qigang Hu,Haibo Jia,Yanru Xin,Liang Luo,Fanling Meng
The misfolding and aggregation of human islet amyloid polypeptide (IAPP) into β-sheet-enriched amyloid fibrils is linked to type 2 diabetes. Antibodies are potent inhibitors of IAPP amyloidogenesis, but their preparation is usually complicated and expensive. Here we have created a multivalent antibody mimic SPEPS@Au through conformational engineering of the complementary-determining regions (CDRs) of antibodies on gold nanoparticles (AuNPs). By immobilizing both terminals of an IAPP-recognizing CDR loop (PEP) on the surface of AuNPs, the active conformation of PEP can simply recur on the gold-based antibody mimic, significantly enhancing the binding affinity between PEP and IAPP. SPEPS@Au mitigated amyloidogenesis of IAPP at low sub-stoichiometric concentrations, even after IAPP started aggregating, and dramatically reduced the amyloidogenesis-induced toxicity and ROS production both in vitro and in vivo. The conformation-reconstructed multivalent antibody mimic not only renders a facile strategy to approach potent amyloidogenesis inhibitors, but also provides new perspectives to exploit NP-based substitutes for antibodies in various applications.
研究领域:
生物技术
·
纳米技术
·
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
MACROMOLECULAR RAPID COMMUNICATIONS
·
2024
·
IF 4.2
Na Feng,Shuting Miao,Xin Guo,Ziyi Yang,Luke Yan,Peng Yang,Jia Kong
Biomimetic slippery liquid-infused porous surfaces (SLIPS) have emerged as a promising solution to solve the limitations of superhydrophobic surfaces, such as inadequate durability in corrosion protection and a propensity for frosting. However, the challenge of ensuring strong, lasting adhesion on diverse materials to enhance the durability of the lubricant layer remains. The research addresses this by leveraging amyloid phase-transitioned lysozyme (PTL) as an adhesive interlayer, conferring stable attachment of SLIPS across a variety of substrates, including metals, inorganics, and polymers. The silica-textured interface robustly secures the lubricant with a notably low sliding angle of 1.15°. PTL-mediated adhesion fortifies the silicone oil attachment to the substrate, ensuring the retention of its repellent efficacy amidst mechanical stressors like ultrasonication, water scrubbing, and centrifugation. The integration of robust adhesion, cross-substrate compatibility, and durability under stress affords the PTL-modified SLIPS exceptional anti-fouling, anti-icing, and anti-corrosion properties, marking it as a leading solution for advanced protective applications.
研究领域:
材料科学
·
生物化学
·
表面工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
·
2021
·
IF 1.571
Yu-Xi Wang,Zhi-Kang Duan,Wan-Yi Shi,Ye Chang,Xiao-Xiao Huang,Shao-Jiang Song
Previous work has shown that the lignans from the twigs and leaves of Archidendron clypearia (Jack) I.C.N. possess anti-β-amyloid aggregation activity. Here we report a new dilignan, archidendronin A (1), along with one known sesquilignan (2). Their structures were determined by extensive spectroscopic methods, including UV, HRESIMS, 1 D and 2 D NMR data. The inhibitory activity on Aβ1-42 aggregation was screened by ThT assay with curcumin as the positive control, and compounds 1 and 2 showed inhibition rate of 60.0% and 64.4% at 20 μM, respectively.
研究领域:
植物化学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Wenjuan Wang,Zhaoyu Liu,Hao Cheng,Min Xu,Zhi Du,Wei Liu,Chaofeng Zhang
Both fibrillogenesis of amyloid β-protein (Aβ) and elevated levels of reactive oxygen species (ROS) contribute to the pathogenesis of Alzheimer's disease (AD). Beyond Aβ aggregation inhibition, the complexity necessitates the development of comprehensive therapeutic interventions for halting AD progression. Herein, a dual-target agent capable of Aβ aggregation inhibition and ROS scavenging was synthesized by doping cerium into carbon dots (Ce CDs). Ce CDs with a high Ce (III)/Ce (IV) ratio of 0.67 can scavenge various ROS, including superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and Aβ 40 -induced ROS, thus mitigating cellular oxidative damage and rescuing cell viability. Additionally, Ce CDs present potent inhibition on Aβ 40 on-pathway fibrillization, disrupting the formation of highly ordered β-sheet structures and increasing cell viability from 50.2 % to 91.9 %. It is validated that the electrostatic interactions between Ce CDs and Aβ 40 are primarily responsible for preventing the conformational transition of Aβ 40 monomers. In vivo experiments with the transgenic Caenorhabditis elegans strain further validate the bifunctionality of Ce CDs in suppression of Aβ fibrillogenesis and attenuation of oxidative stress, thereby demonstrating the potential of combination therapy for AD. This finding highlights the important role of electrostatic interactions between Aβ and inhibitors in regulating Aβ aggregation, and provides new insights into the development of multifunctional agents for AD treatment.
研究领域:
神经科学
·
生物化学
·
材料科学
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产品关联
DOI
PubMed
高影响因子
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