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    Increase in the β-sheet character of an amyloidogenic peptide upon adsorption onto gold and silver surfaces

    , Article ChemPhysChem ; Volume 18, Issue 5 , 2017 , Pages 526-536 ; 14394235 (ISSN) Soltani, N ; Gholami, M. R ; Sharif University of Technology
    Wiley-VCH Verlag  2017
    Fibrillation of amyloid beta (Aβ) peptide is the hallmark of Alzheimer's disease. Given that interactions at the bio–nano interface affect the fibrillation tendency of this peptide, an understanding of the interactions at Aβ peptide–inorganic surfaces on the microscopic level can help to determine the possible neurotoxicity of nanoparticles. Here, the interactions between a fibril-forming peptide, Aβ25–35, and (111) and (100) facets of gold and silver surfaces have been studied by conducting atomistic molecular dynamics simulations. The obtained results indicate that the adsorption onto gold and silver surfaces force the peptide into the β-sheet-rich conformations, which is prone to... 

    Physiological temperature has a crucial role in amyloid beta in the absence and presence of hydrophobic and hydrophilic nanoparticles

    , Article ACS Chemical Neuroscience ; Volume 4, Issue 3 , December , 2013 , Pages 375-378 ; 19487193 (ISSN) Ghavami, M ; Rezaei, M ; Ejtehadi, R ; Lotfi, M ; Shokrgozar, M. A ; Abd Emamy, B ; Raush, J ; Mahmoudi, M ; Sharif University of Technology
    Amyloid beta fibrillation can lead to major disorder of neurons processes and is associated with several neuronal diseases (e.g., Alzheimer's disease). We report here an importance of slight temperature changes, in the physiological range (35-42 °C), on the amyloid fibrillation process in the presence and absence of hydrophilic (silica) and hydrophobic (polystyrene) nanoparticles (NPs). The results highlight the fact that slight increases in temperature can induce inhibitory and acceleratory effects of hydrophobic and hydrophilic NPs on the fibrillation process, respectively. Using further in vivo considerations, the outcomes of this study can be used for considerable modifications on the... 

    Graphene oxide strongly inhibits amyloid beta fibrillation

    , Article Nanoscale ; Volume 4, Issue 23 , 2012 , Pages 7322-7325 ; 20403364 (ISSN) Mahmoudi, M ; Akhavan, O ; Ghavami, M ; Rezaee, F ; Ghiasi, S. M. A ; Sharif University of Technology
    Since amyloid beta fibrillation (AβF) plays an important role in the development of neurodegenerative diseases, we investigated the effect of graphene oxide (GO) and their protein-coated surfaces on the kinetics of Aβ fibrillation in the aqueous solution. We showed that GO and their protein-covered surfaces delay the AβF process via adsorption of amyloid monomers. Also, the large available surface of GO sheets can delay the AβF process by adsorption of amyloid monomers. The inhibitory effect of the GO sheet was increased when we increase the concentration from 10% (in vitro; stimulated media) to 100% (in vivo; stimulated media). Conclusion: our results revealed that GO and their surface... 

    Expression and Purification of Amyloid Beta Recombinant Peptide and the Effecs of Ultrasmall Peptides Enriched in Branch Chain Amino Acids as Inhibitors in Amyloid Formation

    , M.Sc. Thesis Sharif University of Technology Rezaei Adariani, Soheila (Author) ; Kalhor, Hamid Reza (Supervisor)
    Nowdays, it has been shown that protein misfolding is involved in more than forty diseases including Alzheimer’s and Parkinson’s. Alzheimer’s disease is one of the most common neurodegenerative diseases that disrupts brain function. The main cause of this illness is due to formation of extracellular amyloid plaque from a 42-amino acid-peptide called amyloid beta. Amyloidosis is caused by missfolding of peptides and proteins mainly because of physical and chemical changes in biomolecule or their environment.
    Therefore, in this dissertation, using synthetic and recombinant abeta peptide, kinetic of amyloidosis was examined. Ultrasmall peptides (three-amino acid), containing branched chain... 

    Investigation of Novel Bioorthogonal Chemical Reactions on Proteins and Amyloid Formation

    , M.Sc. Thesis Sharif University of Technology Rezaei, Mohsen (Author) ; Kalhor, Hamid Reza (Supervisor)
    Bioorthogonal chemistry defines any reaction, inside or outside the living systems, without interfering with native chemical processes and 3dimensional structure of proteins. In these types of reactions water is the sole solvent; a neutral pH is required; the temperature must be up to 40 oC. The kinetics of reactions must be on the hour scale and the nontoxic reagents with low concentration must be used. One of the simplest methods of visualizing protein molecule is covalent attachment of fluorescein to protein. In this work several fluorescent compounds were synthesized. These novel compounds include acylchloride fluorescein, N-hydroxysuccinimide fluorescein, thiophenol fluorescein, and... 

    The hot sites of α-synuclein in amyloid fibril formation

    , Article Scientific Reports ; Volume 10, Issue 1 , 22 July , 2020 Khammari, A ; Arab, S. S ; Ejtehadi, M. R ; Sharif University of Technology
    Nature Research  2020
    The role of alpha-synuclein (αS) amyloid fibrillation has been recognized in various neurological diseases including Parkinson’s Disease (PD). In early stages, fibrillation occurs by the structural transition from helix to extended states in monomeric αS followed by the formation of beta-sheets. This alpha-helix to beta-sheet transition (αβT) speeds up the formation of amyloid fibrils through the formation of unstable and temporary configurations of the αS. In this study, the most important regions that act as initiating nuclei and make unstable the initial configuration were identified based on sequence and structural information. In this regard, a Targeted Molecular Dynamics (TMD)... 

    Molecular Dynamics Simulation of Aβ42 Neurotoxicity Inhibition in Order to Alzheimer’s Disease Treatment

    , M.Sc. Thesis Sharif University of Technology Khandan, Vahid (Author) ; Firoozabadi, Bahar (Supervisor) ; Saeedi, Mohammad Saeed (Supervisor)
    Alzheimer’s disease (AD) is the most common type of dementia in the elderly. The neuropathology and treatment of AD is not precisely determined yet, but according to the pathological studies, AD is associated with presence of toxic soluble oligomers and insoluble senile plaques formed by amyloidosis of Amyloid Beta (Aβ) in neocortical region of brain. An attractive therapeutic approach to treat AD is to identify small ligands that are capable of binding to critical residues in order to inhibit or reverse Aβ amyloidosis process as source of neurotoxicity. In this area, therapeutic efforts designed various organic agents and most of them focused on the N-terminal sequence of Aβ. The aim of... 

    Identification and Characterization Natural Products from Borage Leaves Extract Acting as Anti-amyloid Inhibitors

    , M.Sc. Thesis Sharif University of Technology Ashrafian, Hossein (Author) ; Kalhor, Hamid Reza (Supervisor) ; Sajadi, Ali Akbar (Co-Advisor)
    Natural products obtained from plant extract are well known as a valuable source for research and assessments which eventuates to the discovery of some compounds possessing biological and pharmacological properties. Our aims have been to investigate and identify some natural products having the ability to effect on protein misfolding. In neurodegenerative disorders, like Alzheimer’s and Parkinson’s, a protein or a peptide undergoes conformational changes, and consequently the protein transform to fibrils coined amyloid. To determine the effective anti-amyloid compounds in natural products, Borage leaves was chosen. The plant extract was extracted using soxhlet and applied to hen white egg... 

    Designing a new multifunctional peptide for metal chelation and Aβ inhibition

    , Article Archives of Biochemistry and Biophysics ; Volume 653 , 2018 , Pages 1-9 ; 00039861 (ISSN) Shamloo, A ; Asadbegi, M ; Khandan, V ; Amanzadi, A ; Sharif University of Technology
    Academic Press Inc  2018
    According to the Amyloid hypothesis, as the foremost scientific explanation for Alzheimer Disease (AD), the neuropathology of AD is related to toxic fragments of amyloid beta (Aβ) protein. Based on this hypothesis, an attractive therapeutic approach was demonstrated to identify multifunctional peptides able to modulate Aβ pathologies as the source of AD. On this premise, a bifunctional polypeptide based on the iAβ5p lead compound, was designed to inhibit Aβ aggregation and free metal ions. Herein, the efficacy of this novel drug in Zn2+ and Cd2+ ion chelation was examined through an integrated technique comprising combined Docking, QM, and MD simulations. MD relaxation of a set of probable... 

    Mechanism Investigation of Metallic Nanoparticles Interaction with Biological Molecules using Molecular Dynamic Simulation

    , M.Sc. Thesis Sharif University of Technology Soltani, Nima (Author) ; Gholami, Mohammad Reza (Supervisor)
    Amyloid β (Aβ) peptide is believed to be associated with the progression of Alzheimer's disease. One of the main obstacles in developments of therapeutic agents to combat progression of Alzheimer's disease, is the presence of the blood–brain barrier (BBB), which prevents the penetration of the majority of drugs. However, nanoscale objects are able to cross the BBB at low concentrations. Therefore, it is worthwhile to study the interactions of these peptides at the interface of nanomaterials. In this work we have employed molecular dynamics, and weighted histogram analysis methods in order to study the dynamic behavior and affinity of Aβ25-35 peptide on metallic surfaces of different... 

    Controlling Amyloid Formation Using Novel Carbon Based Nanoparticles

    , M.Sc. Thesis Sharif University of Technology Yahyazadeh, Amin (Author) ; Kalhor, Hamid Reza (Supervisor)
    Proteins carry out most important roles in the organisms and they have a number of functions including structural, catalytically, regulatory and transportal, However for protein to have functional role they must be able to possess tridimensional structure. Several proteins due to various genetic and physico-chemical conditions have shown to alter their tridimensional structure leading to insoluble fibrilar structure. One of the properties of these insoluble fibrils is conformational change, converting to β-sheet rich structures; the entire process of converting soluble to proteins insoluble fibrils known as amyloid formation. The proteins amyloidosis have been seen as causative role in a... 

    Synthesis of Selected Pyridazine-based Organic Compounds and Investigation of Their Inhibitory Effects Against Amyloid Formation

    , M.Sc. Thesis Sharif University of Technology Ghasemi, Elham (Author) ; Kalhor, Hamid Reza (Supervisor)
    At the molecular level, proteins control almost all the biochemical reactions in the cells. In order for proteins to function, they must be able to fold into their unique 3D structure. Deformation of protein structure due to some environmental phenomena such as pH, high temperature, and stress may cause unfolding of proteins and finally result in formation of protein fibrils called "amyloid". Amyloid has been found in a number of human diseases such as Alzheimer, type II diabetes, and Parkinson. Recently pyridazine has been under spotlight due to its unique chemical properties such as high dipole moment and higher solubility in biological solvents. In this study, we aim at using a... 

    Review on alzheimer's disease: inhibition of amyloid beta and tau tangle formation

    , Article International Journal of Biological Macromolecules ; Volume 167 , 2021 , Pages 382-394 ; 01418130 (ISSN) Ashrafian, H ; Hadi Zadeh, E ; Hasan Khan, R ; Sharif University of Technology
    Elsevier B.V  2021
    It is reported that approximately 40 million people are suffering from dementia, globally. Dementia is a group of symptoms that affect neurons and cause some mental disorders, such as losing memory. Alzheimer's disease (AD) which is known as the most common cause of dementia, is one of the top medical care concerns across the world. Although the exact sources of the disease are not understood, is it believed that aggregation of amyloid-beta (Aβ) outside of neuron cells and tau aggregation or neurofibrillary tangles (NFTs) formation inside the cell may play crucial roles. In this paper, we are going to review studies that targeted inhibition of amyloid plaque and tau protein tangle formation,... 

    Design of peptide-based inhibitor agent against amyloid-β aggregation: Molecular docking, synthesis and in vitro evaluation

    , Article Bioorganic Chemistry ; Volume 102 , September , 2020 Jokar, S ; Erfani, M ; Bavi, O ; Khazaei, S ; Sharifzadeh, M ; Hajiramezanali, M ; Beiki, D ; Shamloo, A ; Sharif University of Technology
    Academic Press Inc  2020
    Formation of the amyloid beta (Aβ) peptide aggregations represents an indispensable role in appearing and progression of Alzheimer disease. β-sheet breaker peptides can be designed and modified with different amino acids in order to improve biological properties and binding affinity to the amyloid beta peptide. In the present study, three peptide sequences were designed based on the hopeful results of LIAIMA peptide and molecular docking studies were carried out onto the monomer and fibril structure of amyloid beta peptide using AutoDock Vina software. According to the obtained interactions and binding energy from docking, the best-designed peptide (D-GABA-FPLIAIMA) was chosen and... 

    Production and Purification of Recombinant Amylin Peptide and Investigating the Effects of Synthetic and Natural Products on Amyloid Fibril Formation

    , M.Sc. Thesis Sharif University of Technology Sherizadeh, Saied (Author) ; KAalhor, Hamid Reza (Supervisor) ; Matloubi Moghaddam, Firouz (Co-Advisor)
    What determines the function of a protein, after its synthesis by the ribosome, is its unique three dimensional structure. The unique structure of protein is achieved through process of folding which is detrimental to protein function. Although this unique structure is stable in a variety of situations, the protein may undergo conformational change, due to slight changes in physiological conditions, affecting the protein structure and function. In certain conditions, the conformational change brings about misfolding of the protein leading to protein aggregation. The protein aggregation can also result in amyloid formation in which a soluble protein is converted to fibrils with specific... 

    Hippocmapal Protein Kinase Mζ Overexpression Effect on Cognitive Performance in a Rat Model of Alzheimer’s Disease

    , M.Sc. Thesis Sharif University of Technology Amini, Niloufar (Author) ; Roosta Azad, Reza (Supervisor) ; Gholamipour Badie, Hamid (Supervisor)
    Alzheimer’s disease (AD) is a neurodegenerative disease which results in synaptic depression and complete destruction in neurons in the final stages. Many pathogenesis has so far been attributed to AD but the most commonly explained pathomechanism is based on the amyloid cascade theory which results in formation of amyloid beta plaques outside and hyper phosphorylated neurofibrillary tangles of tau protein inside the neurons. One of the most well-known symptoms of AD is the disability to learn and form new memories and transform them into long term memory. The most commonly studied mechanism in memory formation, is the “long term potentiation”. Although many mechanisms and molecules are... 

    Simulation of Proteins at Constant pH

    , M.Sc. Thesis Sharif University of Technology Rahmani, Parisa (Author) ; Ejtehadi, Mohammad Reza (Supervisor)
    Proteins are of fundamental importance for life on Earth and participate in virtually every process within cells. The function of a protein depends on its three dimensional structure. If this is disrupted, the protein loses its biological activity. In addition to temperature, pressure and ionic strength, pH is also an important factor that affects the configuration of proteins. Proteins contain acidic and basic residues. Variations in pH lead to changes in distribution of atomic charge, which in turn affect the stability and function of proteins. Protein folding occurs in a specific pH range, a deviation from which may facilitate misfolding or Amyloid aggregation. It is therefore necessary... 

    Synthesis and Structural Activity Relationship (SAR) of Novel Pyridazine-based Inhibitors for Inhibition of Amyloid Fibril Formation, and Biosynthesis and Optimization of L-AsparaginaseII Enzyme for Hydrolysis of Non-Native Substrate

    , M.Sc. Thesis Sharif University of Technology Nazari Khodadadi, Alireza (Author) ; Kalhor, Hamid Reza (Supervisor)
    After proteins, one of the important biological macromolecules, are synthesized by ribosomes,they automatically reach their own special 3-D structure. This native structur or better known as folded state is what determines the function of a protein. In some situations, the proteins become misfolded leading to its lack of biological function through aggregation or fibril formation known as "amyloid". The amyloid fibrils have been shown to be a causative factor in nerve decay such as Alzheimer's. Therefore, inhibition of amyloid formation using different approaches such as synthetic organic and natural compounds has, recently, been under spotlight. A pyridazine basedcompound (RS-0406) has... 

    Design and Construction of Novel Intein Mediated Biosensor in Order to Detect Amyloid Fibrils

    , M.Sc. Thesis Sharif University of Technology Miri, Mohammad (Author) ; Kalhor, Hamid Reza (Supervisor)
    The most important factor in protein's function and its 3D structure is folding. Misfolding or native folding perturbation in some peptides and proteins force them get into amyloid fibril aggregation. It has been observed that these aggregations are the cause of some debilitative diseases especially ones that are related to aging like Alzheimer disease, Hantington's disease, typeII diabets etc. Recently it has been shown that specific regions in human catalase protein interact with some amyloid fibrils, such as Aß, IAPP, PrP etc. Inteins are self-splicing protein enzymes, which excise themselves from the mature protein and join the two flanking adjacent sequences by a new peptide bond in a... 

    Inhibition mechanisms of a pyridazine-based amyloid inhibitor: as a β-sheet destabilizer and a helix bridge maker

    , Article Journal of Physical Chemistry B ; Volume 121, Issue 32 , 2017 , Pages 7633-7645 ; 15206106 (ISSN) Kalhor, H. R ; Jabbari, M. P ; Sharif University of Technology
    Conformational diseases have been investigated extensively in recent years; as a result, a number of drug candidates have been introduced as amyloid inhibitors; however, no effective therapies have been put forward. RS-0406 with pyridazine as its core chemical structure has so far shown promising results in inhibiting amyloid formation. In the present work, using molecular dynamics, we undertook the investigation of RS-0406 interactions with U-shaped Aβ1−42 and Aβ1−40 pentamers, Aβ1−42 monomers, and double-horseshoe-like Aβ1−42. To set better parameters for the small molecule, experimental and computational log P values were obtained. In addition, an analogue of RS-0406 was also simulated...