Publications by authors named "Ebrahim Barzegari"

14 Publications

  • Page 1 of 1

Terminal Peptide Extensions Augment the Retinal IMPDH1 Catalytic Activity and Attenuate the ATP-induced Fibrillation Events.

Cell Biochem Biophys 2021 Jun 17;79(2):221-229. Epub 2021 Mar 17.

Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.

Defects in inosine monophosphate dehydrogenase-1 (IMPDH1) lead to insufficient biosyntheses of purine nucleotides. In eyes, these defects are believed to cause retinitis pigmentosa (RP). Major retinal isoforms of IMPDH1 are structurally distinct from those in other tissues, by bearing terminal extensions. Using recombinant mouse IMPDH1 (mH1), we evaluated the kinetics and oligomerization states of the retinal isoforms. Moreover, we adopted molecular simulation tools to study the possible effect of terminal tails on the function of major enzyme isoforms with the aim to find structural evidence in favor of contradictory observations on retinal IMPDH1 function. Our findings indicated higher catalytic activity for the major mouse retinal isoform (mH1603) along with lower fibrillation capacity under the influence of ATP. However, higher mass oligomerization products were formed by the mH1 (603) isoform in the presence of the enzyme inhibitors such as GTP and/or MPA. Collectively, our findings demonstrate that the structural differences between the retinal isoforms have led to functional variations possibly to justify the retinal cells' requirements.
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http://dx.doi.org/10.1007/s12013-021-00973-2DOI Listing
June 2021

Individuals' Intention to Engage in Outpatient Cardiac Rehabilitation Programs: Prediction Based on an Enhanced Model.

J Clin Psychol Med Settings 2021 Mar 15. Epub 2021 Mar 15.

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, P.O. Box: 67155-1616, Zakariya Razi Blvd., Kermanshah, Iran.

Motivation is an important factor in encouraging individuals to attend rehabilitation and underpins many approaches to engagement. The aims of this study were to develop an accurate model able to predict individual intention to engage in outpatient cardiac rehabilitation (CR) programs based on the first stage of the Model of Therapeutic Engagement integrated into a socio-environmental context. The cross-sectional study in the cardiology ward of an Australian hospital included a total of 217 individuals referred to outpatient CR. Through an ordinal logistic regression, the effect of random forest (RF)-selected profile features on individual intention to engage in outpatient CR was explored. The RF based on the conditional inference trees predicted the intention to engage in outpatient CR with high accuracy. The findings highlighted the significant roles of individuals' 'willingness to consider the treatment', 'perceived self-efficacy' and 'perceived need for rehabilitation' in their intention, while the involvement of 'barriers to engagement' and 'demographic and medical factors' was not evident.
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http://dx.doi.org/10.1007/s10880-021-09771-7DOI Listing
March 2021

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

Bioorg Chem 2021 Apr 8;109:104703. Epub 2021 Feb 8.

Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.
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http://dx.doi.org/10.1016/j.bioorg.2021.104703DOI Listing
April 2021

Structure-Based Screening to Discover New Inhibitors for Papain-like Proteinase of SARS-CoV-2: An Study.

J Proteome Res 2021 01 22;20(1):1015-1026. Epub 2020 Dec 22.

Department of Environmental Health, Mazandaran University of Medical Sciences, Mazandaran 4815733971, Iran.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expresses a multifunctional papain-like proteinase (PLpro), which mediates the processing of the viral replicase polyprotein. Inhibition of PLpro has been shown to suppress the viral replication. This study aimed to explore new anti-PLpro candidates by applying virtual screening based on GRL0617, a known PLpro inhibitor of SARS coronavirus (SARS-CoV). The three-dimensional (3D) structure of SARS-CoV-2 PLpro was built by homology modeling, using SARS-CoV PLpro as the template. The model was refined and studied through molecular dynamic simulation. AutoDock Vina was then used to perform virtual screening where 50 chemicals with at least 65% similarity to GRL0617 were docked with the optimized SARS-CoV-2 PLpro. In this screening, 5-(aminomethyl)-2-methyl--[(1)-1-naphthalen-1-ylethyl]benzamide outperformed GRL0617 in terms of binding affinity (-9.7 kcal/mol). Furthermore, 2-(4-fluorobenzyl)-5-nitro-1-isoindole-1,3(2)-dione (previously introduced as an inhibitor of cyclooxygenase-2), 3-nitro--[(1r)-1-phenylethyl]-5-(trifluoromethyl)benzamide (inhibitor against ), as well as the recently introduced SARS-CoV-2 PLpro inhibitor 5-acetamido-2-methyl--[(1)-1-naphthalen-1-ylethyl]benzamide showed promising affinity for the viral proteinase. All of the identified compounds demonstrated an acceptable pharmacokinetic profile. In conclusion, our findings represent rediscovery of analgesic, anti-inflammatory, antibacterial, or antiviral drugs as promising pharmaceutical candidates against the ongoing coronavirus.
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http://dx.doi.org/10.1021/acs.jproteome.0c00836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770893PMC
January 2021

Immunoinformatic design of a COVID-19 subunit vaccine using entire structural immunogenic epitopes of SARS-CoV-2.

Sci Rep 2020 11 30;10(1):20864. Epub 2020 Nov 30.

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Zakariya Razi Blvd., Kermanshah, Iran.

Coronavirus disease 2019 (COVID-19) is an acute pneumonic disease, with no prophylactic or specific therapeutical solution. Effective and rapid countermeasure against the spread of the disease's associated virus, SARS-CoV-2, requires to incorporate the computational approach. In this study, we employed various immunoinformatics tools to design a multi-epitope vaccine polypeptide with the highest potential for activating the human immune system against SARS-CoV-2. The initial epitope set was extracted from the whole set of viral structural proteins. Potential non-toxic and non-allergenic T-cell and B-cell binding and cytokine inducing epitopes were then identified through a priori prediction. Selected epitopes were bound to each other with appropriate linkers, followed by appending a suitable adjuvant to increase the immunogenicity of the vaccine polypeptide. Molecular modelling of the 3D structure of the vaccine construct, docking, molecular dynamics simulations and free energy calculations confirmed that the vaccine peptide had high affinity for Toll-like receptor 3 binding, and that the vaccine-receptor complex was highly stable. As our vaccine polypeptide design captures the advantages of structural epitopes and simultaneously integrates precautions to avoid relevant side effects, it is suggested to be promising for elicitation of an effective and safe immune response against SARS-CoV-2 in vivo.
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http://dx.doi.org/10.1038/s41598-020-77547-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704662PMC
November 2020

Heterologous expression, purification, and refolding of SRY protein: role of L-arginine as analyzed by simulation and practical study.

Mol Biol Rep 2020 Aug 22;47(8):5943-5951. Epub 2020 Jul 22.

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Escherichia coli is a widely-used cell factory for recombinant protein production, nevertheless, high amount of produced protein is seen in aggregated form. The purpose of this study was to improve the solubility of recombinant bovine sex-determining region Y protein (rbSRY) by exploring the effect of temperature, inducer, and water-arginine mixed solvent. Codon-optimized rbSRY expressed in Rosetta-gami B (DE3) pLysS and purified by NI-NTA His-select affinity chromatography in the native and denaturing conditions. A three-dimensional model of SRY was built and studied through molecular dynamics simulations in water and in the presence of L-arginine as co-solvent. Results indicated the significant effects of temperature and IPTG concentration (P < 0.001) on the solubility of rbSRY. The binding activity of native, inclusion bodies and refolded fractions to anti-rbSRY monoclonal antibody were concentration-dependent (P < 0.001). Based on molecular modeling results, the propensity of fragments in the N-terminal domain to form β-sheet and the relative instability of α-helices in terminal domains are the probable reasons for the high aggregation potential of SRY, which are mitigated in the presence of L-arginine. Altogether, our rbSRY protein was properly produced and applying appropriate culture conditions could help enhance its solubility, refold inclusion bodies, and improve its activity upon refolding.
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http://dx.doi.org/10.1007/s11033-020-05667-1DOI Listing
August 2020

Interactions of insulin with tragacanthic acid biopolymer: Experimental and computational study.

Int J Biol Macromol 2020 Dec 16;164:321-330. Epub 2020 Jul 16.

Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran; Medical Biology Research Center, Health Technologies Institute, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran. Electronic address:

Alternative methods for insulin delivery instead of subcutaneous injection in diabetic patients is of great essential, and biocompatible polymers are one of the most efficient vehicles for this purpose. This research aims to investigate the capability of tragacanthic acid (TA) to bind insulin and release it under physiological conditions without alteration in the structure and conformation of insulin. Interactions between TA and insulin were studied using spectroscopic techniques and computational modeling by docking and molecular dynamics simulations. Our results demonstrate an entropy-driven spontaneous interaction between insulin and TA, where hydrogen bonds act as the main enthalpic contribution. According to our findings, the weak interaction between insulin and TA provides the basis for efficient capture and appropriate release of insulin by TA as a potential part of the insulin delivery system. In conclusion, tragacanth acid can be a proper candidate for insulin delivery.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.07.122DOI Listing
December 2020

Biomedical Applications of Zeolitic Nanoparticles, with an Emphasis on Medical Interventions.

Int J Nanomedicine 2020 21;15:363-386. Epub 2020 Jan 21.

Marquette University School of Dentistry, Milwaukee, WI 53201, USA.

The advent of porous materials, in particular zeolitic nanoparticles, has opened up unprecedented putative research avenues in nanomedicine. Zeolites with intracrystal mesopores are low framework density aluminosilicates possessing a regular porous structure along with intricate channels. Their unique physiochemical as well as physiological parameters necessitate a comprehensive overview on their classifications, fabrication platforms, cellular/macromolecular interactions, and eventually their prospective biomedical applications through illustrating the challenges and opportunities in different integrative medical and pharmaceutical fields. More particularly, an update on recent advances in zeolite-accommodated drug delivery and the prevalent challenges regarding these molecular sieves is to be presented. In conclusion, strategies to accelerate the translation of these porous materials from bench to bedside along with common overlooked physiological and pharmacological factors of zeolite nanoparticles are discussed and debated. Furthermore, for zeolite nanoparticles, it is a matter of crucial importance, in terms of biosafety and nanotoxicology, to appreciate the zeolite-bio interface once the zeolite nanoparticles are exposed to the bio-macromolecules in biological media. We specifically shed light on interactions of zeolite nanoparticles with fibrinogen and amyloid beta which had been comprehensively investigated in our recent reports. Given the significance of zeolite nanoparticles' interactions with serum or interstitial proteins conferring them new biological identity, the preliminary approaches for deeper understanding of administration, distribution, metabolism and excretion of zeolite nanoparticles are elucidated.
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http://dx.doi.org/10.2147/IJN.S234573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983480PMC
April 2020

The functional impact of the C/N-terminal extensions of the mouse retinal IMPDH1 isoforms: a kinetic evaluation.

Mol Cell Biochem 2020 Feb 14;465(1-2):155-164. Epub 2019 Dec 14.

Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.

Mutations in the retinal inosine monophosphate dehydrogenase1 (IMPDH1) gene is believed to be one cause of retinitis pigmentosa (RP). The main structural difference between the mutation-susceptible retinal isoforms with canonical one resides in the C- and N-terminal extensions. There are limited studies on the structure and function of terminal peptide extensions of the IMPDH1 retinal isoforms. Using recombinant murine IMPDH1 (mH1), we evaluated the kinetics of the retinal isoforms along with inhibition by some of the purine nucleotides. Molecular modeling tools were also applied to study the probable effect(s) of the terminal peptide tails on the function of the retinal isoforms. Molecular dynamic simulations indicated the possible impact of the end-terminal segments on the enzyme function through interactions with the enzyme's finger domain, affecting its critical pseudo barrel structure. The higher experimentally-determined K and K values of the retinal mIMPDH1 (546) and mIMPDH1 (603) relative to that of the canonical isoform, mIMPDH1 (514), might clearly be due to these interactions. Furthermore and despite of the canonical isoform, the retinal isoforms of mH1 exhibited no NAD substrate inhibition. The resent data would certainly provide the ground for future evaluation of the physiological significance of these variations.
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http://dx.doi.org/10.1007/s11010-019-03675-9DOI Listing
February 2020

Insights into resistance mechanism of hepatitis C virus nonstructural 3/4A protease mutant to boceprevir using umbrella sampling simulation study.

J Biomol Struct Dyn 2020 Apr 31;38(7):1938-1945. Epub 2019 May 31.

Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Hepatitis C virus can cause inflammation in human liver cells, leading to liver cirrhosis and liver cancer. Based on the World Health Organization reports, about 228 million people in the world have hepatitis C. To date, some inhibitory medicines against the hepatitis C virus nonstructural 3/4A protease, such as boceprevir, have entered clinical trial phases. However, several hepatitis C virus nonstructural 3/4A protease mutations have been recognized to decrease susceptibility of boceprevir to hepatitis C virus. The molecular details behind inhibitor resistance of these single-point mutations are not still understood. Thus, in this research, computational strategies were applied to clarify the inhibitor resistance mechanism. From umbrella sampling simulation and energy profiles, the polar interactions are the main driving force for boceprevir binding. Based on the analyzed R155T mutant, the main reason for the occurrence of boceprevir resistance is the conformation alterations of S4 and extended S2 binding pockets. These changes, lead to decreased binding ability of the key residues to P2 and P4 moieties of boceprevir. Moreover, structural results show that the disappearance of important salt bridges can bring about the great conformation changes of the binding pockets in R155T.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1621212DOI Listing
April 2020

Molecular interaction of fibrinogen with zeolite nanoparticles.

Sci Rep 2019 02 7;9(1):1558. Epub 2019 Feb 7.

Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States.

Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ), located in D-domain, showed the highest level of exposure compared to other sequences/residues.
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http://dx.doi.org/10.1038/s41598-018-37621-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367512PMC
February 2019

Biomolecular Corona Dictates Aβ Fibrillation Process.

ACS Chem Neurosci 2018 07 30;9(7):1725-1734. Epub 2018 Apr 30.

Pharmacutical Sciences Research Center , Kermanshah University of Medical Sciences , Kermanshah 67145-67346 , Iran.

Amyloid beta (Aβ), which forms toxic oligomers and fibrils in brain tissues of patients with Alzheimer's disease, is broadly used as a model protein to probe the effect of nanoparticles (NPs) on oligomerization and fibrillation processes. However, the majority of the reports in the field have ignored the effect of the biomolecular corona on the fibrillogenesis of the Aβ proteins. The biomolecular corona, which is a layer composed of various types of biomolecules that covers the surface of NPs upon their interaction with biological fluids, determines the biological fates of NPs. Therefore, during in vivo interaction of NPs with Aβ protein, what the Aβ actually "sees" is the human plasma and/or cerebrospinal fluid (CSF) biomolecular-coated NPs rather than the pristine surface of NPs. Here, to mimic the in vivo effects of therapeutic NPs as antifibrillation agents, we probed the effects of a biomolecular corona derived from human CSF and/or plasma on Aβ fibrillation. The results demonstrated that the type of biomolecular corona can dictate the inhibitory or acceleratory effect of NPs on Aβ and Aβ fibrillation processes. More specifically, we found that the plasma biomolecular-corona-coated gold NPs, with sphere and rod shapes, has less inhibitory effect on Aβ fibrillation kinetics compared with CSF biomolecular-corona-coated and pristine NPs. Opposite results were obtained for Aβ peptide, where the pristine NPs accelerated the Aβ fibrillation process, whereas corona-coated ones demonstrated an inhibitory effect. In addition, the CSF biomolecular corona had less inhibitory effect than those obtained from plasma.
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http://dx.doi.org/10.1021/acschemneuro.8b00076DOI Listing
July 2018

Colon Cancer and Specific Ways to Deliver Drugs to the Large Intestine.

Anticancer Agents Med Chem 2017 ;17(10):1317-1327

Institute of Biochemistry and Biophysics, University of Tehran, Tehran. Iran.

Background: It has been postulated that colon cancer is the third cause of cancer death worldwide. Recently, colon-targeted drug delivery systems have been developed for improving systemic drug delivery and treatment of local colon associated diseases. Using such drug delivery systems increases the drug's effectiveness and results in reduced systemic side effects. Drug delivery systems formulated for the colon requires that the triggering of drug release mechanism is designed based on the colon's physiological conditions. However, improving the site specificity and drug release kinetics of colon-targeted drug delivery systems is desired and is currently under active research.

Objective: This review discusses colon cancer along with various colon-targeted drug delivery systems such as pro-drug formation, pH-sensitive polymers, hydrogels, time-dependent release systems, bio-adhesive and nanoparticle systems. The aim is to understand the effect of using colon-targeted drug delivery systems on therapeutic effectiveness of the drug by improving its degradation and bioavailability. Colon targeting holds a great promise as a therapeutic approach but it still requires more innovation.

Conclusion: The distribution of the drugs in the colon suffers from problems related to the pH, retention time, micro-flora, and degrading enzymes of gastrointestinal tract. Moreover, these drug delivery systems are capable of overcoming some of the limitations in common targeting approaches. A precise assessment of such systems needs the use of various assaying protocols in order to characterize their traits and clarify their design rationales.
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http://dx.doi.org/10.2174/1871520617666170213142030DOI Listing
October 2017

Zeolite Nanoparticles Inhibit Aβ-Fibrinogen Interaction and Formation of a Consequent Abnormal Structural Clot.

ACS Appl Mater Interfaces 2016 Nov 1;8(45):30768-30779. Epub 2016 Nov 1.

Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.

EMT-type zeolite nanoparticles (EMT NPs) with particle size of 10-20 nm and external surface area of 200 m/g have shown high selective affinity toward plasma protein (fibrinogen). Besides, the EMT NPs have demonstrated no adverse effect on blood coagulation hemostasis. Therefore, it was envisioned that the EMT NPs could inhibit possible β-amyloid (Aβ)-fibrinogen interactions that result in the formation of structurally abnormal clots, which are resistant to lysis, in cerebral vessels of patients with Alzheimer disease (AD). To evaluate this hypothesis, the clot formation and degradation of Aβ-fibrinogen in the presence and absence of the EMT zeolite NPs were assessed. The results clearly showed that the delay in clot dissolution was significantly reduced in the presence of zeolite NPs. By formation of protein corona, the EMT NPs showed a negligible reduction in their inhibitory strength. Docking of small molecules (Aβ-fibrinogen) introduced a novel potential inhibitory candidate. The zeolite NPs showed similar inhibitory effects on binding of fibrinogen to both Aβ(25-35) and/or Aβ(1-42). This indicates that the inhibitory strength of these NPs is independent of Aβ sequence, and it is suggested that the zeolite NPs adsorb fibrinogen and specifically obstruct their Aβ binding sites. Therefore, the zeolite NPs can be the safe and effective inhibitors in preventing Aβ-fibrinogen interaction and consequent cognitive damage.
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http://dx.doi.org/10.1021/acsami.6b10941DOI Listing
November 2016