Publications by authors named "Younes Ghasemi"

170 Publications

In Silico Design and Evaluation of PRAME+FliCΔD2D3 as a New Breast Cancer Vaccine Candidate.

Iran J Med Sci 2021 Jan;46(1):52-60

Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: The most prevalent cancer in women over the world is breast cancer. Immunotherapy is a promising method to effectively treat cancer patients. Among various immunotherapy methods, tumor antigens stimulate the immune system to eradicate cancer cells. Preferentially expressed antigen in melanoma (PRAME) is mainly overexpressed in breast cancer cells, and has no expression in normal tissues. FliCΔD2D3, as truncated flagellin (FliC), is an effective toll-like receptor 5 (TLR5) agonist with lower inflammatory responses. The objective of the present study was to utilize bioinformatics methods to design a chimeric protein against breast cancer.

Methods: The physicochemical properties, solubility, and secondary structures of PRAME+FliCΔD2D3 were predicted using the tools ProtParam, Protein-sol, and GOR IV, respectively. The 3D structure of the chimeric protein was built using I-TASSER and refined with GalaxyRefine, RAMPAGE, and PROCHECK. ANTIGENpro and VaxiJen were used to evaluate protein antigenicity, and allergenicity was checked using AlgPred and Allergen FP. Major histocompatibility complex )MHC( and cytotoxic T-lymphocytes )CTL( binding peptides were predicted using HLApred and CTLpred. Finally, B-cell continuous and discontinuous epitopes were predicted using ABCpred and ElliPro, respectively.

Results: The stability and solubility of PRAME+FliCΔD2D3 were analyzed, and its secondary and tertiary structures were predicted. The results showed that the derived peptides could bind to MHCs and CTLs. The designed chimeric protein possessed both linear and conformational epitopes with a high binding affinity to B-cell epitopes.

Conclusion: PRAME+FliCΔD2D3 is a stable and soluble chimeric protein that can stimulate humoral and cellular immunity. The obtained results can be utilized for the development of an experimental vaccine against breast cancer.
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http://dx.doi.org/10.30476/ijms.2019.82301.1029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812496PMC
January 2021

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants.

Sci Rep 2021 Jan 11;11(1):336. Epub 2021 Jan 11.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Aging is correlated with several complex diseases, including type 2 diabetes, neurodegeneration diseases, and cancer. Identifying the nature of this correlation and treatment of age-related diseases has been a major subject of both modern and traditional medicine. Traditional Persian Medicine (TPM) embodies many prescriptions for the treatment of ARDs. Given that autophagy plays a critical role in antiaging processes, the present study aimed to examine whether the documented effect of plants used in TPM might be relevant to the induction of autophagy? To this end, the TPM-based medicinal herbs used in the treatment of the ARDs were identified from modern and traditional references. The known phytochemicals of these plants were then examined against literature for evidence of having autophagy inducing effects. As a result, several plants were identified to have multiple active ingredients, which indeed regulate the autophagy or its upstream pathways. In addition, gene set enrichment analysis of the identified targets confirmed the collective contribution of the identified targets in autophagy regulating processes. Also, the protein-protein interaction (PPI) network of the targets was reconstructed. Network centrality analysis of the PPI network identified mTOR as the key network hub. Given the well-documented role of mTOR in inhibiting autophagy, our results hence support the hypothesis that the antiaging mechanism of TPM-based medicines might involve autophagy induction. Chemoinformatics study of the phytochemicals using docking and molecular dynamics simulation identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR. Our results hence, provide a basis for the study of TPM-based prescriptions using modern tools in the quest for developing synergistic therapies for ARDs.
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http://dx.doi.org/10.1038/s41598-020-79472-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801619PMC
January 2021

Production and immunological evaluation of epitope-based preventative pneumococcal candidate vaccine comprising immunodominant epitopes from PspA, CbpA, PhtD and PiuA antigens.

Curr Pharm Biotechnol 2020 Dec 30. Epub 2020 Dec 30.

Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz. Iran.

Background: Streptococcus pneumoniae is a leading cause of pneumonia, mostly in children less than five years and elderly people. Although the pneumoniae polysaccharide vaccine (PPV) and pneumonia conjugate vaccines (PCV) are the efficient pneumococcal vaccine in adult and children groups, but the serotype replacement of S. pneumoniae strains causes the reduction in the efficacy of PPV and PCV vaccines. Epitope-based vaccines are a promising alternative to the present capsular antigen vaccines.

Methods: In this study, we evaluated cellular and humoral immune responses induced by our novel designed multi-epitope vaccine in BALB/c mice. CD8+ cytolytic T lymphocytes (CTLs) epitopes were selected from PspA and CbpA antigens, and CD4+ helper T lymphocytes (HTLs) epitopes were chosen from PhtD and PiuA antigens. PorB, the TLR2 agonist, as an adjuvant, was employed to increase the immunogenicity of the vaccine.

Results And Conclusion: The high levels of specific anti-peptide vaccine IgG and an increase in the level of IgG2 in the vaccinated group demonstrated our vaccine could elicit a robust antibody production. The significant increase in IFN-γ, IL-2, TNF-α, IL-4, IL-6, and decrease in IL-10 showed that, the designed vaccine could be proposed as the efficient preventative pneumococcal vaccine in the mouse model.
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http://dx.doi.org/10.2174/1389201022666201231112029DOI Listing
December 2020

Metformin-Loaded PCL/PVA Fibrous Scaffold Preseeded with Human Endometrial Stem Cells for Effective Guided Bone Regeneration Membranes.

ACS Biomater Sci Eng 2021 01 21;7(1):222-231. Epub 2020 Dec 21.

Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 5546914177, Iran.

Many studies have been devoted to investigating the potential of guided bone regeneration (GBR) membranes for bone defect reconstruction. Regardless of approaches for treating damaged bone tissues, a beneficial therapeutic strategy has remained a challenge. In this study, a novel GBR membrane with polycaprolactone (PCL) and poly(vinyl alcohol) (PVA) containing different concentrations of metformin (Met) for improving osteogenic properties was developed. The membranes were evaluated for their hydrophilicity, degradation rate, swelling ratio, drug release, mechanical properties, and biological responses. The results showed a significant increase in hydrophilicity, swelling ratio, and degradation rate and no significant changes in mechanical properties of PCL/PVA membranes with Met concentration enhancement. A decrease in cell viability cultured on the surface of the PCL/PVA membrane was seen when the amount of Met was changed from 10 to 15 wt %. The results of the quantitative real-time polymerase chain reaction (qRT-PCR) also confirmed the higher secretion of osteogenic-related genes in a PCL/PVA/Cell/10 wt % Met scaffold than in the PCL/PVA/Cell sample. Therefore, further studies were conducted using the electrospun PCL/PVA membrane containing human endometrial stem cells (hEnSCs) and 10% Met. Histopathological and histomorphometric results confirmed that PCL/PVA/hEnSCs/10 wt % Met has excellent potential to differentiate hEnSCs into osteogenic lineages and bone regeneration in calvarial defects of rats. The results of this study confirm the high potential of the PCL/PVA/10 wt % Met fibrous membrane preseeded with hEnSCs in GBR applications.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00958DOI Listing
January 2021

Mutational Analysis of Ocriplasmin to Reduce Proteolytic and Autolytic Activity in Pichia pastoris.

Biol Proced Online 2020 Dec 13;22(1):25. Epub 2020 Dec 13.

Medical Biotechnology Department, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Ocriplasmin (Jetrea) is using for the treatment of symptomatic vitreomacular adhesion. This enzyme undergoes rapid inactivation and limited activity duration as a result of its autolytic nature after injection within the eye. Moreover, the proteolytic activity can cause photoreceptor damage, which may result in visual impairment in more serious cases.

Results: The present research aimed to reduce the disadvantages of ocriplasmin using site-directed mutagenesis. To reduce the autolytic activity of ocriplasmin in the first variant, lysine 156 changed to glutamic acid and, in the second variant for the proteolytic activity reduction, alanine 59 mutated to threonine. The third variant contained both mutations. Expression of wild type and three mutant variants of ocriplasmin constructs were done in the Pichia pastoris expression system. The mutant variants were analyzed in silico and in vitro and compared to the wild type. The kinetic parameters of ocriplasmin variants showed both variants with K156E substitution were more resistant to autolytic degradation than wild-type. These variants also exhibited reduced K and V values. An increase in their Km values, leading to a decreased catalytic efficiency (the K/K ratio) of autolytic and mixed variants. Moreover, in the variant with A59T mutation, K and V values have reduced compared to wild type. The mix variants showed the most increase in Km value (almost 2-fold) as well as reduced enzymatic affinity to the substrate. Thus, the results indicated that combined mutations at the ocriplasmin sequence were more effective compared with single mutations.

Conclusions: The results indicated such variants represent valuable tools for the investigation of therapeutic strategies aiming at the non-surgical resolution of vitreomacular adhesion.
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http://dx.doi.org/10.1186/s12575-020-00138-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734836PMC
December 2020

Non-adaptive Evolution of Trimeric Autotransporters in .

Front Microbiol 2020 12;11:560667. Epub 2020 Nov 12.

Pharmaceutical Sciences Research Center, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

species are Gram-negative, facultative intracellular pathogens. They are the main cause of brucellosis, which has led to a global health burden. Adherence of the pathogen to the host cells is the first step in the infection process. The bacteria can adhere to various biotic and abiotic surfaces using their outer membrane proteins. Trimeric autotransporter adhesins (TAAs) are modular homotrimers of various length and domain complexity. They are a diverse, and widespread gene family constituting the type Vc secretion pathway. These adhesins have been established as virulence factors in . To date, no comprehensive and exhaustive study has been performed on the trimeric autotransporter family in the genus. In the present study, various bioinformatics tools were used to provide a novel evolutionary insight into the sequence and structure of this protein family in . To this end, a dataset of all trimeric autotransporters from the genomes was built. Analyses included but were not limited to sequence alignment, phylogenetic tree constructions, codon-based test for selection, clustering of the sequences, and structure (primary to quaternary) predictions. Batch analyzes of the dataset suggested the existence of a few structural domains within the whole population. BatA from the 2308 genome was selected as a reference to describe the features of these structural domains. Furthermore, we examined the structural basis for the observed rigidity and resiliency of the protein structure through a molecular dynamics evaluation, which led us to deduce that the random drift results in the non-adaptive evolution of the trimeric autotransporter genes in the genus. Notably, the modifications have occurred across the genus without interference of gene transmission.
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http://dx.doi.org/10.3389/fmicb.2020.560667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688925PMC
November 2020

Impacts of Magnetic Immobilization on the Recombinant Proteins Structure Produced in Pichia pastoris System.

Mol Biotechnol 2021 Jan 9;63(1):80-89. Epub 2020 Nov 9.

Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Unit 23, 2nd Floor, Almass Building, Alley 29, Ghasrodasht St., Shiraz, Iran.

Pichia pastoris expression system was introduced with post-translation process similar to higher eukaryotes. Preliminary studies were performed toward process intensification and magnetic immobilization of this system. In this experiment, effects of magnetic immobilization on the structure of recombinant protein were evaluated. P. pastoris cell which express human serum albumin (HSA) was used as a model. The cells were immobilized with various concentrations of APTES coated magnetite nanoparticles. HSA production was done over 5 days induction and structure of the product was analyzed by UV-vis, fluorescence, and ATR-FTIR spectroscopy. Second derivative deconvolution method was used to analyze the secondary structure of HSA. P. pastoris cell that were immobilized with 0.5 and 1 mg/mL of nanoparticles were produced HSA with intact structure. But immobilization with 2 mg/mL of nanoparticles resulted in some modifications in the secondary structures (i.e., α-helixes and β-turns) of produced HSA. Based on these data, immobilization of P. pastoris cells with 0.5 or 1 mg/mL of nanoparticles is completely efficient for cell harvesting and has any effect on the structure of recombinant product. These findings revealed that decoration of microbial cells with high concentrations of nanoparticles has some impacts on the structure of secretory proteins.
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http://dx.doi.org/10.1007/s12033-020-00286-4DOI Listing
January 2021

Characterization of the first highly predatory from Iran and its potential lytic activity against principal pathogenic .

Iran J Basic Med Sci 2020 Oct;23(10):1275-1285

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Objectives: -and-like organisms (BALOs) are predatory prokaryotes that attack and kill other Gram-negative bacteria for growth and reproduction. This study describes the isolation, identification, biological properties, and bacteriolytic activity of the first with a broad prey range from Iran.

Materials And Methods: One BALO strain with high predatory potency was isolated from the rhizosphere soil using Enteropathogenic as prey. It was identified and designated as strain SOIR-1 through plaque assays, transmission electron microscopy (TEM), -specific PCRs, and 16S rRNA gene sequence analysis. Biological characterization and analysis of bacteriolytic activity were also performed.

Results: TEM and -specific PCRs confirmed that the strain SOIR-1 belongs to the genus . Analysis of the 16S rRNA gene sequence revealed its close phylogenetic relationship with strains of . The strain SOIR-1 grew within the temperature range of 25-37 C and the pH range of 6.0-8.0, with the optimal predatory activity at 30 C and pH 7.4. It had the highest and lowest bacteriolytic activity toward and with a killing rate of 89.66% and 74.83%, respectively.

Conclusion: Considering the hypothesis of bdellovibrios heterogeneity, identification of new isolates contributes to a deeper understanding of their diversity, their ecological roles, and their promising potential as living antibiotics or biocontrol agents. Bdellovibrios with broad bacteriolytic nature has not previously been reported in sufficient detail from Iran. The results of this study showed the great potential of native strain SOIR-1 in the control and treatment of diseases caused by pathogenic .
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http://dx.doi.org/10.22038/ijbms.2020.43159.10146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585534PMC
October 2020

Development of graphene based nanocomposites towards medical and biological applications.

Artif Cells Nanomed Biotechnol 2020 Dec;48(1):1189-1205

Institute of Sustainable Energy, Universiti Tenaga Nasional (The National Energy University), Jalan IKRAM-UNITEN, Kajang, Malaysia.

Graphene and its derivative materials present high potential towards medical and biological applications, including drug delivery and bioimaging, due to their exceptional properties such as thermal conductivity and high specific surface area. The main focus of this work is to review the current development of graphene materials and the derivatives for biocompatible, bioimaging and drug delivery applications. Also, the synthesis methods with variation of graphene nanocomposites and the functionalisation will be further explained. For the graphene approaches, chemical vapour deposition (CVD) is the best-known technique to make high-quality graphene sheet by growth route with mass production. By considering the organic graphene nanocomposites, the biocompatibility and cytotoxic effects against graphene nanocomposites were evaluated for biomedical employments such as high quality bioimaging and effective drug delivery for cancer treatments. For example, graphene oxide incorporated with PEG and loaded with SN 38 for camptothecin analolgue as anticancer drug and revealed high cytotoxicity has an effect of 1000 times better effect than CPT in HCT-116 cells. Their drug delivery ability for both and applications compared to the controlled drugs such as doxorubicin (DOX) will be discussed accordingly. The graphene and its deriavatives possess some intriguing properties, which will lead to drug delivery due to strong biocompatibility and cyctotoxic effect towards biomedicine applications.
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http://dx.doi.org/10.1080/21691401.2020.1817052DOI Listing
December 2020

Analyzing Signal Peptides for Secretory Production of Recombinant Diagnostic Antigen B8/1 from : An Approach.

Mol Biol Res Commun 2020 Apr;9(1):1-10

Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Recombinant AgB8/1 as the most evaluated antigen for serological diagnosis of Cystic Echinococcosis (CE) can provide early and accurate diagnosis for proper management and treatment of the disease. Thus, the secretory production of this recombinant protein is the main goal and the application of signal peptides at the N terminus of the desired protein can help to achieve this goal. The present study applied few bioinformatics tools to evaluate several signal peptides to offer the best candidate for extracellular production of AgB8/1 of in . The sequences related to signal peptides were obtained from "Signal Peptide Website" and were checked by "UniProt". In addition, UniProt was employed to retrieve the sequence of AgB8/1. Then, the probable signal peptide sequences and their cleavage site locations were determined by SignalP 4.1 followed by evaluation of their physicochemical features, using ProtParam. The solubility of the target recombinant proteins was accessed by SOLpro. Finally, PRED-TAT and ProtCompB were implemented to predict protein secretion pathways and final destinations. Among the 39 candidate signal peptides, ENTC2_STAAU and ENTC1_STAAU are the best ones which are stable and soluble in connection with AgB8/1 and can secrete target protein through Sec pathway. The signal peptides recommended in this investigation are valuable for rational designing of secretory stable and soluble AgB8/1. Such information is useful for future experimental production of the mentioned antigen.
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http://dx.doi.org/10.22099/mbrc.2019.35429.1457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275822PMC
April 2020

Dual spinneret electrospun nanofibrous/gel structure of chitosan-gelatin/chitosan-hyaluronic acid as a wound dressing: In-vitro and in-vivo studies.

Int J Biol Macromol 2020 Nov 20;162:359-373. Epub 2020 Jun 20.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Structural and compositional similarity to the natural extracellular matrix (ECM) is a main characteristic of an ideal scaffold for tissue regeneration. In order to resemble the fibrous/gel structure of skin ECM, a multicomponent scaffold was fabricated using biopolymers with structural similarity to ECM and wound healing properties i.e., chitosan (CS), gelatin (Gel) and hyaluronic acid (HA). The CS-Gel and CS-HA nanofibers were simultaneously electrospun on the collector through dual-electrospinning technique. The presence of polymers, possible interactions, and formation of polyelectrolyte complex were proven by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and thermogravimetric analysis (TGA). The noncomplex component of CS-HA fibers formed a gel state when the scaffold was exposed to the aqueous media, while the CS-Gel fibers reserved their fibrous structure, resulting in formation of fibrous/gel structure. The CS-Gel/CS-HA scaffold showed significantly higher cell proliferation (109%) in the first 24 h comparing with CS (90%) and CS-Gel (96%) scaffolds. Additionally, the initial cell adhesion improved by incorporation of HA. The in-vivo wound healing results in rat elucidated more wound healing capability of the CS-Gel/CS-HA scaffold in which new tissue with most similarity to the normal skin was formed.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.06.181DOI Listing
November 2020

In Silico Elucidation of Deleterious Non-synonymous SNPs in SHANK3, the Autism Spectrum Disorder Gene.

J Mol Neurosci 2020 Oct 10;70(10):1649-1667. Epub 2020 Jun 10.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

SHANK3, a member of SH3 and multiple ankyrin repeat domains (SHANK) proteins, plays a crucial role in synaptic development and functions. Mutations in SHANK3 have been linked to a number of neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorder. In this study, the functional and structural impacts of non-synonymous single-nucleotide polymorphisms (SNPs) on SHANK3 were predicted. Various databases were used to extract 16,894 non-redundant SNPs, out of which 1179 were annotated as missense variants. Missense variants were categorized as deleterious or non-deleterious. Twenty-nine missense variants were unanimously recognized as deleterious and subjected to structural and stability analyses. Mutations, including L47P, G54W, G172D, G250C/D, and G627E, which posed drastic effects on the secondary structure of SHANK3, were modeled. Stability analyses introduced L47P, G54W, and G250D as the most destabilizing mutations, thus they were subjected to molecular dynamics simulation. Simulation revealed significant changes in intramolecular interactions and high fluctuations in residues of 1-350 that significantly affect the ANK functional domain. G250C/D and G635R consensus deleterious mutations were found in the first and second binding domains of SHANK3, and none were found in the post-translational modification sites. This study suggests L47P, G54W, and G250C/D deleterious mutations as priorities for future studies on SHANK3.
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http://dx.doi.org/10.1007/s12031-020-01552-5DOI Listing
October 2020

TGF-β and WNT signaling pathways in cardiac fibrosis: non-coding RNAs come into focus.

Cell Commun Signal 2020 06 9;18(1):87. Epub 2020 Jun 9.

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 40 Blossom Street, Boston, MA, 02114, USA.

Cardiac fibrosis describes the inappropriate proliferation of cardiac fibroblasts (CFs), leading to accumulation of extracellular matrix (ECM) proteins in the cardiac muscle, which is found in many pathophysiological heart conditions. A range of molecular components and cellular pathways, have been implicated in its pathogenesis. In this review, we focus on the TGF-β and WNT signaling pathways, and their mutual interaction, which have emerged as important factors involved in cardiac pathophysiology. The molecular and cellular processes involved in the initiation and progression of cardiac fibrosis are summarized. We focus on TGF-β and WNT signaling in cardiac fibrosis, ECM production, and myofibroblast transformation. Non-coding RNAs (ncRNAs) are one of the main players in the regulation of multiple pathways and cellular processes. MicroRNAs, long non-coding RNAs, and circular long non-coding RNAs can all interact with the TGF-β/WNT signaling axis to affect cardiac fibrosis. A better understanding of these processes may lead to new approaches for diagnosis and treatment of many cardiac conditions. Video Abstract.
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http://dx.doi.org/10.1186/s12964-020-00555-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281690PMC
June 2020

Antibacterial activity of SPIONs versus ferrous and ferric ions under aerobic and anaerobic conditions: a preliminary mechanism study.

IET Nanobiotechnol 2020 Apr;14(2):155-160

Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran.

In modern medicine, major attention has been paid to superparamagnetic iron oxide nanoparticles (SPIONs). Recent studies have shown the antibacterial properties of SPIONs against some Gram-positive and Gram-negative bacterial strains. These nanoparticles (NPs) can bind to bacterial membranes via hydrophobic or electrostatic interactions and pass through cell barriers. In this study, the authors evaluated the antibacterial activity of magnetic NPs in comparison with ferrous and ferric ions. The level of reactive oxygen species (ROS) in the treated Staphylococcus aureus and Escherichia coli bacteria were directly measured by fluorometric detection. The results showed that iron ions and SPIONs had significant dependent antimicrobial activities. SPIONs showed greater inhibitory effects than ferrous and ferric ions against the growth of treated bacterial strains under anaerobic conditions, while in aerobic conditions, ferrous showed the strongest antibacterial activity. In anaerobic conditions, they observed the greatest ROS formation and lowest minimum inhibitory concentration in the SPION-treated group in comparison with the other groups. It seems that the release of iron ions from SPIONs and subsequent activation of ROS pathway are the main antibacterial mechanisms of action. Nevertheless, the greater antibacterial effect of SPIONs in anaerobic conditions represents other mechanisms involved in the antibacterial activity of these NPs.
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http://dx.doi.org/10.1049/iet-nbt.2019.0266DOI Listing
April 2020

Novel versatile 3D bio-scaffold made of natural biocompatible hagfish exudate for tissue growth and organoid modeling.

Int J Biol Macromol 2020 May 6;158:894-902. Epub 2020 May 6.

Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Hagfish exudate is a natural biological macromolecule made of keratin intermediate filament protein skeins and mucin vesicles. Here, we successfully examined this remarkable biomaterial as a substrate for three-dimensional (3D) cell culturing purposes. After the sterilization with chloroform vapor, Dulbecco's modified eagle medium was mixed with the exudate to rupture the vesicles and skeins; a highly soft, adherent, fibrous and biocompatible hydrogel was formed. A variety of cells, including Hela-FUCCI, NMuMG-FUCCI, 10T1/2 and C2C12, was cultured on the hagfish exudate. A remarkable 3D growth by ~2.5 folds after day 3, ~5 folds after day 5, ~10 folds after day 7 and ~15 folds after day 14 were seen compared to day one of culturing in the hagfish exudate scaffold. In addition, the phase contrast, fluorescent and confocal microscopy observations confirmed the organoid shape formation within the three-week culture. The viability of cells was almost 100% indicating the great in vitro and in vivo potential of this exceptional biomaterial with no cytotoxic effect.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.05.024DOI Listing
May 2020

Amino Acids Sequence-based Analysis of Arginine Deiminase from Different Prokaryotic Organisms: An In Silico Approach.

Recent Pat Biotechnol 2020 ;14(3):235-246

Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, P.O. Box 71348-14366, Shiraz, Iran.

Background: Arginine deiminase is a bacterial enzyme, which degrades L-arginine. Some human cancers such as hepatocellular carcinoma (HCC) and melanoma are auxotrophic for arginine. Therefore, PEGylated arginine deiminase (ADI-PEG20) is a good anticancer candidate with antitumor effects. It causes local depletion of L-arginine and growth inhibition in arginineauxotrophic tumor cells. The FDA and EMA have granted orphan status to this drug. Some recently published patents have dealt with this enzyme or its PEGylated form.

Objective: Due to increasing attention to it, we aimed to evaluate and compare 30 arginine deiminase proteins from different bacterial species through in silico analysis.

Methods: The exploited analyses included the investigation of physicochemical properties, multiple sequence alignment (MSA), motif, superfamily, phylogenetic and 3D comparative analyses of arginine deiminase proteins thorough various bioinformatics tools.

Results: The most abundant amino acid in the arginine deiminase proteins is leucine (10.13%) while the least amino acid ratio is cysteine (0.98%). Multiple sequence alignment showed 47 conserved patterns between 30 arginine deiminase amino acid sequences. The results of sequence homology among 30 different groups of arginine deiminase enzymes revealed that all the studied sequences located in amidinotransferase superfamily. Based on the phylogenetic analysis, two major clusters were identified. Considering the results of various in silico studies; we selected the five best candidates for further investigations. The 3D structures of the best five arginine deiminase proteins were generated by the I-TASSER server and PyMOL. The RAMPAGE analysis revealed that 81.4%-91.4%, of the selected sequences, were located in the favored region of arginine deiminase proteins.

Conclusion: The results of this study shed light on the basic physicochemical properties of thirty major arginine deiminase sequences. The obtained data could be employed for further in vivo and clinical studies and also for developing the related therapeutic enzymes.
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http://dx.doi.org/10.2174/1872208314666200324114441DOI Listing
January 2020

Green and Economic Fabrication of Zinc Oxide (ZnO) Nanorods as a Broadband UV Blocker and Antimicrobial Agent.

Nanomaterials (Basel) 2020 Mar 15;10(3). Epub 2020 Mar 15.

School of Engineering, Faculty of Science and Engineering, The University of Waikato, Hamilton 3240, New Zealand.

Zinc oxide (ZnO) nanoparticles have gained widespread interest due to their unique properties, making them suitable for a range of applications. Several methods for their production are available, and of these, controlled synthesis techniques are particularly favourable. Large-scale culturing of produces secretory carbohydrates as a waste product, which have been shown to play an important role in directing the particle size and morphology of nanoparticles. In this investigation, ZnO nanorods were produced through a controlled synthesis approach using secretory carbohydrates from , which presents a cost-effective and sustainable alternative to the existing techniques. Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRD) analysis, transmission electron microscopy (TEM), and UV-Vis spectroscopy were used to characterise the nanorods. The prepared nanorods exhibited a broad range of UV absorption, which suggests that the particles are a promising broadband sun blocker and are likely to be effective for the fabrication of sunscreens with protection against both UVB (290-320 nm) and UVA (320-400 nm) radiations. The antimicrobial activity of the prepared nanorods against Gram-positive and Gram-negative bacteria was also assessed. The nanostructures had a crystalline structure and rod-like appearance, with an average length and width of 150 nm and 21 nm, respectively. The nanorods also demonstrated notable antibacterial activity, and 250 μg/mL was determined to be the most effective concentration. The antibacterial properties of the ZnO nanorods suggest its suitability for a range of antimicrobial uses, such as in the food industry and for various biomedical applications.
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http://dx.doi.org/10.3390/nano10030530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153581PMC
March 2020

Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells.

Cell Biosci 2020 10;10:32. Epub 2020 Mar 10.

5Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. of Iran.

Ovarian cancer is known as a serious malignancy that affects women's reproductive tract and can considerably threat their health. A wide range of molecular mechanisms and genetic modifications have been involved in ovarian cancer pathogenesis making it difficult to develop effective therapeutic platforms. Hence, discovery and developing new therapeutic approaches are required. Medicinal plants, as a new source of drugs, could potentially be used alone or in combination with other medicines in the treatment of various cancers such as ovarian cancer. Among various natural compounds, quercetin has shown great anti-cancer and anti-inflammatory properties. In vitro and in vivo experiments have revealed that quercetin possesses a cytotoxic impact on ovarian cancer cells. Despite obtaining good results both in vitro and in vivo, few clinical studies have assessed the anti-cancer effects of quercetin particularly in the ovarian cancer. Therefore, it seems that further clinical studies may introduce quercetin as therapeutic agent alone or in combination with other chemotherapy drugs to the clinical setting. Here, we not only summarize the anti-cancer effects of quercetin but also highlight the therapeutic effects of quercetin in the ovarian cancer.
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http://dx.doi.org/10.1186/s13578-020-00397-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063794PMC
March 2020

Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids.

Bioorg Med Chem 2020 04 4;28(8):115408. Epub 2020 Mar 4.

Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, CHE 205, 4202 East Fowler Avenue, University of South Florida, Tampa, FL 33620, USA.

This article reports for the first time the synthesis of some novel β-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a-c, 9a-c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-β-lactams 8a-l, 10a-f and 12a-c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay. None of the compounds exert an observable effect on HepG2, MCF-7 and HEK-293 cells, but compounds 7b, 8f, 8g, 8l, 10c, and 10e exhibited excellent growth inhibitory activity (IC < 5 µM) against SW 1116 cells, comparable to that of doxorubicin (IC = 6.9 µM). An evaluation of the antioxidant potential of each of the compounds, performed by diphenylpicrylhydrazyl (DPPH) assay, indicated that 7b, 9a, 9b and 9c have strong free radical scavenging activity. UV absorption titration studies reveal that 7b, 8l, 8g and 8f interact strongly with calf-thymus DNA (CT-DNA) in the order of 8l > 7b > 8f > 8g. Collectively, the in vitro capabilities of some of these morpholino-triazine imines and β-lactams suggest possible applications to development of new antioxidants and DNA binding therapeutics.
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http://dx.doi.org/10.1016/j.bmc.2020.115408DOI Listing
April 2020

Enterobacter sp. Mediated Synthesis of Biocompatible Nanostructured Iron-Polysaccharide Complexes: a Nutritional Supplement for Iron-Deficiency Anemia.

Biol Trace Elem Res 2020 Dec 10;198(2):744-755. Epub 2020 Mar 10.

Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box 1583, 71345 Karafarin Street, Shiraz, Iran.

FDA has approved iron oxide nanoparticles (IONs) coated with organic compounds as a safe material with less toxic effects compared with the naked metal ions and nanoparticles. In this study, the biological and physicochemical characteristics of a nanostructured iron-polysaccharide complexes (Nano-IPC) biosynthesized by Enterobacter sp. were evaluated. Furthermore, the serum biochemical parameters, tissue iron level, red blood cell parameters, and organ ferritin of rats were measured for investigating the effect of the Nano-IPCs in comparison with FeSO as a supplement for iron deficiency. The biosafety data demonstrated 35% increment of viability in Hep-G2 hepatocarcinoma cell lines when treated with nanoparticles (500 μg/mL) for 24 h. Besides, iron concentration in serum and tissue as well as the expression of ferritin L subunit in animals treated with the Nano-IPCs supplement were meaningfully higher than the FeSO-supplemented and negative control animals. Moreover, the expression level of ferritin H subunit and biochemical factors remained similar to the negative control animals in the Nano-IPC-supplemented group. These results indicated that Nano-IPCs can be considered as a nontoxic supplement for patients carrying iron-deficiency anemia (IDA).
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http://dx.doi.org/10.1007/s12011-020-02101-2DOI Listing
December 2020

Current trends in chemical modifications of magnetic nanoparticles for targeted drug delivery in cancer chemotherapy.

Drug Metab Rev 2020 02 21;52(1):205-224. Epub 2020 Feb 21.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Nowadays, magnetic nanoparticles (MNPs) have been rapidly investigated and attracted worldwide attention due to their great potential as mediators of heat for treating hyperthermia and their possibility to deliver drugs at specific locations, which can thereby limit systematic effects. Cancer therapy via MNPs proposes novel properties rather than normal methods such as almost zero side effects and a high-efficiency rate of effectiveness. The key aim of targeted drug delivery is to reduce side effects of the main cancer treatment that other usual chemotherapies will attend to the body, and thus controlling the effectiveness of the drug on a specific location that tumoral tissue exist. Herein, the high potential of MNPs has been studied, and different examples of their effectiveness on drug delivery and hypothermia therapy have been provided.
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http://dx.doi.org/10.1080/03602532.2020.1726943DOI Listing
February 2020

LytU-SH3b fusion protein as a novel and efficient enzybiotic against methicillin-resistant .

Mol Biol Res Commun 2019 Dec;8(4):151-158

Recombinant Protein Laboratory, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Methicillin-resistant (MRSA) is a challenging infectious agent worldwide. The ever growing antibiotic resistance has made the researchers to look for new anti-staphylococcal agents. Autolysins are staphylococcal enzymes that lyse bacterial cell wall for cell division. Autolysins can be used as novel enzybiotics (enzymes have antibiotic effects) for staphylococcal infections. LytU is a newly explored autolysin. SH3b is a potent cell wall binding domain that can be fused to lytic enzymes to increase their activity. The aim of this study was to design a novel and efficient fusion enzybiotic that could lyse staphylococcal cell wall peptidoglycan by disrupting the bacteria. LytU-SH3b fusion construct was synthesized and LytU was amplified through the construct, using overhang PCR. The fusion and native forms that had his-tag were synthesized by recombinant technology in BL21 (DE3) strain and purified utilizing Ni-NTA agarose beads. LytU and LytU-SH3b activity and potency were assessed using plate lysis assay, turbidity reduction assay and minimal inhibitory concentration (MIC) tests. All these tests showed that LytU-SH3b has more activity and potency than LytU. LytU-SH3b has MIC 421 fold lesser than LytU. Finally, LytU-SH3b is a novel and efficient recombinant enzybiotic that can lyse MRSA as an alternative to chemical small molecule antibiotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995334PMC
December 2019

Impact of magnetic immobilization on the cell physiology of green unicellular algae .

Bioengineered 2020 12;11(1):141-153

Department of Medical Nanotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.

Cell immobilization on the magnetic nanoparticles (MNPs) and magnetic harvesting is a novel approach for microalgal cells separation. To date, the effect of these nanoparticles on microalgal cells was only studied over a short period of time. More studies are hence needed for a better understanding of the magnetic harvesting proposes or environmental concerns relating to long-term exposure to nanoparticles. In this study, the impact of various concentrations of MNPs on the microalgal cells growth and their metabolic status was investigated over 12 days. More than 60% reduction in mitochondrial activity and pigments (chlorophyll a, chlorophyll b, and carotenoids) content occurred during the first 6 days of exposure to ≥50 µg/mL nanoparticles. However, more than 50% growth inhibitory effect was seen at concentrations higher than 400 µg/mL. Exposure to MNPs gradually induced cellular adaptation and after about 6 days of exposure to stress generating concentrations (˂400 µg/mL) of IONs, microalgae could overcome the imposed damages. This work provides a better understanding regarding the environmental impact of MNPs and appropriate concentrations of these particles for future algal cells magnetic immobilization and harvesting.
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http://dx.doi.org/10.1080/21655979.2020.1718477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999624PMC
December 2020

In silico Evaluation of PLAC1-fliC As a Chimeric Vaccine against Breast Cancer

Iran Biomed J 2020 05 18;24(3):173-82. Epub 2019 Nov 18.

Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Breast cancer is one of the most prevalent cancers among women. Common cancer treatment methods are not effective enough, and there is a need for a more efficient treatment procedure. Cancer vaccine is a novel immunotherapy method that stimulates humoral and/or cellular immunity against cancer. Placenta-specific protein 1 (PLAC1) is a cancer/testis antigen, prevalent in breast cancer and rarely found in normal tissues. FliC, as a bacterial adjuvant, when fused to PLAC1 can elicit humoral and cellular responses. Therefore, PLAC1-fliC is a chimeric protein, which can be considered a suitable candidate against breast cancer.

Methods: ProtParam was used to evaluate the physicochemical properties of PLAC1-fliC. Second structures were determined using the GOR V server. PLAC1-fliC 3D structure was modeled by Phyre2, and it was refined using GalaxyWEB. The refined model was submitted to RAMPAGE, PROCHECK, and ProSA-web for validation. Antigenicity and allergenicity of the construct were predicted by ANTIGENpro, VaxiJen, AllergenFP, and SDAP databases. Then MHC-I- and MHC-II-binding epitopes of PLAC1-fliC were forecasted by NetMHC 4.0 and NetMHCII 2.3 Servers. Finally, Ellipro and CTLpred were employed to predict B-cell and cytotoxic T lymphocyte epitopes.

Results: The construct was evaluated as a stable fusion protein, which could be antigenic and could stimulate B and T cells against breast cancer.

Conclusion: PLAC1-fliC, as a cancer vaccine candidate, might be suitable and specific for breast cancer, which could evoke humoral and cellular immunity against this type of tumor.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275624PMC
May 2020

Immobilization of Cells by Magnetic Nanoparticles.

Methods Mol Biol 2020 ;2100:427-435

Faculty of Science and Engineering, The University of Waikato, Hamilton, New Zealand.

Cell harvesting is one of the main expensive, labor-intensive, and energy-consuming steps in downstream processing. Cell immobilization has introduced as a valuable strategy for process intensification in biotechnological industries. Here we describe magnetic immobilization as a promising and novel technique for cell immobilization by using magnetic nanoparticles. This technique is based on the decoration of cells with magnetic nanoparticles to make them sensitive to magnetic field. So, the cells can be harvested simply by applying a magnetic separator.
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http://dx.doi.org/10.1007/978-1-0716-0215-7_29DOI Listing
January 2021

Magnetic Immobilization of Cells for the Production of Recombinant Human Serum Albumin.

Nanomaterials (Basel) 2020 Jan 6;10(1). Epub 2020 Jan 6.

Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Magnetic immobilization as a novel technique was used to immobilize recombinant (GS115 Albumin) cells to produce human serum albumin (HSA). In this regard, magnetic nanoparticles (MNPs) coated with amino propyl triethoxy silane (APTES) were synthesized. cells were decorated with MNPs via nonspecific interactions. Decorated cells were magneto-responsible and easily harvested by applying an external magnetic field. The efficiency of magnetic immobilization (E) for cell removal was in direct relation with the MNP concentration and time of exposure to the magnetic field. By increasing the nanoparticles concentration, cells were harvested in a shorter period. Complete cell removal (E ≈ 100) was achieved in ≥0.5 mg/mL of MNPs in just 30 s. HSA is produced in an extremely high cell density (OD ~20) and it is the first time that magnetic immobilization was successfully employed for harvesting such a thick cell suspension. After 5 days of induction the cells, which were immobilized with 0.25 to 1 mg/mL of nanoparticles, showed an increased potency for recombinant HSA production. The largest increase in HSA production (38.1%) was achieved in the cells that were immobilized with 0.5 mg/mL of nanoparticles. These results can be considered as a novel approach for further developments in the -based system.
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http://dx.doi.org/10.3390/nano10010111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022243PMC
January 2020

Effects of Sulfur Starvation on Growth Rates, Biomass and Lipid Contents in the Green Microalga .

Recent Pat Biotechnol 2020 ;14(2):145-153

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 71468-64685, Shiraz, Iran.

Background: Scenedesmus obliquus, a green unicellular chlorophycean microalga, is well-established as a lipid and biomass production platform. The nutrient starvation strategy is considered as a robust platform for lipid production from different microalgal strains.

Objective: The study aimed to analyse the influences of sulfur starvation on the growth rates, and also biomass and lipid production and composition in a naturally isolated strain of S. obliquus.

Methods: The BG-11 culture medium was utilized for preservation and microalgal growth. To monitor the cell growth rates, two different methods, including direct cell counting and also dry cell weight measurement were used. The study was conducted in 28 days composed of two distinct growth modes as 10 days of sulfur-rich and 18 days of sulfur starved media.

Results: The studied S. obliquus strain displayed higher lipid and carbohydrate production levels (34.68% and 34.02%) in sulfur starved medium compared with the sulfur-rich medium (25.84% and 29.08%). Nevertheless, a noticeable reduction (51.36%) in biomass contents and also in cell growth rates (63.36%) was observed during sulfur starvation. The investigated strain was composed of some important fatty acids with potential applications as food, feed and biodiesel.

Conclusion: The observed results implied the possibility of the sulfur starvation strategy to increase lipid production in S. obliquus strain. Besides, the available data from recently published patents reveals the promising potential of the identified lipids from S. obliquus in this study for bioenergy production and other biotechnological purposes.
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http://dx.doi.org/10.2174/1872208314666200109103059DOI Listing
January 2021

Analytical methodologies for determination of methotrexate and its metabolites in pharmaceutical, biological and environmental samples.

J Pharm Anal 2019 Dec 20;9(6):373-391. Epub 2019 Jun 20.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Methotrexate (MTX) is a folate antagonist drug used for several diseases, such as cancers, various malignancies, rheumatoid arthritis (RA) and inflammatory bowel disease. Due to its structural features, including the presence of two carboxylic acid groups and its low native fluorescence, there are some challenges to develop analytical methods for its determination. MTX is metabolized to 7-hydroxymethotrexate (7-OH-MTX), 2,4-diamino-N10-methylpteroic acid (DAMPA), and the active MTX polyglutamates (MTXPGs) in the liver, intestine, and red blood cells (RBCs), respectively. Additionally, the drug has a narrow therapeutic range; hence, its therapeutic drug monitoring (TDM) is necessary to regulate the pharmacokinetics of the drug and to decrease the risk of toxicity. Due to environmental toxicity of MTX; its sensitive, fast and low cost determination in workplace environments is of great interest. A large number of methodologies including high performance liquid chromatography equipped with UV-visible, fluorescence, or electrochemical detection, liquid chromatography-mass spectroscopy, capillary electrophoresis, UV-visible spectrophotometry, and electrochemical methods have been developed for the quantitation of MTX and its metabolites in pharmaceutical, biological, and environmental samples. This paper will attempt to review several published methodologies and the instrumental conditions, which have been applied to measure MTX and its metabolites within the last decade.
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http://dx.doi.org/10.1016/j.jpha.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931080PMC
December 2019

Effect of chemical modification with carboxymethyl dextran on kinetic and structural properties of L-asparaginase.

Anal Biochem 2020 02 9;591:113537. Epub 2019 Dec 9.

Department of Biochemistry, School of Veterinary Medicine, Shiraz University, Shiraz, 71345, Iran.

l-asparaginase is a chemotherapy agent in the treatment of childhood leukemia. l-asparaginase has several side effects and a short blood half-life in patients. Chemical modification of l-asparaginase can decrease its side effects and improve its pharmacokinetic properties. The aim of this project was twofold: to chemically modify l-asparaginase with carboxymethyl dextran via carbodiimide cross linker, and to evaluate and compare the biochemical and structural properties of the native and modified enzymes. Chemical modification was done at 25 °C, in 0.1 M phosphate buffer, pH 7.2, and in the presence of N-hydroxysuccinimide and carbodiimide. Electrophoresis and free amino groups determination confirmed the chemical modification. Biochemical studies showed that the chemical modification could result in higher specific activity and stability of the modified enzyme. Structural studies further confirmed the chemical modification and revealed conformational changes in the modified enzyme. Taken together, the results showed that chemical modification with carboxymethyl dextran brings about improvement of biochemical properties through several changes in the structural attributes of l-asparaginase and might enhance its applicability in the treatment of childhood leukemia.
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http://dx.doi.org/10.1016/j.ab.2019.113537DOI Listing
February 2020

The interaction of phages and bacteria: the co-evolutionary arms race.

Crit Rev Biotechnol 2020 Mar 2;40(2):119-137. Epub 2019 Dec 2.

Pharmaceutical Sciences Research Center, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

Since the dawn of life, bacteria and phages are locked in a constant battle and both are perpetually changing their tactics to overcome each other. Bacteria use various strategies to overcome the invading phages, including adsorption inhibition, restriction-modification (R/E) systems, CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) systems, abortive infection (Abi), etc. To counteract, phages employ intelligent tactics for the nullification of bacterial defense systems, such as accessing host receptors, evading R/E systems, and anti-CRISPR proteins. Intense knowledge about the details of these defense pathways is the basis for their broad utilities in various fields of research from microbiology to biotechnology. Hence, in this review, we discuss some strategies used by bacteria to inhibit phage infections as well as phage tactics to circumvent bacterial defense systems. In addition, the application of these strategies will be described as a lesson learned from bacteria and phage combats. The ecological factors that affect the evolution of bacterial immune systems is the other issue represented in this review.
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http://dx.doi.org/10.1080/07388551.2019.1674774DOI Listing
March 2020