Publications by authors named "Abolfazl Barzegari"

78 Publications

Preparation, characterization, and antibacterial properties of hybrid nanofibrous scaffolds for cutaneous tissue engineering.

Hum Cell 2021 Nov 17;34(6):1682-1696. Epub 2021 Sep 17.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Since polymeric nanofibrous scaffolds have been widely used in tissue regeneration, the risk of bacterial infections should not be neglected. In the present work, poly-caprolactone-silk fibroin-soluble eggshell membrane-silver nanoparticles (PCL-SF-SESM-AgNPs) and caprolactone-silk fibroin-soluble eggshell membrane-chitosan (PCL-SF-SESM-CS) scaffolds were fabricated via the electrospinning method for cutaneous regeneration. The composition, morphology, hydrophilicity, and mechanical features of prepared scaffolds were evaluated using Fourier transform infrared (FT-IR), scanning electron microscope (SEM), tensile, and water contact angle tests. The existence of AgNPs in PCL/SF/SESM/AgNPs nanofibers was confirmed by UV-visible, Transmission electron microscopes (TEM), and X-Ray Diffraction (XRD) patterns. Besides, cell adhesion, proliferation, and differentiation process of cutaneous progenitor cells, namely basal cell carcinoma (BCCs), toward keratinocyte-like cells were evaluated using MTT analysis, DAPI, Immunofluorescence imaging (IF), and Real-Time Quantitative Reverse Transcription PCR (QRT-PCR) assay. The results indicated that prepared nanofibrous mats are appropriate candidates for cutaneous regeneration and in advanced in vivo applications could be used. Lastly, the antimicrobial potential of prepared nanofibers against microorganisms such as E. coli, S. aureus, and C. Albicans was analyzed using the disc diffusion method. Results revealed that chitosan-containing nanofibrous scaffolds indicate inhibition against S. aureus, but PCL-SF-SESM as control group not. In addition, against C. albicans any antifungal activity was not observed.
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http://dx.doi.org/10.1007/s13577-021-00588-yDOI Listing
November 2021

Astaxanthin protects mesenchymal stem cells from oxidative stress by direct scavenging of free radicals and modulation of cell signaling.

Chem Biol Interact 2021 Jan 17;333:109324. Epub 2020 Nov 17.

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida 33328, USA. Electronic address:

Recent evidence has shown that mesenchymal stem cells (MSCs) play vital roles in cell therapy of ischemia/hypoxia damaged tissues. However, after the transplantation, they might undergo apoptosis due to oxidative stress. Thus, some strategies have been developed to support stem cells in harsh conditions, including pre-treatment of the cells with antioxidants. Of various antioxidants, in this study, astaxanthin (ATX) was used to protect adipose-derived MSCs against oxidative stress. The MSCs were exposed to different doses of hydrogen peroxide, and then the expression of key genes involved in the redox signaling pathway was studied, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH quinine oxidoreductase 1 (NQO1). The balance of intracellular reactive oxygen species was detected with the H2DCFDA molecular probe. Additionally, for the detection of apoptosis and protective effect of ATX, the DAPI/Phallacidin and annexin V cell staining were performed. The results of cellular studies revealed that ATX reduced the HO-induced cell apoptosis and oxidative stress. Furthermore, after the induction of oxidative stress, the cells' native antioxidants (HO-1 and NQO1) were overexpressed but they were modulated with ATX treatments (p < 0.023). Based on our findings, ATX could increase the expression of Nrf2 as a key transcription factor of antioxidant enzymes (p < 0.05). These findings support the notion that ATX can act as an effective antioxidant in the pre-treatment of MSCs before cell therapy. Thus, to enhance the viability of stem cells during the transplantation in harsh conditions, the concurrent use of ATX in cell therapy modalities is proposed.
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http://dx.doi.org/10.1016/j.cbi.2020.109324DOI Listing
January 2021

Nrf-2 as a therapeutic target in acute kidney injury.

Life Sci 2021 Jan 13;264:118581. Epub 2020 Oct 13.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Multifaceted cellular pathways exhibit a crucial role in the preservation of homeostasis at the molecular, cellular, and organism levels. One of the most important of these protective cascades is Nuclear factor E2-related factor (Nrf-2) that regulates the expression of several genes responsible for cellular detoxification, antioxidant function, anti-inflammation, drug/xenobiotic transportation, and stress-related factors. A growing body of evidence provides information regarding the protective role of Nrf-2 against a number of kidney diseases. Acute kidney injury (AKI) is a substantial clinical problem that causes a huge social burden. In the kidneys, Nrf-2 exerts a dynamic role in improving the injury triggered by inflammation and oxidative stress. Understanding of the exact molecular mechanisms underlying AKI is vital in order to determine the equilibrium between renal adaptation and malfunction and thus reduce disease progression. This review highlights the role of Nrf-2 targeting against AKI and provides evidence that targeting Nrf-2 to prevail oxidative damage and its consequences might exhibit protective effects in kidney diseases.
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http://dx.doi.org/10.1016/j.lfs.2020.118581DOI Listing
January 2021

Molecular pathophysiology of acute kidney injury: The role of sirtuins and their interactions with other macromolecular players.

J Cell Physiol 2021 05 28;236(5):3257-3274. Epub 2020 Sep 28.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Acute kidney injury (AKI), a rapid drop in kidney function, displays high mortality and morbidity, and its repeated or severe status can shift into chronic kidney disease or even end-stage renal disease. How and which events cause AKI still is controversial. In addition, no specific therapies have emerged that can attenuate AKI or expedite recovery. Some central mechanisms including tubular epithelial cells injury, endothelial injury, renal cell apoptosis, and necrosis signaling cascades, and inflammation have been reported in the pathophysiology of AKI. However, the timing of the activation of each pathway, their interactions, and the hierarchy of these pathways remain unknown. The main molecular mechanisms that might be complicated in this process are the mitochondrial impairment and alteration/shifting of cellular metabolites (e.g., acetyl-CoA and NAD /NADH) acting as cofactors to alter the activities of many enzymes, for instance, sirtuins. Moreover, alteration of mitochondrial structure over the fusion and fission mechanisms can regulate cellular signaling pathways by modifying the rate of reactive oxygen species generation and metabolic activities. The aim of this review is to better understand the underlying pathophysiological and molecular mechanisms of AKI. In addition, we predicted the main other molecular players in interaction with sirtuins as energy/stresses monitoring proteins for the development of future approaches in the treatment or prevention of ischemic AKI.
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http://dx.doi.org/10.1002/jcp.30084DOI Listing
May 2021

Nesting and fate of transplanted stem cells in hypoxic/ischemic injured tissues: The role of HIF1α/sirtuins and downstream molecular interactions.

Biofactors 2020 Sep 16. Epub 2020 Sep 16.

INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, Villetaneuse, France.

The nesting mechanisms and programming for the fate of implanted stem cells in the damaged tissue have been critical issues in designing and achieving cell therapies. The fracture site can induce senescence or apoptosis based on the surrounding harsh conditions, hypoxia, and oxidative stress (OS). Respiration deficiency, disruption in energy metabolism, and consequently OS induction change the biophysical, biochemical, and cellular components of the native tissue. Additionally, the homeostatic molecular players and cell signaling might be changed. Despite all aforementioned issues, in the native stem cell niche, physiological hypoxia is not toxic; rather, it is vitally required for homing, self-renewal, and differentiation. Hence, the key macromolecular players involved in the support of stem cell survival and re-adaptation to a new dysfunctional niche must be understood for managing the cell therapy outcome. Hypoxia-inducible factor 1-alpha is the master transcriptional regulator, involved in the cell response to hypoxia and the adaptation of stem cells to a new niche. This protein is regulated by interaction with sirtuins. Sirtuins are highly conserved NAD+-dependent enzymes that monitor the cellular energy status and modulate gene transcription, genome stability, and energy metabolism in response to environmental signals to modulate the homing and fate of stem cells. Herein, new insights into the nesting of stem cells in hypoxic-ischemic injured tissues were provided and their programming in a new dysfunctional niche along with the involved complex macromolecular players were critically discussed.
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http://dx.doi.org/10.1002/biof.1674DOI Listing
September 2020

Designing a light-activated recombinant alpha hemolysin for colorectal cancer targeting.

Bioimpacts 2020 2;10(3):187-193. Epub 2019 Nov 2.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Colorectal cancer (CRC) is one of the main health burden worldwide, which can cause major economic and physiological problems along with relatively high rate of mortality. It is important to develop new methods for the localized delivery of recombinant protein therapeutics, in large part due to the failure of conventional therapies in most cases. Since Nissle 1917 (EcN) does not produce any virulence factors, here we used these bacteria with the light-activated promoter system to deliver therapeutic agents in the desired location and time. In this study, alpha hemolysin (SAH), after codon usage optimization, was cloned into blue light activating vector (pDawn) and transferred to EcN strain. Then, the functionality and cytotoxicity of secreted alpha hemolysin was evaluated in the SW480 colon cancer cell line by using different experiments, including blood agar test, flow cytometry analysis, and DAPI staining. Our findings revealed that EcN can produce functional SAH under the blue light irradiation against SW480 cancer cells. Moreover, cytotoxicity assays confirmed the dose- and time-dependent toxicity of this payload (SAH) against SW480 cancer cells. Based on our results, EcN is proposed as an appropriate light-activated vehicle for delivery of anticancer agents to the target cancer cells/tissues.
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http://dx.doi.org/10.34172/bi.2020.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416006PMC
November 2019

induces apoptosis in gastric cancer cells via modulation of signaling pathways in .

Bioimpacts 2020 28;10(2):65-72. Epub 2019 Jun 28.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Gastric cancer is considered the second prevalent cause of death around the world. This type of cancer is generally induced by which could colonize within the gastric mucosa of the infected cases. To date, triple antibiotic therapy has routinely been utilized for controlling the induced infection. However, this strategy has been unsuccessful, in large part because of issues such as occurring point mutations in the genome that can induce resistance to the antibiotics administered. Recently, it has been shown that different probiotics may have strong anti-cancer effects, in which they are capable of inhibiting by both immunological and non-immunological mechanisms. Here, we aimed at finding possible anti-cancer impacts of the probiotic bacterium on gastric cancer, AGS cells. The anti-cancer effects of the conditioned media of the locally isolated on the AGS cells were evaluated by different analyses such as flow cytometry, DNA ladder assay, DAPI staining, and RT-PCR. Our findings showed that the conditioned media of can inhibit both and AGS cells through up-/down-regulation of PTEN, Bax, TLR4, and AKT genes. The exudates of the probiotic bacteria can increase the expression of PTEN, Bax, and TLR4, and also decrease the expression of AKT gene. In agreement with different reports, our results proved the anti-cancer effects of the locally isolated through some immunological cell signaling pathways. Accordingly, it seems the probiotics could be considered as at least a complementary treatment for different types of malignancies.
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http://dx.doi.org/10.34172/bi.2020.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186545PMC
June 2019

Medicinal signaling cells: A potential antimicrobial drug store.

J Cell Physiol 2020 11 30;235(11):7731-7746. Epub 2020 Apr 30.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Medicinal signaling cells (MSCs) are multipotent cells derived from mammalian bone marrow and periosteum that can be extended in culture. They can keep their ability in vitro to form a variety of mesodermal phenotypes and tissues. Over recent years, there has been great attention over MSCs since they can impact the organ transplantation as well as autoimmune and bacterial diseases. MSCs can secrete different bioactive factors such as growth factors, antimicrobial peptides/proteins and cytokines that can suppress the immune system and prevent infection via direct and indirect mechanisms. Moreover, MSCs are able to increase bacterial clearance in sepsis models by producing antimicrobial peptides such as defensins, cathelicidins, lipocalin and hepcidin. It is the aim of the present review to focus on the antibacterial effector functions of MSCs and their mechanisms of action against the pathogenic microbes.
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http://dx.doi.org/10.1002/jcp.29728DOI Listing
November 2020

The role of Piezo proteins and cellular mechanosensing in tuning the fate of transplanted stem cells.

Cell Tissue Res 2020 Jul 25;381(1):1-12. Epub 2020 Mar 25.

INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Sorbonne Paris Nord, 93430, Villetaneuse, France.

Differentiation of stem cells can be modulated by a combination of internal and external signals, including mechanical cues from the surrounding microenvironment. Although numerous chemical and biological agents have been recognized in regulating stem cells' fate, little is known about their potential to directly sense the mechanical signals to choose differentiation into a specific lineage. The success of any stem cell transplantation effort, however, hinges on thorough understanding of the fate of these cells under different signals, including mechanical cues. Various proteins are involved in the mechanical sensing process. Of these, Piezo proteins, as the ion channels activated by membrane tension and mechanical signals, play an important role in translating the information of mechanical forces such as rigidity and topography of the extracellular matrix to the intracellular signaling pathways related to stem cell homing and differentiation. They also play a key role in terms of shear stresses and tensile loads in expansion systems. This review highlights key evidence for the potential of mechanically gated ion channels expressed by human stem cells, and the mechanotransduction and past mechanomemory in the fate of transplanted stem cells. With this knowledge in mind, by controlling the tissue-specific patterns of mechanical forces in the scaffolds, we may further improve the regulation of homing, the differentiation, and the fate of transplanted stem cells.
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http://dx.doi.org/10.1007/s00441-020-03191-zDOI Listing
July 2020

The Battle of Probiotics and Their Derivatives Against Biofilms.

Infect Drug Resist 2020 26;13:659-672. Epub 2020 Feb 26.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Biofilm-related infections have been a major clinical problem and include chronic infections, device-related infections and malfunction of medical devices. Since biofilms are not fully available for the human immune system and antibiotics, they are difficult to eradicate and control; therefore, imposing a global threat to human health. There have been avenues to tackle biofilms largely based on the disruption of their adhesion and maturation. Nowadays, the use of probiotics and their derivatives has gained a growing interest in battling against pathogenic biofilms. In the present review, we have a close look at probiotics with the ultimate objective of inhibiting biofilm formation and maturation. Overall, insights into the mechanisms by which probiotics and their derivatives can be used in the management of biofilm infections would be warranted.
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http://dx.doi.org/10.2147/IDR.S232982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049744PMC
February 2020

Bioengineered smart bacterial carriers for combinational targeted therapy of solid tumours.

J Drug Target 2020 Aug-Sep;28(7-8):700-713. Epub 2020 Mar 16.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Despite many endeavours for the development of new anticancer drugs, effective therapy of solid tumours remains a challenging issue. The current cancer chemotherapies may associate with two important limitations, including the lack/trivial specificity of treatment modalities towards diseased cells/tissues resulting in undesired side effects, and the emergence of drug-resistance mechanisms by tumour cells causing the failure of the treatment. Much attention, therefore, has currently been paid to develop smart and highly specific anticancer agents with maximal therapeutic impacts and minimal side effects. Among various strategies used to target cancer cells, bacteria-based cancer therapies (BCTs) have been validated as potential gene/drug delivery carriers, which can also be engineered to be used in diagnosis processes. They can be devised to selectively target the tumour microenvironment (TME), within which they may preferentially proliferate in the necrotic and anaerobic parts - often inaccessible to other therapeutics. BCTs are capable to sense and respond to the environmental signals, upon which they are considered as smart microrobots applicable in the controlled delivery of therapeutic agents to the TME. In this review, we aimed to provide comprehensive insights into the potentials of the bioengineered bacteria as smart and targeted bio-carriers and discuss their applications in cancer therapy.
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http://dx.doi.org/10.1080/1061186X.2020.1737087DOI Listing
September 2021

Anticancer effect of bacteria on cervical cancer: Molecular aspects and therapeutic implications.

Life Sci 2020 Apr 6;246:117413. Epub 2020 Feb 6.

Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich-Alexander-Universität of Erlangen-Nürnberg, Germany.

Cervical cancer is the second common cancer and the third leading cause of cancer deaths among women in less developed countries. It has been indicated that changes in vaginal microbiome play an important role in the occurrence and development of cervical cancer. However, studies have shown that probiotics play an effective role in fighting cancer by affecting pathogenic bacteria, inducing cancer cells apoptosis, and other anticancer activities. Therefore, the purpose of the present study is reviewing the anticancer effect of cervicovaginal bacteria and their potential for cervical cancer treatment.
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http://dx.doi.org/10.1016/j.lfs.2020.117413DOI Listing
April 2020

Mitochondria-targeted antioxidant mito-TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells.

J Cell Physiol 2020 07 28;235(7-8):5628-5636. Epub 2020 Jan 28.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

The cell therapy of damaged tissue, which is linked to hypoxia condition might fail, in large part due to the emergence of oxidative stress (OS) and/or mitochondrial dysfunctions. Thus, the invigoration of stem cells against oxidative stress could be a reliable strategy to improve the cell therapy outcome. Of various antioxidants, mito-Tempo (mito-T) is one of the potent antioxidants that could target and neutralize the mitochondrial oxidative stress. In this study, for the induction of hypoxia and oxidative stress in mitochondria of the mesenchymal stem cells (MSCs) isolated from human adipose tissue, antimycin A (AMA) was used and then several parameters were analyzed, including cell viability and cell cycle arrest of MSCs exposed to AMA, mito-T, antioxidant potential, redox homeostasis, and signaling pathways in MSCs under oxidative stress. Based on our findings, the treated MSCs were found to impose a high resistance to the OS-induced apoptosis, which correlated with the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway required to manage OS. Upon exposure of the MSCs to high oxidative stress conditions using AMA, the cells failed to scavenge. The use of mito-T was found to alleviate the damage induced by oxidative stress through both direct functions of the free radical scavenging and the interplay in terms of cell signaling pathways including the upregulation of the Nrf2 pathway. These findings may pave the way in the stem cell therapy for the hypoxia-mediated tissue damage.
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http://dx.doi.org/10.1002/jcp.29495DOI Listing
July 2020

PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells.

Bioimpacts 2020 25;10(1):27-36. Epub 2019 Jul 25.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 51656-65811, Iran.

Currently, drug-induced reactive oxygen species (ROS) mediating apoptosis pathway have extensively been investigated in designing effective strategies for colorectal cancer (CRC) chemotherapy. Bovine pancreatic ribonuclease A (RNase A) represents a new class of cytotoxic and non-mutagenic enzymes, and has gained more attention as a potential anticancer modality; however, the cytosolic ribonuclease inhibitors (RIs) restrict the clinical application of this enzyme. Nowadays, nanotechnology-based diagnostic and therapeutic systems have provided potential solutions for cancer treatments. In this study, the gold nanoparticles (AuNPs) were synthesized, stabilized by polyethylene glycol (PEG), functionalized, and covalently conjugated with RNase A. The physicochemical properties of engineered nanobiomedicine (AuNPs-PEG-RNase A) were characterized by scanning electron microscope (SEM), dynamic light scattering (DLS), and UV-vis spectrum. Then, its biological impacts including cell viability, apoptosis, and ROS production were evaluated in the SW-480 cells. The engineered nanobiomedicine, AuNPs-PEG-RNase A, was found to effectively induce apoptosis in SW-480 cells and result in a significant reduction in cancer cell viability. Besides, the maximum production of ROS was obtained after the treatment of cells with an IC50 dose of AuNPs-PEG-RNase A. Based on the efficient ROS-responsiveness and the anticancer activity of RNase A of the engineered nanomedicine, this nanoscaled biologics may be considered as a potential candidate for the treatment of CRC.
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http://dx.doi.org/10.15171/bi.2020.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977588PMC
July 2019

The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation.

J Cell Physiol 2020 06 17;235(6):5072-5083. Epub 2020 Jan 17.

INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Université Paris 13, Paris, France.

Embryoid bodies (EBs) are the three-dimensional aggregates of pluripotent stem cells that are used as a model system for the in vitro differentiation. EBs mimic the early stages of embryogenesis and are considered as a potential biomimetic body in tuning the stem cell fate. Although EBs have a spheroid shape, they are not formed accidentally by the agglomeration of cells; they are formed by the deliberate and programmed aggregation of stem cells in a complex topological and biophysical microstructure instead. EBs could be programmed to promisingly differentiate into the desired germ layers with specific cell lineages, in response to intra- and extra-biochemical and biomechanical signals. Hippo signaling and mechanotransduction are the key pathways in controlling the formation and differentiation of EBs. The activity of the Hippo pathway strongly relies on cell-cell junctions, cell polarity, cellular architecture, cellular metabolism, and mechanical cues in the surrounding microenvironment. Although the Hippo pathway was initially thought to limit the size of the organ by inhibiting the proliferation and the promotion of apoptosis, the evidence suggests that this pathway even regulates stem cell self-renewal and differentiation. Considering the abovementioned explanations, the present study investigated the interplay of the Hippo signaling pathway, mechanotransduction, differentiation, and proliferation pathways to draw the molecular network involved in the control of EBs fate. In addition, this study highlighted several neglected critical parameters regarding EB formation, in the interplay with the Hippo core component involved in the promising differentiation.
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http://dx.doi.org/10.1002/jcp.29455DOI Listing
June 2020

Identification of mutations in and genes associated with prolificacy of Markhoz goats.

Arch Anim Breed 2019 14;62(2):565-570. Epub 2019 Oct 14.

School of Advanced Medical Sciences, Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.

The Markhoz is a local goat breed in the Kurdistan region of Iran. The mohair obtained from these animals plays an important cultural role and is used for making local clothes in the Kurdistan region. This breed is a low-fecundity local goat, and searching for genes associated with fertility of these goats is important for their breeding. Moreover, this research is complementary to prior studies of candidate genes associated with fertility. The growth differentiation factor 9 () and bone morphogenetic protein 15 () are attractive candidates expressed by the oocyte and are associated with increased ovulation rate in sheep. However, there are no reports on single nucleotide polymorphisms associated with fertility of Markhoz goats. Hence, we studied these candidate genes and found two novel mutations (g.233C A and g.755T G) in exon I and in exon II, respectively. Furthermore, we investigated their association with prolificacy. These nucleotide changes are detectable with the PCR-RFLP method and can be used in the screening for highly fecund goats. Both of the mutations significantly increased litter size in heterozygote form for and homozygote form for in this goat breed. Homozygote females for the mutation were not identified in the Markhoz breed, which is similar to the situation found in Belclare sheep, small-tailed Han sheep, and Jining Grey goats.
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http://dx.doi.org/10.5194/aab-62-565-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853135PMC
October 2019

Modulatory Role of Vaginal-Isolated Lactococcus lactis on the Expression of miR-21, miR-200b, and TLR-4 in CAOV-4 Cells and In Silico Revalidation.

Probiotics Antimicrob Proteins 2020 09;12(3):1083-1096

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Ovarian cancer (OC) is a leading cause of death among women worldwide. Various evidences suggest that oncomiRs and Toll-like receptor 4 (TLR-4) signaling pathways appear to be key players in the initiation and progression of OC. It seems there exists a continuous intercommunication between cancer cells and normal microbiota of the vagina. The biological impacts of vaginal isolated lactococcus lactis on CAOV-4 cells were investigated using several molecular biology experiments, including flow cytometry, DAPI staining, DNA ladder, and scratch assay. The expression of microRNAs (miRNAs/miRs) 21, 200b, and TLR-4 in the CAOV-4 cells was also evaluated by the real-time RT-PCR assay. Furthermore, an integrative in silico analysis was conducted using normalized web-available microarray data (GSE14407) to revalidate the experimental findings and identify potential biomarkers in ovarian cancer. Protein-protein interactions (PPIs) network was studied by means of the STRING database using Cytoscape v3.6.1. The miRNA target genes were identified using the dbDEMC v2.0, miRTarBase, and miRDB databases. Our data demonstrated that L. lactis probiotic candidate downregulates TLR-4, miR-21, and miR-200b expression levels, which correlates with induction of apoptosis as confirmed by DAPI staining, DNA ladder assay, annexin V/PI staining, and inhibition of migration validated by scratch assay. By in silico analysis, several targets (miR-17-5p-BCL2, miR-21-5p-MKNK2, miR-129-5p-CDK6) were identified, while BCL2, CCNB1, and VEGFA were found as the hub proteins in the miRNA-target and PPI networks. Further, downregulation of the TLR-4, miR-21, and miR-200b was partially validated by the in silico analysis. Based on our findings, the vaginal isolated probiotic strain presents great potential to control the ovarian cancer which may provide beneficial impact on the clinical management of ovarian cancer.
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http://dx.doi.org/10.1007/s12602-019-09596-9DOI Listing
September 2020

Isolation of a Novel Anti-KDR3 Single-chain Variable Fragment Antibody from a Phage Display Library.

Iran J Allergy Asthma Immunol 2019 Jun 8;18(3):289-299. Epub 2019 Jun 8.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran AND Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Vascular endothelial growth factor receptor 2 (VEGFR-2) is known as one of the important antigens playing a vital role in angiogenesis. In this study, phage display technology (PDT) was used to produce a single-chain variable fragment (scFv) antibody against a region of the domain 3 in VEGFR-2 called kinase insert domain receptor 3 (KDR3). After designing the KDR3 peptide and biopanning, a colony was chosen for scFv antibody expression. Following expression and purification; western blotting, dot blotting and immunofluorescence (IF) were used to evaluate the antibody function. Surface plasmon resonance (SPR) was also employed to measure affinity of produced antibody. Once a colony was selected and transferred to the expression host, the scFv antibody was expressed in the expected range of 28 kDa. Using a designed chromatography column, antibody purification was found to be about 95%. In this study, a novel scFv with the capability of binding to KDR3 was isolated and purified and its intracellular function was investigated and verified.
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http://dx.doi.org/10.18502/ijaai.v18i3.1122DOI Listing
June 2019

The conundrum of dietary antioxidants in cancer chemotherapy.

Nutr Rev 2020 01;78(1):65-76

R. Ilghami and M. R. Mashayekhi are with the Department of Genetics, Faculty of Basic Science, Tabriz Branch, Islamic Azad University, Tabriz, Iran. A. Barzegari is with the Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran. D. Letourneur, M. Crepin, and G. Pavon-Djavid are with the INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France.

Although chemotherapy succeeds in reducing tumor burden, the efficacy is limited due to acquired drug resistance and often irreparable side effects. Studies show that antioxidants may influence the response to chemotherapy and its side effects, although their use remains controversial. The evidence shows that some chemo-drugs induce oxidative stress and lead to normal tissue apoptosis and the entry of cancer cells to a dormant G0 state. Through the suppression of oxidative stress, antioxidants could protect normal cells and bring the tumor out of dormancy so as to expose it to chemotherapies. This review is focused on the redox biology of cancer/normal cells and association of reactive oxygen species with drug resistance, cancer dormancy, and side effects. To this end, evidence from cellular, animal, and clinical studies is provided to better understand the conundrum of dietary antioxidants in cancer chemotherapy.
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http://dx.doi.org/10.1093/nutrit/nuz027DOI Listing
January 2020

Investigation the effect of oleoylethanolamide supplementation on the abundance of Akkermansia muciniphila bacterium and the dietary intakes in people with obesity: A randomized clinical trial.

Appetite 2019 10 24;141:104301. Epub 2019 May 24.

Nutrition Research Center, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Akkermansia muciniphila bacterium is one of the inhabitant gut microbiota involving in the energy homeostasis and inhibition of the inflammations. The present study was designed to evaluate the effects of Oleoylethanolamide (OEA) supplementation on the abundance of A. muciniphila and the dietary intakes in obese people. In this randomized, double-blind, controlled clinical trial, 60 eligible obese people were selected and divided randomly into two groups including OEA group (received two capsules containing 125 mg of OEA daily) and placebo group (received two capsules containing 125 mg of starch daily). The treatment lasted for 8 weeks. Dietary intakes were evaluated according to the three -day food record and, were analyzed by the Nutritionist 4 software. In order to evaluate the changes in the abundance of A. muciniphila bacterium, faeces samples were collected at baseline and at the end of study. The targeting of the 16S rRNA gene in A. muciniphila was measured by the quantitative real-time PCR analysis. For OEA group, the energy and carbohydrate intakes decreased significantly after adjusting for baseline values and confounder factors; (p = 0.035), the amount of carbohydrate was reported as 422.25 (SD = 103.11) gr and 368.44 (SD = 99.08) gr; (p = 0.042)), before and after the treatment, respectively. The abundance of A. muciniphila bacterium increased significantly in OEA group compared to placebo group (p < 0.001). Considering the accumulating evidence identified OEA as a novel, safe, and efficacious pharmaceutical agent increasing the abundance of A. muciniphila bacterium and modifying the energy balance, therefore it is suggested to use its supplement for treatment of the obese people. However, future studies are needed to confirm the positive results obtained in this study.
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http://dx.doi.org/10.1016/j.appet.2019.05.032DOI Listing
October 2019

Purification of a Novel Anti-VEGFR2 Single Chain Antibody Fragment and Evaluation of Binding Affinity by Surface Plasmon Resonance.

Adv Pharm Bull 2019 Feb 21;9(1):64-69. Epub 2019 Feb 21.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The single-chain variable fragment (scFv) domain of antibodies is now considered as one of the therapeutic tools that can be produced by phage display technology (PDT). Antibody purification is one of the most important steps in antibodies production. The aim of study was purification and characterization of anti-VEGFR2 scFv antibody fragments. After the coating of vascular endothelial growth factor receptor 2 (VEGFR2) peptide in ELISA microplates, the phage display library of Tomlinson was used for antibody isolation. The targeted scFv was purified by chromatography using a zeolite-based column. The purity and functional assessment of purified scFv were evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting techniques, respectively. Affinity binding was evaluated by surface plasmon resonance (SPR). The desired scFv was selected after four stages of biopanning. SDS-PAGE analysis showed a 28 kDa scFv with high purity (>90%). The western bloting analysis confirmed the binding of produced scFv antibody to the desired peptide. The affinity binding of scFv antibody analyzed by SPR was about 60 μM. In this study, the novel scFv antibody against VEGFR2 peptide was purified by chromatography column containing zeolite. Based on our findings the produced antibody may be applied for diagnosis or targeting of VEGFR2 in antibody-based therapy strategies.
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http://dx.doi.org/10.15171/apb.2019.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468230PMC
February 2019

Isolation and characterization of a novel scFv antibody fragments specific for Hsp70 as a tumor biomarker.

J Cell Biochem 2019 09 18;120(9):14711-14724. Epub 2019 Apr 18.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Many studies have shown that more than 50% of tumors express heat shock protein 70 kDa (Hsp70) at the plasma membrane surface while not seen in normal cells, therefore it is a promising therapeutic target in human cancers. Hence, we used phage display technology to produce a single-chain fragment variable (scFv) antibody against human Hsp70. For this, a target peptide from human Hsp70 was designed using bioinformatics studies and was chemically synthesized. Then, the selection was performed using four rounds of biopanning with a stepwise decreased amount of the target peptide. Fourteen positive scFv clones were selected using monoclonal phage enzyme-linked immunosorbent assay screening, which was further characterized by means of the polymerase chain reaction and DNA sequencing. Among them, the G6 clone was selected to express scFv into the Escherichia coli. Expression and purification of the scFv shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and confirmed by Western blot analysis. In silico analysis confirmed specific binding of the scFv to Hsp70 in CDR regions. The specificity of the scFv measured by surface plasmon resonance and immunofluorescence of the A549 human lung carcinoma cell line confirmed the in vitro function of the scFv. Based upon these findings, we propose a novel anti-human Hsp70 scFv as potential immunotherapy agents that may be translated into preclinical/clinical applications.
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http://dx.doi.org/10.1002/jcb.28732DOI Listing
September 2019

Apoptotic Effect of Saccharomyces cerevisiae on Human Colon Cancer SW480 Cells by Regulation of Akt/NF-ĸB Signaling Pathway.

Probiotics Antimicrob Proteins 2020 03;12(1):311-319

Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Drug resistance is one of the major problems, which causes recurrence of cancers. Therefore, complementary treatments are needed to improve the impacts of chemotherapy agents. The effect of probiotics as cancer-preventing agents through involvement in the activation of apoptotic pathways has been established. The present study sought to investigate how the heat-killed form of Saccharomyces cerevisiae (as a probiotic) could affect the Akt/NF-kB-induced apoptosis in colon cancer cells, the SW480 cell line. The cytotoxic effects of heat-killed yeast (HKY) and 5-fluorouracil (5-FU, as a positive control drug) were assayed using the MTT method. Morphological changes followed by apoptosis were examined using DAPI staining. The transcription and translation level of apoptosis genes were explored with qRT-PCR and western blotting. The data were analyzed using GraphPad Prism V6.0 Software. The results showed that HKY could induce apoptosis in colon cancer cell line through downregulation of p-Akt1, Rel A, Bcl-XL, pro-caspase 3, and pro-caspase 9 expressions, and upregulation of BAX, cleaved caspase-3, and cleaved caspase-9. Besides, Akt protein expression was not affected. It is noticeable that HKY had a better modulating effect on BAX expression compared with 5-FU. It was able to modulate Akt/NF-kB signaling pathway followed by the apoptotic cascade.
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http://dx.doi.org/10.1007/s12602-019-09528-7DOI Listing
March 2020

Evaluation of ovarian cancer risk in granulosa cells treated with steroid-depleted endometriosis serum: Role of NF-κB/RelA and AKT.

J Cell Physiol 2019 07 4;234(7):12011-12018. Epub 2018 Dec 4.

Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Despite at the beginning known as a benign disease, endometriosis is defined as a risk factor for developing ovarian carcinoma. The effect of endometriosis on ovarian malignancy is known but its role in granulosa cell tumor is still unclear.

Methods And Materials: In this study, serum samples were collected from patients with endometriosis and divided into whole and steroid-depleted groups. Desertification was performed according to the charcoal-dextran protocol and sera were added to the culture media of granulosa cells retrieved from tubal or male factor infertile women. Quantitative real-time polymerase chain reaction and flow cytometry were performed to determine the expression level of inflammatory and apoptotic genes and apoptosis level of granulosa cells. The total concentration of lipid was measured using gas chromatography method in the granulosa cells.

Results: Results revealed that the expression of AKT and NF-κB/RelA gene was significantly higher in the granulosa cells treated with steroid-depleted serum obtained from patients with distrificated endometriosis (DE) compared with the control group (9.39- and 7.9-folds, respectively; p < 0.0001). In the DE group, the declined pattern of expression was observed for the genes related to apoptosis. The synthesis of saturated fatty acids was significantly decreased; however, unsaturated fatty acids showed increased levels in the DE group.

Conclusion: The effect of steroids on endometriosis is contradictory. The level of cortisol and sex hormones could be affected by endometriosis, causing alterations of the disease progression. Reduced level of steroid hormones in patients with endometriosis may be considered as a critical risk factor for granulosa cell tumor.
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http://dx.doi.org/10.1002/jcp.27862DOI Listing
July 2019

Effect of Lactobacillus Rhamnosus on serum uremic toxins (phenol and P-Cresol) in hemodialysis patients: A double blind randomized clinical trial.

Clin Nutr ESPEN 2018 12 5;28:158-164. Epub 2018 Sep 5.

Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Uremic toxins such as p-cresol and phenol are suggested to be associated with higher mortality in hemodialysis patients. The aim of this study was to investigate the effects of probiotics on some serum uremic toxin levels in hemodialysis patients.

Methods: Patients undergoing hemodialysis in a university dialysis center were enrolled in this randomized controlled double blind clinical trial. The patients received probiotic (Lactobacillus Rhamnosus) for duration of 4 weeks. All data were presented as the mean ± SD. Statistical analyses were performed by SPSS statistical software. Paired t-test was used to compare pre- and post-treatment p-cresol levels. P values less than .05 were considered statistically significant.

Results: A total of 42 hemodialysis patients (32 male and 10 female) were enrolled in this study. The mean ± SD age of the patients in Lactobacillus Rhamnosus and placebo groups were 57.05 ± 13.96 and 59.67 ± 15.04 years, respectively. Values of uremic toxins before treatment did not differ statistically between groups but they were significantly lower in Lactobacillus Rhamnosus group compared with placebo group (P < .05). Total Phenol and p-cresol levels were associated with sodium, energy, carbohydrate, fat and protein intake and fiber consumption, accompanying by hemodialysis hours per week in linear regression analyses.

Conclusions: This study demonstrated that probiotics could be a promising target in hemodialysis patients with the capability of decreasing serum phenolic uremic toxins in this population.

Trial Registration: IRCT20154182017N21 Date:09/12/2016.
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http://dx.doi.org/10.1016/j.clnesp.2018.08.010DOI Listing
December 2018

Astaxanthin-Loaded Nanostructured Lipid Carriers for Preservation of Antioxidant Activity.

Molecules 2018 Oct 11;23(10). Epub 2018 Oct 11.

INSERM U1148, Laboratory for Vascular Translational Science, University Paris 13, Sorbonne Paris Cit. 99, Av. Jean-Baptiste Clément, 93430 Villetaneuse, France.

Astaxanthin is a xanthophyll carotenoid showing efficient scavenging ability and represents an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies. However, its high lipophilicity and thermolability often limits its antioxidant efficacy in human applications. Here, we developed a formulation of lipid carriers to protect astaxanthin's antioxidant activity. The synthesis of natural astaxanthin-loaded nanostructured lipid carriers using a green process with sunflower oil as liquid lipid is presented. Their antioxidant activity was measured by α-Tocopherol Equivalent Antioxidant Capacity assay and was compared to those of both natural astaxanthin and α-tocopherol. Characterizations by dynamic light scattering, atomic force microscopy, and scattering electron microscopy techniques were carried out and showed spherical and surface negative charged particles with z-average and polydispersity values of ~60 nm and ~0.3, respectively. Astaxanthin loading was also investigated showing an astaxanthin recovery of more than 90% after synthesis of nanostructured lipid carriers. These results demonstrate the capability of the formulation to stabilize astaxanthin molecule and preserve and enhance the antioxidant activity.
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http://dx.doi.org/10.3390/molecules23102601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222411PMC
October 2018

Isolation and molecular identification of Lactobacillus with probiotic potential from abomasums driven rennet.

Food Chem 2019 Jan 20;272:709-714. Epub 2018 Aug 20.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Lactobacillus species are beneficial for the functional food industry and preventive medicine. The complex microflora of traditional cheese depends on the cheese types (e.g., homemade rennets). Here, the abomasum driven rennet was assessed for the existence of lactobacilli. For differentiating lactobacilli, the bacterial suspension was screened for the acid and bile resistance. The isolated bacteria were evaluated for antibiotic susceptibility and antagonistic impacts on other pathogenic bacteria. The 16S rDNA gene was evaluated by the amplified ribosomal DNA restriction analysis (ARDRA) recruiting the restriction enzyme Taq I and compared to the virtually digested patterns of previous reports on lactobacilli. The isolates were examined by random amplified polymorphic DNA (RAPD) and distinctive lactobacilli were sequenced. ARDRA and RAPD data showed three distinct lactobacilli strains, including L. acidophilus, L. planetarum, and L. fermentum. The homemade rennet is proposed as the novel source of probiotic strains as an alternative to the traditional cheeses.
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http://dx.doi.org/10.1016/j.foodchem.2018.08.081DOI Listing
January 2019

Stable transformation of Spirulina (Arthrospira) platensis: a promising microalga for production of edible vaccines.

Appl Microbiol Biotechnol 2018 Nov 29;102(21):9267-9278. Epub 2018 Aug 29.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

The planktonic blue-green microalga Spirulina (Arthrospira) platensis possesses important features (e.g., high protein and vital lipids contents as well as essential vitamins) and can be consumed by humans and animals. Accordingly, this microalga gained growing attention as a new platform for producing edible-based pharmaceutical proteins. However, there are limited successful strategies for the transformation of S. platensis, in part because of an efficient expression of strong endonucleases in its cytoplasm. In the current work, as a pilot step for the expression of therapeutic proteins, an Agrobacterium-based system was established to transfer gfp:gus and hygromycin resistance (hyg) genes into the genome of S. platensis. The presence of acetosyringone in the transfection medium significantly reduced the transformation efficiency. The PCR and real-time RT-PCR data confirmed the successful integration and transcription of the genes. Flow cytometry and β-glucuronidase (GUS) activity experiments confirmed the successful production of GFP and the enzyme. Moreover, the western blot analysis showed a ~ 90 kDa band in the transformed cells, indicating the successful production of the GFP:GUS protein. Three months after the transformation, the gene expression stability was validated by histochemical, flow cytometry, and hygromycin B resistance analyses.
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http://dx.doi.org/10.1007/s00253-018-9296-7DOI Listing
November 2018

Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination.

Gastric Cancer 2019 01 25;22(1):23-36. Epub 2018 Aug 25.

Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Helicobacter pylori affect around 50% of the population worldwide. More importantly, the gastric infection induced by this bacterium is deemed to be associated with the progression of distal gastric carcinoma and gastric mucosal lymphoma in the human. H. pylori infection and its prevalent genotype significantly differ across various geographical regions. Based on numerous virulence factors, H. pylori can target different cellular proteins to modulate the variety of inflammatory responses and initiate numerous "hits" on the gastric mucosa. Such reactions lead to serious complications, including gastritis and peptic ulceration, gastric cancer and gastric mucosa-associated lymphoid structure lymphoma. Therefore, H. pylori have been considered as the type I carcinogen by the Global Firm for Research on Cancer. During the two past decades, different reports revealed that H. pylori possess oncogenic potentials in the gastric mucosa through a complicated interplay between the bacterial factors, various facets, and the environmental factors. Accordingly, numerous signaling pathways could be triggered in the development of gastrointestinal diseases (e.g., gastric cancer). Therefore, the main strategy for the treatment of gastric cancer is controlling the disease far before its onset using preventive/curative vaccination. Increasing the efficiency of vaccines may be achieved by new trials of vaccine modalities, which is used to optimize the cellular immunity. Taken all, H. pylori infection may impose severe complications, for resolving of which extensive researches are essential in terms of immune responses to H. pylori. We envision that H. pylori-mediated diseases can be controlled by advanced vaccines and immunotherapies.
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http://dx.doi.org/10.1007/s10120-018-0867-1DOI Listing
January 2019

Apelin, a promising target for Alzheimer disease prevention and treatment.

Neuropeptides 2018 Aug 23;70:76-86. Epub 2018 May 23.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high outbreak rates. It is estimated that about 35 million individuals around the world suffered from dementia in 2010. AD is expected to increase twofold every 20 years and, by 2030, approximately 65 million people could suffer from this illness. AD is determined clinically by a cognitive impairment and pathologically by the production of amyloid beta (Aβ), neurofibrillary tangles, toxic free radicals and inflammatory mediators in the brain. There is still no treatment to cure or even alter the progressive course of this disease; however, many new therapies are being investigated and are at various stages of clinical trials. Neuropeptides are signaling molecules used by neurons to communicate with each other. One of the important neuropeptides is apelin, which can be isolated from bovine stomach. Apelin and its receptor APJ have been shown to broadly disseminate in the neurons and oligodendrocytes of the central nervous system. Apelin-13 is known to be the predominant neuropeptide in neuroprotection. It is involved in the processes of memory and learning as well as the prevention of neuronal damage. Studies have shown that apelin can directly or indirectly prevent the production of Aβ and reduce its amounts by increasing its degradation. Phosphorylation and accumulation of tau protein may also be inhibited by apelin. Apelin is considered as an anti-inflammatory agent by preventing the production of inflammatory mediators such as interleukin-1β and tumor necrosis factor alpha. It has been shown that in vivo and in vitro anti-apoptotic effects of apelin have prevented the death of neurons. In this review, we describe the various functions of apelin associated with AD and present an integrated overview of recent findings that, in general, recommend apelin as a promising therapeutic agent in the treatment of this ailment.
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http://dx.doi.org/10.1016/j.npep.2018.05.008DOI Listing
August 2018
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