Publications by authors named "Shirin Eyvazi"

31 Publications

The role of circadian genes in the pathogenesis of colorectal cancer.

Gene 2021 Dec 19;804:145894. Epub 2021 Aug 19.

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Colorectal cancer (CRC) is the third most frequent cancer in human beings and is also the major cause of death among the other gastrointestinal cancers. The exact mechanisms of CRC development in most patients remains unclear. So far, several genetically, environmental and epigenetically risk factors have been identified for CRC development. The circadian rhythm is a 24-h rhythm that drives several biologic processes. The circadian system is guided by a central pacemaker which is located in the suprachiasmatic nucleus (SCN) in the hypothalamus. Circadian rhythm is regulated by circadian clock genes, cytokines and hormones like melatonin. Disruptions in biological rhythms are known to be strongly associated with several diseases, including cancer. The role of the different circadian genes has been verified in various cancers, however, the pathways of different circadian genes in the pathogenesis of CRC are less investigated. Identification of the details of the pathways in CRC helps researchers to explore new therapies for the malignancy.
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http://dx.doi.org/10.1016/j.gene.2021.145894DOI Listing
December 2021

Colorectal cancer treatment using bacteria: focus on molecular mechanisms.

BMC Microbiol 2021 07 19;21(1):218. Epub 2021 Jul 19.

Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran.

Background: Colorectal cancer which is related to genetic and environmental risk factors, is among the most prevalent life-threatening cancers. Although several pathogenic bacteria are associated with colorectal cancer etiology, some others are considered as highly selective therapeutic agents in colorectal cancer. Nowadays, researchers are concentrating on bacteriotherapy as a novel effective therapeutic method with fewer or no side effects to pay the way of cancer therapy. The introduction of advanced and successful strategies in bacterial colorectal cancer therapy could be useful to identify new promising treatment strategies for colorectal cancer patients.

Main Text: In this article, we scrutinized the beneficial effects of bacterial therapy in colorectal cancer amelioration focusing on different strategies to use a complete bacterial cell or bacterial-related biotherapeutics including toxins, bacteriocins, and other bacterial peptides and proteins. In addition, the utilization of bacteria as carriers for gene delivery or other known active ingredients in colorectal cancer therapy are reviewed and ultimately, the molecular mechanisms targeted by the bacterial treatment in the colorectal cancer tumors are detailed.

Conclusions: Application of the bacterial instrument in cancer treatment is on its way through becoming a promising method of colorectal cancer targeted therapy with numerous successful studies and may someday be a practical strategy for cancer treatment, particularly colorectal cancer.
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http://dx.doi.org/10.1186/s12866-021-02274-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287294PMC
July 2021

Recent Advances on Immune Targeted Therapy of Colorectal Cancer Using bi-Specific Antibodies and Therapeutic Vaccines.

Biol Proced Online 2021 Jul 1;23(1):13. Epub 2021 Jul 1.

Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran.

Colorectal cancer (CRC) is a universal heterogeneous disease that is characterized by genetic and epigenetic alterations. Immunotherapy using monoclonal antibodies (mAb) and cancer vaccines are substitute strategies for CRC treatment. When cancer immunotherapy is combined with chemotherapy, surgery, and radiotherapy, the CRC treatment would become excessively efficient. One of the compelling immunotherapy approaches to increase the efficiency of CRC therapy is the deployment of therapeutic mAbs, nanobodies, bi-specific antibodies and cancer vaccines, which improve clinical outcomes in patients. Also, among the possible therapeutic approaches for CRC patients, gene vaccines in combination with antibodies are recently introduced as a new perspective. Here, we aimed to present the current progress in CRC immunotherapy, especially using Bi-specific antibodies and dendritic cells mRNA vaccines. For this aim, all data were extracted from Google Scholar, PubMed, Scopus, and Elsevier, using keywords cancer vaccines; CRC immunotherapy and CRC mRNA vaccines. About 97 articles were selected and investigated completely based on the latest developments and novelties on bi-specific antibodies, mRNA vaccines, nanobodies, and MGD007.
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http://dx.doi.org/10.1186/s12575-021-00147-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245152PMC
July 2021

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

Exp Mol Pathol 2021 Oct 21;122:104664. Epub 2021 Jun 21.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.
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http://dx.doi.org/10.1016/j.yexmp.2021.104664DOI Listing
October 2021

Long non-coding RNAs as potential biomarkers in the prognosis and diagnosis of lung cancer: A review and target analysis.

IUBMB Life 2021 02 24;73(2):307-327. Epub 2020 Dec 24.

Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Science, Tabriz, Iran.

Long non-coding RNAs (lncRNA) have been emerged as a novel class of molecular regulators in cancer. They are dysregulated in many types of cancer; however, there is not enough knowledge available on their expression and functional profiles. Lung cancer is the leading cause of the cancer deaths worldwide. Generally, lncRNAs may be associated with lung tumor pathogenesis and they may act as biomarkers for the cancer prognosis and diagnosis. Compared to other invasive prognostic and diagnostic methods, detection of lncRNAs might be a user-friendly and noninvasive method. In this review article, we selected 27 tumor-associated lncRNAs by literature reviewing to further discussing in detail for using as diagnostic and prognostic biomarkers in lung cancer. Also, in an in silico target analysis, the "Experimentally supported functional regulation" approach of the LncTarD web tool was used to identifying the target genes and regulatory mechanisms of the selected lncRNAs. The reports on diagnostic and prognostic potential of all selected lncRNAs were discussed. However, the target genes and regulatory mechanisms of the 22 lncRNAs were identified by in silico analysis and we found the pathways that are controlled by each target group of lncRNAs. They use epigenetic mechanisms, ceRNA mechanisms, protein interaction and sponge mechanism. Also, 10, 23, 5, and 28 target genes for each of these mechanisms were identified, respectively. Finally, each group of target genes controls 50, 12, 7, and 2 molecular pathways, respectively. In conclusion, LncRNAs could be used as biomarkers in lung cancer due to their roles in control of several signaling pathways related to lung tumors. Also, it seems that lncRNAs, which use epigenetic mechanisms for modulating a large number of pathways, could be considered as important subjects for lung cancer-related diagnostic and prognostic biomarkers.
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http://dx.doi.org/10.1002/iub.2430DOI Listing
February 2021

Potential Roles of MyomiRs in Cardiac Development and Related Diseases.

Curr Cardiol Rev 2021 ;17(4):e010621188335

Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.

Muscle-specific miRNAs, which are known as MyomiRs, are crucial regulatory elements for cardiovascular development. MyomiRs are abundantly expressed in the myocardium and regulate certain aspects of physiological and pathological processes in myocardiocytes, including cardiovascular development, myocardial remodeling, and arise for cardiovascular diseases through different mechanisms, such as epigenetic pathways. Clinical and experimental studies have confirmed the myomiRs as promising diagnostic biomarkers for the early diagnosis of cardiac disorders. In this review, we have summarized recent findings in the field of epigenetic modulations of myomiRs and cardiac regeneration associated with cardiac diseases.
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http://dx.doi.org/10.2174/1573403X16999201124201021DOI Listing
October 2021

Recent developments in antibody derivatives against colorectal cancer; A review.

Life Sci 2021 Jan 19;265:118791. Epub 2020 Nov 19.

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular & Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Colorectal cancer (CRC) is the fourth most common cause of cancer and mortality worldwide and is the third most common cancer in men and women. Surgery, radiotherapy, and chemotherapy are conventionally used for the treatment of colorectal cancer. However, these methods are associated with various side effects on normal cells. Thus, new studies are moving towards more effective and non-invasive methods for treatment of colorectal cancer. Targeted therapy of CRC is a promising new approach to enhance the efficiency and decrease the toxicity of the treatment. In targeted therapy of CRC, antibody fragments can directly inhibit tumor cell growth and proliferation. They also can act as an ideal carrier for targeted delivery of anticancer drugs. In the present study, the structure and function of different formats of antibody fragments, immune-targeted therapy of CRC using antibody fragments will be discussed.
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http://dx.doi.org/10.1016/j.lfs.2020.118791DOI Listing
January 2021

Recent Advances in Therapeutic Peptides for Breast Cancer Treatment.

Curr Protein Pept Sci 2021 ;22(1):74-88

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Breast cancer is a heterogeneous malignancy and is the second leading cause of mortality among women around the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapeutic approaches for the treatment of this malignancy. Among the novel methods, therapeutic peptides that target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acid monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides, such as specific binding on tumor cells surface, low molecular weight, and low toxicity on normal cells, make the peptides appealing therapeutic agents against solid tumors, particularly breast cancer. Also, the National Institutes of Health (NIH) describes therapeutic peptides as a suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells that can be used in the treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines that have been developed for the treatment of breast cancer.
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http://dx.doi.org/10.2174/1389203721999201117123616DOI Listing
May 2021

Synthesis and application of [email protected] double hydroxide as an anti-inflammatory drugs nanocarrier.

J Nanobiotechnology 2020 Oct 29;18(1):155. Epub 2020 Oct 29.

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

Background: Magnetic nanocomposites with a core-shell nanostructure have huge applications in different sciences especially in the release of the drugs, because of their exclusive physical and chemical properties. In this research, [email protected] double hydroxide [email protected] nanostructure was synthesized by the facile experiment and is used as novel drug nanocarrier.

Methods: Magnetic nanospheres were synthesized by a facile one-step solvothermal route, and then, layered double hydroxide nanoflakes were prepared on the magnetic nanospheres by coprecipitation experiment. The synthesized nanostructures were characterized by FTIR, XRD, SEM, VSM, and TEM, respectively. After intercalation with Ibuprofen and Diclofenac as anti-inflammatory drugs and using exchange anion experiment, the basal spacing of synthesized layered double hydroxides was compared with brucite nanosheets from 0.48 nm to 2.62 nm and 2.22 nm, respectively.

Results: The results indicated that Ibuprofen and Diclofenac were successfully intercalated into the interlay space of LDHs via bridging bidentate interaction. In addition, in-vitro drug release experiments in pH 7.4, phosphate-buffered saline (PBS) showed constant release profiles with Ibuprofen and Diclofenac as model drugs with different lipophilicity, water solubility, size, and steric effect.

Conclusion: The [email protected] and [email protected] had the advantage of the strong interaction between the carboxyl groups with higher trivalent cations by bridging bidentate, clarity, and high thermal stability. It is confirmed that [email protected] multicore-shell nanostructure may have potential application for constant drug delivery.
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http://dx.doi.org/10.1186/s12951-020-00718-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596963PMC
October 2020

Molecular mechanisms associated with quinolone resistance in Enterobacteriaceae: review and update.

Trans R Soc Trop Med Hyg 2020 10;114(10):770-781

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Quinolones are broad-spectrum antibiotics, which are used for the treatment of different infectious diseases associated with Enterobacteriaceae. During recent decades, the wide use as well as overuse of quinolones against diverse infections has led to the emergence of quinolone-resistant bacterial strains. Herein, we present the development of quinolone antibiotics, their function and also the different quinolone resistance mechanisms in Enterobacteriaceae by reviewing recent literature.

Methods: All data were extracted from Google Scholar search engine and PubMed site, using keywords; quinolone resistance, Enterobacteriaceae, plasmid-mediated quinolone resistance, etc.

Results And Conclusion: The acquisition of resistance to quinolones is a complex and multifactorial process. The main resistance mechanisms consist of one or a combination of target-site gene mutations altering the drug-binding affinity of target enzymes. Other mechanisms of quinolone resistance are overexpression of AcrAB-tolC multidrug-resistant efflux pumps and downexpression of porins as well as plasmid-encoded resistance proteins including Qnr protection proteins, aminoglycoside acetyltransferase (AAC(6')-Ib-cr) and plasmid-encoded active efflux pumps such as OqxAB and QepA. The elucidation of resistance mechanisms will help researchers to explore new drugs against the resistant strains.
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http://dx.doi.org/10.1093/trstmh/traa041DOI Listing
October 2020

Transplantation of Stem Cells as a Potential Therapeutic Strategy in Neurodegenerative Disorders.

Curr Stem Cell Res Ther 2021 ;16(2):133-144

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Stem cells are considered to have significant capacity to differentiate into various cell types in humans and animals. Unlike specialized cells, these cells can proliferate several times to produce millions of cells. Nowadays, pluripotent stem cells are important candidates to provide a renewable source for the replacement of cells in tissues of interest. The damage to neurons and glial cells in the brain or spinal cord is present in neurological disorders such as Amyotrophic lateral sclerosis, stroke, Parkinson's disease, multiple sclerosis, Alzheimer's disease, Huntington's disease, spinal cord injury, lysosomal storage disorder, epilepsy, and glioblastoma. Therefore, stem cell transplantation can be used as a novel therapeutic approach in cases of brain and spinal cord damage. Recently, researchers have generated neuron-like cells and glial-like cells from embryonic stem cells, mesenchymal stem cells, and neural stem cells. In addition, several experimental studies have been performed for developing stem cell transplantation in brain tissue. Herein, we focus on stem cell therapy to regenerate injured tissue resulting from neurological diseases and then discuss possible differentiation pathways of stem cells to the renewal of neurons.
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http://dx.doi.org/10.2174/1574888X15666200628141314DOI Listing
October 2021

Epigenetic modifications in gastric cancer: Focus on DNA methylation.

Gene 2020 Jun 18;742:144577. Epub 2020 Mar 18.

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Gastric cancer is a complex heterogeneous disease which is the fourth prevalent malignancy worldwide. Although, several diagnosis and treatment are available for the gastric cancer patients, however the malignancy is still the third leading cause of cancer-related death in the world. Beside the genetic and environmental factors, epigenetic alterations are also involved in the emergence of gastric cancer. Epigenetics alterations are heritable changes which regulate gene expression without occurring changes in DNA sequence. Epigenetic changes mostly include DNA methylation, histon post-translational modifications, chromatin remodeling and non-coding RNAs. Among the mentioned epigenetic modifications, DNA methylation is a major epigenetic process that plays a key role in different stages of evolution and cancer development. In this review, we address all types of related epigenetic modifications in gastric cancer by focus on DNA methylation by reviewing the recent literatures. Understanding of molecular mechanisms of epigenetics alterations in gastric cancer development helps researchers to identify new epigenetic drugs against the malignancy.
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http://dx.doi.org/10.1016/j.gene.2020.144577DOI Listing
June 2020

Evaluation of Mutations in 23S rRNA, rdxA and frxA Genes of Helicobacter pylori in Paraffin-Embedded Gastric Biopsy Specimens from Iranian Gastric Cancer and Gastritis Patients.

J Gastrointest Cancer 2021 Mar;52(1):207-211

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Purpose: Helicobacter pylori (H. pylori) infection is considered as one of the main cause of gastric cancer. Treatment failure of the infection often occurs due to antibiotic resistance. Herein, we aimed to evaluate the mutations in 23S rRNA gene of H. pylori which are associated with clarithromycin resistance and in rdxA and frxA genes of the bacterium which may be associated with metronidazole resistance, in paraffin-embedded gastric biopsies from patients with gastric adenocarcinoma and gastritis in Tabriz, the northwest of Iran.

Methods: In the study, 80 paraffin-embedded tissue sections from 40 gastric cancer and 40 gastritis patients in the Imam Reza hospital, Tabriz, Iran were collected. The existence of ureC gene was verified by PCR method. Genotypical clarithromycin resistance was investigated by real-time PCR method and determination of the melting temperature. PCR reaction and sequencing were used for the evaluation of mutations in rdxA and frxA genes.

Results: The results of ureC amplification showed that DNA of H. pylori was present in the 82.66% of the obtained DNA samples. About 45.16% of samples were resistant to the clarithromycin and 53.22% of them were resistant to the metronidazole. Based on the results from real-time PCR, the frequency of mutations was as follow A2143G 64.28%, A2142G 44.44% and A2142C 1.11%. The mutations of rdxA gene were 66.66% missense, 30.30% frameshift and 3.03% non-sense. The mutations of frxA gene were 36.36% missense, 54.54% frameshift and non-sense 9.09%.

Conclusion: A2143G mutation is the most frequent mutation among clarithromycin resistant genes in Iran. Also, missense and frameshift mutations are frequent in rdxA and frxA genes. Screening for these mutations could help researchers to investigate the most effective anti-H. pylori antibiotics and to prevent antibiotic resistance.
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http://dx.doi.org/10.1007/s12029-020-00386-zDOI Listing
March 2021

The oncogenic roles of bacterial infections in development of cancer.

Microb Pathog 2020 Apr 30;141:104019. Epub 2020 Jan 30.

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Initiation of cancer is interconnected with different factors like infections. It has been estimated that infections, particularly viruses, participate in about 20% of all cancers. Bacteria as the most common infectious agents are also reported to be emerging players in the establishment of malignant cells. Microbial infections are able to modulate host cell transformation for promoting malignant features through the production of carcinogenic metabolites participating in inflammation responses, disruption of cell metabolism, and integrity and also genomic or epigenetic manipulations. It seems that the best example of the role of bacteria in cancer promotion is Helicobacter pylori infection, which is related to gastric cancer. World Health Organization (WHO) describes bacterium as class I carcinogens. Several bacterial infections have been reported in association with prevalent cancers. In this review, we will summarize the role of known bacterial infections in the initiation of the main common cancers, which show high mortality in the world. Examining the microbiomes in cancer patients is important and necessary to better understand the pathogenesis of this disease and also to plan therapeutic interventions.
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http://dx.doi.org/10.1016/j.micpath.2020.104019DOI Listing
April 2020

Critical roles of long noncoding RNAs in breast cancer.

J Cell Physiol 2020 06 17;235(6):5059-5071. Epub 2020 Jan 17.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Breast cancer is a major clinical challenge that affects a wide range of the female population and heavily burdens the health system. In the past few decades, attempts have been made to understand the etiology of breast cancer, possible environmental risk factors, and the genetic predispositions, pathogenesis, and molecular aberrations involved in the process. Studies have shown that breast cancer is a heterogeneous entity; each subtype has its specific set of aberrations in different cell signaling pathways, such as Notch, Wnt/β-catenin, transforming growth factor-β, and mitogen-activated protein kinase pathways. One novel group of molecules that have been shown to be inducted in the regulation of multiple cell signaling pathways is the long noncoding RNAs (lncRNAs). These molecules have important implications in the regulation of multiple signaling pathways by interacting with various genes, affecting the transcription process, and finally, playing roles in posttranslational control of these genes. There is growing evidence that lncRNAs are involved in the process of breast cancer formation by effecting the aforementioned signaling pathways, and that this involvement can have significant diagnostic and prognostic values in clinical contexts. The present review aims to elicit the significance of lncRNAs in the regulation of cell signaling pathways, and the resulting changes in cell survival, proliferation, and invasion, which are the hallmarks of breast cancer.
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http://dx.doi.org/10.1002/jcp.29442DOI Listing
June 2020

Anticancer Impacts of Terminalia catappa Extract on SW480 Colorectal Neoplasm Cell Line.

J Gastrointest Cancer 2021 Mar;52(1):99-105

Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Daneshgah Street, Tabriz, Iran.

Purpose: Colorectal cancer (CRC) is one of the most lethal and prevalent cancers throughout the world. Despite the remarkable advance in the field, drug resistance still remains as an unresolved problem in cancer. Hence, finding effective compounds with minimal side effects to fight cancer is of central priority. Herbal products have been traditionally used to prevent and treat a variety of diseases.

Methods: In the present study, the antitumor effect of Terminalia catappa plant ethanolic extract (TCE) was assessed on SW480 CRC model cell line. In this regard, effects of TCE were evaluated on the proliferation, apoptosis, and migration of SW480 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Annexin V/PI flow cytometry, and scratch tests, respectively. Furthermore, changes in the expression of genes involved in these events including Bax, Bcl-2, Caspase 3, Caspase 8, Caspase 9, MMP-13, miR-21, and miR-34a were measured by quantitative real-time PCR (qRT-PCR).

Results: According to the MTT results, TCE reduced the proliferation of SW480 cells significantly. The flow cytometry test also revealed a notable rate of apoptosis induction after TCE treatment. An inhibitory effect on cell migration was also evident in scratch test. Expression patterns of the assessed genes also changed subsequent to TCE treatment.

Conclusion: The results of this study indicated that T. catappa could be considered as a potential source of anticancer compounds and a candidate for further investigations.
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http://dx.doi.org/10.1007/s12029-019-00349-zDOI Listing
March 2021

MicroRNAs in breast cancer: Roles, functions, and mechanism of actions.

J Cell Physiol 2020 06 14;235(6):5008-5029. Epub 2019 Nov 14.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor-κ B, phosphoinositide-3-kinase/Akt, and extracellular-signal-regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.
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http://dx.doi.org/10.1002/jcp.29396DOI Listing
June 2020

CpG Islands Methylation Analysis of CDH11, EphA5, and HS3ST2 Genes in Gastric Adenocarcinoma Patients.

J Gastrointest Cancer 2020 Jun;51(2):579-583

Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Purpose: Gastric cancer is an aggressive disease which is the fourth prevalent malignancy in the world. Beside the genetic factors, epigenetic alterations such as promoter CpG island hyper methylation are involved in the emergence of gastric cancer. Herein, we investigated the methylation status of CDH11, EphA5, and HS3ST2 genes in patients with and without gastric adenocarcinoma for the first time.

Methods: In the study 40 paraffin-embedded tissue sections from gastric adenocarcinoma patients and 40 specimens from patients with functional dyspepsia were taken. DNA extraction was performed using a modified salting out method. Epizen DNA methylation kit was used to the bisulfite DNA conversion. The methylation status of CDH11, EphA5, and HS3ST2 genes were analyzed by methylation-specific PCR (MSP) technique.

Results: Among the 80 specimens, 71 DNA samples were achieved (34 gastric adenocarcinoma patients and 37 control patients). The results showed that CDH11, EphA5, and HS3ST2 genes are methylated in 28 (82.45%), 19 (55.88%), and 26 (76.47%) of 34 DNA samples from gastric adenocarcinoma patients, respectively, whereas, these genes are methylated in 7 (18.91%), 9 (24.32%) and 7 (18.91%) of 37 samples from noncancerous patients, respectively. Statistical analyses using a chi-squared test showed that there is a statistically significant difference in methylation level of CDH11, EphA5, and HS3ST2 genes between gastric cancer and uncancerous patients (p < 0.05).

Conclusion: To the best of our knowledge, this is the first report on methylation of CDH11, EphA5, and HS3ST2 promoters' in gastric adenocarcinoma patients using MSP. Identification of novel cancer-related molecular mechanisms can be useful in detection of new treatment strategies.
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http://dx.doi.org/10.1007/s12029-019-00290-1DOI Listing
June 2020

Dysregulated expression of STAT1, miR-150, and miR-223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis.

J Cell Biochem 2019 12 18;120(12):19810-19824. Epub 2019 Jul 18.

Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Coronary artery disease (CAD) is a multicellular disease characterized by chronic inflammation. Peripheral blood-mononuclear cells (PBMCs), as a critical component of immune system, actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in perturbed PBMC expression. STAT1 is believed to be relevant to CAD pathogenesis through regulating key inflammatory processes and modulating STAT1 expression play key roles in fine-tuning CAD-related inflammatory processes. This study evaluated PBMC expressions of STAT1, and its regulators (miR-150 and miR-223) in a cohort including 72 patients with CAD with significant ( ≥ 50%) stenosis, 30 patients with insignificant ( < 50%) coronary stenosis (ICAD), and 74 healthy controls, and assessed potential of PBMC expressions to discriminate between patients and controls. We designed quantitative real-time polymerase chain reaction (RT-qPCR) assays and identified stable reference genes for normalizing PBMC quantities of miR-150, miR-223, and STAT1 applying geNorm algorithm to six small RNAs and five mRNAs. There was no significant difference between CAD and ICAD patients regarding STAT1 expression. However, both groups of patients had higher levels of STAT1 than healthy controls. miR-150 and miR-223 were differently expressed across three groups of subjects and were downregulated in patients compared with healthy controls, with the lowest expression levels being observed in patients with ICAD. ROC curves suggested that PBMC expressions may separate between different groups of study subjects. PBMC expressions also discriminated different clinical manifestations of CAD from ICADs or healthy controls. In conclusion, the present study reported PBMC dysregulations of STAT1, miR-150, and miR-223, in patients with significant or insignificant coronary stenosis and suggested that these changes may have diagnostic implications.
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http://dx.doi.org/10.1002/jcb.29286DOI Listing
December 2019

Transient induction of Cdk9 in the early stage of differentiation is critical for myogenesis.

J Cell Biochem 2019 11 30;120(11):18854-18861. Epub 2019 Jun 30.

Molecular Medicine Research Center, Biomedicine institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Cdk9 is a serine-threonine protein kinase that has been recognized as a regulator of cardiac differentiation. Recently, we have reported that transient induction of Cdk9 using noncoding RNA targeting Cdk9 sequences results in efficient cardiac differentiation. Concerning Cdk9 regulatory roles, here, we proposed whether constant overexpression of Cdk9 might influence the differentiation of myoblast C2C12 cells into myotubes. We overexpressed Cdk9 in mouse myoblast C2C12 cells to investigate its regulatory roles on myogenic differentiation. Upon Cdk9 overexpression, the expression level of myogenic regulatory factors was determined. Moreover, the expression profile of three important myomiRs consist of miR 1, 133 and 206 was examined during the differentiation process. Although Cdk9 expression is necessary for inducing differentiation in the early stage of myogenesis, continuous Cdk9 expression inhibits differentiation by modulating myomiRs and myogenic gene expression. Our results indicate that the transient induction of Cdk9 in the early stage of differentiation is critical for myogenesis.
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http://dx.doi.org/10.1002/jcb.29204DOI Listing
November 2019

Antibody-drug therapeutic conjugates: Potential of antibody-siRNAs in cancer therapy.

J Cell Physiol 2019 08 25;234(10):16724-16738. Epub 2019 Mar 25.

Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Codelivery is a promising strategy of targeted delivery of cytotoxic drugs for eradicating tumor cells. This rapidly growing method of drug delivery uses a conjugate containing drug linked to a smart carrier. Both two parts usually have therapeutic properties on the tumor cells. Monoclonal antibodies and their derivatives, such as Fab, scFv, and bsAb due to targeting high potent have now been attractive candidates as drug targeting carrier systems. The success of some therapeutic agents like small interfering RNA (siRNA), a small noncoding RNAs, with having problems such as enzymatic degradation and rapid renal filtration need to an appropriate carrier. Therefore, the aim of this study is to review the recent enhancements in development of antibody drug conjugates (ADCs), especially antibody-siRNA conjugates (SRCs), its characterizations and mechanisms in innovative cancer therapy approaches.
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http://dx.doi.org/10.1002/jcp.28490DOI Listing
August 2019

Expression pattern of miR-21, miR-25 and PTEN in peripheral blood mononuclear cells of patients with significant or insignificant coronary stenosis.

Gene 2019 May 6;698:170-178. Epub 2019 Mar 6.

Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran. Electronic address:

Coronary artery disease (CAD) is primarily caused by atherosclerosis, which is a series of chronic inflammatory processes leading to the initiation and progression of vascular endothelial cell injury enhancing plaque formation. As critical components of the immune system, peripheral blood mononuclear cells (PBMCs) actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in altered PBMC expression pattern. This study explored PBMC expression levels of miR-21, miR-25 and PTEN in patients with angiographically proven significant coronary stenosis (the CAD group), patients with insignificant coronary stenosis (the ICAD group) and healthy subjects, and assessed potentials of PBMC expressions in discriminating groups of study subjects. In-silico analysis was also performed to obtain insights into CAD-related pathways and biological processes that may be influenced by altered miRNA expressions. A reduced level of PBMC miR-21 was observed in the ICAD group compared to the CAD group (P: 0.004) or healthy controls (P: 0.0001). PBMC miR-21 level was negatively correlated with the PTEN expression (Spearman r: -0.43, P: 3.9e-09). The PTEN expression was increased in the CAD or ICAD group compared to the control group (CAD vs. controls P: 0.0003, ICAD vs. controls P: 0.03). A stepwise increase in PBMC miR-25 levels was observed from healthy controls to ICADs and CAD patients (Kruskal-Wallis P: 7.68e-12). PBMC gene expressions had reasonable power to discriminate between pairs of study groups. PBMC miR-21 levels were able to discriminate ICADs from both CADs and controls and miR-25 levels had potentials to differentiate among all pairs of study groups (i.e. CADs-ICADs, CADs-controls, CADs-all other subjects, ICADs-controls). PBMC PTEN expression was able to discriminate patients with CAD or ICAD from control subjects. Overrepresentation enrichment analysis of experimentally validated targets of miR-21 and miR-25 highlighted key biological processes and pathways, such as "angiogenesis" and "leukocyte cell-cell adhesion", that may be influenced by dysregulation of PBMC miR-21 and miR-25. In conclusion, these findings suggest that patients with insignificant coronary stenosis may have a distinct PBMC miRNA expression profile than those with significant stenosis or healthy controls.
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http://dx.doi.org/10.1016/j.gene.2019.02.074DOI Listing
May 2019

Immune therapy of melanoma: Overview of therapeutic vaccines.

J Cell Physiol 2019 Jan 31. Epub 2019 Jan 31.

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Melanoma is the most serious type of skin cancer which develops from the occurrence of genetic mutations in the melanocytes. Based on the features of melanoma tumors such as location, genetic profile and stage, there are several therapeutic strategies including surgery, chemotherapy, and radiotherapy. However, because of the appearance resistance mechanisms, the efficiency of these treatments strategies may be reduced. It has been demonstrated that therapeutic monoclonal antibodies can improve the efficiency of melanoma therapies. Recently, several mAbs, such as nivolumab, pembrolizumab, and ipilimumab, were approved for the immunotherapy of melanoma. The antibodies inhibit immune checkpoint receptors such as CTL4 and pd-1. Another therapeutic strategy for the treatment of melanoma is cancer vaccines, which improve clinical outcomes in patients. The combination therapy using antibodies and gene vaccine give us a new perspective in the treatment of melanoma patients. Herein, we present the recent progressions in the melanoma immunotherapy, especially dendritic cells mRNA vaccines by reviewing recent literature.
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http://dx.doi.org/10.1002/jcp.28181DOI Listing
January 2019

Layered double hydroxide nanoparticles as an appealing nanoparticle in gene/plasmid and drug delivery system in C2C12 myoblast cells.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):436-442

e Department of Chemistry, Faculty of Science , University of Maragheh , Maragheh , Iran.

Gene and drug delivery systems need crucial update in the issue of nanocarriers. Layered double hydroxides (LDHs) are known as biocompatible inorganic lamellar nanomaterials with versatile properties. In the present study, Zn/Al-LDH nanoparticle was synthesized and characterized by FTIR, XRD, SEM, TEM and Zeta potential tests and then intercalated with valproate and methyldopa by co-precipitation and ion exchange methods. These nanocarriers were applied as high activity nanolayers-based delivery systems. On the other hand, Zn/Al-LDH + plasmid/gene (pCEP4/Cdk9) evaluated on C2C12 myoblast cells. Co-operation loading indicated high efficiency of sorting and release of drugs. Additionally, the Real-Time PCR and Western blotting results for plasmid-gene (pCEP4/Cdk9) delivery showed that Zn/Al-LDH nanoparticles can be used as an effective carrier in cellular uptake and release of genes for gene therapy. Easy and cost-effective production of Zn/Al-LDH nanoparticles proposed them as potential alternatives for the traditional routs of drug/gene delivery.
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http://dx.doi.org/10.1080/21691401.2018.1559182DOI Listing
December 2019

CDK9 as an Appealing Target for Therapeutic Interventions.

Curr Drug Targets 2019 ;20(4):453-464

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran.

Cyclin Dependent Kinase 9 (CDK9) as a serine/threonine kinase belongs to a great number of CDKs. CDK9 is the main core of PTEF-b complex and phosphorylates RNA polymerase (RNAP) II besides other transcription factors which regulate gene transcription elongation in numerous physiological processes. Multi-functional nature of CDK9 in diverse cellular pathways proposes that it is as an appealing target. In this review, we summarized the recent findings on the molecular interaction of CDK9 with critical participant molecules to modulate their activity in various diseases. Furthermore, the presented review provides a rationale supporting the use of CDK9 as a therapeutic target in clinical developments for crucial diseases; particularly cancers will be reviewed.
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http://dx.doi.org/10.2174/1389450119666181026152221DOI Listing
May 2020

Overview of CD24 as a new molecular marker in ovarian cancer.

J Cell Physiol 2019 03 14;234(3):2134-2142. Epub 2018 Oct 14.

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women. The high mortality rate is due to lack of early symptoms, late diagnosis, limited treatment options, and also emerging of drug resistance. Todays, molecular markers have become promising in tumor-targeted therapy. Several molecular markers have been known in OC immunotherapy. Identification of the specific molecular markers with prognostic significance is interested. CD24 is a small sialoglycoprotein which is localized in lipid rafts through its glycosylphosphatidylinositol (GPI) anchor. It has been reported that CD24 is overexpressed in many cancers including OC. Also, CD24 is identified as a cancer stem cell marker in OC. The CD24 expression is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in cancer cells is not clearly understood. Recently, CD24 has been identified as an independent prognostic marker of survival in patients with OC. In this study, we reviewed the molecular targets in OC immune-targeted therapy and also presented an overview of the new molecular marker CD24 and its association with the OC by reviewing the recent literature.
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http://dx.doi.org/10.1002/jcp.27581DOI Listing
March 2019

Critical microRNAs in Lung Cancer: Recent Advances and Potential Applications.

Anticancer Agents Med Chem 2018 ;18(14):1991-2005

Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran.

Background: MicroRNAs (miRNAs) play an important role in the regulation of various genes involved in cell growth, development and the maintenance of body homeostasis. They are closely linked to different human diseases, particularly in cancers. Amplification and overexpression of some miRNAs that are called 'oncomiRs' or down-regulation of tumor suppressor miRNAs are associated with genetic alterations that are sufficient to drive tumorigenesis in humans. Lung cancer is the leading cause of cancer-related deaths worldwide. The high mortality rate of lung cancer is not changed even with recent advances in cancer treatment. Several studies demonstrated that miRNAs are involved in the pathogenesis of lung cancer that they negatively or positively regulate gene and protein expression by acting as oncogenes or tumor suppressors.

Objective: This article reviewed the current knowledge on the role of miRNAs and their target genes in lung cancer and discussed the potential use of some miRNAs as novel therapeutic agents in lung cancer.

Method: Firstly, we collected and summarized all research and review and research articles in databases including Scopus and PubMed. Then, we used related keywords that are important to lung cancer target therapy and their diagnostic and prognostic values.

Results: Based on collected articles and research, recognizing critical microRNA and controlling the expression of this microRNA by antagonist oligonucleotides like antagomiRs or anti-miRs and microRNA mimicking will have a remarkable role in treating lung cancer.

Conclusion: Many research studies have shown that a combination of chemotherapy plus knockdown or mimicking microRNA is effective and useful in the cancers treatment like lung cancer.
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http://dx.doi.org/10.2174/1871520618666180808125459DOI Listing
July 2019

Antibody Based EpCAM Targeted Therapy of Cancer, Review and Update.

Curr Cancer Drug Targets 2018 ;18(9):857-868

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Todays, after four decades from the discovery of monoclonal antibodies by Kohler and Milstein in 1975, a dozen of antibodies are used in cancer targeted therapy with different strategies. The success of these antibodies depends on the specificity of antigens expressed on the cancer cells. Epithelial Cell Adhesion Molecule (EpCAM), a homophilic cell-cell adhesion glycoprotein is a well- known tumor antigen, which expresses on epithelial tumors and circulating tumor cells as well as cancer stem cells. The EpCAM signaling pathway is associated with proliferation, differentiation and adhesion of epithelial cancer cells. Here we review EpCAM structure, expression profile and its signaling pathway in cancer cells. In addition, we focused on structure, mechanism of action and success of anti EpCAM antibodies which have been used in different clinical trials. Based on literatures, Edrecolomab showed limited efficacy in the phase III studies. The wholly human monoclonal antibody Adecatumumab is dose- and target-dependent in metastatic breast cancer patients expressing EpCAM. The chimeric antibody, Catumaxomab, has been approved for the treatment of malignant ascites; however, this Mab showed considerable results in intrapleural administration in cancer patients. Anti EpCAM toxin conjugated antibodies like, Oportuzumab Monatox (scFv antibody and Pseudomonas exotoxin A (ETA)), Citatuzumab Bogatox (Fab fragment with bouganin toxin) and immono-conjugate antibody Tucotuzumab (monoclonal antibody with IL2), have shown acceptable results in different clinical trials. Almost, all of the antibodies were well-tolerated; however, still more clinical trials are needed for the approval of antibodies for the treatment of specific tumors.
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http://dx.doi.org/10.2174/1568009618666180102102311DOI Listing
September 2019

Identification of a novel single chain fragment variable antibody targeting CD24-expressing cancer cells.

Immunol Lett 2017 10 1;190:240-246. Epub 2017 Sep 1.

Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

CD24 is a heavy glycosylated protein that is overexpressed in numerous cancer and cancer stem cells. It is involved in the development, invasion, and metastasis of the cancer cells. CD24 can be considered in targeted cancer therapy as a new target. Here, phage display technology was used for the identification of novel scFv antibodies against CD24. To do so, the CD24 protein was expressed and purified from a stable transgenic CHO cell line. The cells were developed by using a CD24 encoding construct, which targets the 18S rRNA gene. The recombinant CD24 was used in the biopanning process. Four rounds of biopanning were performed with the Tomlinson J library. The polyclonal phage ELISA and DNA sequencing of the selected colonies confirmed that specific binders have been enriched during the biopanning process. Based on the DNA sequencing results, three phage-displaying scFv were obtained and their specificity to CD24 was verified in the monoclonal phage ELISA. The results showed that clone 3 (called J) has the highest affinity to CD24 and also is the most abundant clone (80%) among the three clones. Therefore, J was selected for further analyses. In order to produce soluble J-scFv, the phage was transfected to E. coli BL21 pLysS. Soluble J scFv was expressed and purified successfully. The soluble J scFv showed appropriate affinity to recombinant CD24 in the ELISA analysis. Also, the immunocytochemistry experiment showed that the purified J scFv can bind to the CD24 expressing A549 cells. So, the scFv may be useful in the targeted delivery of drugs or diagnostic nanoparticles to the CD24 expressing cancer cells. To the best of our knowledge, this study is the first report to identify an scFv antibody against CD24, using the phage display method.
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http://dx.doi.org/10.1016/j.imlet.2017.08.028DOI Listing
October 2017

Involvement of CD24 in Multiple Cancer Related Pathways Makes It an Interesting New Target for Cancer Therapy.

Curr Cancer Drug Targets 2018 ;18(4):328-336

Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

CD24 (cluster of differentiation 24) is a small heavy glycosylated protein, which is overexpressed in many cancer and some cancer stem cells and is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in these processes is not fully understood, however, in this article, it has been tried to present a collection of cancer-related mechanisms attributed to CD24. Based on the literature, CD24 dis-regulates different signaling pathways in various cancer cells, including; Src kinases, STAT3, EGFR, Wnt/β-catenin and MAPK. Src kinases play an important role in the signaling pathways which activate p38 MAPK and STAT3 pathways. Akt and ERK are downstream effectors of CD24-activated EGFR, which promote cell proliferation, invasion and metastasis. CD24 increases the expression of HER2 by the activation of NF-κB transcription factor. Moreover, CD24 up-regulates the expression of miR-21 oncomir through the activation of Src kinases. Identification of the details of these pathways and also new pathways will help researchers to explore new CD24 targeted therapies.
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http://dx.doi.org/10.2174/1570163814666170818125036DOI Listing
June 2019
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