2024-03-29T12:04:35+04:30 http://ibj.pasteur.ac.ir/browse.php?mag_id=78&slc_lang=en&sid=1
78-1858 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Study Break: Bacterial Cancer Marjan Mohammadi Rarely, do we think of cancer as “bacterial”, such that we are often told that “cancer is NOT contagious” Persistent bacterial infections cause persistent irritation of the host’s defense systems, which when ineffective in eradication of the infection, result in a multitude of self-destructive damages. This in some cases occurs to such severity that the resulting cellular hyper-proliferation provides grounds for increased chances of writing errors (gene mutations) and decreased chances of corrections (gene repair). This is the basis of inflammation-induced cancer where presence of pathogens or other stimuli induce a chronic state of inflammation, yielding an array of defective cycles. Normal flora or pathogen A very popular example is the chronic infection of the vast majority of humans with Helicobacter pylori (Hp). Hp has infected and lived with humans for over 50,000. Such a long history of co-existence has even encouraged some to erroneously categorize Hp, as a member of the “normal flora”.  This scenario would be acceptable, except for the fact that Hp is a major cause of disease in humans. The established Koch’s postulate, firstly by human volunteers and then laboratory animals, disqualified Hp as a member of the normal flora. Since Hp is picked up during childhood, such chronicity of infection (for several decades) allows for several multifaceted interactions to transpire between the “infecting microorganism”, the “infected host” and the “surrounding environment”. The whole of this triad (host/pathogen/environment) constitutes a number of potential susceptibility/risk factors, the combination of which identifies the small fraction (2-3%) of the infected subjects who develop this silent and mortal cancer, at later decades of life. Thus, Hp has been declared as a type I carcinogen, by the International Agency for Cancer Research (IARC) in early 1990’s. Dangers of chronic inflammation Rudolph Virchow (1821-1902), a famous German pathologist, simplified “cancer” as a “wound that never heals”. In the case of Hp infection, the bacteria colonize a very convenient location in the stomach (underneath the mucus layer), where they firmly adhere to the apical lining of the gastric epithelium, while protected from the destructive gastric acid (by means of its alkaline producing urease) and the flood of peristalsis (by means of its multiple array of adhesins; i.e the blood group binding antigen: BabA). The various virulence factors (i.e. CagA, VacA, NapA, HrtA, etc ) produced by Hp pass through the epithelial lining, reaching the bloodstream recruiting the first line of  the heavily-armed troops (the innate immune cells: neutrophils, eosinophils and basophils) to the basal side of the epithelial membrane, with distinct orders to contain and eliminate the infection. However, being unable to reach the invader (Hp) at the apical (luminal) side, they not only fail to eradicate the infection, but the constant supplies of bacterial antigens aggravate them, resulting in the release of their ammunition (defensins, hydrolyzing enzymes, toxic nitrogens and oxygens, etc.), which actually miss the pre-assigned target (Hp) and inflict damages on the surrounding tissue (“active” inflammation). Considering the source of antigens (Hp) remains undefeated on the apical side, the “second line” of defense (adaptive immune cells: antibody producing/helper/cytotoxic lymphocytes) are called in and added to the “first line”. These, too, encounter the same ordeal and end up persisting and releasing their warheads (cytokines, chemokines and antibodies), sustaining “chronic” inflammation. To add insult to injury, Hp expresses antigens (i.e. Lewis histo-group determinants in O-specific chains of its LPS) that mimic host proteins, which may either trigger an auto-immune response, or at least, aid in its camouflage and persistence. Altogether, the body remains under attack by its own troops for as long as the clever invader (pathogen) remains out of reach. CagA: a bacterial oncoprotein Once Hp is securely attached to the apical side of the gastric epithelial membrane, it forms a syringe (type IV secretory system; T4SS: CagM, CagT, Cag3, CagX, CagY), originating from its horizontally acquired cag pathogenicity island (cagPAI), which injects a multi-potential effector protein, namely CagA, into the epithelial cells. CagA (cytotoxin associated gene A) has proven oncogenic in such a multitude of ways that it can rightly stand for “cancer associated gene A”. Upon injection of CagA into epithelial cells, it undergoes two phosphorylation-dependent and –independent pathways which results in alterations in cellular morphology (cytoskeletal rearrangement), proliferation and differentiation. As a consequence, epithelial tight junctions are impaired, the hummingbird phenotype (cell scattering and elongation) is observed and the inflammatory pathways are activated. Moreover, CagA takes part in the aberrant hypermethylation (silencing) of tumor suppressor genes (p53, MGMT, PTEN, p16, etc) and deregulation of cancer-associated microRNAs (miR-21, miR-26a, miR-101, let-7, etc). Gastric oncogenesis It is believed that the intestinal type of gastric adenocarcinoma is the end result of a cascade of histopathologic changes including non-atrophic gastritis, atrophic gastritis, intestinal metaplasia (gastric to intestinal trans-differentiation) and dysplasia (dedifferentiation), which is primarily triggered by Hp infection. At which point during this stepwise process does Hp become dispensable to the carcinogenic process, namely the “point of no return”, remains unclear.  Loss of balance between cellular proliferation and apoptosis may explain the development of a tumor. At the stage of tumor initiation, mutagenic changes take place (including initiation of plasticity; epithelial to mesenchymal transition: EMT). At which time the tight regulation on cellular proliferation, differentiation and survival is lifted, giving way to tumor promotion (mitogenic/epigenetic changes and accumulation of pre-neoplastic cells), followed by tumor progression (higher rates of mutations creating grounds for malignant transformation), eventually leading to metastasis of the neoplastic cell via the bloodstream to distant sites, where additional tumors are established (mesenchymal to epithelial transition: MET) and expanded. Having come to the conclusion that a bacterium (Hp) causes cancer (of the stomach) and stomach cancer is the third leading cause of cancer mortality worldwide, is antibiotic therapy of infected subjects a simplified solution to a very complicated problem?! More details in: Role of Bacteria in Oncogenesis. AH. Chang and J Parsonnet. Clin Microbiol Rev; 2010. Vol. 23, No. 4: p. 837–857. Mass Eradication of Helicobacter pylori to Prevent Gastric Cancer: Theoretical and Practical Considerations. YC Lee et al.  2016. Gut and Liver, Vol. 10, No. 1: pp. 12-26. Pathogenesis of Helicobacter pylori infection. S Backert et al. 2016.  Helicobacter; 21 (Suppl. 1): 19–25 Pathogenic mechanisms of the oncoprotein CagA in H. pylori-induced gastric cancer. Yin Chen et al.2016. Oncology Reports. Ahead of Print. Bacterial Cancer 2017 1 01 1 2 http://ibj.pasteur.ac.ir/article-1-1858-en.pdf
78-1816 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 The Role of Long Non-Coding RNAs in Ovarian Cancer Elahe Nikpayam Behnoosh Tasharrofi Shaghayegh Sarrafzadeh Soudeh Ghafouri-Fard s.ghafourifard@sbmu.ac.ir Background: Ovarian cancer is the most fatal tumor of female's reproductive system, and several genetics and environmental factors are involved in its development. Various studies have already identified suitable biomarkers to facilitate the early detection, prognosis evaluation, and the assessment of treatment response. However, the aim of this review was to investigate the role of long non-coding RNAs (lncRNAs) in tumorigenesis process of ovarian cancer and their potential applications as ovarian cancer biomarkers. Methods: We performed an online literature search of the MEDLINE/PubMed databases using the key words ovarian cancer, lncRNA, and biomarker. Results: We found that several lncRNAs have been shown to be deregulated in ovarian cancer and the specific mechanism of their enrollment in ovarian cancer has been defined for a few of them. In addition, expression profiling has revealed an association between lncRNAs and patients’ survival, metastasis potential as well as treatment response. Conclusions: Expression profiling as well as methylation analysis of lncRNAs in ovarian cancer may lead to the identification of novel biomarkers that can help in the classification of patients based on prognosis and treatment response. Ovarian cancer lncRNA Biomarker 2017 1 01 3 15 http://ibj.pasteur.ac.ir/article-1-1816-en.pdf 10.18869/acadpub.ibj.21.1.3
78-1768 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Methylation Status of H19/IGF2 Differentially Methylated Region in in vitro Human Blastocysts Donated by Healthy Couples Marzieh Derakhshan-Horeh Farid Abolhassani abolhasf@sina.tums.ac.ir Farnoosh Jafarpour Ashraf Moini Khadijeh Karbalaie Sayyed Morteza Hosseini Somayyeh Ostadhosseini Mohammad Hossein Nasr-Esfahani* mh.nasr-esfahani@royaninstitute.org Backgrund: Imprinted genes are a unique subset of few genes, which have been differentially methylated region (DMR) in a parental origin-dependent manner during gametogenesis, and these genes are highly protected during pre-implantation epigenetic reprogramming. Several studies heve shown that the particular vulnerability of imprinting genes during suboptimal pre- and peri-conception microenvironments often occur by assisted reproduction techniques (ART). This study investigated the methylation status of H19/IGF2 DMR at high-quality expanding/expanded human blastocysts donated by healthy individuals to evaluate the risks linked to ART. Method: Methylation levels of H19/IGF2 DMR were analyzed by bisulfite conversion and sequencing at 18 CpG sites (CpGs) located in this region. Result: Results showed that the overall percentage of methylated CpGs and the proportion of hyper-methylated clones of H19/IGF2 DMR in analyzed blastocysts were 37.85±4.87% and 43.75±5.1%, respectively. For validation of our technique, the corresponding methylation levels of peripheral human lymphocytes were defined (49.52±1.86% and 50%, respectively). Conclusion: Considering the absence of in vivo produced human embryos, it is not possible to conclude that the methylation found in H19/IGF2 DMR is actually normal or abnormal. Regarding the possible risks associated with ART, the procedures should be optimized in order to at least reduce some of the epigenetic risks. Blastocyst Genomic imprinting H19/IGF2 DMR Human Reproductive technique 2017 1 01 16 23 http://ibj.pasteur.ac.ir/article-1-1768-en.pdf 10.18869/acadpub.ibj.21.1.16
78-1696 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Hypoxia Pre-Conditioned Embryonic Mesenchymal Stem Cell Secretome Reduces IL-10 Production by Peripheral Blood Mononuclear Cells Majid Lotfinia Shirin Lak Nastaran Mohammadi Ghahhari Behrooz Johari Faezeh Maghsood Sara Parsania Bahareh Sadegh Tabrizi Mehdi Kadivar kadivar@pasteur.ac.ir Background: Mesenchymal stem cells (MSCs) are important candidates for MSC-based cellular therapy. Current paradigm states that MSCs support local progenitor cells in damaged tissue through paracrine signaling. Therefore, study of paracrine effects and secretome of MSCs could lead to the appreciation of mechanisms and molecules associated with the therapeutic effects of these cells. This study analyzed anti-inflammatory and immune-modulatory effects of MSC secretomes derived from embryonic stem cells (ESCs) and bone marrow cells after hypoxia and normoxia preconditioning. Methods: ESCs differentiated into MSCs and characterized by flow cytometry and differentiation into adipocytes and osteoblasts. The experimental groups consisted of individual groups of ESC-MSCs and BM-MSCs (bone marrow-derived mesenchymal stromal cells), which were preconditioned with either hypoxia or normoxia for 24, 48 and 72 h.  After collecting the cell-free medium from each treatment, secretomes were concentrated by centrifugal filters. Using a peripheral blood mononuclear cell (PBMC) assay and ELISA, IL-10 concentration in PBMCs was evaluated after their incubation with different secretomes from preconditioned and non-preconditioned MSCs. Results: A significant difference was observed between ESC-MSC normoxia and ESC-MSC hypoxia in IL-10 concentration, and normoxia secretomes increased IL-10 secretion from PBMCs. Moreover, the strongest IL-10 secretion from PBMCs could be detected after the stimulation by ESC-MSC conditioned secretomes, but not BM-MSC conditioned medium. Conclusions: Human hypoxia preconditioned ESC-MSC secretome indicated stronger immune-modulatory effects compared to BM-MSC conditioned medium. It could be suggested that induced MSCs confer less immune-modulatory effects but produce more inflammatory molecules such as tumor necrosis α, which needs further investigation. Embryonic stem cell Mesenchymal stem cell Hypoxia 2017 1 01 24 31 http://ibj.pasteur.ac.ir/article-1-1696-en.pdf 10.18869/acadpub.ibj.21.1.24
78-1799 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures Ali Gharibi Loron Soroush Sardari Jamshid Narenjkar Mohammad Sayyah sayyahm2@pasteur.ac.ir Background: Resistance to antiepileptic drugs as well as intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA), make it as a good candidate for designing and development of the new anticonvulsant medications. Methods: Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, biological activity score of Professional Association for SQL Server and structural requirements suggested by pharmacophore design. Anticonvulsant activity of compounds were tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection to mice. Results: Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in PTZ test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Conclusion: Common electrochemical features and 3-dimensional spatial structures of the effective compounds suggest involvement of the anticonvulsant mechanisms similar to the parent compound DHA.  Epilepsy Drug screening Pentylenetetrazole (PTZ) Maximal electroshock (MES) 2017 1 01 32 39 http://ibj.pasteur.ac.ir/article-1-1799-en.pdf 10.18869/acadpub.ibj.21.1.32
78-1701 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Evaluation of Prevalence, Homology and Immunogenicity of Dispersin among Enteroaggregative Escherichia coli Isolates from Iran Mohammad Reza Asadi Karam Ali Akbar Rezaei Seyed Davar Siadat Mehri Habibi Saeid Bouzari saeidbouzari@yahoo.com Background: Diarrhea, caused by enteroaggregative Escherichia coli (EAEC), is an important cause of illness and death. Numerous virulent factors have been described in EAEC. However, their prevalence was highly variable among EAECs of distinct geographic locations. Studies have shown that dispersin (antiaggregation protein, aap) is one of the important and abundant virulent factors in EAEC. In this study, we aimed to determine the presence, conservation and immunogenicity of aap gene in EAEC isolated from Iranian patients. Methods: PCR amplification of aap gene in the EAEC isolates was performed, and the aap gene was cloned in pBAD-gIIIA vector. The sequence of aap gene was analyzed using the ExPASy and BLAST tools. Expression of aap gene was performed in E. coli Top10, and expression confirmation was carried out by SDS-PAGE and Western-blot techniques. Rabbits were immunized with purified dispersin protein emulsified with Freund’s adjuvant. Sera were collected and examined for antibody response. Finally, in vitro efficacy of dispersin and anti-dispersin was evaluated. Results: The results of PCR showed the presence of aap gene in all of the EAEC isolates with significant homology. Finally, the significant difference between the levels of IgG response in dispersin-injected rabbits and control group was observed. Conclusion: Our results were in accordance with other studies that reported the presence of dispersin in the EAEC isolates with high conservation and immunogenicity. Hence, dispersin could be a promising candidate for any probable prevention against EAEC infections. Enteroaggregative E. coli Diarrhea Enzyme-linked immunosorbent assay 2017 1 01 40 47 http://ibj.pasteur.ac.ir/article-1-1701-en.pdf 10.18869/acadpub.ibj.21.1.40
78-1755 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Screening of Alginate Lyase-Producing Bacteria and Optimization of Media Compositions for Extracellular Alginate Lyase Production Hadis Tavafi Ahya Abdi- Ali abdialya@alzahra.ac.ir Parinaz Ghadam Sara Gharavi Background: Alginate is a linear polysaccharide consisting of guluronate (polyG) and mannuronate (polyM) subunits. Methods: In the initial screening of alginate-degrading bacteria from soil, 10 isolates were able to grow on minimal medium containing alginate. The optimization of cell growth and alginate lyase (algL) production was carried out by the addition of 0.8% alginate and 0.2-0.3 M NaCl to the culture medium. Of 10 isolates, one was selected based on its fast growth rate on minimal 9 medium containing 0.4% sodium alginate. The selected bacterium, identified based on morphological and biochemical characteristics as well as 16S rDNA sequence data, was confirmed to be an isolate belonging to the genus Bacillus and designated as Bacillus sp. TAG8. Resuls: The results showed the ability of Bacillus sp. TAG8 to utilize alginate as a sole carbon source. Bacillus sp. TAG8 growth and algL production were augmented with an increase in sodium alginate concentration and also by the addition of 0.2-0.3 M NaCl. Molecular analysis of TAG8 algL gene showed 99% sequence identity with algL of Pseudomonas aeruginosa PAO1. algL produced by Bacillus sp. TAG8 cleaved both polyM and polyG blocks in alginate molecule as well as acetylated alginate residues, confirming the bifunctionality of the isolated lyase. Conclusion: The identification of novel algL genes from microbial communities constitutes a new approach for exploring lyases with specific activity against bacterial alginates and may thus contribute to the eradication of persistent biofilms from clinical samples. Alginate Bacillus spp. Alginate lyase Pseudomonas biofilm 2017 1 01 48 56 http://ibj.pasteur.ac.ir/article-1-1755-en.pdf 10.18869/acadpub.ibj.21.1.48
78-1644 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Seroepidemiology of HTLV-1 and HTLV-2 Infection in Neyshabur City, North-Eastern Iran, during 2010-2014 Mohammad Salehi Seyyed Khalil Shokouhi Mostafavi Abdolmajid Ghasemian Mahmoud Gholami Abdolrahim Kazemi-Vardanjani bacteriology94@gmail.com Mohammad Karim Rahimi Background: Retroviruses of human T-lymphotropic viruses (HTLV-1 and HTLV-2) have been demonstrated to be endemic in the north-eastern region of Iran. This study aims to determine HTLV-1 and HTLV-2 prevalence among healthy individuals in Neyshabur City during 2010-2014. Methods: A total of 8054 blood samples were collected from healthy participants in Neyshabur, North-Eastern Iran. The blood samples were screened for the presence of specific antibodies against HTLV-1 and HTLV-2 by using ELISA according to the manufacturer’s instructions. Results: The overall seropositivity rate for HTLV-1 and HTLV-2 was found to be 6.55% (528 out of 8054) among participants. Conclusion: Both HTLV-1 and HTLV-2 were demonstrated to be at a high rate in healthy individuals. However, a smaller number of asymptomatic carriers were found in this study, as compared to those identified in previous investigations in the city.   Human T-lymphotropic viruse Seroepidemiology Enzyme-linked immunosorbent assay Iran 2017 1 01 57 60 http://ibj.pasteur.ac.ir/article-1-1644-en.pdf 10.18869/acadpub.ibj.21.1.57
78-1710 2024-03-29 10.1002
Iranian Biomedical Journal IBJ 1028-852X 2008-823X 10.61186/ibj 2017 21 1 Association of PTPN22 rs2476601 Polymorphism with Rheumatoid Arthritis and Celiac Disease in Khuzestan Province, Southwestern Iran Zahra Abbasi Seyed Reza Kazemi Nezhad kazemi_reza@scu.ac.ir Mahdi Pourmahdi-Broojeni Elham Rajaei Background: Single-nucleotide polymorphism (SNP) rs2476601 within protein tyrosine phosphatase non-receptor type 22 gene (PTPN22) has been shown to be a risk factor for different autoimmune diseases. This study explored the association of 1858 C/T SNP with rheumatoid arthritis (RA) and celiac disease (CD) in a region covering south-west of Iran. Methods: Totally, 52 patients with CD, 120 patients with RA and 120 healthy subjects were selected. The samples were genotyped for the rs2476601 in PTPN22 gene using the tetra-amplification refractory mutation system polymerase chain reaction. Results: The frequency of +1858T risk allele was significantly increased in both RA (P=0.021, OR=2.56, 95%CI=1.19-5.47) and CD (P=0.002, OR=3.87, 95%CI=1.68-8.95) patients, as compared to the control group. However, no association was found between the +1858C/T PTPN22 gene SNP and the anti-cyclic citrullinated peptide and rheumatoid factor positivity in RA patients. Conclusions: PTPN22 gene could play a crucial role in people’s susceptibility to some autoimmune diseases. Celiac disease PTPN22 Rheumatoid factor Rheumatoid arthritis 2017 1 01 61 66 http://ibj.pasteur.ac.ir/article-1-1710-en.pdf 10.18869/acadpub.ibj.21.1.61