Publications by authors named "Hossein Khanahmad"

113 Publications

Viewpoints on the Role of Transient Receptor Potential Melastatin Channels in Cardiovascular System and Disease: A Systematic Review.

Curr Probl Cardiol 2021 Oct 10:101012. Epub 2021 Oct 10.

Department of Genetics and Molecular biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Transient receptor potential (TRP) family play critical roles in cardiovascular system. TRPM family as largest TRP subfamily is non-voltage Ca2+-activated selective channels which has 8 members. This study aimed to discuss the role of TRPM family in cardiovascular system and diseases. Systematic search was performed covering PubMed, ISI Web of Science, and Google Scholar from inception until June 2021 using related keywords and Mesh terms for English studies with human, animal and in-vitro subjects. Finally 10 studies were selected for data extraction. Reviewing the articles showed that TRPM2, TRPM4, TRPM5, TRPM6 and TRPM7 play important roles in cardiovascular system and diseases. TRPM2 could be activated by reactive oxygen species (ROS) and effects on cardiac injury and cardiac fibrosis. TRPM7 and TRPM6 also have been reported to be associated with cardiac fibrosis and atrial fibrosis development respectively. TRPM4 channels contributed to resting membrane potential of cerebral artery smooth muscle cells and atrial contraction. TRPM5 channels are bitter taste sensors and prevent high salt intake and consequently high blood pressure due to the high salt intake. In conclusion based on the proof of the effectiveness of some members of TRPM family in the cardiovascular system, research on other members of this channel group seems to be useful and necessary to find their possible connection to the cardiovascular system.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.101012DOI Listing
October 2021

Tracking antibiotic resistance genes and class 1 integrons in Escherichia coli isolates from wastewater and agricultural fields.

Water Sci Technol 2021 Sep;84(5):1182-1189

Department of Environmental Health Engineering, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran E-mail:

Considering high concentrations of multidrug-resistant bacteria and antibiotic resistance genes (ARGs) in wastewater, agricultural reuse of treated wastewater may be a public health threat due to ARG dissemination in different environmental compartments, including soil and edible parts of crops. We investigated the presence of antibiotic-resistant Escherichia coli as an indicator bacterium from secondary treated wastewater (STWW), water- or wastewater-irrigated soil and crop samples. ARGs including bla, bla, tet-W, sul1, cml-A, erm-B, along with intI1 gene in E. coli isolates were detected via molecular methods. The most prevalent ARGs in 78 E. coli isolates were sul1 (42%), followed by bla (19%), and erm-B (17%). IntI1 as a class 1 integrons gene was detected in 46% of the isolates. Cml-A was detected in STWW isolates but no E. coli isolate from wastewater-irrigated soil and crop samples contained this gene. The results also showed no detection of E. coli in water-irrigated soil and crop samples. Statistical analysis showed a correlation between sul1 and cml-A with intI1. The results suggest that agricultural reuse of wastewater may contribute to the transmission of antibiotic-resistant bacteria to soil and crop. Further research is needed to determine the potential risk of ARB associated with the consumption of wastewater-irrigated crops.
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http://dx.doi.org/10.2166/wst.2021.288DOI Listing
September 2021

Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer.

Res Pharm Sci 2021 Oct 19;16(5):447-454. Epub 2021 Aug 19.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Redirected chimeric antigen receptor (CAR) T-cells can recognize and eradicate cancer cells in a major histocompatibility complex independent manner. Genetic engineering of T cells through CAR expression has yielded great results in the treatment of hematological malignancies compared with solid tumors. There has been a constant effort to enhance the effectiveness of these living drugs, due to their limited success in targeting solid tumors. Poor T cell trafficking, tumor-specific antigen selection, and the immunosuppressive tumor microenvironment are considered as the main barriers in targeting solid tumors by CAR T-cells. Here, we reviewed the current state of CAR T-cell therapy in breast cancer, as the second cancer-related death in women worldwide, as well as some strategies adopted to keep the main limitations of CAR T-cells under control. Also, we summarized various approaches that have been developed to enhance the therapeutic outcomes of this treatment in solid tumors targeting.
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http://dx.doi.org/10.4103/1735-5362.323911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407156PMC
October 2021

Antibiotic resistance and class 1 integron genes distribution in irrigation water-soil-crop continuum as a function of irrigation water sources.

Environ Pollut 2021 Nov 8;289:117930. Epub 2021 Aug 8.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

The increasing demand for fresh water coupled with the need to recycle water and nutrients has witnessed a global increase in wastewater irrigation. However, the development of antibiotic resistance hotspots in different environmental compartments, as a result of wastewater reuse is becoming a global health concern. The effect of irrigation water sources (wastewater, surface water, fresh water) on the presence and abundance of antibiotic resistance genes (ARGs) (bla, tet-W, sul1, cml-A, and erm-B) and class 1 integrons (intI1) were investigated in the irrigation water-soil-crop continuum using quantitative real-time PCR (qPCR). Sul1 and bla were the most and least abundant ARGs in three environments, respectively. The abundance of ARGs and intI1 significantly decreased from wastewater to surface water and then fresh water. However, irrigation water sources had no significant effect on the abundance of ARGs and intI1 in soil and crop samples. Principal component analysis (PCA) showed that UV index and air temperature attenuate the abundance of ARGs and intI1 in crop samples whereas the air humidity and soil electrical conductivity (EC) promotes the ARGs and intI1. So that the climate condition of semi-arid regions significantly affects the abundance of ARGs and intI1 in crop samples. The results suggest that treated wastewater might be safely reused in agricultural practice in semi-arid regions without a significant increase of potential health risks associated with ARGs transfer to the food chain. However, further research is needed for understanding and managing ARGs transfer from the agricultural ecosystem to humans through the food chain.
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http://dx.doi.org/10.1016/j.envpol.2021.117930DOI Listing
November 2021

The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy.

Int J Mol Sci 2021 May 21;22(11). Epub 2021 May 21.

Istituto Italiano di Tecnologia, Centre for Materials Interface, viale Rinaldo Piaggio 34, 56025 Pisa, Italy.

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.
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http://dx.doi.org/10.3390/ijms22115438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196740PMC
May 2021

Novel Approach to Overcome Defects of Cell-SELEX in Developing Aptamers against Aspartate β-Hydroxylase.

ACS Omega 2021 Apr 13;6(16):11005-11014. Epub 2021 Apr 13.

Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Research, Isfahan University of Medical Sciences, Isfahan 8174673461, I. R. Iran.

Cell-based aptamer selection (Cell-SELEX) against predefined protein targets that benefits using the native form of the targets is the most promising approach to achieve aptamer probes capable of recognizing targets under both in vitro and in vivo conditions. The major disadvantages in Cell-SELEX are the imperfectness of the negative selection step and the lengthy procedure of selection. Here, we introduced the Counter-SELEX as part of our modified Cell-SELEX and implemented deep sequencing to overcome these shortcomings in developing aptamers against aspartate β-hydroxylase (ASPH) as a known tumor marker. In parallel with the conventional Cell-SELEX, five consecutive cycles of counter selection were accomplished using sequences bound to negative cells (the Counter-SELEX) to detect oligos that are not specific for ASPH. After high-throughput sequencing, the representative of each promising achieved family was subjected to further confirmatory analysis via flow cytometry, followed by the fluorescence immunostaining of histopathological sections. Implementing our innovative complementary method, annoying mis-selected sequences in Cell-SELEX enriched pools were effectively identified and removed. According to the affinity assay on the cells displaying ASPH, three aptamers, AP-Cell 1, AP-Cell 2, and AP-Cell 3, with values of 47.51, 39.38, and 65.23 nM, respectively, were obtained, while AP-Cell 1 and 3 could then successfully spot ASPH displayed on the tissues. Our study showed that the Counter-SELEX could be considered as a complementary method for Cell-SELEX to overcome the imperfectness of the negative selection step. Moreover, high-throughput nucleotide sequencing could help to shorten the overall process.
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http://dx.doi.org/10.1021/acsomega.1c00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153902PMC
April 2021

The challenging nature of primary T lymphocytes for transfection: Effect of protamine sulfate on the transfection efficiency of chemical transfection reagents.

Res Pharm Sci 2020 Oct 19;15(5):437-446. Epub 2020 Oct 19.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Background And Purpose: The optimization of an effective non-viral gene delivery method for genetic manipulation of primary human T cells has been a major challenge in immunotherapy researches. Due to the poor transfection efficiency of conventional methods in T cells, there has been an effort to increase the transfection rate in these cells. Protamine is an FDA-approved compound with a documented safety profile that enhances DNA condensation for gene delivery.

Experimental Approach: In this study, the effect of protamine sulfate on the transfection efficiency of standard transfection reagents, was evaluated to transfect primary human T cells. In this regard, pre-condensation of DNA was applied using protamine, and the value of the zeta potential of DNA/protamine/cargo complexes was determined. T cells were transfected with DNA/protamine/cargo complexes. The transfection efficiency rate was evaluated by flow cytometry. Also, the green fluorescent protein expression level and cytotoxicity of each complex were identified using real-time polymerase chain reaction and MTT assay, respectively.

Findings/results: Our results demonstrated that protamine efficiently increases the positive charge of DNA/cargo complex without any cytotoxic effect on the primary human T cells. We observed that the transfection efficiency in DNA/protamine/ Lipofectamine 2000 and DNA/protamine/TurboFect™ was 87.2% and 78.9%, respectively, while transfection of T cells by Lipofectamine 2000 and TurboFect™ would not result in sufficient transfection.

Conclusion And Implications: Protamine sulfate enhanced the transfection rate of T cells; and could be a promising non-viral gene delivery method to achieve a safe, rapid, cost-effective, and efficient system which will be further applied in gene therapy and T cells manipulation methods.
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http://dx.doi.org/10.4103/1735-5362.297846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879792PMC
October 2020

The impact of neutrophil extracellular trap from patients with systemic lupus erythematosus on the viability, CD11b expression and oxidative burst of healthy neutrophils.

BMC Immunol 2021 02 5;22(1):12. Epub 2021 Feb 5.

Department of Immunology, Medical School, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan, IR, 81746-73695, Iran.

Background: NET (neutrophil extracellular trap) has been shown to directly influence inflammation; in SLE (systemic lupus erythematosus), it is reportedly a plausible cause for the broken self-tolerance that contributes to this pathology. Meanwhile, the role of NET is not easily explicable, and there is a serious discrepancy in the role of NET in SLE pathology and generally inflammation; in particular, the interactions of neutrophils with NET have been rarely inspected. This study evaluates the effect of NET on neutrophils in the context of SLE. The neutrophils were incubated by the collected NET (from SLE patients and healthy controls) and their expression of an activation marker, viability and oxidative burst ability were measured.

Results: The level of cell mortality, CD11b expression and the oxidative burst capacity were elevated in NET-treated neutrophils. Also, the elevation caused by the SLE NET was higher than that produced by the healthy NET.

Conclusion: The decreased neutrophil viability was not due to the increase in apoptosis; rather, it was because of the augmentation of other inflammatory cell-death modes. The upregulation of CD11b implies that NET causes neutrophils to more actively contribute to inflammation. The increased oxidative burst capacity of neutrophils can play a double role in inflammation. Overall, the effects induced by NET on neutrophils help prolong inflammation; accordingly, the NET collected from SLE patients is stronger than the NET from healthy individuals.
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http://dx.doi.org/10.1186/s12865-021-00402-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863477PMC
February 2021

Comparison of Expression Levels of miR-29b-3p and miR-326 in T Helper-1 and T Helper-17 Cells Isolated from Responsive and Non-responsive Relapsing-remitting Multiple Sclerosis Patients Treated with Interferon-beta.

Iran J Allergy Asthma Immunol 2020 Aug 25;19(4):416-425. Epub 2020 Aug 25.

Isfahan Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.

T helper type 1 (Th1) and Th17 Cells with distinct cytokine profiles including interferon-gamma (IFN-γ) and interleukin 17 (IL-17) have a pivotal role in neuroinflammation and myelin destruction in the central nervous system (CNS) in MS. MicroRNA-29b (MiR-29b) and miR-326 contribute to regulating Th1 and Th17 differentiation and altered expression of the miRNAs could be associated with response to treatment in multiple sclerosis (MS). Therefore, our study aimed to evaluate the percentage of Th1 and Th17 and determining the expression levels of miR-29b-3p and miR-326 in these lymphocyte subpopulations between responsive and non-responsive to interferon beta (IFN-β) therapy in relapsing-remitting multiple sclerosis (RRMS) patients. The present study was performed on 40 RRMS patients following treatment with IFN-β. The percentage of Th1 cells and Th17 cells were determined by flow cytometry in responsive and non-responsive patients. The expression levels of miR-29b-3p and miR-326 were assessed in Th1 and Th17 cells by quantitative polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to evaluate the plasma levels of IFN-γ and IL-17A. No significant difference was observed in the percentage of Th1 and Th17 cells as well as the expression levels of miR-29b-3p and miR-326 (in Th1 and Th17, respectively) in treated patients. Also, we did not find any significant difference in IFN-γ and IL-17A plasma concentration between responsive or non-responsive to IFN-β therapy in patients with RRMS. IFN-β may regulate other miRNAs in Th1 and Th17 cells than miR29b-3p and miR-326 in MS patients.
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http://dx.doi.org/10.18502/ijaai.v19i4.4116DOI Listing
August 2020

Generation of HBsAg DNA aptamer using modified cell-based SELEX strategy.

Mol Biol Rep 2021 Jan 5;48(1):139-146. Epub 2021 Jan 5.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran.

Aptamers as potential alternatives for antibodies could be employed against hepatitis B surface antigen (HBsAg), the great hallmark and first serological marker in HBV, for further theragnostic applications. Therefore, isolation HBsAg specific aptamer was performed in this study with a modified Cell-SELEX method. HEK293T overexpressing HBsAg and HEK293T as target and control cells respectively, were incubated with single-stranded rounds of DNA library during six SELEX and Counter SELEX rounds. Here, we introduced the new modified Cell-SELEX using deoxyribonuclease I digestion to separate single stranded DNA aptamers against the HBsAg. Characterization and evaluation of selected sequences were performed using flow cytometry analysis. The results led to isolation of 15 different ssDNA clones in six rounds of selection which were categorized to four clusters based on common structural motifs. The evaluation of SELEX progress showed growth in aptamer affinity with increasing in the cycle number. Taken together, the application of modified cell-SELEX demonstrated the isolation of HBsAg-specific ssDNA aptamers with proper affinity. Modified cell-SELEX as an efficient method can shorten the selection procedure and increase the success rate while the benefits of cell-based SELEX will be retained. Selected aptamers could be applied in purification columns, diagnostic kits, and drug delivery system against HBV-related liver cancer.
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http://dx.doi.org/10.1007/s11033-020-05995-2DOI Listing
January 2021

An innovative cell selection approach in developing human cells overexpressing aspartyl/asparaginyl β-hydroxylase.

Res Pharm Sci 2020 Jun 3;15(3):291-299. Epub 2020 Jul 3.

Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Background And Purpose: Aspartyl/asparaginyl β-hydroxylase (ASPH) is abundantly expressed in malignant neoplastic cells. The establishment of a human cell line overexpressing ASPH could provide the native-like recombinant protein needed for developing theranostic probes. In the process of transfection, the obtained cells normally contain a range of cells expressing the different levels of the target of interest. In this paper, we report on our simple innovative approach in the selection of best-transfected cells with the highest expression of ASPH using subclone selection, quantitative real-time polymerase chain reaction, and gradual increment of hygromycin concentration.

Experimental Approach: To achieve this goal, human embryonic kidney (HEK 293T) cells were transfected with an ASPH-bearing pcDNA3.1/Hygro(+) vector. During antibiotic selection, single accumulations of the resistant cells were separately cultured and the ASPH mRNA levels of each flask were evaluated. The best subclones were treated with a gradually increasing amount of hygromycin. The ASPH protein expression of the obtained cells was finally evaluated using flow cytometry and immunocytochemistry.

Findings / Results: The results showed that different selected subclones expressed different levels of ASPH. Furthermore, the gradual increment of hygromycin (up to 400mg/mL) improved the expression of ASPH. The best relative fold change in mRNA levels was 57.59 ± 4.11. Approximately 90.2% of HEK cells overexpressed ASPH on their surface.

Conclusion And Implications: The experiments indicated that we have successfully constructed and evaluated a recombinant human cell line overexpressing ASPH on the surface. Moreover, our innovative selection approach provided an effective procedure for enriching highly expressing recombinant cells.
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http://dx.doi.org/10.4103/1735-5362.288436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540811PMC
June 2020

Vitamin D can be effective on the prevention of COVID-19 complications: A narrative review on molecular aspects.

Int J Vitam Nutr Res 2020 Aug 19:1-13. Epub 2020 Aug 19.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

The widespread COVID-19 pandemic has been, currently, converted to a catastrophic human health challenge. Vitamin D (VD) and its metabolites have been used as a palliative treatment for chronic inflammatory and infectious diseases from ancient times. In the current study, some molecular aspects of the potential effects of VD against COVID-19 side-effects have been discussed. An arguable role in autophagy or apoptosis control has been suggested for VD through calcium signaling at the mitochondrial and ER levels. 1,25(OH)2D3 is also an immunomodulator that affects the development of B-cells, T-cells, and NK cells in both innate and acquired immunity. The production of some anti-microbial molecules such as defensins and cathelicidins is also stimulated by VD. The overexpression of glutathione, glutathione peroxidase, and superoxide dismutase, and down-regulation of NADPH oxidase are induced by VD to reduce the oxidative stress. Moreover, the multi-organ failure due to a cytokine storm induced by SARS-CoV2 in COVID-19 may be prevented by the immunomodulatory effects of VD. It can also downregulate the renin-angiotensin system which has a protective role against cardiovascular complications induced by COVID-19. Given the many experimental and molecular evidences due to the potential protective effects of VD on the prevention of the COVID-19-induced morbidities, a VD supplementation is suggested to prevent the lethal side-effects of the infection. It is particularly recommended in VD-deficient patients or those at greater risk of serious or critical effects of COVID-19, including the elderly, and patients with pre-existing chronic diseases, especially those in nursing homes, care facilities, and hospitals.
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http://dx.doi.org/10.1024/0300-9831/a000676DOI Listing
August 2020

Evaluation of the Anti-Leishmanial Effect of Recombinant α-Toxin.

Infect Drug Resist 2020 15;13:2355-2364. Epub 2020 Jul 15.

Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Leishmaniasis is an infectious disease common in tropical and subtropical regions caused by the genus , which is transmitted by the bite of female sandflies. In this study, we evaluate the anti-leishmanial effect of recombinant α-toxin protein alone and the combination with glucantime through in vitro and in vivo.

Materials And Methods: Production, expression, and purification of recombinant α-toxin were evaluated by SDS-PAGE and Western blotting techniques. The antileishmanial activities of the purified α-toxin plus and without glucantime were examined in vitro and in vivo.

Results: The results indicated successful expression of α-toxin as a 48 kDa band on SDS-PAGE and Western blot methods. Also, evaluation of α-toxin IC showed the strong fatal effect of it, and glucantime on medium proliferated promastigotes at lower concentrations compared with glucantime or α-toxin alone. Moreover, in vivo surveys showed that at the end of treatment courses, the mean of lesion size diminished in glucantime plus α-toxin treated mice versus negative control groups (p < 0.001). Also, there was a significant difference in the parasite burden of the spleen and liver of the control versus the test groups (p < 0.001).

Conclusion: The results showed recombinant α-toxin has synergistic effects with glucantime in destroying parasites.
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http://dx.doi.org/10.2147/IDR.S257561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369417PMC
July 2020

Recombinant C-Reactive Protein: A Potential Candidate for the Treatment of Cutaneous Leishmaniasis of BALB/c Mice Caused by Leishmania major.

Acta Parasitol 2021 Mar 16;66(1):53-59. Epub 2020 Jul 16.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Hezarjerib Street, 8174643446, Isfahan, Iran.

Purpose: Leishmaniasis, a widespread parasitic disease, is a public health concern that is endemic in more than 90 countries. Owing to the drug resistance and also undesirable complications, designing new therapeutic methods are essential. C-reactive protein (CRP) is an acute phase protein of plasma with several immune modulatory functions. This study aimed to evaluate the effect of human recombinant CRP (hrCRP) on treating cutaneous leishmaniasis in mice models.

Methods: hrCRP was expressed in E. coli Rosetta-gami and extracted from the SDS-PAGE gel. Male BALB/c mice were inoculated subcutaneously at the base of their tails by 1 × 10 stationary-phase of Leishmania major promastigotes (MHRO/IR/75/ER) suspended in sterile phosphate buffered saline (PBS). Nodules and subsequently, ulcers developed 14 days post-injection. 1.5 µg of the purified protein was administered on lesions of pre-infected mice by Leishmania major in the intervention group for five consecutive days.

Results: The mean area of the lesions was decreased by about seven folds in the intervention group as compared to the control group after two weeks of the treatment (p = 0.024). The results were verified by the real-time polymerase chain reaction so that the parasite burden was determined 2 times in the control group as compared to the intervention group (p = 0.02). Two weeks after treatment, the conversion of the lesions to scars in the intervention group was observed.

Conclusion: The results indicate a potential therapeutic role for hrCRP in improving cutaneous leishmaniasis due to Leishmania major in mice models. The healing was in a stage-dependent manner.
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http://dx.doi.org/10.1007/s11686-020-00251-wDOI Listing
March 2021

Producing Soluble Human Programmed Cell Death Protein-1: A Natural Supporter for CD4+T Cell Cytotoxicity and Tumor Cells Apoptosis.

Iran J Biotechnol 2019 Dec 1;17(4):e2104. Epub 2019 Dec 1.

Immunology Department, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Programmed cell death protein-1 (PD-1)/PD-L1 pathway is one of the immune checkpoint pathways involved in the regulation of the immune responses and the suppression of anti-tumor defense. PD-1/PD-L1 blocking antibodies improve immune responses such as cytotoxic activity of CD8/CD4T cells and increase mortality of tumor cells as well; however, their use is accompanied by adverse side effects.

Objectives: We aimed to produce a native blocker of human PD-1/PD-L1, for developing T cells cytotoxicity and tumor cells apoptosis.

Materials And Methods: We designed and cloned soluble human PD-1-GFP-pcDNA3.1/hygro construct in strain TOP10 cells and then transfected this construct into the HEK cells. The concentration of the secreted shPD-1 in the supernatant was measured and the supernatant was used for blocking PD-L1 on the MDA-MB-231 cells. The cytotoxicity of CD8/CD4T cells and the apoptosis of MDA-MB-231 cells, under the influence of shPD-1 in the co-culture of T cells with the MDA-MB-231 cells, were evaluated using flow cytometry technique.

Results: The GFP expression in the transfected cells illustrated the successful designing, transfection, and production of shPD-1. Soluble human PD-1 concentration in the supernatant of the transfected HEK cells was significantly higher than the untransfected cells. In addition, shPD-1 significantly blocked PD-L1 on the MDA- MB-231 cells, improved the cytotoxicity of CD4T cells, and increased the apoptosis of MDA-MB-231 cells.

Conclusion: Overall, increased CD4T cell cytotoxicity and tumor cells apoptosis under the influence of shPD-1, confirmed the effectiveness of shPD-1 as a natural blocker of PD-L1and as an augmenter of the anti-tumorimmune responses.
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http://dx.doi.org/10.30498/IJB.2019.85180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357696PMC
December 2019

Evaluation of Silencing Effect of miR-133a-5p Mimic on TIM-3 Expression in AML (HL-60) Cell Line.

Indian J Clin Biochem 2020 Jul 4;35(3):359-366. Epub 2019 Jun 4.

Department of Genetic and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Acute myelogenous leukemia (AML) is a complex blood malignancy leading to immature leukemic stem cells (LSCs) proliferation. T cell immunoglobulin mucin-3 (TIM-3) is known as a biomarker of AML LSCs. Several microRNAs (miRNAs) can affect gene expression in AML. In this study, the silencing effect of miR-133a-5p on TIM-3 expression in AML cell lineage (HL-60) was investigated. It's been hypothesized that miR-133a-5p may suppress the TIM-3 expression in AML cell line. Initially, miRNA-TIM-3 prediction, enrichment, and network analysis were done. Then, miR-133a-5p mimic was transfected into HL-60 cells. The TIM-3 protein and gene expression were measured by flow cytometry analysis and real-time PCR, respectively. MTT assay was also carried out. Based on the Bioinformatics predictions, miR-133a-5p was able to silence TIM-3 expression. Also, significant pathways pertained to miR-133a-5p were obtained using enrichment analysis. According to this, miR-133a-5p was mainly engaged in the MAPK signaling pathway and Nicotine addiction pathway using the KEGG database. The TIM-3 protein expression of the transfected cells was measured as 17.15 ± 8.87% ( = 0.001). A 52.48% significant gene silencing in mRNA level was obtained in comparison to the negative control. Despite of down regulation of TIM-3, HL-60 cell viability has not been significantly changed. It has been finally confirmed that miR-133a-5p could strongly suppress TIM-3 expression in AML cell line. Presumably, down regulation of TIM-3 could affect MAPK and Nicotine addiction signaling pathways.
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http://dx.doi.org/10.1007/s12291-019-00834-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326904PMC
July 2020

Evaluation of the Effects of Valproic Acid Treatment on Cell Survival and Epithelial-Mesenchymal Transition-Related Features of Human Gastric Cancer Cells.

J Gastrointest Cancer 2021 Jun;52(2):676-681

Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran.

Purpose: Metastasis is the most important feature of gastric cancer accounting for more than 90% of tumor-related mortality. As one of the main modulators of epithelial-mesenchymal transition (EMT), histone deacetylase inhibitors (HDACI) are considered rational candidates for cancer therapy. Valproic acid (VPA) is a HDACI with reported controversial effects on the EMT. The main aim of the current study was to evaluate the effects of VPA treatment on cell survival and EMT-related features of human gastric cancer cells (AGS).

Methods: Methyl-thiazoltetrazolium (MTT) assay was utilized to assess the effect of VPA on the proliferation rate of cells. Apoptotic cell death was detected with Annexin V/PI staining. Migratory ability of cells following VPA treatment was assessed using a Boyden chamber test. The expression of EMT markers in AGS cells was analyzed using quantitative real-time RT-PCR.

Results: Treatment with VPA significantly inhibited AGS cell proliferation compared with control. An increased rate of early and late apoptotic cells was observed following VPA exposure. It was demonstrated that VPA significantly diminished the cell migratory ability in AGS gastric cancer cells. Furthermore, treatment with VPA significantly decreased the expression of E-cadherin but increased the Vimentin expression.

Conclusions: Our results showed that VPA induces apoptosis and inhibits the cell proliferation and the migratory ability of AGS gastric cancer cells and may prove useful in the development of therapeutic agents for human gastric cancer. However, these preliminary findings call for further investigations to clarify the precise molecular mechanisms by which VPA modulates the EMT process in a cell type-specific manner.
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http://dx.doi.org/10.1007/s12029-019-00332-8DOI Listing
June 2021

Targeting of cholera toxin A () gene by zinc finger nuclease: pitfalls of using gene editing tools in prokaryotes.

Res Pharm Sci 2020 Apr 11;15(2):182-190. Epub 2020 May 11.

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

Background And Purpose: The study was launched to use zinc finger nuclease (ZFN) technology to disrupt the cholera toxin gene () for inhibiting CT toxin production in .

Experimental Approach: An engineered ZFN was designed to target the catalytic site of the gene. The coding sequence of ZFN was cloned to pKD46, pTZ57R T/A vector, and plasmid and transformed to Top10 and . The efficiency of ZFN was evaluated by colony counting.

Findings/results: No expression was observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blotting in transformed . The gene sequencing did not show any mutation. Polymerase chain reaction on pKD46-ZFN plasmid had negative results. Transformation of Top10 with T/A vectors containing whole ZFN sequence led to 7 colonies all of which contained bacteria with self-ligated vector. Transformation with left array ZFN led to 24 colonies of which 6 contained bacteria with self-ligated vector and 18 of them contained bacteria with vector/left array. Transformation of with vectors containing whole ZFN did not produce any colonies. Transformation with left array vectors led to 17 colonies containing bacteria with vector/left array. Left array protein band was captured using western blot assay.

Conclusions And Implications: ZFN might have off target on bacterial genome causing lethal double-strand DNA break due to lack of non-homologous end joining (NHEJ) mechanism. It is recommended to develop ZFNs against bacterial genes, engineered packaging host with NHEJ repair system is essential.
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http://dx.doi.org/10.4103/1735-5362.283818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306252PMC
April 2020

Aptamer-based approaches for molecular detection of cancer.

Res Pharm Sci 2020 Apr 11;15(2):107-122. Epub 2020 May 11.

Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I. R. Iran.

Cancer is typically associated with abnormal production of various tumor-specific molecules known as tumor markers. Probing these markers by utilizing efficient approaches could be beneficial for cancer diagnosis. The current widely-used biorecognition probes, antibodies, suffer from some undeniable shortcomings. Fortunately, novel oligonucleotide-based molecular probes named aptamers are being emerged as alternative detection tools with distinctive advantages compared to antibodies. All of the existing strategies in cancer diagnostics, including those of detection, can potentially implement aptamers as the detecting moiety. Several studies have been performed in the field of cancer detection over the last decade. In order to direct future studies, it is necessary to comprehensively summarize and review the current status of the field. Most previous studies involve only a few cancer diagnostic strategies. Here, we thoroughly review recent significant advances on the applications of aptamer in various detection strategies. Furthermore, we will discuss the status of diagnostic aptamers in clinical trials.
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http://dx.doi.org/10.4103/1735-5362.283811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306249PMC
April 2020

Selenium supplementation can relieve the clinical complications of COVID-19 and other similar viral infections.

Int J Vitam Nutr Res 2021 Jun 9;91(3-4):197-199. Epub 2020 Jun 9.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

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http://dx.doi.org/10.1024/0300-9831/a000663DOI Listing
June 2021

Single-Strand DNA-Like Oligonucleotide Aptamer Against Proprotein Convertase Subtilisin/Kexin 9 Using CE-SELEX: PCSK9 Targeting Selection.

Cardiovasc Drugs Ther 2020 08;34(4):475-485

Department of Molecular Biology and Genetics, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.

Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) serves a key regulatory function in the metabolism of low-density lipoprotein (LDL)-cholesterol (LDL-C) through interaction with the LDL receptor (LDLR) followed by its destruction that results in the elevation of the plasma levels of LDL-C. The aims of the present study were to separate and select a number of single-stranded DNA (ssDNA) aptamers against PCSK9 from a library pool (n > 10) followed by their characterization.

Methods: The aptamers obtained from the DNA-PCSK9 complexes which presented the highest affinity against PCSK9 were separated and selected using capillary electrophoresis evolution of ligands by exponential enrichment (CE-SELEX). The selected aptamers were amplified and cloned into a T/A vector. The plasmids from the positive clones were extracted and sequenced. The Mfold web server was used to predict the secondary structure of the aptamers.

Results: Following three rounds of CE-SELEX, the identified anti-PCSK9 ssDNA aptamers, namely aptamer 1 (AP-1) and aptamer 2 (AP-2), presented half maximal inhibitory concentrations of 325 and 327 nM, lowest dissociation constants of 294 and 323 nM, and most negative Gibbs free energy values of - 9.17 and - 8.28 kcal/mol, respectively.

Conclusion: The results indicated that the selected aptamers (AP-1 and AP-2) induced potent inhibitory effects against PCSK9. Further in vivo studies demand to find out AP-1 and AP-2 aptamers as suitable candidates, instead of antibodies, for using in therapeutic purposes in patients with hypercholesterolemia and cardiovascular disease.
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http://dx.doi.org/10.1007/s10557-020-06986-yDOI Listing
August 2020

Evaluation of transgenic Leishmania infantum expressing mLLO-BAX-SMAC in the apoptosis of the infected macrophages in vitro and in vivo.

Parasite Immunol 2020 11 11;42(11):e12726. Epub 2020 Sep 11.

Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: Leishmaniasis is an important infectious disease that develops because of escaping parasite from the host immune system or preventing host macrophages apoptosis. Recently, the development of transgenic methods and the manipulation of the parasite genome has provided many advantages. So, in this study, the effect of the transgenic Leishmania infantum expressing mLLO-BAX-SMAC proteins was examined in accelerating host cell apoptosis.

Method: The entire coding sequence of designed codon-optimized mLLO-Bax-Smac was cloned in the pLexyNeo2 vector and integrated downstream of the 18srRNA locus of L infantum genome by homologous recombination. Next, the expression of mLLO-BAX-SMAC fusion protein was evaluated by the Western blotting technique and the pathogenesis of transgenic parasite was surveyed in vitro and in vivo.

Results: The results of PCR and Western blot confirmed proper integration and expression of mLLO-Bax-Smac sequence into the 18srRNA locus of L infantum. Flow cytometry showed accelerating apoptosis of transgenic Leishmania-infected macrophages compared to wild-type parasite. Also, transgenic parasites were less virulent as a fewer parasitic burden was found in the spleen and liver of transgenic-infected mice compared to the control.

Conclusion: The data suggested that the transgenic L infantum expressing BAX-SMAC can be used as an experimental model for developing vaccination against leishmaniasis.
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http://dx.doi.org/10.1111/pim.12726DOI Listing
November 2020

A potential protective role of losartan against coronavirus-induced lung damage.

Infect Control Hosp Epidemiol 2020 06;41(6):752-753

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

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http://dx.doi.org/10.1017/ice.2020.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137531PMC
June 2020

Evaluation of long-chain acyl-coenzyme A synthetase 4 (ACSL4) expression in human breast cancer.

Res Pharm Sci 2020 Feb 20;15(1):48-56. Epub 2020 Feb 20.

Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Background And Purpose: Breast cancer (BC) is one of the major causes of female cancer-related death. It has recently been demonstrated that metabolic reprogramming including alteration in lipid metabolism is indicated in various types of cancer. The enzymes of the acyl-coenzyme A synthetase long-chain family (ACSLs) are responsible for converting fatty acids to their corresponding fatty acyl-coenzyme A esters which are essential for some lipid metabolism pathways. ACSL4 is one of the isoforms of ACSLs and has a marked preference for arachidonic and eicosapentaenoic acids. The objective of this study was to evaluate ACSL4 expression, its prognostic significance, and its correlation with p53 tumor suppressor in BC patients.

Experimental Approach: In this study 55 pairs of fresh samples of BC and adjacent non-cancerous tissue were used to analyze ACSL4 expression, using real-time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other studied variables was also examined using the IHC technique.

Findings / Results: ACSL4 expression was significantly higher in BC tissues compared to the adjacent normal tissue. This upregulation was negatively correlated with Ki-67 and age, and positively correlated with p53 status. The correlation between ACSL4 and p53 may indicate the role of p53 in the regulation of lipid metabolism in cancer cells, in addition to its role in the regulation of ferroptosis cell death.

Conclusion And Implications: Our results indicated that the expression of ACSL4 may be considered as a prognostic indicator and potential therapeutic target in BC. However, further studies are needed to confirm the significance of these findings.
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http://dx.doi.org/10.4103/1735-5362.278714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053294PMC
February 2020

A Novel Strategy for Enhance Potentiation of Meglumine antimoniate against In Vitro.

Iran J Parasitol 2019 Oct-Dec;14(4):542-551

Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Background: We aimed to design a different method of drug delivery for increased transfer of the choice drug (meglumine antimoniate) within the host cells. Therefore, listeriolysin O (LLO), a bacterial product which is a member of pore-forming peptides was used as an enhancer factor with meglumine antimoniate in order to facilitate the transition of the drug across macrophage membrane.

Methods: LLO was produced in Isfahan University of Medical Sciences in 2016, by expressing the gene in and purified using affinity chromatography. Cytotoxicity of the purified protein was investigated in an in vitro model of macrophage infection.

Results: LLO was cytotoxic against murine macrophage cells (J774-A1) and amastigote forms of (MRHO/IR/75/ER). It was less toxic to macrophages (CC50=2.56 μg ml ±0.09) than to the parasites (IC50=1.72 μg ml ±0.07). Moreover, noncytotoxic concentration of LLO (0.006 ug ml) potentiated the cytotoxicity induced by low dose concentration of meglumine antimoniate. Very little dose of meglumine antimoniate was needed when combined with the LLO (IC50=12.63 μg ml ±0.13) in comparison with the cytotoxicity induced when the drug is used alone (IC50=46.17 μg ml ±0.28).

Conclusion: The combination of pore-forming proteins with anti-leishmanial agents could increase the advantage of anti-leishmanial drugs. Since lower concentrations of anti-leishmanial drugs can reduce undesirable side effects of chemotherapy trials carried out in animal models and then in humans with this system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028224PMC
February 2020

Selection and characterization of single-stranded DNA aptamers against interleukin-5.

Res Pharm Sci 2019 Dec 11;14(6):515-523. Epub 2019 Dec 11.

Department of Medicine and Genetics, School of Medicine, Ilam University of Medical Sciences, Ilam, I.R. Iran.

Asthma as a chronic inflammatory disorder is associated with many cytokines like interleukin-5 (IL-5) which plays essential role in eosinophil differentiation and maturation. Accordingly, blockage of IL-5 using mepalizumab has been considered as a promising therapeutic approach for asthma. Despite the monocolonal antibody advantages, some restrictions provided an acceptable background for alternative agents like aptamers which could replace with antibodies. In the current study, aptamer isolation against IL-5 molecule was intended, according to the valuable benefits of aptamers over antibodies. HEK-293T/IL-5 cell was constructed to select aptamer using cell-systematic evolution of ligands by exponential enrichment (SELEX) method. Integration of the IL-5 fragment to genome of the HEK-293T was verified by polymerase chain reaction on the genomic DNA of the transfected cells. Moreover, IL-5 protein expression on the cell surface was confirmed using flow cytometry analysis. Then, cell SELEX was carried out in 12 rounds and isolated aptamers were evaluated by flow cytometry analysis. The selected clones were then sequenced and assessed for any possible secondary structure. The results of this study led to the selection of 19 different single-stranded DNA clones after 12 rounds of selection which were clustered to five groups based on common structural motifs. In conclusion, the findings revealed the isolation of IL-5-specific single-stranded DNA aptamers, which can further be substituted with mepolizumab.
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http://dx.doi.org/10.4103/1735-5362.272560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937751PMC
December 2019

Expression and clinicopathological significance of lipin-1 in human breast cancer and its association with p53 tumor suppressor gene.

J Cell Physiol 2020 07 22;235(7-8):5835-5846. Epub 2020 Jan 22.

Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.

Breast cancer (BC) is an important cause of female cancer-related death. It has recently been demonstrated that metabolic disorders including lipid metabolism are a hallmark of cancer cells. Lipin-1 is an enzyme that displays phosphatidate phosphatase activity and regulates the rate-limiting step in the pathway of triglycerides and phospholipids synthesis. The objective of this study was to evaluate lipin-1 expression, its prognostic significance, and its correlation with p53 tumor suppressor in patients with BC. In this study, 55 pairs of fresh samples of BC and adjacent noncancerous tissue were used to analyze lipin-1, using quantitative real-time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other clinicopathological variables and p53 was also examined using IHC technique. The cell migration was studied in MCF-7 and MDA-MB231 cells following the inhibition of lipin-1 by propranolol. Our results show that the relative expression of lipin-1 messenger RNA was significantly higher in BC tissues compared with the adjacent normal tissue and its inhibition reduced cell migration in cancer cells. This upregulation was negatively correlated with histological grade of tumor and p53 status (p = .001 and p = .034) respectively and positively correlated with the tumor size (p = .006). Our results also seem to indicate that the high lipin-1 expression is related to a good prognosis in patients with BC. The expression of lipin-1 may be considered as a novel independent prognostic factor. The inhibition of lipin-1 may also have therapeutic significance for patients with BC. The correlation between lipin-1 and p53 confirms the role of p53 in the regulation of lipid metabolism in cancer cells.
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http://dx.doi.org/10.1002/jcp.29523DOI Listing
July 2020

MicroRNAs as the actors in the atherosclerosis scenario.

J Physiol Biochem 2020 Feb 5;76(1):1-12. Epub 2019 Dec 5.

Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.

Atherosclerosis is considered as the most common cardiovascular disease and a leading cause of global mortality, which develops through consecutive steps. Various cellular and molecular biomarkers such as microRNAs are identified to be involved in atherosclerosis progression. MicroRNAs are a group of endogenous, short, non-coding RNAs, which are able to bind to specific sequences on target messenger RNAs and thereby modulate gene expression post-transcriptionally. MicroRNAs are key players in wide range of biological processes; thus, their expression level is regulated in pathophysiological conditions. Ample evidences including in vitro and in vivo studies approved a critical role of microRNAs in epigenetic and the sequential processes of atherosclerosis from risk factors to plaque formation, progression, and rupture. Based on these findings, miRNAs seems to be promising candidates for therapeutic approach. This review summarizes the role of miRNAs in atherosclerosis development, epigenetic, and therapy. Moreover, the application of exosomes in miRNA delivery, and/or their prognostic and diagnostic values are also discussed.
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http://dx.doi.org/10.1007/s13105-019-00710-7DOI Listing
February 2020

The role of Bax in the apoptosis of Leishmania-infected macrophages.

Microb Pathog 2020 Feb 25;139:103892. Epub 2019 Nov 25.

Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Skin Disease and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address:

Background: Leishmania is a protozoan parasite that nests in macrophages and is responsible for the Leishmaniasis disease. In spite of different defense pathways, last strategy of macrophage for killing parasite is apoptosis process. By permeableizing the mitochondrial outer membrane (MOM). As breaching MOM releases apoptogenic factors like cytochrome-c which activate caspases that result in the destruction of the cell. In this review, we summarized the appropriate manuscripts regarding the bax includes, its different types and the effect of bax on the apoptosis of Leishmania and parasite-infected macrophages.

Methods: Information about the role of BAX in the apoptosis of parasite-infected macrophage of recent articles were surveyed by searching computerized bibliographic database PubMed and Google Scholar entering the keywords BAX and leishmaniasis.

Results: The common studies revealed Leishmania use different survival strategies for inhibiting macrophage apoptosis. As Leishmania by preventing homooligomerization or upregulating the anti-apoptotic molecule Bcl-2 can prohibits proteins of host-cell apoptosis such as Bax that is required for mitochondrial permeabilisation during apoptosis.

Conclusion: With regard to the supportive role of bax in apoptosis and the preventive role of Leishmania in its function, it seems that expression of bax gene in parasite by technologies like transgenic or down regulating of anti-apoptotic molecule Bcl-2 by miRNA could be prompted the apoptosis process of infected-macrophages and inhibited extensive spread of Leishmania and the resulting lesions.
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http://dx.doi.org/10.1016/j.micpath.2019.103892DOI Listing
February 2020
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