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   Table of Contents - Current issue
Coverpage
March-April 2023
Volume 18 | Issue 2
Page Nos. 112-230

Online since Thursday, January 19, 2023

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REVIEW ARTRICLE  

Acetyl-L-carnitine for the prevention of taxane-induced neuropathy in patients with breast cancer: a systematic review and meta-analysis p. 112
Mahnaz Momenzadeh, Amir Aria, Keyvan Ghadimi, Azadeh Moghaddas
DOI:10.4103/1735-5362.367791  
Background and purpose: Peripheral neuropathy is one of the most prevalent and undesirable side effects of taxane-containing chemotherapy regimens. This study aimed to investigate the effect of acetyl-L-carnitine (ALC) on the prevention of taxane-induced neuropathy (TIN). Experimental approach: MEDLINE, PubMed, Cochrane Library, Embase, Web of Science, and Google scholar were systemically applied as electronic databases from 2010 to 2019. The current systematic review was carried out based on the main considerations of PRISMA preferential reporting items for systematic review and meta-analyses. Since there was no significant discrepancy, the random-effect model was used for 12-24 weeks’ analysis (I2 = 0%, P = 0.999). Findings/Results: Twelve related titles and abstracts were found during the search, 6 of them were excluded in the first phase. In the second phase, the full text of the remaining 6 articles was comprehensively evaluated and 3 papers were rejected. Finally, 3 articles complied with the inclusion criteria and pooled analyses. The meta-analysis showed a risk ratio of 0.796 (95% CI between 0.486 and 1.303), so, the effects model was used for 12-24 weeks’ analysis (I2 = 0%, P = 0.999) since no significant discrepancies were observed. There was no evidence of ALC’s positive effect on the prevention of TIN during 12 weeks, and it was revealed that ALC significantly increased TIN in 24 weeks. Conclusion and implications: According to our findings, the hypothesis that ALC had a positive effect on preventing TIN in 12 weeks has not been proved; however, ALC led to an increase in the TIN in 24 weeks.
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ORIGINAL ARTICLES Top

Identifying potential ligand molecules EGFR mediated TNBC targeting the kinase domain-identification of customized drugs through in silico methods p. 121
Hima Vyshnavi, Krishnan Namboori
DOI:10.4103/1735-5362.367792  
Background and Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer in which three hormone receptors are negative. This work aimed at identifying customized potential molecules inhibiting epidermal growth factor receptor (EGFR) by exploring variants using the pharmacogenomics approaches. Experimental approach: The pharmacogenomics approach has been followed to identify the genetic variants across the 1000 genomes continental population. Model proteins for the populations have been designed by including genetic variants in the reported positions. The 3D structures of the mutated proteins have been generated through homology modeling. The kinase domain present in the parent and the model protein molecules has been investigated. The docking study has been performed with the protein molecules against the kinase inhibitors evaluated by the molecular dynamic simulation studies. Molecular evolution has been performed to generate the potential derivatives of these kinase inhibitors suitable for the conserved region of the kinase domain. This study considered variants within the kinase domain as the sensitive region and remaining residues as the conserved region. Findings/Results: The results reveal that few kinase inhibitors interact with the sensitive region. Among the derivatives of these kinase inhibitors molecules, the potential kinase inhibitor that interacts with the different population models has been identified Conclusions and implications: This study encompasses the importance of genetic variants in drug action as well as in the design of customized drugs. This research gives way to designing customized potential molecules inhibiting EGFR by exploring variants using the pharmacogenomics approaches.
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Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody p. 138
Ilnaz Rahimmanesh, Yasaman Esmaili, Elham Ghafouri, Seyed Hossein Hejazi, Hossein Khanahmad
DOI:10.4103/1735-5362.367793  
Background and purpose: Despite the widespread utilization of cancer vaccines with specified antigens, the use of whole tumor cell lysates in tumor immunotherapy would be a very promising approach that can overcome several significant obstacles in vaccine production. Whole tumor cells provide a broad source of tumor-associated antigens and can activate cytotoxic T lymphocytes and CD4+ T helper cells concurrently. On the other hand, as an effective immunotherapy strategy, recent investigations have shown that the multi-targeting of tumor cells with polyclonal antibodies, which are also more effective than monoclonal antibodies at mediating effector functions for target elimination, might minimize the escape variants. Experimental approach: We prepared polyclonal antibodies by immunizing rabbits with the highly invasive 4T1 breast cancer cell line. Findings/Results: In vitro investigation indicated that the immunized rabbit serum inhibited cell proliferation and induced apoptosis in target tumor cells. Moreover, in vivo analysis showed enhanced anti-tumor efficacy of whole tumor cell lysate in combination with tumor cell-immunized serum. This combination therapy proved beneficial in significant inhibition of the tumor growth and the established tumor was entirely eradicated in treated mice. Conclusion and implications: Serial intravenous injections of tumor cell immunized rabbit serum significantly inhibited tumor cell proliferation and induced apoptosis in vitro and in vivo in combination with whole tumor lysate. This platform could be a promising method for developing clinical-grade vaccines and open up the possibility of addressing the effectiveness and safety of cancer vaccines.
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Protective effects of protocatechuic acid against doxorubicin- and arsenic trioxide-induced toxicity in cardiomyocytes p. 149
Shafiee Fatemeh, Leila Safaeian, Fatemeh Gorbani
DOI:10.4103/1735-5362.367794  
Background and purpose: Some chemotherapeutic drugs are associated with an increased risk of cardiotoxicity in patients. Protocatechuic acid (PCA) is a phenolic acid with valuable cardiovascular, chemo-preventive, and anticancer activities. Recent studies have shown the cardioprotective effects of PCA in several pathological conditions. This investigation aimed to assess the possible protective effects of PCA on cardiomyocytes against toxicities caused by anti-neoplastic agents, doxorubicin (DOX), and arsenic trioxide (ATO). Experimental approach: H9C2 cells were exposed to DOX (1 μM) or ATO (35 μM) after 24 h pretreatment with PCA (1-100 μM). MTT and lactate dehydrogenase (LDH) tests were used to define cell viability or cytotoxicity. Total oxidant and antioxidant capacities were evaluated by measuring hydroperoxides and ferric-reducing antioxidant power (FRAP) levels. Expression of the TLR4 gene was also quantitatively estimated by real-time polymerase chain reaction. Findings/Results: PCA showed a proliferative effect on cardiomyocytes and significantly enhanced cell viability and reduced cytotoxicity of DOX and ATO during MTT and LDH assays. Pretreatment of cardiomyocytes with PCA significantly decreased hydroperoxide levels and elevated FRAP value. Moreover, PCA meaningfully decreased TLR4 expression in DOX-and ATO-treated cardiomyocytes. Conclusions and implications: In conclusion, antioxidant and cytoprotective activities were found for PCA versus toxicities caused by DOX and ATO in cardiomyocytes. However, further in vivo investigations are recommended to assess its clinical value for the prevention and treatment of cardiotoxicity induced by chemotherapeutic agents.
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A comparative study of the arazyme-based fusion proteins with various ligands for more effective targeting cancer therapy: an in-silico analysis p. 159
Rezvan Mehrab, Hamid Sedighian, Fattah Sotoodehnejadnematalahi, Raheleh Halabian, Abbas Ali Imani Fooladi
DOI:10.4103/1735-5362.367795  
Background and purpose: Recently, the use of immunotoxins for targeted cancer therapy has been proposed, to find new anticancer drugs with high efficacy on tumor cells with minimal side effects on normal cells. we designed and compared several arazyme (AraA)-based fusion proteins with different ligands to choose the best-targeted therapy for interleukin 13 receptor alpha 2 (IL13Rα2)-overexpressed cancer cells. For this purpose, IL13Rα2 was selected as a receptor and IL13 and IL13.E13K were evaluated as native and mutant ligands, respectively. In addition, Pep-1 and A2b11 were chosen as the peptide ligands for targeted cancer therapy. Experimental approach: Several bioinformatics servers were used for designing constructs and optimization. The structures of the chimeric proteins were predicted and verified by I-TASSER, Q-Mean, ProSA, Ramachandran plot, and Verify3D program. Physicochemical properties, toxicity, and antigenicity were predicted by ProtParam, ToxinPred, and VaxiJen. HawkDock, LigPlot+, and GROMACS software were used for docking and molecular dynamics simulation of the ligand-receptor interaction. Findings/Results: The in silico results showed AraA-A2b11 has higher values of confidence score and Q-mean score was obtained for high-resolution crystal structures. All chimeric proteins were stable, non-toxic, and non-antigenic. AraA-(A(EAAAK)4ALEA(EAAAK)4A)2-IL13 retained its natural structure and based on ligand-receptor docking and molecular dynamic analysis, the binding ability of AraA-(A(EAAAK)4ALEA(EAAAK)4A)2-IL13 to IL13Rα2 was sufficiently strong. Conclusion and implications: Based on the bioinformatics result AraA-(A(EAAAK)4ALEA(EAAAK)4A)2-IL13 was a stable fusion protein with two separate domains and high affinity with the IL13Rα2 receptor. Therefore, AraA-(A(EAAAK)4ALEA(EAAAK)4A)2-IL13 fusion protein could be a new potent candidate for target cancer therapy.
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N-Acetylcysteine attenuated pulmonary fibrosis induced by bleomycin via immunomodulation responses p. 177
Zahra Maghsadi, Abbas Azadmehr, Ali Akbar Moghadamnia, Farideh Feizi, Negar Hamidi
DOI:10.4103/1735-5362.367796  
Background and purpose: Pulmonary fibrosis (PF) is a chronic and life-threatening interstitial lung disease. N-acetyl cysteine (NAC) is an antioxidant pharmaceutically available to reduce endothelial dysfunction, inflammation, and fibrosis, however, the therapeutic effect of NAC on PF has not been clearly identified. This research aimed to investigate the possible therapeutic impact of NAC on PF induced by bleomycin in the rat model. Experimental approach: Rats received intraperitoneal injections of NAC at 150, 300, and 600 mg/kg for 28 days before bleomycin, while the positive and negative control groups were treated with bleomycin alone and normal saline, respectively. Then, rats’ lung tissues were isolated and leukocyte infiltration and also collagen deposition were evaluated using hematoxylin and eosin and Mallory trichrome stainings, respectively. In addition, the levels of IL-17, and TGF-β cytokines in bronchoalveolar lavage fluid and hydroxyproline in homogenized lung tissues were assayed using the ELISA method. Findings/Results: Histological findings indicated that NAC decreased leukocyte infiltration, collagen deposition, and fibrosis score in the bleomycin-induced PF tissue. Moreover, NAC significantly reduced TGF-β and hydroxyproline levels at 300-600 mg/kg, as well as IL-17 cytokine at 600 mg/kg. Conclusion and implications: NAC showed a potential anti-fibrotic effect by reducing hydroxyproline and TGF-β as well as an anti-inflammatory effect by decreasing IL-17 cytokine. So, it may be administered as a prophylactic or therapeutic candidate agent to attenuate PF via immunomodulatory effects. Although, future studies are suggested.
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Effect of metformin alone and in combination with etoposide and epirubicin on proliferation, apoptosis, necrosis, and migration of B-CPAP and SW cells as thyroid cancer cell lines p. 185
Ghazaleh Ghavami, Ebrahimi Ramin Kiasari, Faezeh Pakzad, Soroush Sardari
DOI:10.4103/1735-5362.367797  
Background and purpose: There has not been a comprehensive study on the simultaneous effects of metformin, etoposide, and epirubicin on thyroid cancer cells. Hence, the current research proposed the in vitro study on the effect of metformin alone and in combination with etoposide and epirubicin on the rate of proliferation, apoptosis, necrosis, and migration against B-CPAP and SW-1736 cells as thyroid cancer cell lines. Experimental approach: MTT-based proliferation assay, combination index method, flow cytometry, and scratch wound healing assays were used to evaluate the simultaneous effects of the three approved drugs against thyroid cancer cells. Findings/Results: This study showed that the toxic concentration of metformin on normal Hu02 cells was more than 10 folds higher than B-CPAP and SW cancerous cells. Metformin in combination with epirubicin and etoposide could increase percentages of B-CPAP and SW cells in early and late apoptosis and necrosis phases in comparison with their single concentrations, significantly. Metformin in combination with epirubicin and etoposide could arrest the S phase in B-CPAP and SW cells, significantly. Metformin in combination with epirubicin and etoposide could reduce ~100% migration rate, whereas single concentrations of epirubicin and etoposide could reduce ~50% migration rate. Conclusion and implication: Combined treatment of metformin with anticancer drugs epirubicin and etoposide can increase the mortality in thyroid cancer cell lines and reduce the toxicity of these drugs on the normal cell line, which could be the starting point for proposing a new combination strategy in the therapy of thyroid cancer to induce more potency and reduce acute toxicity.
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Neuroprotective effects of alpha-lipoic acid on radiation-induced brainstem injury in rats p. 202
Elham Motallebzadeh, Fatemeh Aghighi, Zarichehr Vakili, Sayyed Alireza Talaei, Mehran Mohseni
DOI:10.4103/1735-5362.367798  
Background and purpose: Alpha-lipoic acid (ALA) is an antioxidant with radioprotective properties. We designed the current work to assess the neuroprotective function of ALA in the presence of oxidative stress induced by radiation in the brainstem of rats. Experimental approach: Whole-brain radiations (X-rays) was given at a single dose of 25 Gy with or without pretreatment with ALA (200 mg/kg BW). Eighty rats were categorized into four groups: vehicle control (VC), ALA, radiation-only (RAD), and radiation + ALA (RAL). The rats were given ALA intraperitoneally 1 h before radiation and killed following 6 h, thereafter superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and total antioxidant capacity (TAC) in the brainstem were measured. Furthermore, a pathological examination was carried out after 24 h, 72 h, and five days to determine tissue damage. Findings/Results: The findings indicated that MDA levels in the brainstem were 46.29 ± 1.64 μM in the RAD group and decreased in the VC group (31.66 ± 1.72 μM). ALA pretreatment reduced MDA levels while simultaneously increasing SOD and CAT activity and TAC levels (60.26 ± 5.47 U/mL, 71.73 ± 2.88 U/mL, and 227.31 ± 9.40 mol/L, respectively). The greatest pathological changes in the rat’s brainstems were seen in RAD animals compared to the VC group after 24 h, 72 h, and 5 days. As a result, karyorrhexis, pyknosis, vacuolization, and Rosenthal fibers vanished in the RAL group in three periods. Conclusion and implications: ALA exhibited substantial neuroprotectivity following radiation-induced brainstem damage.
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Cost-effectiveness and cost-utility analysis of type-2 diabetes screening in pharmacies in Iran p. 210
Mohammadreza Amirsadri, Elahe Torkpour
DOI:10.4103/1735-5362.367799  
Background and purpose: Several studies have shown the effectiveness of screening programs in decreasing the costs and disutility of type-2 diabetes and related complications. As there is a growth in the incidence of type-2 diabetes amongst the Iranian population, the cost-effectiveness of performing type-2 diabetes screening tests in community pharmacies of Iran was evaluated in this study from the payer’s perspective. The target population consisted of two hypothetical cohorts of 1000 people 40 years of age without a prior diagnosis of diabetes, for the intervention (screening test) and no-screening groups. Experimental approach: A Markov model was developed to evaluate the cost-effectiveness and cost-utility of a type-2 diabetes screening test in community pharmacies in Iran. A 30-year time horizon was considered in the model. Three screening programs with 5-year intervals were considered for the intervention group. The evaluated outcomes were quality-adjusted life-years (QALYs) for cost-utility-analysis and life-years-gained (LYG) for cost-effectiveness-analysis. To examine the robustness of the results, one-way and probabilistic-sensitivity analyses were applied to the model. Findings/Results: The screening test represented both more effects and higher costs. The incremental effects in the base-case scenario (no-discounting) were estimated to be 0.017 and 0.0004 (approximately 0) for QALYs and LYG, respectively. The incremental cost was estimated to be 2.87 USD/patient. The estimated incremental-cost-effectiveness ratio was 164.77 USD/QALY. Conclusion and implications: This study indicated that screening for type-2 diabetes in community pharmacies of Iran could be considered highly cost-effective, as it meets the WHO criteria of the annual GDP per capita ($2757 in 2020).
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Effects of oleic acid and/or exercise on diet-induced thermogenesis and obesity in rats: involvement of beige adipocyte differentiation and macrophage M1 inhibition p. 219
Abeer Salama, Mohamed M Amin, Azza Hassan
DOI:10.4103/1735-5362.367800  
Background and purpose: Obesity is a public health problem and the existence of beige adipocytes has got interested as a potential therapeutic involvement for obesity and obesity-associated diseases. Adipose tissue M1 macrophage inhibition, also, has a vital role in obesity via down-regulating adipose tissue inflammation and the use of natural compounds such as oleic acid with exercise has been proposed. The present study aimed to evaluate the possible effects of oleic acid and exercise on diet-induced thermogenesis and obesity in rats. Experimental approach: Wister albino rats were categorized into six groups. Group I: normal control, group II: oleic acid group (9.8 mg/kg; orally), group III: high-fat diet (HFD), group IV: HFD plus oleic acid, group V: HFD plus exercise training, group VI: HFD plus exercise training and oleic acid. Findings/Results: Oleic acid administration and/or exercise significantly decreased body weight, TG, and cholesterol, as well as elevated HDL levels. Furthermore, oleic acid administration and/or exercise reduced serum MDA, TNF-α, and IL-6 levels, elevated the levels of GSH and irisin, increased the expression of UCP1, CD137, and CD206, and reduced CD11c expression. Conclusion and implications: Oleic acid supplementation and/or exercise could be used as therapeutic agents for treating obesity via its antioxidant and anti-inflammatory activities, stimulation of beige adipocyte differentiation, and macrophage M1 inhibition.
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