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   Table of Contents - Current issue
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November-December 2019
Volume 14 | Issue 6
Page Nos. 471-573

Online since Wednesday, December 11, 2019

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REVIEW ARTRICLE  

Receptor targeting drug delivery strategies and prospects in the treatment of rheumatoid arthritis p. 471
Jaber Emami, Zahra Ansarypour
DOI:10.4103/1735-5362.272534  
Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by cartilage damage, bone tissue destruction, morphological changes in synovial fluids, and synovial joint inflammation. The inflamed synovial tissue has potential for passive and active targeting because of enhanced permeability and retention effect and the existence of RA synovial macrophages and fibroblasts that selectively express surface receptors such as folate receptor β, CD44 and integrin αVβ. Although there are numerous interventions in RA treatment, they are not safe and effective. Therefore, it is important to develop new drug or drug delivery systems that specifically targets inflamed/swollen joints but attenuates other possible damages to healthy tissues. Recently some receptors such as toll-like receptors (TLRs), the nucleotide-binding oligomerization domain-like receptors, and Fc-γ receptor have been identified in synovial tissue and immune cells that are involved in induction or suppression of arthritis. Analysis of the TLR pathway has moreover suggested new insights into the pathogenesis of RA. In the present paper, we have reviewed drug delivery strategies based on receptor targeting with novel ligand-anchored carriers exploiting CD44, folate and integrin αVβ as well as TLRs expressed on synovial monocytes and macrophages and antigen presenting cells, for possible active targeting in RA. TLRs could not only open a new horizon for developing new drugs but also their antagonists or humanized monoclonal antibodies that block TLRS specially TLR4 and TLR9 signaling could be used as targeting agents to antigen presenting cells and dendritic cells. As a conclusion, common conventional receptors and multifunctional ligands that arte involved in targeting receptors or developing nanocarriers with appropriate ligands for TLRs can provide profoundly targeting drug delivery systems for the effective treatment of RA.
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ORIGINAL ARTICLES Top

Hepatoprotective potential and antioxidant activity of Allium tripedale in acetaminophen-induced oxidative damage p. 488
Sahel Ghobadi, Dara Dastan, Meysam Soleimani, Amir Nili-Ahmadabadi
DOI:10.4103/1735-5362.272535  
Allium tripedale (A. tripedale) is a species of wild Allium native to northwest Iran that its hepatoprotective effects have not yet been confirmed. This study investigated the effect of A. tripedale plant against acetaminophen (APAP)-induced acute liver damage. After preliminary studies, the A. tripedale methanol fraction (ATMF) was selected for in vivo study. Thirty-six rats were divided into six groups of 6 each and treated by gavage as follows: groups 1 and 2 received normal saline; group 3 received 400 mg/kg of ATMF; and groups 4-6 were treated with 100, 200, and 400 mg/kg of ATMF, respectively. After two consecutive weeks, except groups 1 and 3, rats were administered with an oral single dose of APAP (2 g/kg). After 48 h, blood and liver samples were collected for histological and biochemical examinations. The results showed that APAP caused a significant increase in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase serum levels, lipid peroxidation (all with P < 0.001) and hepatic nitric oxide (P < 0.01). In addition, APAP led to the depletion of the total antioxidant capacity, total thiol group (both with P < 0.001), and structural alterations in the hepatic tissue. Following administration of ATMF extract, a significant improvement was observed in the functional and oxidative stress markers of hepatic tissue alongside histopathologic changes. In conclusion, the present study showed that the administration of ATMF might prevent hepatic oxidative damage by improving oxidant/antioxidant balance in animals exposed to APAP.
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Nano-SnCl4.SiO2, an efficient catalyst for synthesis of benzimidazole drivatives as antifungal and cytotoxic agents p. 496
Leila Zamani, Zeinab Faghih, Kamiar Zomorodian, Bi Bi Fatemeh Mirjalili, Asghar Jalilian, Soghra Khabnadideh
DOI:10.4103/1735-5362.272536  
The concept of green chemistry has made significant impact on many frontages including the use of green solvents or sustainable catalyst materials. Benzimidazole ring is an important nitrogen-containing heterocyclic, which exhibits a broad spectrum of bioactivities and are widely utilized by the medicinal chemists for drug discovery. A simple and efficient method was developed for the synthesis of some benzimidazole derivatives via reaction of o-phenylenediamine and substituted aldehydes in the presence of nano-SnCl4/SiO2 as a mild catalyst. Ten 2-substituted benzimidazole compounds (J1-J10) were synthesized. All compounds were evaluated against different species of yeasts and filament fungi using broth micro dilution method as recommended by clinical and laboratory standard institute. Among these compounds, the active ones were chosen for their cytotoxic activities evaluation against MCF-7 and A549 cell lines using MTT method. Compound J2 showed the best antifungal activity against all tested species. Compounds J5-J7 had also desirable antifungal activities. Our cytotoxic results were also similar to the antifungal activities except for J7 which had no cytotoxic activity.
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Effects of pre-transplant L-carnitine supplementation on primary graft dysfunction in liver transplant recipients: a pilot, randomized, placebo-controlled clinical trial p. 504
Behrouz Khajeh, Simin Dashti-Khavidaki, Mohsen Nasiri-Toosi, Keyhan Mohammadi, Atefeh Jafari
DOI:10.4103/1735-5362.272537  
Primary graft dysfunction (PGD) and non-function (PNF) happen in 8.7-24.7% and 0.9-7.2% of liver transplant recipients, respectively. These phenomena increase treatment cost and patients’ death. This study assessed the effect of L-carnitine supplementation on the incidences of PNF/PGD in liver transplant recipients. This randomized, placebo-controlled, clinical trial was performed on adult liver transplant recipients. Patients took L-carnitine syrup 500 mg three times daily or placebo from the time of including in transplant waiting list until the day of transplant surgery (median 14 days, 1-192 days). Thirty-three patients in L-carnitine and 39 patients in placebo group completed the study. Although not statistically significant, PNF and PGD happened less frequently among recipients in L-carnitine compared with placebo group (3% vs. 12.8% for PNF; 15.2% vs. 30.8% for PGD). Alanine aminotransferase (ALT) and aspartate aminotransferase were lower in L-carnitine group at day 3 after transplantation. ALT declined more significantly within 48 h after transplantation in L-carnitine arm (median 120.50 vs. 79 IU/L; P = 0.03). One-month patients’ survival was significantly higher in L-carnitine versus placebo group (97% vs. 74.4%; P = 0.008). The rates of PNF and PGD in L-carnitine group were approximately one-fourth and one-half of placebo group respectively. One-month patients’ survival was higher in L-carnitine group.
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Selection and characterization of single-stranded DNA aptamers against interleukin-5 p. 515
Mina Jamalvandi, Hossein Khanahmad, Shiva Irani, Sayad Bastaminezhad
DOI:10.4103/1735-5362.272560  
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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Possible antioxidant mechanism of coenzyme Q10 in diabetes: impact on Sirt1/Nrf2 signaling pathways p. 524
Fatemeh Samimi, Maryam Baazm, Ebrahim Eftekhar, Sadegh Rajabi, Mohammad Taghi Goodarzi, Farideh Jalali Mashayekhi
DOI:10.4103/1735-5362.272561  
Oxidative stress is a major complication in diabetes mellitus. The aim of this study was to investigate potential antioxidant activity of coenzyme Q10 (Co Q10) against hyperglycemia-induced oxidative stress in diabetic rat and unraveling its mechanism of action by focusing on silent information regulator 1 (Sirt1) and nuclear factor E2-related factor 2 (Nrf2) mRNA expression level. Furthermore, the activity of two Nrf2-dependent antioxidant enzymes (superoxide dismutase and catalase) in the liver of diabetic rats was studied. After induction of diabetes in rats using streptozotocin (55 mg/kg), rats were divided into five groups of six each. Groups 1 and 2 (healthy control groups) were injected with isotonic saline or sesame oil; group 3 received Co Q10 (10 mg /Kg /day), group 4, as a diabetic control, received sesame oil; and group 5 was diabetic rats treated with Co Q10. Afterwards, serum and liver samples were collected, and oxidative stress markers, lipid profile, as well as the expression of Sirt1 and Nrf2 genes were measured. Diabetes induction significantly reduced expression level of Sirt1 and Nrf2 mRNAs and also declined catalase, superoxide dismutase activities, and total thiol groups levels in diabetic group in comparison to healthy controls, while a significant increase was found in the levels of malondialdehyde and lipid profile. Co Q10 treatment significantly up-regulated Sirt1 and Nrf2 mRNA levels along with an increase in catalase activity in diabetic group as compared with untreated diabetic rats. Furthermore, Co Q10 caused a marked decrease in malondialdehyde levels and significantly improved lipid profile. Our data demonstrated that Co Q10 may exert its antioxidant activity in diabetes through the induction of Sirt1/Nrf2 gene expression.
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Synthesis, molecular docking, and antiepileptic activity of novel phthalimide derivatives bearing amino acid conjugated anilines p. 534
Azar Asadollahi, Mehdi Asadi, Faezeh Sadat Hosseini, Zeinab Ekhtiari, Mahmood Biglar, Massoud Amanlou
DOI:10.4103/1735-5362.272562  
A series of N-aryl-2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanamides derivatives were synthesized in two steps. Phthalic anhydride and phenylalanine are first reacted under microwave radiation to form 2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoic acid, which finally took part in an amidation reaction with different anilines. The final products were characterized by infrared, proton nuclear magnetic resonance (1H NMR) and mass spectroscopy techniques. The antiepileptic activity of the synthesized compounds at a fixed dose of 10 mg/kg was evaluated by pentylenetetrazole at 70 mg/kg induced seizure threshold method in male mice (n = 5) and compared with aqueous DMSO (10 %, v/v; as negative control) and thalidomide (70 mg/kg; as positive control). The results indicated that compounds 5c, 5e, and 5f as well as thalidomide significantly have higher latency time than what observed with aqueous DMSO (P < 0.05). The seizure latency threshold for 5e and 5f were statistically similar to the results of thalidomide but compound 5c showed significantly higher latency time than thalidomide. While, the electron-deficient benzene ring (5a and 5b) has demonstrated the lowest activity but compound 5e, which is the most electron rich product among tested compounds, showed good antiepileptic activity. Molecular docking was performed in order to understand how the synthetized compounds, interact with gamma-aminobutyric acid (GABA)A receptor. Docking results were in good harmony with experimental data and indicated that lowest binding energy belongs to compound 5c, which has strongest interactions with the active site of GABAA receptor. Compound 5c could be used for further investigation.
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Evaluation and comparison of the antidepressant-like activity of Artemisia dracunculus and Stachys lavandulifolia ethanolic extracts: an in vivo study p. 544
Reza Jahani, Dariush Khaledyan, Ali Jahani, Elham Jamshidi, Mohammad Kamalinejad, Mona Khoramjouy, Mehrdad Faizi
DOI:10.4103/1735-5362.272563  
Several studies have supported the preventive and therapeutic values of phenolic compounds including chlorogenic acid, syringic acid, vanillic acid, ferulic acid, caffeic acid, luteolin, rutin, catechin, kaempferol, and quercetin in mental disorders. Since these secondary metabolites are reported as the phenolic compounds of Artemisia dracunculus (A. dracunculus) and Stachys lavandulifolia (S. lavandulifolia), the main aim of this study was the evaluation and comparison of the phenolic contents, flavonoids, and antidepressant-like activity of Artemisia dracunculus with Stachys lavandulifolia. Antidepressant-like activity of the extracts was evaluated in the forced swimming test (FST) and the tail suspension test (TST). Moreover, the open field test was conducted to evaluate the general locomotor activity of mice following treatment with the extracts. Since phenolic compounds and flavonoids play main roles in pharmacological effects, the phenolic and flavonoid contents of the extracts were measured. Though significant difference between the phenolic contents of the extracts was not observed, but S. lavandulifolia exhibited higher flavonoid contents. Animal treatment with extracts decreased the immobility times in both FST and TST compared to the vehicle group without any significant effect on the locomotor activity of animals. Also, S. lavandulifolia at 400 mg/kg showed higher potency in both tests compared to A. dracunculus. Our results provided promising evidence on the antidepressant-like activity of both extracts which could be related to flavonoids as the main components of the extracts, but more studies need to be conducted to specify the main compounds and the mechanisms involved in the observed effects.
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Efficient expression of EpEX in the cytoplasm of Escherichia coli using thioredoxin fusion protein p. 554
Farideh Rasooli, Atieh Hashemi
DOI:10.4103/1735-5362.272564  
Recombinant epithelial cell adhesion molecule extracellular domain (EpEX) has a high potential as a candidate for passive and active immunotherapy as well as cancer vaccination. In the present study, EpEX was expressed as a thioredoxin fusion protein in Escherichia coli (E. coli). The effect of different hosts and expression conditions on the expression level of the fusion protein was also evaluated. Moreover, the effect of temperature and isopropyl-ß-d-thiogalactopyranoside (IPTG) concentration on protein solubility was assessed. The codon optimized-synthetic gene was cloned into pET32a (+) expression vector and transformed into E. coli BL21 (DE3), RosettaTM (DE3), and OrigamiTM (DE3). The protein expression was confirmed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. Lowering the expression temperature to 16 °C and IPTG concentration to 0.5 mM also dramatically increased the volumetric productivity of the fusion protein. In optimum culture condition, high-level expression of the target fusion protein was detected in RosettaTM (DE3) and OrigamiTM (DE3) (207 and 334 μg/mL, respectively), though they were expressed as inclusion bodies. No improvement was observed in the solubility of the fusion protein by reducing the temperature or IPTG concentration even when expressed in a TrxB/gor mutant strain. Results showed that Trx tag combined with other strategies utilized here could be effective to achieve high level of protein production but not effective in solubility improvement. However, new approaches might be necessary to enhance the solubility of EpEX in the E. coli system.
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Naringenin potentiated β-sitosterol healing effect on the scratch wound assay p. 566
Manal Mohammad Abbas, Naseer Al-Rawi, Manal Ahmad Abbas, Iqbal Al-Khateeb
DOI:10.4103/1735-5362.272565  
In the present investigation scratch wound assay was used to study the ability of several combinations of each flavonoid (chrysin, naringenin or resveratrol) with β-sitosterol to heal wounds in vitro. MTT test was performed to determine if the combination of flavonoid with β-sitosterol was toxic to fibroblasts or not. Also, superoxide dismutase (SOD) activity and interleukin-1ß (IL-1β) concentrations were measured. The best closure rates were obtained with β-sitosterol combined with naringenin and β-sitosterol combined with resveratrol. The combination that produced the best closure rate namely β-sitosterol with naringenin increased SOD activity significantly. However, this combination was not better than naringenin or β-sitosterol alone in reducing IL-β concentration. The results of MTT test indicated that the combination as well as β-sitosterol alone or naringenin alone has no toxic effect on fibroblasts. In conclusion, the combination of β-sitosterol and naringenin exerted a synergistic effect on wound closure without decreasing the viability of fibroblasts, increased antioxidant defense mechanism and decreased IL-β.
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