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   Table of Contents - Current issue
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November-December 2017
Volume 12 | Issue 6
Page Nos. 434-534

Online since Friday, November 3, 2017

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ORIGINAL ARTICLES  

Protective effects of coenzyme Q10 and L-carnitine against statin-induced pancreatic mitochondrial toxicity in rats p. 434
Melina Sadighara, Jalal Pourahamad Joktaji, Valiollah Hajhashemi, Mohsen Minaiyan
DOI:10.4103/1735-5362.217424  
Statins are widely used in patients with hyperlipidemia and whom with high risk of cardiovascular diseases. Unfortunately, statins also exert some adverse effects on the liver and pancreas and enhance the risk of type 2 diabetes mellitus. The objective of the present research was to investigate the protective effects of coenzyme Q10 (Co-Q10) and L-carnitine (LC) on statins induced toxicity on pancreatic mitochondria in vivo. Seven groups of male Wistar rats received atorvastatin (20 mg/kg, p.o.), atorvastatin + Co-Q10 (10 mg/kg, i.p.), atorvastatin + LC (500 mg/kg, i.p.), lovastatin (80 mg/kg, p.o), lovastatin + Co-Q10 (10 mg/kg, i.p.), and lovastatin + LC (500 mg/kg, i.p.). Serum glucose and insulin levels were measured before and after two weeks of treatment, while the pancreas was removed and toxic effects of statins, as well as the protective effects of Co-Q10 and LC were assessed. The results showed that atorvastatin and lovastatin significantly increased glucose level and decreased insulin secretion. The glucose level in Co-Q10 and LC groups was significantly lower than statins alone groups. The findings also showed that statin groups had higher rate of pancreatic toxicity including higher level of reactive oxygen species production, decreased cytochrome c oxidase activity, collapse of mitochondrial membrane potential and swelling in comparison to controls. These factors were significantly diminished by co-administration of Co-Q10 or LC compared to statin groups alone. Additionally, supplements caused a significant increase in serum insulin and succinate dehydrogenase activity. Our study provided new evidence supporting beneficial effects of Co-Q10 and LC on statin-induced pancreatic toxicity.
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Synthesis, characterization, cytotoxic screening, and density functional theory studies of new derivatives of quinazolin-4(3H)-one Schiff bases p. 444
Rezvan Rezaee Nasab, Farshid Hassanzadeh, Ghadam Ali Khodarahmi, Mahmoud Mirzaei, Mahboubeh Rostami, Ali Jahanian-Najaf abadi
DOI:10.4103/1735-5362.217425  
A series of novel derivatives of quinazolinone Schiff bases were synthesized from benzoic acid starting material and evaluated for potential cytotoxic activities against the human breast adenocarcinoma (MCF-7) and the human colon adenocarcinoma (HT-29) cell lines. Compared to the reference drug, these compounds showed good cytotoxic activities against studied cell lines especially compounds 4d and 4e. The ground-state geometries of these compounds (4a-g) were optimized at the B3LYP/6–31G* density functional theory (DFT) level. Then maximum absorptions electron affinity, ionization potential, electronegativity (χ), energy gap (Egap), hardness (η), softness (S), electrophilicity (ω), and electrophilicity index (ωi) were calculated and discussed. The quantitative structure-activity relationship (QSAR) properties including the physicochemical parameters were also evaluated and studied. The computed properties of our novel synthesized compounds were compared with erlotinib compound.
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The silencing effect of miR-30a on ITGA4 gene expression in vitro: an approach for gene therapy p. 456
Leila Darzi, Maryam Boshtam, Laleh Shariati, Shirin Kouhpayeh, Azam Gheibi, Mina Mirian, Ilnaz Rahimmanesh, Hossein Khanahmad, Mohammad Amin Tabatabaiefar
DOI:10.4103/1735-5362.217426  
Integrins are adhesion molecules which play crucial roles in cell-cell and cell-extracellular matrix interactions. Very late antigen-4 or α4β1 and lymphocyte Peyer’s patch adhesion molecule-1 or α4β7, are key factors in the invasion of tumor cells and metastasis. Based on the previous reports, integrin α4 (ITGA4) is overexpressed in some immune disorders and cancers. Thus, inhibition of ITGA4 could be a therapeutic strategy. In the present study, miR-30a was selected in order to suppress ITGA4 expression. The ITGA4 3' UTR was amplified, cloned in the Z2827-M67-(ITGA4) plasmid and named as Z2827-M67/3'UTR. HeLa cells were divided into five groups; (1) untreated without any transfection, (2) mock with Z2827-M67/3'UTR transfection and X-tremeGENE reagent, (3) negative control with Z2827-M67/3'UTR transfection alone, (4) test with miR-30a mimic and Z2827-M67/3'UTR transfection and (5) scramble with miR-30a scramble and Z2827-M67/3'UTR transfection. The MTT assay was performed to evaluate cell survival and cytotoxicity in each group. Real-time RT-PCR was applied for the ITGA4 expression analysis. The findings of this study showed that miR-30a downregulated ITGA4 expression and had no effect on the cell survival. Due to the silencing effect of miR-30a on the ITGA4 gene expression, this agent could be considered as a potential tool for cancer and immune disorders therapy.
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Preparation and in vitro characterization of retinoic acid-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) micelles p. 465
Ebrahim Shakiba, Saeedeh Khazaei, Marziyeh Hajialyani, Bandar Astinchap, Ali Fattahi
DOI:10.4103/1735-5362.217427  
In order to achieve the controlled release of all-trans-retinoic acid (ATRA), poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) copolymer with average molecular weight of 5.34 kDa was synthesized. The nanosized micelles were prepared from copolymer by nano-precipitation method. Critical association concentration (CAC) of micelles was measured by fluorimetry and results indicated low CAC value of micelles (1.9 × 10-3 g/L). ATRA was encapsulated in the core of micelles using different ratios of drug to copolymer. In the case of 10% drug to polymer ratio, more than 80% of the drug was released within 3 days, whereas for ratio of 2% more than 90% of the drug was released within 3 h. The cytotoxic study performed by MTT assay showed that H1299 survival percent decreased significantly (P ≤ 0.05) after exposure to drug-loaded micelles, while no proliferation inhibition effect was observed by either free ATRA or blank PCL-PEG-PCL micelles.
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Thymoquinone protects the rat kidneys against renal fibrosis p. 479
Rahimeh Bargi, Fereshteh Asgharzadeh, Farimah Beheshti, Mahmoud Hosseini, Mehdi Farzadnia, Majid Khazaei
DOI:10.4103/1735-5362.217428  
Thymoquinone (TQ) is the main active ingredient of Nigella sativa seeds with various pharmacological effects. The aim of this study was to investigate the effect of TQ on renal fibrosis and permeability and oxidative stress status in lipopolysaccharide (LPS)-induced inflammation in male rats. Eighty male Wistar rats were divided into 5 groups as follow: control (received normal saline), LPS (1 mg/kg/day), and LPS+TQ (by doses of 2, 5 and 10 mg/kg/day). After three weeks, the biochemical parameters such as blood urea nitrogen (BUN) and creatinine in serum samples, oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase (CAT) activities in renal tissue homogenate and renal permeability (evaluated by Evan’s blue dye method) were measured and renal fibrosis was evaluated, histologically using Masson’s trichrome staining. LPS administration induced renal fibrosis (1.49 ± 0.08 vs. 7.15 ± 0.18%) and significantly increased renal permeability (6.03 ± 1.05 vs. 13.5 ± 1.04 μg evans blue(EB)/g tissue), serum BUN and creatinine levels and oxidative stress marker (MDA) (P < 0.05), while, it reduced anti-oxidative markers including total thiol group, SOD and CAT activities (P < 0.05). Administration of TQ significantly improved these alterations which were dose-dependent in oxidative stress markers, renal permeability (TQ 2, 5 and 10 mg/kg: 10.7 ± 0.3, 9.2 ± 1.4 and 11.5 ± 0.6 μg EB/g tissue; respectively) and fibrosis (TQ 2, 5 and 10 mg/kg: 6.09 ± 0.7, 4.26 ± 0.14 and 2.52 ± 0.08%; respectively). In conclusion, administration of TQ reduced renal fibrosis and permeability and improved oxidative stress status. Thus, TQ can be considered in conditions accompanied with chronic inflammation at least as a part of treatment strategy.
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Anticlastogenic, radiation antagonistic, and anti-inflammatory activities of Persea americana in albino Wistar rat model p. 488
Amith Kumar, Reshma Kumarchandra, Rajalakshmi Rai, Ganesh Sanjeev
DOI:10.4103/1735-5362.217429  
The present study was undertaken to evaluate the anti-inflammatory activity and antigenotoxic effect of hydroalcoholic leaf extract of Persea americana (P. americana) in albino Wistar rats against whole body X-ray irradiation. Rats were orally administered with (25, 50, 100, 200, and 400 mg/kg body weight) of P. americana leaf extract for five days. On the fifth day after last administration, animals were exposed to whole body X-rays of 8 Gy. Based on Kaplan Meier’s survival analysis, 100 mg/kg body weight was selected as an optimum dose for radioprotection. The radioprotective potential was analysed by bone marrow micronucleus test and comet assay in peripheral blood lymphocytes. Biochemical estimations were performed in liver tissue homogenates. DNA damage indicators analysed through comet assay displayed significant reduction in olive tail movement (P < 0.01), percentage DNA in tail (P < 0.05) and tail length (P < 0.001) in pretreated group when compared to radiation group. P. americana leaf extract restored the levels of reduced glutathione, catalase, and reduced the levels of lipid peroxidation, protein carbonyls, and cyclooxygenase-2 levels in liver homogenates of pre-treated group. Decrease in micronucleated polychromatic erythrocytes (P < 0.05) was witnessed in P. americana pretreated group when compared to radiation control. Pretreatment also resulted in the increase of animal survival with dose reduction factor of 1.28. Our findings for the first time demonstrated that P. americana offers significant protection to rats from whole body exposure to X-rays and helps in antagonising the radiation effects, thereby combating acute radiation induced damage in living systems.
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Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety p. 500
Sedighe Sadeghian-Rizi, Ghadamali Ali Khodarahmi, Amirhossein Sakhteman, Ali Jahanian-Najafabadi, Mahboubeh Rostami, Mahmoud Mirzaei, Farshid Hassanzadeh
DOI:10.4103/1735-5362.217430  
In this study a series of diarylurea derivatives containing quinoxalindione group were biologically evaluated for their cytotoxic activities using MTT assay against MCF-7 and HepG2 cell lines. Antibacterial activities of these compounds were also evaluated by Microplate Alamar Blue Assay (MABA) against three Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi), three Gram-positive (Staphylococcus aureus, Bacillus subtilis and Listeria monocitogenes) and one yeast-like fungus (Candida albicans) strain. Furthermore, molecular docking was carried out to study the binding pattern of the compounds to the active site of B-RAF kinase (PDB code: 1UWH). Molecular dynamics simulation was performed on the best ligand (16e) to investigate the ligand binding dynamics in the physiological environment. Cytotoxic evaluation revealed the most prominent cytotoxicity for 6 compounds with IC50 values of 10-18 μM against two mentioned cell lines. None of the synthesized compounds showed significant antimicrobial activity. The obtained results of the molecular docking study showed that all compounds fitted in the binding site of enzyme with binding energy range of -11.22 to -12.69 kcal/mol vs sorafenib binding energy -11.74 kcal/mol as the lead compound. Molecular dynamic simulation indicated that the binding of ligand (16e) was stable in the active site of B-RAF during the simulation.
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Effects of Cornus mas fruit hydro-methanolic extract on serum antioxidants, lipid profile, and hematologic parameters following cisplatin-induced changes in rats p. 510
Atefe Mohammadzadeh Vardin, Bita Abdollahi, Morteza Kosari-Nasab, Mehran Mesgari Abbasi
DOI:10.4103/1735-5362.217431  
Cisplatin (Cis) has serious adverse side-effects that limit its clinical use. The mechanism underlying the effects is complex, including mitochondrial oxidative stress and inflammation. This study investigated whether Cornus mas, a fruit with high antioxidant contents, hydro-methanolic extract (CME) can modulate the cisplatin-induced changes. Forty Wistar rats were divided into a control group, Cis group, CME group, CME 300 + Cis group, and the CME 700 + Cis group. After the intervention, blood samples were taken for biochemical and hematological analysis. CME analysis showed noticeable total phenol and total antioxidant contents. The plasma glutathione peroxidase and catalase levels were significantly decreased and malondialdehyde and blood hemoglobin levels were significantly increased in the Cis group, which were reversed to the control levels in the CME + Cis groups. In the CME group, the red blood cell count was significantly lower and the red cell distribution width and hemoglobin distribution width levels were significantly higher. In the Cis-treated group, white blood cells, neutrophils, monocytes, basophils, and large unstained cells were significantly increased and lymphocytes were significantly decreased when compared with the control group that was reached to non-significant levels in CME 700 + Cis group. The blood cholesterol and high density lipoprotein in all CME-treated groups were significantly decreased. The eosinophils increased in the CME group significantly. The results showed considerable total antioxidant and total phenol contents and relative protective effects of CME against Cis-induced antioxidant and hematologic changes in rats.
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Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines p. 517
Mahshid Mohammadian, Shima Zeynali, Anahita Fathi Azarbaijani, Mohammad Hassan Khadem Ansari, Fatemeh Kheradmand
DOI:10.4103/1735-5362.217432  
The use of heat shock protein 90 inhibitors like 17-allylamino-17-demethoxy-geldanamycin (17-AAG) has been recently introduced as an attractive anticancer therapy. It has been shown that 17-AAG may potentiate the inhibitory effects of some classical anticolorectal cancer (CRC) agents. In this study, two panels of colorectal carcinoma cell lines were used to evaluate the effects of 17-AAG in combination with capecitabine and oxaliplatin as double and triple combination therapies on the proliferation of CRC cell lines. HT-29 and all HCT-116 cell lines were seeded in culture media in the presence of different doses of the mentioned drugs in single, double, and triple combinations. Water-soluble tetrazolium-1 (WST-1) assay was used to investigate cell proliferation 24 h after treatments. Then, dose-response curves were plotted using WST-1outputs, and IC50 values were determined. For double and triple combinations respectively 0.5 × IC50 and 0.25 × IC50 were used. Data was analyzed with the software CompuSyn. Drug interactions were analyzed using Chou-Talalay method to calculate the combination index (CI).The data revealed that 17-AAG shows a potent synergistic interaction (CI < 1) with oxaliplatin and capecitabine in double combinations (0.5 × IC50) in both cell lines. In the case of triple combinations, the findings showed an antagonistic interaction (CI > 1) in HT-29 and a synergistic effect (CI < 1) in HCT-116 (0.25 × IC50) cell lines. It was concluded that double combinations of 17-AAG with oxaliplatin or capecitabine might be effective against HCT-116 and HT-29 cell lines. However, in triple combinations, positive results were seen only against HCT-116. Further investigation is suggested to confirm the effectiveness of these combinations in clinical trials.
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Synthesis and evaluation of antimicrobial activity of cyclic imides derived from phthalic and succinic anhydrides p. 526
Elham Jafari, Najmeh Taghi jarah-Najafabadi, Ali Jahanian-Najafabadi, Safoora Poorirani, Farshid Hassanzadeh, Sedighe Sadeghian-Rizi
DOI:10.4103/1735-5362.217433  
Cyclic imides are a group of compounds which have valuable biological properties including cytotoxic, anti-inflammatory, antibacterial and antifungal activities. In this study, succinic and phthalic anhydrides were treated with glycinamide in pyridine to yield the corresponding amic acids. These amic acids underwent ring closure with acetic anhydride and anhydrous sodium acetate to form cyclic imides. In another procedure, succinic and phthalic anhydrides upon reaction with 2-amino-benzylamine in pyridine gave the corresponding cyclic imides. The imides were screened for their antimicrobial activities against three types of bacteria and one type of fungi. Phthalimide derived from benzylamine exhibited remarkable antimicrobial activity against E. coli.
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