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ORIGINAL ARTICLES
Isolation of bacteriophages against multidrug resistant Acinetobacter baumannii
Hasan Ghajavand, Bahram Nasr Esfahani, Asghar Havaei, Hossein Fazeli, Reyhaneh Jafari, Sharareh Moghim
September-October 2017, 12(5):373-380
DOI:10.4103/1735-5362.213982  PMID:28974975
Increasing multiple drug resistant (MDR) strains of Acinetobacter baumannii has aggravated curiosity in development of alternative therapy. Bacteriophages are often considered as alternative agents for controlling A. baumannii infections. In the present study two lytic phages for MDR A. baumannii were isolated and their efficacy and host ranges were evaluated. The phages were isolated from hospital wastewater. Electron microscopy revealed that IsfAB78 might belong to Myoviridae and IsfAB39 to Podoviridae. Initial characterization of phages showed that they have narrow host range and failed to infect relative and non- relative bacteria. Both phages decreased the A. baumannii turbidity significantly, indicating that these isolated phages may be considered as candidates for phage therapy.
  1,607 207 2
Development of a nanoprecipitation method for the entrapment of a very water soluble drug into Eudragit RL nanoparticles
Sara Salatin, Jaleh Barar, Mohammad Barzegar-Jalali, Khosro Adibkia, Farhad Kiafar, Mitra Jelvehgari
January-February 2017, 12(1):1-14
DOI:10.4103/1735-5362.199041  PMID:28255308
Rivastigmine hydrogen tartrate (RHT), one of the potential cholinesterase inhibitors, has received great attention as a new drug candidate for the treatment of Alzheimer's disease. However, the bioavailability of RHT from the conventional pharmaceutical forms is low because of the presence of the blood brain barrier. The main aim of the present study was to prepare positively charged Eudragit RL 100 nanoparticles as a model scaffold for providing a sustained release profile for RHT. The formulations were evaluated in terms of particle size, zeta potential, surface morphology, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Drug entrapment efficiency and in vitro release properties of lyophilized nanoparticles were also examined. The resulting formulations were found to be in the size range of 118 nm to 154 nm and zeta potential was positive (+22.5 to 30 mV). Nanoparticles showed the entrapment efficiency from 38.40 ± 8.94 to 62.00 ± 2.78%. An increase in the mean particle size and the entrapment efficiency was observed with an increase in the amount of polymer. The FTIR, XRD, and DSC results ruled out any chemical interaction between the drug and Eudragit RL100 polymer. RHT nanoparticles containing low ratio of polymer to drug (4:1) presented a faster drug release and on the contrary, nanoparticles containing high ratio of polymer to drug (10:1) were able to give a more sustained release of the drug. The study revealed that RHT nanoparticles were capable of releasing the drug in a prolonged period of time and increasing the drug bioavailability.
  1,473 303 8
Dramatic improvement in dissolution rate of albendazole by a simple, one-step, industrially scalable technique
Saeed Ghanbarzadeh, Aram Khalili, Abolghasem Jouyban, Shahram Emami, Yousef Javadzadeh, Mohammad Solhi, Hamed Hamishehkar
November-December 2016, 11(6):435-444
DOI:10.4103/1735-5362.194868  PMID:28003836
Low solubility and dissolution rate are the primary challenges in the drug development which substantially impact the oral absorption and bioavailability of drugs. Due to the poor water solubility, Albendazole (ABZ) is poorly absorbed from the gastrointestinal tract and shows low oral bioavailability (5%) which is a major disadvantage for the systemic use of ABZ. To improve the solubility and dissolution rate of ABZ, different classes of hydrophilic excipients such as sugars (lactose, sucrose, and glucose), polyols (mannitol and sorbitol), ionic surfactant (sodium lauryl sulfate) and non-ionic surfactant (Cremophor A25) were co-spray dried with ABZ. The crystallinity changes in the processed drug were characterized by differential scanning calorimetry and X-Ray diffraction methods were used to interpret the enhanced solubility and dissolution rate of the drug. Results showed that the solubility and dissolution rate of ABZ were increased 1.8-2.6 folds and 3-25 folds, respectively. Unexpectedly, SLS decreased the solubility index of drug powder even lower than the unprocessed drug which was attributed to drug-SLS ionic interaction as depicted from Fourier transform infrared spectroscopy. It was concluded that by applying the facile, one-step, industrially scalable technique and the use of small amounts of excipient (only 4% of the formulation), a great improvement (21 folds) in dissolution rate of ABZ was achieved. This finding may be used in the pharmaceutical industries for the formulation of therapeutically efficient dosage forms of class II and IV drugs classified in biopharmaceutical classification system.
  1,370 209 1
Synthesis, characterization, and stability study of desloratadine multicomponent crystal formation
Ahmad Ainurofiq, Rachmat Mauludin, Diky Mudhakir, Sundani Nurono Soewandhi
March-April 2018, 13(2):93-102
DOI:10.4103/1735-5362.223775  PMID:29606963
This study describes the formation of multicomponent crystal (MCC) of desloratadine (DES). The objective of this study was to discover the new pharmaceutical MCC of DES using several coformers. The MCC synthesis was performed between DES and 26 coformers using an equimolar ratio with a solvent evaporation technique. The selection of the appropriate solvent was carried out using 12 solvents. The preview of the MCC of DES was performed using polarized light microscopy (PLM). The formation of MCC was confirmed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The accelerated stability of MCC at 40 °C and relative humidity of 75% was investigated using PXRD and FTIR. Depending on the prior evaluation, DES and benzoic acid (BA) formed the MCC. PLM and SEM results showed that crystal habit of combination between DES and BA differed from the constituent components. Moreover, the diffractogram pattern of DES-BA was distinct from the constituent components. The DSC thermogram showed a new peak which was distinct from both constituent components. The FTIR study proved a new spectrum. All characterizations indicated that a new solid crystal was formed, ensuring the MCC formation. In addition, DES-BA MCC had both chemical and physical stabilities for a period of 4 months.
  1,152 225 2
REVIEW ARTRICLE
Oligonucleotide aptamers: potential novel molecules against viral hepatitis
Mina Mirian, Hossein Khanahmad, Leila Darzi, Mansour Salehi, Hojjat Sadeghi-Aliabadi
March-April 2017, 12(2):88-98
DOI:10.4103/1735-5362.202447  PMID:28515761
Viral hepatitis, as an international public health concern, seriously affects communities and health system. In recent years, great strides have been taken for development of new potential tools against viral hepatitis. Among these efforts, a valuable strategy introduced new molecules called “aptamers”. Aptamers as potential alternatives for antibodies could be directed against any protein in infected cells and any components of viral particles. In this review, we will focus on recent advances in the diagnosis and treatment of viral hepatitis based on aptamer technology. In recent years, various types of aptamers including RNA and DNA were introduced against viral hepatitis. Some of these aptamers can be utilized for early and precise diagnosis of hepatitis infections and other group selected as therapeutic tools against viral targets. Designing diagnostic and therapeutic platforms based on aptamer technology is a promising approach in viral infections. The obtained aptamers in the recent years showed obvious potential for use as diagnostic and therapeutic tools against viral hepatitis. Although some modifications to increase the biostability and half-life of aptamers are underway, it seems these molecules will be a favorable substitute for monoclonal antibody in near future.
  1,077 199 3
Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: applications, advantages and disadvantages
Parisa Ghasemiyeh, Soliman Mohammadi-Samani
July-August 2018, 13(4):288-303
DOI:10.4103/1735-5362.235156  PMID:30065762
During the recent years, more attentions have been focused on lipid base drug delivery system to overcome some limitations of conventional formulations. Among these delivery systems solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery systems due to the ease of manufacturing processes, scale up capability, biocompatibility, and also biodegradability of formulation constituents and many other advantages which could be related to specific route of administration or nature of the materials are to be loaded to these delivery systems. The aim of this article is to review the advantages and limitations of these delivery systems based on the route of administration and to emphasis the effectiveness of such formulations.
  1,062 213 3
ORIGINAL ARTICLES
Twin arginine translocation system in secretory expression of recombinant human growth hormone
Mohammad Reza Bagherinejad, Hamid Mir-Mohammad Sadeghi, Daryoush Abedi, C Perry Chou, Fatemeh Moazen, Mohammad Rabbani
November-December 2016, 11(6):461-469
DOI:10.4103/1735-5362.194871  PMID:28003839
Recombinant protein production in E. coli has several advantages over other expression systems. Misfolding, inclusion body formation, and lack of eukaryotic post translational modification are the most disadvantages of this system. Exporting of correctly folded proteins to the outside of reductive cytoplasmic environment through twin-arginine system could help to pass these limiting steps. Two signal sequences, TorA and SufI are used at N-terminal of human growth hormone (hGH) bearing DsbA gene sequence at C-terminal to enhance folding. The synthetic cassettes including the signal sequence, hGH and DsbA were transformed into E. coli BL21 (DE3) to study the effect of signal sequence and DsbA chaperone on translocation and folding of the protein. The results confirmed using signal sequence at N-terminal of targeted protein and coexpression with DsbA could transport proteins to the periplasmic space and culture media compared to control groups. Although there is no protein band of somatropin in SDS-Page of culture media samples when using SufI as signaling sequence, the study demonstrated TorA signal sequence could transport the target protein to the culture media. However, there was a considerable amount of hGH in periplasmic space when using SufI compared to control.
  1,060 162 -
High level expression of recombinant human growth hormone in Escherichia coli: crucial role of translation initiation region
Mahsa Ghavim, Khalil Abnous, Fatemeh Arasteh, Sahar Taghavi, Maryam Sadat Nabavinia, Mona Alibolandi, Mohammad Ramezani
March-April 2017, 12(2):168-175
DOI:10.4103/1735-5362.202462  PMID:28515770
For high-throughput production of recombinant protein in Escherichia coli (E. coli ), besides important parameters such as efficient vector with strong promoter and compatible host, other important issues including codon usage, rare codons, and GC content specially at N-terminal region should be considered. In the current study, the effect of decreasing the percentage of GC nucleotides and optimizing codon usage at N-terminal region of human growth hormone (hGH) cDNA on the level of its expression in E. coli were investigated. Mutation in cDNA of hGH was performed through site-directed mutagenesis using PCR. Then, the mutant genes were amplified and cloned into the expression vector, pET-28a. The new constructs were transformed into the BL21(DE3) strain of E. coli and chemically induced for hGH expression. At the final stage, expressed proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), scanning gel densitometry, and western blot. SDS-PAGE scanning gel densitometry assay and western blot analysis revealed higher expression level of hGH by using the two new expressions constructs (mutant genes vectors with decreasing GC content and optimized-codon usage at N-terminal of cDNA) in comparison with wild gene expression vector. Obtained results demonstrated that decreasing the GC nucleotide content and optimization of codon usage at N-terminal of the hGH cDNA could significantly enhance the expression of the target protein in E. coli. Our results highlight the important role of both 5´ region of the heterologous genes in terms of codon usage and also GC content on non-host protein expression in E. coli.
  1,022 191 1
Preparation and in vitro-in vivo evaluation of acyclovir floating tablets
Rahim Bahri-Najafi, Abolfazl Mostafavi, Naser Tavakoli, Somayeh Taymouri, Mohammad-Mehdi Shahraki
March-April 2017, 12(2):128-136
DOI:10.4103/1735-5362.202451  PMID:28515765
In the current study, floating dosage form containing acyclovir was developed to increase its oral bioavailability. Effervescent floating tablets containing 200 mg acyclovir were prepared by direct compression method with three different rate controlling polymers including Hydroxypropyl methylcellulose K4M, Carbapol 934, and Polyvinylpyrrolidone. Optimized formulation showed good floating properties and in vitro drug release characteristics with mean dissolution time and dissolution efficacy of about 4.76 h and 54.33%, respectively. X-ray radiography exhibited that the tablet would reside in the stomach for about 5 ± 0.7 h. After oral administration of floating tablet containing 200 mg acyclovir, the Cmax, Tmax, and AUC0–∞ of optimized gastroretentive formulation were found to be 551 ± 141 ng/mL, 2.75 ± 0.25 h and 3761 ± 909.6 ng/mL/h, respectively.
  991 195 -
Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies
Ayyub Mojaddami, Amirhossein Sakhteman, Masood Fereidoonnezhad, Zeinab Faghih, Atena Najdian, Soghra Khabnadideh, Hossein Sadeghpour, Zahra Rezaei
January-February 2017, 12(1):21-30
DOI:10.4103/1735-5362.199043  PMID:28255310
Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.
  991 178 5
Cytotoxic effects of Pinus eldarica essential oil and extracts on HeLa and MCF-7 cell lines
Najmeh Sarvmeili, Abbas Jafarian-Dehkordi, Behzad Zolfaghari
November-December 2016, 11(6):476-483
DOI:10.4103/1735-5362.194887  PMID:28003841
Several attempts have so far been made in the search of new anticancer agents of plant origin. Some studies have reported that different species of Pine genus possess cytotoxic activities against various cancer cell lines. In the present study, we evaluated the cytotoxic effects of Pinus eldarica bark and leaf extracts or leaf essential oil on HeLa and MCF-7 tumor cell lines. Hydroalcoholic and phenolic extracts and the essential oil of plant were prepared. Total phenolic contents of the extracts were measured using Folin-Ciocalteu reagent. Essential oil components were determined by gas chromatography-mass spectroscopy (GC-MS). Cytotoxic activity of the extracts and essential oil against HeLa and MCF-7 tumor cell lines were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The polyphenolic content of hydroalcoholic and phenolic extracts of the bark and hydroalcoholic extract of the leaf were 48.31%, 47.2%, and 8.47%, respectively. According to the GC-MS analysis, the major components of the leaf oil of P. eldarica were: ß -caryophyllene (14.8%), germacrene D (12.9%), α-terpinenyl acetate (8.15%), α -pinene (5.7%), and -α humulene (5.9%). Bark extracts and leaf essential oil of P. eldarica significantly reduced the viability of both HeLa and MCF-7 cells in a concentration dependent manner. However, leaf extract showed less inhibitory effects against both cell lines. The essential oil of P. eldarica was more cytotoxic than its hydroalcoholic and phenolic extracts. The terpenes and phenolic compounds were probably responsible for cytotoxicity of P. eldarica. Therefore, P. eldarica might have a good potential for active anticancer agents.
  983 184 3
A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors
Sedighe Sadeghian-Rizi, Amirhossein Sakhteman, Farshid Hassanzadeh
November-December 2016, 11(6):445-453
DOI:10.4103/1735-5362.194869  PMID:28003837
In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600E B-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site.
  925 182 1
In vitro antioxidant and cytotoxic potential of different parts of Tephrosia purpurea
Ramamoorthy Padmapriya, Sankar Ashwini, Ramasamy Raveendran
January-February 2017, 12(1):31-37
DOI:10.4103/1735-5362.199044  PMID:28255311
The antioxidant and cytotoxic properties of four major parts of methanolic extracts of Tephrosia purpurea including leaves, root, stem and seed were investigated and compared. In vitro antioxidant activity of T. purpurea extracts was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), reducing power assay and antihemolytic assay. In vitro cytotoxic effect of T. purpurea extracts on SW620 colorectal cancer cell line was studied using 3-(4, 5-dimethylthiazolyl -2,5-diphenyl-tetrazolium bromide (MTT) assay. Folin-ciocalteu and aluminium chloride methods were used to determine the total phenolic and flavonoid contents respectively. Among the four extracts studied, leaves extract showed the highest antioxidant activity, DPPH: 186.3 ± 14.0 μg/mL, FRAP: 754.2 ± 50.9 μmol Fe(II)/mg and reducing power activity: 65.7 ± 4.2 μg/mg of quercetin equivalent (QE/mg) and there was no significant difference observed in antihemolytic activity. Leaves extract showed effective cytotoxicity on colorectal cancer cells (IC 50 : 95.73 ± 9.6 μg/mL) and also had the higher total phenolic (90.5 ± 6.7 μg/mg of gallic acid equivalent (GAE/mg) and flavonoid content (21.8 ± 5.4 μg QE/mg). These results suggest higher antioxidant and cytotoxic activities of leaves extract in comparison with other extracts and these activities could be due to the presence of rich phenolic and flavonoid content.
  934 143 -
Protective effect of curcumin on lead acetate-induced testicular toxicity in Wistar rats
Sri Agus Sudjarwo, Giftania Wardani Sudjarwo, Koerniasari
September-October 2017, 12(5):381-390
DOI:10.4103/1735-5362.213983  PMID:28974976
In recent years, the use of the antioxidant in reducing heavy metal toxicities has increased worldwide. Curcumin has been reported to have a strong antioxidant activity. In this study, we investigated the protective effects of curcumin on lead acetate-induced testicular damage in rats. The sample used 40 male rats divided into 5 groups: negative control (rats were given daily with corn oil); positive control (rats were given daily with lead acetate 50 mg/kg BW orally once in a day for 35 days); and the treatment group (rats were given the curcumin 100 mg, 200 mg, and 400 mg/kg BW orally once in a day for 40 days, and on the 5th day, were given lead acetate 50 mg/kg BW one h after the curcumin administration). After 40 days, levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in testicular tissue, and sperm count, motility and viability in the epididymis were measured in rats. Testis samples were also collected for histopathological studies. Results showed that lead acetate administration significantly decreased the SOD, GPx, and increased MDA levels. Lead acetate also decreased the sperm count, motility, viability, and altered histopathological testis (testicular damage, necrosis of seminiferous tubules and loss of spermatid) compared to the negative control. However, administration of curcumin significantly improved the histopathological in testis, increased the sperm count, motility, viability, and also significantly increased the SOD, GPx, and decreased MDA in testis of lead acetate-treated rats. From the results of this study we concluded that the curcumin could be a potent natural product provide a promising protective effect against lead acetate induced testicular toxicity in rats.
  858 179 1
Comparative effects of chronic administrations of gabapentin, pregabalin and baclofen on rat memory using object recognition test
Asma Salimzade, Ali Hosseini-Sharifabad, Mohammad Rabbani
May-June 2017, 12(3):204-210
DOI:10.4103/1735-5362.207201  PMID:28626478
Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits.
  908 128 -
Bioprocess and downstream optimization of recombinant human growth hormone in Pichia pastoris
Saeed Azadi, Seyed Kazem Sadjady, Seyed Alireza Mortazavi, Nasser Naghdi, Arash Mahboubi, Roya Solaimanian
May-June 2018, 13(3):222-238
DOI:10.4103/1735-5362.228953  PMID:29853932
The methylotrophic yeast Pichia pastoris is a well-established expression host, which is often used in the production of protein pharmaceuticals. This work aimed to evaluate the effect of various concentrations of ascorbic acid in mixed feeding strategy with sorbitol/methanol on productivity of recombinant human growth hormone (r-hGH). The relevant concentration of ascorbic acid (5, 10, or 20 mmol) and 50 g/L sorbitol were added in batch-wise mode to the medium at the beginning of induction phase. The rate of methanol addition was increased stepwise during the first 12 h of production and then kept constant. Total protein and r-hGH concentrations were analyzed and the results compared with sorbitol/methanol feeding using one-way analysis of variance. Moreover, an effective clarification process using activated carbon was developed to remove process contaminants like pigments and endotoxins. Finally, a three-step chromatographic process was applied to purify the product. According to the obtained results, addition of 10 mmol ascorbic acid to sorbitol/methanol co-feeding could significantly increase cell biomass (1.7 fold), total protein (1.14 fold), and r-hGH concentration (1.43 fold). One percent activated carbon could significantly decrease pigments and endotoxins without any significant changes in r-hGH assay. The result of the study concluded that ascorbic acid in combination with sorbitol could effectively enhance the productivity of r-hGH. This study also demonstrated that activated carbon clarification is a simple method for efficient removal of endotoxin and pigment in production of recombinant protein in the yeast expression system.
  836 167 -
Lovastatin prevents bleomycin-induced DNA damage to HepG2 cells
Marjan Nasiri, Mahmoud Etebari, Abbas Jafarian-Dehkordi, Shahla Moradi
November-December 2016, 11(6):470-475
DOI:10.4103/1735-5362.194876  PMID:28003840
Lovastatin as a member of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors is used as a lipid-lowering agent. It can also inhibit the formation of hydrogen peroxide and superoxide anion and finally leads to decline in oxidative stress processes. Here, we evaluated whether lovastatin can increase DNA damage resistance of HepG2 cells against genotoxicity of the anticancer drug bleomycin (BLM). HepG2 cells were incubated with different concentrations of lovastatin (0.1, 0.5, 1, 5 µM) before exposure to BLM (0.5 µg/mL for one h). The genotoxic dose of BLM and lovastatin was separately determined and comet assay was used to evaluate the genotoxicity. After trapping cells in agarose coated lames, they were lysed and the electrophoresis was done in alkaline pH, then colored and monitored by florescent microscope. The results of this study indicated that lovastatin in doses lower than 5 µM has genoprotective effect and in doses higher than 50 µM is genotoxic. In conclusion, lovastatin is able to protect genotoxic effects of BLM in HepG2 cells. Further studies are needed to elucidate the mechanism(s) involved in this process.
  875 120 2
Preparation and characterization of an injectable thermosensitive hydrogel for simultaneous delivery of paclitaxel and doxorubicin
Mahboubeh Rezazadeh, Vajihe Akbari, Elham Amuaghae, Jaber Emami
May-June 2018, 13(3):181-191
DOI:10.4103/1735-5362.228918  PMID:29853928
In the current study, we aimed to develop a novel injectable thermosensitive hydrogel for simultaneous intra-tumoral administration of paclitaxel (PTX) and doxorubicin hydrochloride (DOX). At first, mixed micelles composed of Pluronic F127 and α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was loaded with PTX and their physicochemical properties including particle size, zeta potential, drug loading content, entrapment efficiency, and the drug release were investigated in details. In the second step, the optimized PTX-loaded micelles prepared in the first step were incorporated into the thermosensitive Pluronic F127/hyaluronic acid (PF127/HA) hydrogel containing fixed amount of DOX. Gel formation temperature, rheological properties, injectability, degradation rates of the hydrogel, and the release rate of PTX and DOX from the hydrogel were examined. The mean particle sizes and zeta potentials of the PTX-loaded micelles were 157.5 ± 20.1 nm and -9.6 ± 1.1 mV, respectively. The entrapment efficiency of the formulation was about 51%. The hydrogel containing PTX-loaded micelles and DOX existed as a solution with low viscosity at 4 °C converted to a semisolid upon increasing the temperature to 35 °C. DOX was completely released from the hydrogel within 12 h, while 40-80% of PTX could be released from the different formulations during 3 days. This novel thermosensitive hydrogel prepared in the current study could be efficiently used for co-delivery of PTX and DOX in solid tumor types.
  802 188 3
The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population
Fariba Emadian Razavi, Asghar Zarban, Fatemeh Hajipoor, Mohsen Naseri
May-June 2017, 12(3):211-221
DOI:10.4103/1735-5362.207202  PMID:28626479
The genetic factors are determinants in required dosage changes of warfarin among which are polymorphisms of CYP2C9 and VKORC1 genes. The present study aimed to determine the allele and genotype frequency of CYP2C9 and VKORC1 genes in Birjand population. This study was conducted on 120 individuals who referred to Imam Reza and Vali-Asr hospitals for PT/INR test. After extracting the genomic DNA, the considered sequences were amplified by PCR, and restriction fragment length polymorphism analysis was done by AvaII and KpnI enzymes to determine allele polymorphisms. Moreover, related sequences of VKORC1, after amplification, were sequenced for determining the genotype. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium, observed heterozygosity, expected heterozygosity, and polymorphism information content were calculated by PowerMarker V 3.25 software. Amongst 120 individuals in this study with the mean age of 58.12 ± 12.7 years, 80.8%, 9.1%, and 10% exhibited the alleles of 1, 2, and 3 CYP2C9 gene, respectively. The genotype frequencies of 1/1, 1/2, 2/2, 3/1, 3/2, and 3/3 of this gene were found to be 64.1, 15.8, 0, 17.5, 2.5, and 0 %, respectively. In -1639 G>A region, VKORC1 had normal homozygote genotype (GG) and in 1173 C>T region, heterozygote (CT) with the frequency of 48.7% and 45.9% had the most prevalence. Compared with other populations, there is a considerable difference between the allele frequency of CYP2C9 and VKORC1 genetic variance. Since 35.8% of the selected populations carry an abnormal allele causing sensitivity to warfarin, the specialists at medical centers must be informed about the genotypes of patients before prescribing warfarin.
  784 204 2
Anxiolytic-like effect of hydroalcoholic extract of ripe pistachio hulls in adult female Wistar rats and its possible mechanisms
Mohammad Rostampour, Elham Hadipour, Shahrbano Oryan, Bahram Soltani, Farshid Saadat
November-December 2016, 11(6):454-460
DOI:10.4103/1735-5362.194870  PMID:28003838
The present study was designed to study the preventive effect of hydroalcoholic extract of ripe pistachio hulls (RPH) in the elevated plus maze model of anxiety. One hundred twenty female wistar rats in their estrous cycle were divided into 15 groups of 8 each and received various concentrations of hydroalcoholic extract of RPH except the control groups. Elevated plus maze was used to measure the level of anxiety. Percentage of time spent in the open arms (%OAT), percentage of the number of entries into the open arms (%OAE), locomotor activity, and time spent in the closed arms (CAT), and the number of entries in to the closed arms (CAE) were measured and compared. Dose-response experiments showed that only 10 mg/kg dose of RPH extract significantly increased %OAT (P < 0.001) and %OAE (P < 0.05) compared to the control group, indicating anti-anxiety effects of the extract. Also, pentylenetetrazol and an estrogen receptor antagonist (ERA) tamoxifen could block anti-anxiety effects of the extract (P < 0.001). It was also noticed that tamoxifen was able to significantly reduce locomotor activity. As the RPH extract showed a preventive effect in experimental model of anxiety, it might be concomitantly administered with other anxiolytic medications.
  865 115 1
Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents
Parvin Asadi, Ghadamali Khodarahmi, Hossein Farrokhpour, Farshid Hassanzadeh, Lotfollah Saghaei
May-June 2017, 12(3):233-240
DOI:10.4103/1735-5362.207204  PMID:28626481
In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran–imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical / molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment.
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Development of dry powder inhaler containing tadalafil-loaded PLGA nanoparticles
Jaleh Varshosaz, Somayeh Taymouri, Hamed Hamishehkar, Razieh Vatankhah, Shadi Yaghubi
May-June 2017, 12(3):222-232
DOI:10.4103/1735-5362.207203  PMID:28626480
Inhalable dry powders containing poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were developed for the delivery of tadalafil (TAD) for treatment of life-treating pulmonary arterial hypertension. Taguchi design was employed to evaluate the effects of different formulation variables on the physicochemical characteristics of PLGA-NPs prepared using emulsion solvent evaporation method. Inhalable PLGA-NPs of TAD were successfully prepared by co-spray drying the PLGA-NPs with inert carriers. Physicochemical characteristics and in vitro deposition of the aerosolized drug were also evaluated. The optimized formulation was prepared using 7.5 mg of PLGA, 2.5 mg of TAD, sonication time of 6 min and 2% polyvinyl alcohol (PVA) as the stabilizer. The optimized aqueous/oil phase ratio for PLGA-NPs preparation was 10:1. Polymer/drug ratio was the most effective parameter on the release efficiency. Encapsulation efficiency, zeta potential and particle size of PLGA-NPs were more affected by aqueous/organic phase ratio. The spray dried powders containing PLGA-NPs had a mass median aerodynamic diameter (MMAD) in the range of 1.4–2.8 μm that was suitable for TAD delivery to the deep region of lung. The presence of L- leucine in mannitol containing formulations decreased the interparticulate forces between particles and increased significantly the process yield and fine particle fraction (FPF). The results indicated that prepared dry powders containing TAD-loaded PLGA-NPs were suitable for inhalation and has the potential for the treatment of pulmonary arterial hypertension.
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The protective effect of sodium benzoate on aluminum toxicity in PC12 cell line
Rita Arabsolghar, Jamileh Saberzadeh, Forouzan Khodaei, Rozhin Abbasi Borojeni, Marjan Khorsand, Marzieh Rashedinia
September-October 2017, 12(5):391-400
DOI:10.4103/1735-5362.213984  PMID:28974977
Sodium benzoate (SB) is one of the food additives and preservatives that prevent the growth of fungi and bacteria. SB has been shown to improve the symptoms of neurodegenerative disease such as Alzheimer's disease. The aim of this study was to evaluate the effect of SB on the cell survival and cellular antioxidant indices after exposure to aluminum maltolate (Almal) in PC12 cell line as a model of neurotoxicity. The cells exposed to different concentrations of SB (0.125 to 3 mg/mL) in the presence of Almal (500 µM) and cell viability, the level of reactive oxygen species (ROS), glutathione content and catalase activity were measured. The results showed that low concentrations of SB caused an increase in the cell survival, but cell viability was reduced in high concentrations. SB could neither prevent the level of ROS production nor change glutathione content. SB (0.5 mg/mL) significantly increased the catalase enzyme activity as compared to the Almal. This study suggested that SB did not completely protect the cell to aluminum- induced free radicals toxicity. Possibly SB improves the symptoms of neurodegenerative disease by other mechanisms.
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Inhibitory effects of different fractions of Nepeta satureioides on melanin synthesis through reducing oxidative stress
Seyed Ahmad Emami, Rezvan Yazdian-Robati, Mohammad Sadeghi, Javad Baharara, Elaheh Amini, Farzaneh Salek, Zahra Tayarani-Najaran
March-April 2017, 12(2):160-167
DOI:10.4103/1735-5362.202455  PMID:28515769
Nepeta satureioides Boiss. has been used in traditional medicine of eastern countries and is famous for its medicinal properties. The aim of this study was to evaluate the effect of methanol (MeOH), n-hexane and dichloromethane (CH2Cl2) fractions of the extract on melanin synthesis and oxidative stress in B16F10 melanoma cell line. The B16F10 cell line viability after treatment with increasing concentrations of different fractions of the plant (5-60 μg/mL) was measured using MTT assay. The inhibitory effect on synthesis of melanin, mushroom tyrosinase activity, cellular tyrosinase and oxidative stress were determined by the colorimetric and fluorometric methods. The data showed that at concentrations below 60 μg/mL, fractions did not show significant toxicity on melanoma cells. The amount of melanin synthesis by MeOH and CH2Cl2 fractions and mushroom tyrosinase activity by the MeOH fraction declined in B16F10 cells. In addition to the capacity of MeOH, n- hexane and CH2Cl2 fractions in decreasing the amount of reactive oxygen species (ROS) in melanoma cells, all fractions revealed remarkable antioxidant activity. The melanogenesis inhibitory and antioxidant effects of N. satureioides on B16F10 cells may suggest this plant as a new pharmaceutical agent in reducing skin pigment and skin aging in cosmetic industry.
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Factors affecting liposomes particle size prepared by ethanol injection method
Sherif Shaker, Ahmed Rifaat Gardouh, Mamdouh Mostafa Ghorab
September-October 2017, 12(5):346-352
DOI:10.4103/1735-5362.213979  PMID:28974972
Ethanol injection is one of the techniques frequently used to produce liposomes which favors both simplicity and safety. In this process, an ethanolic solution of lipids is rapidly injected into an aqueous medium through a needle, dispersing the phospholipids throughout the medium and promoting the vesicle formation. Being a critical parameter that determines the fate of liposome and its distribution, we studied different factors affecting the particle size of liposomes including different phospholipid (Phosal® 53 MCT) and cholesterol concentrations and the use of different types of non-ionic surfactants at fixed Phosal® 53 MCT concentration of 50 mg per formulation. Both Phosal® 53 MCT and cholesterol concentration had direct effect on liposomes particle size. Non-ionic surfactants produced liposomes of smaller particle size when compared to conventional liposomes formed using Phosal® 53 MCT 300 mg per formulation only, whereas this effect was diminished when higher Phosal® 53 MCT to cholesterol ratios were used that obviously increased liposomes size. Smaller liposomes sizes were obtained upon using non-ionic surfactants of lower hydrophilic/hydrophobic balance (HLB) as both Tween 80 and Cremophor RH 40 produced liposomes of smaller particle size compared to Poloxamer 407. The smallest liposomes particle size was successfully obtained in the formulation comprising 300 mg Phosal® MCT, 150 mg cholesterol and 50 mg Tween 80.
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