فهرست مطالب

Pharmaceutical Research - Volume:17 Issue: 3, 2018
  • Volume:17 Issue: 3, 2018
  • تاریخ انتشار: 1397/05/04
  • تعداد عناوین: 32
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  • Mahboobeh Raeiszadeh, Abbas Pardakhty, Fariba Sharififar, Mehrnaz Mehrabani, Hojjat Nejat Mehrab-Kerman, Mitra Mehrabani * Pages 804-817
    Traditionally, Myrtus communis (myrtle) has been used for treatment of several kinds of disorders. However, there are some factors, namely, low solubility and permeability, which restrict use of myrtle extract (ME) in medical applications. Regarding these limitations, the aim of the present study was to develop a new niosomal formulation to enhance ME stability and permeability.
    Briefly, several niosomal formulations were prepared by non-ionic surfactants and cholesterol with different molar ratios. Afterward, size, entrapment efficiency (EE%), release and stability of niosomal myrtle extract (nME) were investigated. The effect of ME and nME on viability of 3T3 cells was evaluated using MTT assay. Antibacterial activity of ME and nME was also assessed against staphylococcus aureus, staphylococcus epidermidis, Escherichia coli, Micrococcus luteus, and Bacillus subtilis.
    Sizes of niosomes were 5.3±0.3 to 15.9±2.2 µm with 4.1±0.3 to 26.9±1.7 mV zeta potential. The EE% of niosomes was varied from 45.4% to 93.4%. An in vitro release study on F5 formulation (Span60: Tween60: cholesterol (3:3:4 molar ratio)) revealed that about 36.9%, 38.5% and 26.7% of phytoconstituents were released within 12h from acetate cellulose membrane, 0.45 µm, regenerated cellulose membrane, 0.45 µm, and cellophane dialysis sack, 12000 Da, respectively. F5 formulation significantly showed lower toxicity on cells. It had higher antibacterial activity that has been shown by lower MICs and higher zone of inhibition compared to ME.
    Overall, F5 formulation in the presence of 4% ME produced stable multi lamellar vesicles with optimal in-vitro release and EE%. This formulation also exhibited better antibacterial activity than ME.
    Keywords: encapsulation efficiency, Myrtus communis, myrtle, phytoniosome, release, stability
  • Manijeh Mohammadian, Taherehsadat Jafarzadeh, Mohammad Erfan *, Fatemeh Pashaei Soorbaghi Pages 818-829
    Silica aerogels are porous and extremely lightweight nano-materials shows interesting properties. These materials, because of biocompatibility, non-harmful to the body and special physical characteristics such as large surface area and low density have great potential for use in a drug delivery system (DDS). The focus of this study is the evaluation of the effects of silica aerogels on improving the release rate of Ketoprofen as a relevant model drug of poorly soluble drugs in water. The in-vitro release rate of a conventional crystalline form of pure drug and three samples of drug loaded silica aerogels with different densities, 0.033, 0.080, and 0.24 g/cm3 were measured and investigated. The results show that all three samples of silica aerogels considerably increased (p
    Keywords: Release kinetic model, Drug delivery, Silica aerogel, Ketoprofen, Drug dissolution
  • Hamideh Sobhani, Parastoo Tarighi, Seyed Naser Ostad, Alireza Shafaati, Nastaran Nafissi-Varcheh, Reza Aboofazeli * Pages 830-850
    This study was planned to explore the capability of nanoemulsions (NEs) consisting of CapryolTM 90 and oleic acid for the delivery of rapamycin (RAP). Permeability and cytotoxicity of RAP-loaded NEs were also inspected. Pseudo-ternary phase diagrams were created with oleic acid and CapryolTM 90 (as oil phase) and four surfactants and co-surfactants at various weight ratios (Rsm). Selected NEs from O/W region on the phase diagrams with the drug concentration of 1 mg/mL, were prepared via the spontaneous emulsification technique, characterized for particle size and subjected to stability tests at various temperatures over 9-12 months. Cumulative drug release was determined for a period of 48 h using a dialysis sac. The assay of RAP was determined using HPLC technique. Cytotoxicity of NEs was evaluated by MTT assay on breast cancer cell line, namely SKBR-3. The permeability of RAP-loaded NEs across Caco-2 monolayers was assessed by measurement of TEER (transepithelial electrical resistance) value. The intracellular uptake of coumarin 6-loaded NEs by SKBR-3 cells was also investigated using florescence microscopy. NEs containing oleic acid/Tween 20/propylene glycol, CapryolTM 90/Tween 20/iso-propanol, and CapryolTM 90/CremophorÒ RH40/TranscutolÒP showed more cytotoxicity and permeability compared with the RAP methanolic solution. The minimum toxic concentration of RAP in NE formulations was found to be 7.5 µg/mL. The highest intracellular uptake was observed for the NE composed of CapryolTM 90/Tween 20/iso-propanol which was in consistent with the results obtained from cytotoxicity and permeability tests. The overall results implicated that this novel carrier was effective for enhancing RAP permeation in Caco-2 cell membrane along with enhancement of cytotoxicity.
    Keywords: Rapamycin, Nanoemulsion, Phase diagram, MTT, TEER
  • Mohammad Mazloum-Ardakani *, Mahboobe Abolhasani-Soorki, Ali Khoshro, Fariba Sabaghian, Bibi-Fatemeh Mirjalili Pages 851-863
    In the present paper, electrochemical methods were used to investigate the behavior of ascorbic acid at a carbon paste electrode modified with 2,2'-((1E)-(1,2 phenylenebis(azanylylidene)) bis(methanylylidene))bis(benzene-1,4-diol) (PBD) and oxidized multiwall carbon nanotubes. The modified carbon paste electrode showed high electrocatalytic activity toward ascorbic acid; the current was enhanced significantly relative to the situation prevailing when an unmodified carbon paste electrode was used. Cyclic voltammetry was used to investigate the redox properties of this modified electrode at various solution pH values and at various scan rates. Using differential pulse voltammetry, the calibration curves for AA were obtained over the range of 1.0–80.0 and 80–4000.0 μM, respectively. The detection limit was 0.3 μM. The present method provides a simple method for selective detection of ascorbic acid. DPV also was used for simultaneous determination of AA, uric acid, and tryptophan at the modified electrode. Finally, the proposed electrochemical sensor was used for determinations of these substances in in biological systems and pharmaceutical samples.
    Keywords: Sensor, Ascorbic acid, Uric Acid, Tryptophan, Carbon nanotube
  • Gholamreza Bahrami, Hamid Nabiyar, Komail Sadrjavadi, Mohsen Shahlaei * Pages 864-882
    This study describes a simple and rapid approach of monitoring ibuprofen (IBP). Unfolded principal component analysis-artificial neural network (UPCA-ANN) and excitation-emission spectra resulted from spectrofluorimetry method were combined to develop new model in the determination of IBF in human serum samples. Fluorescence landscapes with excitation wavelengths from 235 to 265 nm and emission wavelengths in the range 300–500 nm were obtained. The figures of merit for the developed model were evaluated. High performance liquid chromatography (HPLC) technique was also used as a standard method. Accuracy of the method was investigated by analysis of the serum samples spiked with various concentration of IBF and an average relative error of prediction of 0.18% was obtained. The results indicated that the proposed method is an interesting alternative to the traditional techniques normally used for determination of IBF such as HPLC.
    Keywords: Ibuprofen, Excitation-emission fluorescence matrices, Principal component analysis, Artificial neural network, Data Reduction
  • Ehsan Faghih-Mirzaei, Mohammad Seifi, Mehdi Abaszadeh *, Kamiar Zomorodian, Helila Helali Pages 883-895
    A novel one-pot two step tandem reaction for the synthesis of indolizine-1-carbonitrile derivatives (5a-i) was identified. The route comprises 1,3-dipolar cycloaddition reaction of aromatic aldehyde derivatives (1a-i), malononitrile (2) and 1-(2-(4-bromophenyl)-2-oxoethyl)-2-chloropyridin-1-ium (4) under ultrasound irradiation at room temperature in the presence of triethylamine at acetonitrile. The product compounds were tested against bacteria and fungi. It was revealed that compound 5b had the most antifungal activity (range MICs = 8–32 µg/mL) and compound 5g had the most antibacterial activity (range MICs = 16–256 µg/mL). Molecular docking of compounds (5a-i) into fungal 14α-demethylase and bacterial protein tyrosine phosphatase active sites were also performed and probable binding mode of compounds 5b and 5g were determined.
    Keywords: Indolizine-1-carbonitriles, 1, 3-Dipolar cycloaddition, Ultrasound irradiation, Antifungal activity, Antibacterial activity, Molecular docking
  • Maryam Iman, Sina Fakhari, Mohammad Jahanpanah, Nima Naderi, Asghar Davood * Pages 896-905
    Objective(s)
    Anticonvulsant activity of phthalimide was discovered in 2000 by molecular hybridization of thalidomide and ameltolide. In our previous research we have reported some new 4-substituted derivatives of phthalimide with good activity against the tonic and clonic seizures
    Material and
    Methods
    A series of novel 4-flurophthalimides that designed using bioisosteric replacement were synthesized by condensation of 4-flurophthalic anhydride with appropriate arylamines. The purity of these compounds was determined by TLC and the chemical structures were confirmed by IR and 1H-NMR spectroscopy. Anticonvulsant activity of prepared compounds was evaluated using MES and PTZ models.
    Results
    Some of designed compounds significantly protected against the PTZ-induce seizure that compound 10 with lipophilic and flexible aromatic moiety was more potent than reference drug phenytoin and was the most potent in this series of phthalimide derivatives. In the MES model prepared phthalimide do not showed efficient activity.
    Conclusion
    The prepared compounds are active in clonic seizure.
    Keywords: 4-flurophthalimides, anticonvulsant, MES, PTZ, isoindole
  • Masoud Faghih Akhlaghi, Marjan Daeihamed, Seyed Abdolmajid Ayatollahi, Farzad Kobarfard, Athar Ata * Pages 906-916
    Based on the existing structure activity relationship for proteasome inhibitors, a number of substituted aryl-2-nitrovinyl derivatives have been synthesized as Michael acceptor and their cytotoxicity and proteasome inhibitory effects were evaluated on two cancer cell lines. Compound 2d exhibited IC50 values of 0.71 and 17.79 μM comparable to bortezomib against MCF-7 and PC-3, respectively. The results show that the electronic properties and steric hindrance can affect the interaction of these small molecules with their receptor at the active site of the enzyme while the presence of CH2OH group on α-carbon of Michael acceptor is favorable, and para substitution of OMe on phenyl ring of β-carbon can increase the inhibitory potencies.
    Molecular docking studies confirm our experimental findings about mode of binding of our compounds with 20S proteasome.
    Keywords: Proteasome inhibitor, Small molecule, ?, ?-unsaturated nitro, Michael acceptor, Aryl-2-nitrovinyl
  • Mona Mosayebnia, Sedigheh Rezaeianpour, Pedram Rikhtechi, Zahra Hajimahdi, Davood Beiki, Farzad Kobarfard, Omid Sabzevari, Mohsen Amini, Khosrou Abdi, Soraya Shahhosseini * Pages 917-926
    The basic chemical structure of most prostate specific membrane antigen (PSMA) inhibitors which are now in pre-clinical and clinical studies is Glu-Ureido-based peptides. Synthesis of urea-based PSMA inhibitors includes two steps: 1- isocyanate intermediate formation and 2- urea bond formation. In current methods, isocyanate is formed in liquid phase and then reacts with amine existing in liquid phase or bound to solid phase for urea bond formation. In this study, we developed a new facile method for formation of both isocyanate and urea on solid phase under standard peptide coupling conditions. The solid phase-bound isocyanate served as intermediate to form urea bond. To monitor reaction progress qualitative test (Kaiser Test) and On-Bead FT-IR spectroscopy were used. The structure of Glutamate-Urea-Lysine (EUK) was confirmed using LC-Mass and 1H-NMR. This novel method successfully applied to synthesize of another urea-based peptide containing a sequence of Glu-Urea-Lys(OMe)-GABA-Tyr-Tyr-GABA and the bifunctional linker hydrazinonicotinamide (HYNIC) as well.
    Keywords: PSMA, Glutamate-Urea-Lysine, urea bond, solid phase, Isocyanate
  • Mona Navaei-Nigjeh, Mahdi Gholami, Maryam Sadat Fakhri-Bafghi, Maryam Baeeri, Mohammad Abdollahi * Pages 927-939
    Chlorpyrifos (CP), an acetylcholinesterase (AChE) inhibitor, is used throughout the world as an insecticide in agriculture and an eradicating agent for termites around homes. In this present study, CP is considered as an oxidative agent which we examine the protective role of zinc oxide nanoparticles (ZnO NPs) in CP-treated lymphocytes of human. Lymphocytes isolated by Ficoll and exposed to 75 µg/ml CP either alone or in combination with logarithmic doses of ZnO NPs (0/1, 1, 10, 100 µg/ml). After a 3-day incubation period, the viability and oxidative stress markers were determined. Then, the levels of tumor necrosis factor-α (TNF-α), as inflammatory index along with AChE activity and cell death were evaluated. Our results showed that incubation with CP significantly increase the percent of cell death, activities of caspase-3 and -9, level of TNF-α and also promote the levels of biomarkers which play important roles in oxidative stress. On the other hand, the activity of AChE and levels of total antioxidant power (TAP) decreased in CP-treated lymphocytes. In contrast, lymphocytes treated with different concentrations of ZnO NPs, as antioxidant agents, showed a significant decrease in the percent of mortality as well as the levels of TNF-α, as compared with CP-treated lymphocytes. Besides, ZnO NPs increased the levels of AchE and TAP in 0/1, 1, 10, 100 µg/ml, among them the meaningful change was observed in 1 µg/ml. In conclusion, results declare the protective effects of ZnO NPs in prevention of cytotoxic activity of the organophosphates CP in the lymphocytes.
    Keywords: Chlorpyrifos, Human lymphocytes, Organophosphorus pesticide, Oxidative stress, Zinc oxide nanoparticles
  • Ziba Moghadasi, Shahla Jamili *, Delavar Shahbazzadeh, Kamran Pooshang Bagheri Pages 940-955
    Numerous proteins and peptides in venomous marine animals are potentially active molecules with pharmacological properties. Particular condition of the Persian Gulf as a closed ecosystem is a good opportunity to study of biological activities and toxicity of venomous animals. In this study, Stichodactyla haddoni (S. haddoni), a sea anemone, selected to tracing for possible pharmaceutical agents and toxicological characterization. Analgesic, edematic, dermonecrotic, LD50, phospholipase, and proteolytic activities of the venom were estimated. LD50 was recorded at 675µg by intraperitoneal injection. Analgesic activitiy of crude venom on Balb/c mice at both 100 and 150 µg were dose dependent as a linear trend. Three folds increase of activity was seen at both 100 and 150 µg after 240 min comparing to activity of morphine at 200 µg. The crude venom at amount of 0.23 µg produced 50% hemolysis. The highest edematogenic activity was seen on Balb/c mice just two hours after injection for both 168 µg (157%) and 335 µg (247%). The crude venom at 675 µg made 4 mm inflammation area on rabbit skin after 3 h but the amount of 1000 µg induced 8 mm necrosis area. Potent analgesic activity of the venom was seen below its toxic dose that was very greater than the other sea anemones in the other geographical areas. The results indicate that a persistent edematogenic activity could be happened after envenomation. Instant potent edematogenic and rapid dermonecrotic activity were significant phenomena. HD50 at 0.23 µg indicates that a very potent hemolytic agent exists in the venom. The results would also be of high value to better management of envenomation. This study confirmed the great value of further studies on the Persian Gulf S. haddonivenom.
    Keywords: Stichodactyla haddoni, Venom, Toxicity, Analgesic activity, The Persian Gulf sea anemone
  • Mohammad Hassan Houshdar Tehrani *, Abdolhamid Bamoniri, Bi Bi Fatemeh Mirjalil, Mohammadreza Gholibeikian Pages 956-963
    In this work, linear and cyclic disulfide heptapeptides of Longicalycinin A have been successfully synthesized by solid phase methodology with Fmoc /t-Bu and solution phase, respectively. 2-Chlorotrityl chloride resin (2-CTC) was used as a solid support. The synthesized linear disulfide analogue of Longicalycinin A was cleaved from the resin as a protected peptide. The final deprotection was performed by treatment with TFA 95% containing scavengers to achieve the deprotected linear disulfide analogue of Longicalycinin A which was characterized by different instrumental methods using LC-MS and FT-IR. Macrocyclization of deprotected linear peptide was done by an oxidating reagent. Linear and cyclic disulfide heptapeptides of Longicalycinin A were evaluated their toxic activity against cell lines of HepG2 and HT-29 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reagent in MTT assay. The synthetic analogues showed a relative good activity against cell lines of HepG2 and HT-29 with IC50 values from 10.33 µg/mL to 12.45 µg/mL, in comparison to the standard drug 5-fluorouracil (5-FU). Safety profiles of the synthesized linear and cyclic disulfide analogues of Longicalycinin A were also examined on skin fibroblast cells. Between the linear and cyclic disulfide heptapeptides of Longicalycinin A, the cyclic peptide showed a considerable toxic activity on the cancerous cell lines along with a low safety result on normal cells. Therefore, the linear disulfide heptapeptide of Longicalycinin A would be encouraging to develop new anticancer agents.
    Keywords: Longicalycinin A analogue_Disulfide band_Anticancer_MTT assay_Apoptosis
  • Zeinab Vafaei-Pour, Mohammad Shokrzadeh, Monireh Jahani, Fatemeh Shaki * Pages 964-975
    Context: Gestational diabetes is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Diabetes during pregnancy increases the incidences of congenital anomalies, in a mother and her embryo. Oxidative stress has been implicated to be responsible in diabetic embryopathy.
    Objective
    In this study, we used nanoceria as an antioxidant for amelioration of diabetic embryopathy in diabetic mice.
    Methods
    The female mice were divided into 5 groups (6 mice per group). Diabetes was induced by a single dose of streptozotocin (60 mg/kg IP) that dissolved in citrate buffer (pH= 4.6). Blood glucose was checked in 0,5,10, 15 days of pregnancy. The diabetic state was confirmed when the blood glucose concentration exceeded 200 mg/dl. On the Day 16 of pregnancy, all animals were anesthetized with ether and embryos were excised, then oxidative stress, pathological parameters, number of implantations, miscarriage and live embryo was assayed.
    Results
    Histological study showed that diabetes induced abortion; decrease in weight of mothers, embryo and the number of embryos. In diabetic mice, significant increase in lipid peroxidation (LPO), ROS formation and protein carbonyl content were observed. Glutathione (GSH) concentration is found to be decreased in embryo tissue in diabetic mice. Nanoceria treatment significantly inhibited embryonic oxidative stress and also pathologic changes in diabetic mice.
    Conclusions
    Our research showed that diabetes act as a teratogen agent for fetal development and nanoceria abrogated diabetes induced embryopathy via its antioxidant effects. So, early detection of diabetes in pregnancy and antioxidant administration can attenuate these complications.
    Keywords: Diabetes, pregnancy, Teratogenicity, Nanoceria, Oxidative stress
  • Mohammad Naderi Alizadeh, Mohsen Rashidi, Ahad Muhmmadinejad, Taraneh Moeini Zanjani, Seyed Ali Ziai * Pages 976-985
    Umbelliprenin is a sesquiterpene coumarin with vitro anti-carcinogenic activities. The aim of this study was to investigate the antitumor effects of umbelliprenin in animal models of colorectal cancer. The cytotoxic effects of umbelliprenin were explored on CT26 and L929by MTT assay. In this study, colorectal tumors developed in mice by intradermal injection of CT26 cell line. Tumor size, serum levels of IFN-γ and IL-4 by ELISA, and Ki-67, MMP2, MMP9, VEGF and E-cadherin markers by IHC method were evaluated. The results showed that umbelliprenin inhibited the cancer cells in a concentration-dependent manner. IC50 Evaluation showed that L929 cells were more resistant to Umbelliprenin than CT26 cells. Umbelliprenin treatment in both tumor-bearing mice and control normal mice showed significantly increased IFN-γ and decreased IL-4(P
    Keywords: Umbelliprenin, Colorectal cancer, cytotoxic effect, Anti-carcinogenic effect, Immunohistochemistry, CT26, Anti-angiogenesis
  • Parisa Ebrahimisadr, Fatemeh Ghaffarifar *, John Horton, Abdolhosein Dalimi, Zohreh Sharifi Pages 986-994
    The parasites of genus Leishmania are the causative agents of one of the most widespread and devastating diseases. According to follow-up data, these medications may provoke adverse drug reactions, drug resistance, relapse as well as financial burden. The mechanism of action of opioid drugs are primarily exerted via transmembrane G-protein coupled receptors. One of the potent synthetic immunomodulator agents is imiquimod with low molecular weight and unknown mechanism of action. Monocyte and macrophage are the primary site of action for imiquimod. Nalmefene is a well-known opioid antagonist agent which simultaneously inhibits these receptors and augments intracellular pathogenicity, hence providing opportunities to investigate their function. The aim of present work was evaluating the effect of morphine, imiquimod and nalmephen on the Leishmania major and investigating cytotoxic effect this drug on the uninfected macrophage and infected macrophage for detected early apoptosis, necrosis and secondry apoptosis by flowcytometry method. In this study we used morphine, imiquimod, nalmefene and Glucantime. We treated promastigotes, macrophages and infected macrophages with above drugs, and the apoptosis evaluated by flow cytometry. The results showed that in all concentration of morphine more than 98% of promastigotes remained alive that it is deduced that morphine lacks any lethal effect on L. major after 24 h, whereas in groups treated with Glucantime alone or in combination with Nalmephene and Imiquimod, 84.13%, 88.96% and86.72% of promastigotes were alive, respectively. The results of macrophage treatment with morphine, imiquimod and nalmefene demonstrated that most necrosis has occurred in nalmefene group (6.54%).
    Keywords: morphine, imiquimod, nalmefene, Apoptosis, Leishmania major
  • Mohammad Hadi Zarei, Farshad Hoseini Shirazi, Marjan Aghvami, Jalal Pourahmad * Pages 995-1007
    Perfluorinated compounds (PFCs) such as perfluorooctanesulfonate (PFOS) are stable chemicals that accumulate in biological matrix. Toxicity of these compounds including immunotoxicity has been demonstrated in experimental models and wildlife. Although limited number of studies examined the effects of PFOS on human lymphocytes but so far no research has investigated the complete mechanisms of PFOS cytotoxicity toward human lymphocytes. The main goal of this investigation was to find out the mechanisms underlying the cytotoxic effect of PFOS toward human lymphocytes using accelerated cytotoxicity mechanisms screening (ACMS) technique. Human lymphocytes were isolated from blood of healthy donors using Ficoll-paquePLUS standard method. Cell viability was determined following 12 h of incubation of human lymphocytes with 100-500 μM PFOS. Our results showed that IC50 concentration (163.5 μM) of PFOS reduced viability of human lymphocytes approximately 50% via increased ROS formation, lipid peroxidation, glutathione depletion and damage to cell sub organelles such as mitochondria and lysosomes. Besides, in this study we demonstrated involvement of cellular proteolysis and activation of caspase-3 in PFOS induced lymphocyte cytotoxicity. We finally concluded that at environmentally related concentration, PFOS can induce toxic effect toward human lymphocytes through induction of oxidative stress and damage to cell sub organelles.
    Keywords: Perfluorooctanesulfonate (PFOS), Reactive oxygen species (ROS), Human lymphocyte, Cellular proteolysis, Lysosomal membrane integrity, Cytotoxicity
  • Maryam Fanian, Maedeh Bahmani, Mojdeh Mozafari, Samaneh Naderi, Marziyeh Alizadeh Zareie, Mohammad Ali Okhovat, Jamileh Saberzadeh, Ali Dehshahri, Mohammad Ali Takhshid * Pages 1008-1017
    Metastasis to lymph nodes and distant organs is the main challenge in the treatment of papillary thyroid cancer. In the current investigation, we aimed to evaluate the synergistic effects of celecoxib (CX) and sodium valproate (VPA) against cell survival, invasiveness properties, and expression of metalloproteinase-2 and -9 (MMP-2 and MMP-9) in papillary thyroid cancer cell line, BCPAP cells. The effect of CX and VPA on B-CPAP cells viability and apoptosis were investigated using MTT assay and annexin V/7-AAD flowcytometry, respectively. The effects of the drugs on invasiveness properties of B-CPAP cells and expression of MMP-2 and MMP-9 were evaluated using transwell assay and real time PCR, respectively. MTT assay showed that CX and VPA decreased viability of B-CPAP cells dose dependently (IC50 32.4µM and 6.8 mM, respectively). Combination of CX (5 μm) and VPA (2.5 and 5 mM) increased apoptosis, and reduced cell migration and invasion of B-CPAP cell, synergistically. Real time PCR results showed that both CX (5 µM) and VPA (2.5 and 5 mM) reduced MMP-2 expression (P
    Keywords: Papillary thyroid cancer, Apoptosis, Invasion, Migration, Celecoxib, Sodium Valproate
  • Bibi Marjan Razavi, Ali Alyasin, Hossein Hosseinzadeh, Mohsen Imenshahidi * Pages 1018-1025
    Crocus sativus L. (saffron) is a widely used food additive for its color and taste. The hypotensive effects of saffron have been shown in previous studies. The aim of this study was to evaluate the mechanism of vasodilatory effects induced by saffron on isolated rat aorta.
    To study the vasodilatory effects of saffron aqueous extract (0.5, 1 and 2 mg/mL), isolated rat thoracic aorta rings were contracted by 10−6 M phenylephrine (PE) or KCl 80 mM. The vasodilatory effect of saffron was also evaluated both on intact and denuded endothelium aortic rings. To study the role of nitric oxide and prostacyclin in relaxation induced by saffron, aortic rings were incubated by L-NAME (10-6 M) and indomethacin (10-5 M) respectively for 20 min. Saffron induced relaxation in endothelium-intact aortic rings precontracted with PE in a concentration dependent manner. The obtained relaxation induced by the highest saffron concentration in endothelium-intact aortic rings precontracted with KCl was less than that observed in endothelium-intact aortic rings precontracted with PE. The relaxant activity of saffron was abolished by incubation of aortic rings with L-NAME but not in the presence of indomethacin. Also, the vasodilatory activity of saffron was partially abolished in endothelium denuded aortic rings. Saffron induced relaxation in isolated rat aortic rings might be due particularly to its effect on endothelium via nitric oxide synthase pathway and partly due to the effect on vascular smooth muscle cells via L type voltage dependent calcium channels.
    Keywords: Crocus sativus L, Saffron, Isolated rat aorta, L-NAME, Indomethacin, Hypertension
  • Asmaa Abdellah, Ashraf F. El Baz, Emad Mahrous, Alaa A. Abd El Maksoud, Ibrahim A. Ibrahim, Azza Abdel-Monem*, Shang-Tian Yang Pages 1026-1035
    Biotransformation of isoflavones glycosides into the aglycone form is essential to attain the maximum bioavailability. The factors affecting deglycosylation of genistin in soy flour using commercial β-glucosidase enzyme were evaluated. The presence of genistin in soy flour was confirmed by isolation through chromatographic fractionation and identification by spectral method. Two-levels Plackett-Burman design was applied and effective variables for genistein production were determined. Agitation rate, enzyme concentration, and reaction time, owing to their significant positive effect, and pH, owing to its significant negative effect, were further evaluated using Box-Behnken model. Accordingly the optimal combination of the major reaction affecting factors was ―enzyme concentration, 1 IU; agitation speed, 250 rpm; reaction time, 5 h and pH 4. The concentration of genistein can be increased by 9.91 folds (from 0.8 mg/g in the non biotransformed soy flour to 7.93 mg/g in the biotransformed one) using the determined optimal combination of major reaction affecting factors. The antioxidant activity of the non biotransformed and biotransformed soy flour extracts was determined by DPPH method. It was found that biotransformation increase the antioxidant activity by two folds. The concentration causing a 50% reduction of DPPH absorbance (EC50) were 10 and 5 mg/mL for the non biotransformed and biotransformed soy flour extracts, respectively.
    Keywords: β-Glucosidase, Biotransformation, Genistein, Response surface methodology, Antioxidant
  • Esra Eroglu Ozkan *, Nurten Ozsoy, Tugba Yilmaz Ozden, Gul Ozhan, Afife Mat Pages 1036-1046
    In the present work we carried out a phytochemical and biological investigation on three endemic Hypericum species, i.e. Hypericum thymbrifolium, Hypericum spectabile and Hypericum pseudolaeve from Anatolia in order to discover new sources of natural compounds for the treatment of inflammatory and neurodegenerative disorders. HPLC-DAD analysis indicated that two naphthodianthrones (pseudohypericin and hypericin) together with chlorogenic acid, rutin, hyperoside, isoquercitrin, kaempferol, quercitrin, quercetin, amentoflavone, and hyperforin are the main compounds present in the methanol extracts. After chemical characterization, all extracts were in-vitro biologically assayed for antioxidant potential by lipid peroxidation inhibitory activity, DPPH, FRAP assays, and superoxide radical scavenging avtivity, for AChE inhibitory activity by Ellman’s method, for COX inhibitory activity by using enzyme immunoassay (EIA) kit, for cytotoxic activity on HeLa and NRK-52E cell lines by MTT assay. The superoxide radical scavenging activity and lipid peroxidation inhibitor activity of H. spectabile (EC50 = 0.430 mg/mL) were more remarkable than that of H. thymbrifolium and H. pseudolaeve. The extracts showed moderate inhibitory activity on AChE (from 49.37 to 63.41%). The best inhibitory activity against COX-1 (71.77 and 77.04%, respectively) and COX-2 (64.14 and 72.23%, respectively) were shown by H. thymbrifolium and H. spectabile, which may be due to their richest chlorogenic acid content (0.29576 and 0.23567%, respectively). Cytotoxicity screening results showed that the extracts did not demonstrate significant cytotoxic activity. It was concluded that the most promising extract with antioxidant, anti-inflammatory, and AChE inhibition potential is H. spectabile.
    Keywords: Hypericum, Endemic, HPLC, Chemical composition, Cyclooxygenase inhibition, Alzheimer's disease
  • Belma Zengin Kurt, Isil Gazioglu*, Fatih Sonmez, Ece Sevgi Pages 1047-1056
    Turkey has highly rich floras of medicinal and aromatic plants because of having various climate conditions in different regions. One of these regions is Middle Black Sea Region, especially Ordu Province. Extracts of 10 edible plants (Arum maculatum L., Hypericum orientale L., Ornithogalum sigmoideum Freyn et Sint., Silene vulgaris Garcke var. macrocarpa, Plantago lanceolata L., Achillea millefolium L. subsp. pannonica, Rumex crispus L., Rumex acetosella L., Capsella bursa-pastoris L., Coronopus squamatus Asch.), grown in Ordu, Turkey, were prepared with different solvents (hexane, ethanol and water, separately) and their anticholinestrase and antiaflatoxigenic activities were evaluated. Additionally, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the extracts were assayed. The ethanol extract of R. acetosella exhibited the highest antioxidant activity (A0.5 value of 25.31 μg/mL, for CUPRAC activity; IC50 value of 23.73 μg/mL, for ABTS activity). The hexane extract of C. bursa-pastoris showed the strongest inhibition against AChE enzyme with IC50 value of 7.24 μg/mL, and the hexane extract of A. millefolium subsp. pannonica had the highest BChE activity with IC50 value of 6.40 μg/mL. The ethanol extract of P. lanceolata exhibited the strongest inhibition against aflatoxin with 88% inhibition.
    Keywords: Anticholinesterase activity, Antioxidant activity, Antiaflatoxigenic activity, Rumex acetosella, Capsella bursa-pastoris, Plantago lanceolata
  • Arezoo Azizsoltani, Khosro Piri *, Sahar Behzad, Masoud Soleimani, Mina Nekouei, Zahra Mahmoudi, Asad Kazemi Pages 1057-1067
    Glycyrrhiza glabra has been used as a flavoring and sweetener agent, in addition to its therapeutic properties. It is rich in phytoestrogen and may prevent osteoporosis caused by estrogen deficiency; however, there is no evidence for its effects on proliferation and osteogenesis in mesenchymal stem cells. So, we were encouraged to investigate whether the ethyl acetate extract of licorice root as a source of phytoestrogen can act similar to estrogen in cell culture. Furthermore, the analysis of the licorice extract (LE) based on HPLC-DAD-ESI-MS indicated that LE comprises phytoestrogen compounds, such as glabridin and glabrene. In this study, the effects of LE on proliferation of human bone-marrow mesenchymal stem cells (hBM-MSCs) were investigated using MTT assay. In addition, its effects on the osteogenesis were evaluated using alkaline phosphatase activity (ALP), calcium deposition, and bone specific gene expression such as ALP, osteocalcin, Runx2, and BMP-2. The quantitative gene expression was studied by real-time RT-PCR. Our results showed a significant increase in proliferation in presence of LE in concentration 10-50 μg/mL. The differentiation of hBM-MSCs increased in doses of LE (10-25 μg/mL) compared to the control group. The effects of LE were similar to those of 17β-estradiol (E2) (10-8 M) and were abolished by ICI 182,780 an antagonist of estrogen receptor (ER) (10-7), indicating that the stimulatory effects of LE occur through estrogen receptor-mediated mechanism . Taking these into account, LE may be a potential candidate for prevention of osteoporosis in menopausal women.
    Keywords: Glycyrrhiza glabra, Fabaceae, Phytoestrogen, Osteoporosis, Mesenchymal stem cell, Differentiation
  • Mehdi Hassanpour, Omid Cheraghi, Belal Brazvan, Amirataollah Hiradfar, Nasser Aghamohammadzadeh, Reza Rahbarghazi, Mohammad Nouri * Pages 1068-1080
    By virtue of lifestyle change, incidence of type 2 diabetes is increasingly being raised with different up-surging pathologies. This condition found to disqualify endothelial progenitor cells during neo-vascularization. Besides to an aborted differentiation property, malfunctioned paracrine activities exacerbate vascular abnormalities. It is found nano-scaled exosomes play essential roles on reciprocal cell-cell cross-talk harboring bioactive molecules. To address the effect of diabetic serum on exosome secretion capacity, human endothelial progenitor cells were isolated from healthy volunteer and exposed to both healthy and diabetic sera for 7 days. Cell survival was assessed by the conventional MTT and Annexin V/PI staining protocol. In addition, an in vitro tubulogenesis assay, migration and LDL uptake capacity were investigated. We also measured the amount of exosomes by acetylcholine esterase activity and then expression profiles of three genes involved in exosome signaling pathway, including CD63, Alix and Rab27a, revealed by Real-time PCR method. Flow cytometry analysis showed that compared with control group necrosis level was increased by 1.6 folds in EPCs exposed to diabetic sera after 7 day (p
    Keywords: Endothelial progenitor cells, Diabetes, Exosome activity, Migration, Ac-LDL uptake
  • Hamed Zare, Parviz Owlia *, Hossein Vahidi, Maryam Hosseindokht Khujin Pages 1081-1092
    Selenium (Se) as a vital trace element has many biological activities such as anti-inflammation and anti-oxidation. Selenomethionine as an organic selenium plays a vital role in the response to oxidative stress. At present, Saccharomyces cerevisiae is one of the best microorganisms that has the ability to accumulate selenium. Production of Seleno-yeast was done by growing Saccharomyces cerevisiae in the presence of water soluble selenium salt (Na2SeO3) as a part of the medium. The yield of selenium biotransformation and yeast biomass can be improved by optimizing the process conditions in two steps. First, the effects of several culture parameters (culture conditions and culture media) were studied using the Plackett-Burman design. After that, determining the optimum levels of the effective parameters was performed by Box-Behnken response surface methodology. Optimization of the conditions was performed with the aim of simultaneously optimizing the biomass and selenium biotransformation. In this investigation, the effect of the eleven culture parameters was studied with Plackett-Burman design. Then, four significant culture parameters such as glucose concentration, aeration, selenium concentration, and temperature were optimized with Box-Behnken response surface methodology.
    Keywords: Selenium, Yeast, Plackett-Burman, Box-Behnken, Optimization
  • Mehrdad Afarid, Ali Sadeghi Sarvestani, Feisal Rahat, Ali Azimi * Pages 1093-1098
    Aim: Several ocular and systemic complications have been reported after the bevacizumab intravitreal injection. This study aims at reporting the main indications for the bevacizumab intravitreal injection in our center, the intravitreal injection method in this study, and the incidence of the post-injection complication, such as endophthalmitis.
    Methods
    This study is a retrospective review of the consecutive intravitreal bevacizumab (Avastin®) injections for 359 patients between 2011 and 2013 at a single institute (Poostchi Clinic of Ophthalmology). Before the injection, a drop containing 5 ml Ciprofloxacin and 5 ml Betadine 10% was applied 3 times at the intervals of 10 minutes. The eye lashes, upper and lower eyelids and caruncle were swabbed with Betadine 10% but the lid speculum, drape and conjunctival washing were not conducted.The patients were followed up 8 weeks after the injection for the evaluation of any complications.
    Results
    In this study, 1376 intravitreal injection of bevacizumab in 479 eyes of 359 patients were enrolled. Among them, 141patients (39.3%) were men and 218 (60.7%) were women.The mean age (±SD) of the patients was 61.48 (±11.21) years. On average, each patient received 3.83 (the range 1-13) injections. The most common indications for the bevacizumab intravitreal injection were diabetic retinopathy, choroidal neovascularization, and central retinal vein occlusion.None of the patients developed endophthalmitis, retinal detachment, or other adverse effects.
    Conclusions
    This study showed that the above-mentioned method of the intravitreal bevacizumab injection is easy and safe. The future studies involving more participants are required for the evaluation of rare complications.
    Keywords: Bevacizumab, Intravitreal, Injection, Endophthalmitis, complication
  • Mohammad Haji Aghajani, Farzad Kobarfard, Seyedpouzhia Shojaei, Froozan Ahmadpour, Olia Safi, Neda Kazeminia, Naeime Zarepishe, Mohammad Sistanizad * Pages 1099-1104
    The aim of current study was evaluating the frequency of clopidogrel resistance and its impact on clinical outcome of patients in Iranian patients.
    Patients undergoing percutaneous coronary intervention in Imam Hussein Medical center, Tehran, Iran, who received standard dosage of clopidogrel (Plavix®, Sanofi, France, 600 mg loading dose and 75 mg/day afterward) were recruited. Platelet aggregation was measured using light transmission aggregometer. The patients were categorized as responder (platelet aggregation less than 43%) and non-responder (platelet aggregation more than 43%). All patients were evaluated for major adverse cardio vascular events one month and 3 years after the angioplasty based on MACE criteria by phone contact.
    One hundred and five patients with average age of 60.30±12.2 years entered the study of whom 26 (24.76%) did not respond to clopidogrel. None of patients experienced cardiac events one month after PCI. Three years after PCI, data was collected from 55 (69.62%) and 10 (38.46%) subjects in responder and non-responder groups, respectively. MACE criteria was positive in 4 patients, 3 (5.45%) in responder and 1 (10%) in non-responder group (p= 0.28). We did not find any significant differences between clopidogrel resistance and past medical history. In drug history 1 (1.26%) and 4 (15.38%) patients received omeprazole with clopidogrel in responder and none-responder group, respectively (p= 0.003).
    This study showed 24.76% resistance to clopidogrel in Iranian population but, we did not find any correlation between clopidogrel resistance and cardiac events in follow up maybe due to study limitations particularly missed follow-up in non-responder patients.
    Keywords: percutaneous coronary intervention, drug resistance, platelet aggregation, MACE, light transmission aggregometer
  • Sayed Hesam Sharifnia, Mehdi Mohammadzadeh*, Gelareh Arzani, Jamshid Salamzadeh, Sayed Abolfazl Abolfazli, Alireza Zali, Ali Reza Khoshdel Pages 1105-1115
    Prescription decision making is a complicated phenomenon influenced by many factors including drug strength, the patient’s context, prescriber characteristics, health facilities, payment type and pharmaceutical marketing. To evaluate the associations between each influenced factor and drug prescription method of Iranian physicians, we conducted an exploratory research, utilizing a questionnaire as quantitative research instrument. A sample of 460 physicians was asked to fill out the questionnaire, yielding 84% response rate. The statistical analysis from the collected data demonstrated that Iranian physicians mostly paid attention to the payment type, the patients’ individual factors and the products’ characteristics while prescribing a medicine. In addition, it was revealed that marketing expenditures did not have a high influence on the physicians’ demand for pharmaceutical products in Iran. The obtained results may be useful for Iranian pharmaceutical companies’ marketing strategy planners as well as the patients who are the exact consumers of the prescribed medicines.
    Keywords: Prescription behavior, Pharmaceutical Marketing, Consumer, Payer's factors, Product's factors, Environmental factors
  • Mohsen Ebrahimi, Mohammad Javad Khoushnoud, Majid Zia-Behbahani * Pages 1116-1124
    Certain organophosphorus esters such as diisopropylfluorophosphate (DFP) cause delayed neuropathy by inhibition of neuropathy target esterase (NTE) keeping neuron in normal function. In this study, effects of neurobion alone and in combination with dexamethasone on DFP–induced delayed neuropathy were evaluated. Thirty-five mice were divided to five groups that each group consists 7 mice. Except group1 (Normalgroup), group2 received normal saline and 1h later, 1 mg/kg DFP, groupe3,4 and 5 received 150 mg/kg neurobion, 2mg/kg dexamethasone and 150mg/kg neurobion plus 2mg/kg dexamethasone, respectively and 1h later 1mg/kg DFP. Twenty one days after last injection, mice were killed by decapitation under deep anesthesia. NTE level was determined in brain and though there was no significant difference between groups, neurobion and neurobion plus dexamethasone partly - not significantly (p > 0.05) - were be able to prevent reduction of NTE in brain caused by DFP. Histopathological evaluation of sciatic nerves belonged to groups, showed that neurobion and neurobion plus dexamethasone significantly suppressed harmful effect of DFP e.g. demyelination and micro-cavitation in nerve.
    We also evaluated activity of acetylcholine esterase (AChE), concentration of glutathione (GSH) and malondialdehyde (MDA) levels in serum. Results showed dexamethasone (p
    Keywords: Organophosphorus compound, DFP, delayed neuropathy, neuropathy target esterase, neurobion
  • Farzaneh Dastan *, Hamidreza Jamaati, Habib Emami, Roodabeh Haghgoo, Raha Eskandari, Seyedeh Shadab Hashemifard, Fatemeh Khoddami, Zahra Mirshafiei Langari Pages 1125-1129
    Background
    Albumin is known as a human blood product, with high cost and limited availability. Several studies have demonstrated the extent in which albumin is being utilized in controversial indications not supported or weakly supported by the available literature.
    Objective
    To rationalize the use of albumin and to decrease the inappropriate cost of this expensive drug.
    Methods
    A two phase study, with equal length of 66-days, comprising an observational drug utilization evaluation and a pharmacist-led audit and feedback interventional study, was conducted in a tertiary referral hospital in Tehran, Iran. The results of the interventional phase including the introduction of evidence-base guideline for albumin via a pharmacist-led audit and feedback intervention was compared to the ones from the observational phase.
    Results
    A total of 90 and 45 patients were included in the phase one and phase two of the study respectively. During the initial phase, 1870 albumin vials were used, of which 1467 (78.4%) vials were prescribed inappropriately. Inappropriate use of albumin was decreased significantly by 79.3% (p
    Conclusion
    Introduction of evidence based guideline in conjugation with pharmacist-led audit and feedback can significantly decrease the inappropriate use of albumin. These results also demonstrate shifting towards a more evidence-based practice, which can increase patient’s safety and enhance quality of care.
    Keywords: Cost Saving, Clinical pharmacy, Drug utilization evaluation, Intervention study, Albumin, Inappropriate prescribing
  • Marziye Jafari, Shahram Ala *, Kaveh Haddadi, Abbas Alipour, Mojtaba Mojtahedzadeh, Saeid Ehteshami, Saeid Abediankenari, Misagh Shafizad, Ebrahim Salehifar, Foroogh Khalili Pages 1130-1140
    Acute kidney injury (AKI) occurs both after traumatic brain injury (TBI) and after hypertonic saline administration; furosemide may be useful in preventing AKI indirectly. Serum neutrophil gelatinase-associated lipocalin (sNGAL) is superior to serum creatinine (sCr) in diagnosing early AKI. We compared the administration of hypertonic saline plus furosemide (HTS) versus hypertonic saline (HTS), using sCr and sNGAL to investigate kidney injury in patients with TBI.
    This randomized, single-blind clinical trial was conducted from August 2016 to July 2017 in a neurosurgical intensive care unit, and included patients with a Glasgow Coma Score (GCS) 7-13 and brain edema. One group (n= 22) received hypertonic saline 5% (100 mL over 60 min then 20 mL/h) plusfurosemide (40 mg over 60 min then 0.05 mg/kgper hour) for 72 h. The other group (n = 21) received only hypertonic saline 5%, in the samedose as noted above. The sCr and sNGAL concentrations, GCS, and length of stay were measured.
    Mean ± SD differences were -51.15 (47.07) and 9.96 (64.23) ng/mL for sNGAL and -0.12 (0.22) and -0.005 (0.2) mg/dL for sCr in HTS group and HTS group respectively (both p
    Keywords: Neutrophil Gelatinase-associated Lipocalin, Serum Creatinine, Furosemide, Hypertonic saline, Traumatic brain injury
  • Shahram Darabi *, Ali Noori-Zadeh, Hojjat Allah Abbaszadeh, Farzad Rajaei Pages 1141-1149
    Bone marrow stromal stem cells (BMSCs) play a significant role in cell therapy. These cells quickly die after transplantation to the affected area due to oxidative stress. The natural disaccharide, trehalose which can be known as autophagy inducer. The present study aimed to investigate the role of trehalose in preventing BMSCs from oxidative stress caused by H2O2.
    BMSCs were isolated from the adult rats. The cells were divided into three groups: (a) control; (b) 100 µM H2O2; (c) 100 µM H2O2 and trehalose 3%. The morality rate was analyzed by viability test. Immunocytochemistry and Western blot was used in order to evaluate p62 protein and LC3II/LC3I ratio, respectively. In order to evaluate apoptosis, cleaved caspase-3 protein was used. In viability test, the survival rate for BMSCs after 8 h were 82%, 72%, 49%, and 39% (for groups who received 50, 100, 200, and 400 µM H2O2, respectively) compared to the control group. Pre-treatment with the use of trehalose 3% increased cell survivals. The levels of p62 protein, were increased in the cells under H2O2 treatment, while the levels of p62 protein in the cytoplasm, as autophagy inclusions, reduced for the group with trehalose pre-treatment. In addition, trehalose caused to increase LC3II/LC3I ratio and decreased the expression of cleaved caspase-3.Trehalose decreased apoptosis and increased the autophagy and survival levels of the cells against H2O2. Due to the unique properties of trehalose and its low toxicity, it can be used as a pharmaceutical agent in cellular transplantation to reduce oxidative stress.
    Keywords: Stress oxidative, Autophagy, Apoptosis, Bone marrow stromal cells, Trehalose