فهرست مطالب

Pharmaceutical Research - Volume:17 Issue:4, 2018
  • Volume:17 Issue:4, 2018
  • تاریخ انتشار: 1397/07/16
  • تعداد عناوین: 41
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  • Hadis Soroush, Fatemeh Ghorbani, Bidkorbeh *, Seyed Alireza Mortazavi, Ali Mehramizi Pages 1150-1163
    The aim of this study was to prepare orally disintegrating tablets (ODTs) containing dexamethasone (DEX) by direct compression method with sufficient hardness and rapid disintegration time. In order to save time, money, and human resources in designing and improvement of formulation, the statistical software Design Expert is used. Box–Behnken response surface methodology was applied to evaluate and optimize the effects of concentrations of three excipients, Kollidon CL-SF (X1), Pearlitol SD200 (X2), and Prosolv SMCC (X3) as independent factors on four responses: percentage of drug released after 5 min, disintegrating time, hardness, and friability. Thirteen formulations offered by the Box–Behnken design were prepared by direct compression method and ultimate weight of 200 mg, while the amount of DEX was 4 mg. All formulations were characterized for parameters such as diameter, hardness, weight, thickness, friability, and disintegration time. Following the statistical results, the effects of independent variables on responses were evaluated and the optimum formulation regarding acceptable responses consisted of 15% Kollidon, 39.66% Pearlitol, and 7.5% Prosolv which showed 95.28% release of the drug after 5 min, disintegrating time of 30 sec, 6.1 kg hardness, and 0.12% of friability with an acceptable taste as the optimized formulation.
    Keywords: Orally disintegrating tablet, Design of experiment, Dexamethasone, Optimization
  • Bahare Miri, Negar Motakef, Kazemi, Seyed Abbas Shojaosadati *, Ali Morsali Pages 1164-1171
    In the present study, a nanoporous metal organic framework (MOF) based on iron metal and amino terephthalate ligand MIL-101-NH2-Fe has been used as a carrier for loading and in vitro release of 5-flurouracil (5-FU) anticancer drug. The 5-FU drug loaded MOF was 13 wt % by using thermogravimetric analysis (TGA). The 5-FU release was monitored under physiological condition at 37°C, pH 7.4 in simulated body fluid (SBF) by using spectrophotometry. The drug demonstrated a slow release profile where 98% of the drug was released in 4 days. Loading of drug was characterized by Fournier transform infrared (FTI-IR) and thermogravimetric analysis (TGA). The crystalline structure was monitored by using X-ray powder diffraction (XRD) and after loading of drug in the MOF, the pattern of samples was remained the same. The morphology and size of samples was showed by using scanning electron microscopy (SEM) and based on the MOF has a length of 500 nm and an average diameter of 200 nm. These structural characterizations were performed to verify the 5-FU drug loading in MIL-101-NH2-Fe. The MOF stability was studied by measuring the iron concentration in the SBF solution with atomic absorption spectroscopy (AAS). The MTT assay method was assessed the ability of this drug delivery system on overcoming MCF-7 breast cancer cells in comparison with the free drug and the carrier alone. Based on the results, this drug loaded nanoparticle could achieve more cell death as compared to the free 5-FU drug.
    Keywords: Metal Organic Framework, MIL-101-NH2-Fe, 5-Flurouracil, drug delivery system
  • Sonia Alavi, Seyed Alireza Mortazavi * Pages 1172-1181
    Intranasal route, ensuring suitable bioavailability of medicines under circumvention of the gastrointestinal degradation and hepatic first-pass elimination, has been a popular choice for drug delivery. Among nasal dosage forms, mucoadhesive solid inserts have been shown to resist mucociliary clearance and provide a prolonged nasal residence time. Hence, the purpose of this study was the preparation and characterization of nasal inserts composing of polyelectrolyte complexes (PECs) based on k-carrageenan (k-CA) and chitosan (CS) to boost therapeutic efficacy of sumatriptan succinate in the treatment of migraine headache.
    k-CA/CS PECs were developed in different molar ratios, subjected to lyophilization in small inserts in the presence of sumatriptan succinate, and finally investigated for water uptake ability, mucoadhesive potential, and drug release profile.
    The formation of PEC between the two polymers was affirmed by Fourier transform infrared spectroscopy (FTIR). Based on the results, it was revealed that the polyanion/polycation molar ratio plays a critical role in modulating the characteristics of the inserts, and among all the formulations, the one comprising k-CA/CS PEC with molar ratio of (4:1), (k-CA/CS (4:1)), demonstrated the highest water uptake ability and mucoadhesive potential and provided a more controlled release of sumatriptan succinate.
    This study illustrates the potential of the lyophilized inserts based on the k-CA/CS PECs, especially k-CA/CS (4:1), for efficient delivery of sumatriptan succinate via the nasal route of administration and suggests a potential therapeutic approach for the termination of migraine attacks.
    Keywords: Sumatriptan succinate, k-carrageenan -chitosan polyelectrolyte complexes, Freeze-dried inserts, Water uptake ability, Mucoadhesion strength, In-vitro drug release, Nasal drug delivery
  • Najmeh Rezaee Moghadam, Seyed Rafie Arefhosseini, Afshin Javadi, Farzaneh Lotfipur, Masood Ansarin, Elnaz Tamizi, Mahboob Nemati * Pages 1182-1190
    Contamination of food producing animals by veterinary drug residues, particularly quinolones, is an essential issue in food safety that causes increasing concern in consumers. The aim of this study was to investigate the occurrence of enrofloxacin and its main metabolite, ciprofloxacin, in chicken tissue samples slaughtered in Tabriz, Iran. Totally 250 samples including liver, muscle, gizzard, heart and skin were studied. Dispersive liquid-liquid microextraction technique (DLLME) was used as a simple, high performance, low-cost and fast sample pre-treatment method that followed by a high-performance liquid chromatography with UV detection for quantitative analysis. The residues of enrofloxacin were detected and quantified in 26 liver (52%) and 10 skin (20%) samples and ciprofloxacin residues were detected in 3 skin (6%) samples and accurately determined in 15 liver (30%) samples, however they were not detected in gizzard, heart and muscle samples. The results showed the accumulation of enrofloxacin and ciprofloxacin residues in chicken liver and skin.
    Keywords: Enrofloxacin, Ciprofloxacin, Dispersive liquid-liquid microextraction (DLLME), HPLC, Chicken
  • Ahmadreza Amraei *, Ali Niazi Pages 1191-1200
    In this study, the direct determination of cefixime as an anti-bacterial agent, in pharmaceutical formulations, urine and human blood plasma was conducted based on spectrophotometric measurements using parallel factor analysis (PARAFAC) and partial least squares (PLS). The calibration set was composed of fourteen solutions in the range of 0.50- 9.00 µg mL-1. PLS models were calculated at each pH applied to determine a set of synthetic cefixime solutions. The best model was acquired at pH 1.02 (PLS-pH 1.02). The ability of the method for the analysis of real samples was considered by determination of cefixime in pharmaceutical preparations, urine and plasma with satisfactory results. The calculated model with PARAFAC showed good prediction capability with root mean square error of prediction (RMSEP) of 0.12 for cefixime. The acid dissociation constants (pKa) of cefixime play a fundamental role in the mechanism of activity of cefixime. The pKa of cefixime were estimated by DATAN program using the corresponding absorption spectra-pH data. The calculated pKa values of cefixime were 1.89 and 3.80 for pKa1 and pKa2 respectively
    Keywords: Cefixime, PARAFAC, Pharmaceutical preparations, Urine, Plasma, DATAN, Acid dissociation constant
  • Urszula Karczmarczyk *, Wioletta Wojdowska, Renata Miko?Ajczak, Michal Maurin, Ewa Laszuk, Piotr Garnuszek Pages 1201-1208
    Introduction: This work presents a comparative biological evaluation of 90Y- and 177Lu- labelled DOTA-SCN and DOTA-NHS conjugated to Rituximab in tumour-bearing mice.
    Materials and methods
    Two DOTA derivatives, p-SCN-Bn-DOTA and DOTA-NHS-ester were conjugated to Rituximab and then freeze-dried kit formulations were prepared, as previously described [1]. Tissue distribution was investigated in tumour-bearing (Raji s.c.) male Rj:NMRI-Foxn1nu/Foxn1nu mice at different time points after administration of 177Lu-DOTA-Rituximab or 90Y-DOTA-Rituximab (6 MBq/10 μg per mouse). In addition, tumour images were acquired with a PhotonIMAGERTM after injection of 90Y-DOTA(SCN)-Rituximab. Results and Conclusion: All radioimmunoconjugates were obtained with high radiolabelling yield (RCP > 98%) and specific activity of ca. 0.6 GBq/mg. The conjugates were stable in human serum and in 0.9% NaCl, however, progressive aggregation was observed with time, in particular for DOTA(SCN) conjugates. Both 177Lu- and 90Y-DOTA(SCN)-Rituximab revealed slow blood clearance. The maximum tumour uptake was found 72 h after injection of 177Lu-DOTA(SCN)-Rituximab 9.3 ID/g. A high radioactivity uptake was observed in liver and spleen, confirming the hepatobiliary excretion route. The results obtained by the radioactive optical imaging harmonize with those from the biodistribution study.
    Keywords: anti-CD20, 177Lu - 90Y, radiolabeling, Rituximab, DOTA chelator, animal study
  • Fereshteh Ghazizadeh, Solmaz Ghaffari *, Seyedeh Fatemeh Mirshojaei, Mohammad Mazidi, Shirzad Azarmi Pages 1209-1216
    In this study Isoniazid (INH) as one of the first line drugs in treatment of Tuberculosis was investigated to be loaded in Solid Lipid Nanoparticles (SLNs) for reducing hepatotoxicity as well as prolonging drug release. High shear homogenization method was performed to prepare INH SLNs. To compare biodistribution of INH before and after loading in SLNs, INH was labeled by Technetium 99 (Tc99) after derivatization. The particle size of the prepared SLNs was 167 and 200 nm before and after lyophilization, respectively. Loading efficiency was calculated using the reverse method and release study was performed by using the dialysis sack method. Loading efficiency was 98%, and more than 85% of the loaded drug released in 3 h. Differential Scanning calorimeter (DSC) studieswere performed for evaluating of the probability of happening hydrogen bonds or other chemical interactions between cholesterol as carrier and isoniazid as active pharmaceutical ingredient. The results could support the probability of hydrogen bond formation between cholesterol and INH. Gamma Scintigraphy studies showed that after administering INH SLNs, longer drug retention in the body was obtained compared to free INH. Quantitative gamma counting showed that the concentration of INH in the liver and intestines could be decreased by using nanotechnology.
    Keywords: Isoniazid, Solid Lipid Nanoparticles, lyophilization, Tc-99m, Biodistribution, Gamma scintigraphy
  • Masood Fereidoonnezhad, Azar Mostoufi *, Maryam Eskandari, Samaneh Zali, Fariba Aliyan Pages 1217-1228
    Alzheimer’s disease (AD) as a complicated and progressive neurodegenerative disorder is the most common form of dementia and memory loss. On account of the multifactorial etiology of AD, the multi-target-directed ligand (MTDL) approach is a promising method in searching new drug candidates for this disease. Here, in this paper more than 500 tacrine-coumarin hybrids have been designed and drug-likeness, molecular docking and descriptor analysis of them were performed to find out a drug candidate with less toxicity and better binding affinity than tacrine. The docking analysis was carried out using human acetylcholineesterase (1ACJ), human butyrylcholineesterase (4BDS) and β-secretase (BACE1) (1W51) enzymes using AutoDock 4.2 and Vina. The promising results were obtained on the types of interactions. Based on docking on three targets and PLIF studies, the compounds that have better results were introduced as good candidates for synthesis. The validity of docking protocols was verified using a set of known active ligands and decoys on these targets.
    Keywords: Multi-target-directed ligand, Drug-likeness, Molecular docking, PLIF studies, Alzheimer?s disease
  • Seyedeh Mahbobeh Mahdavi, Azizollah Habibi *, Hadi Dolati, Seyyed Mohammad Shahcheragh, Soroush Sardari, Parisa Azerang Pages 1229-1239
    The focus of our study is the synthesis and biological activity evaluation of a series of 4H-Pyran compounds and schiff bases fused 4H-Pyran derivatives which are known to possess a wide variety of biological activities. In this paper at first a simple and efficient one-pot synthesis of 4H-Pyran s from the three-component reaction between malononitrile, aldehydes, and active methylene compounds in the presence of N-methylmorpholine (NMM) as catalyst at room temperature is reported, the reaction between these synthesized products and trimethylorthoformateor triethylorthoformateto produce schiff base compounds were also considered. The key advantages of synthesis of 4H-Pyran derivatives are short reaction time, high yield, and simple work-up. Then, these compounds were evaluated for anti-Mycobacterium activity against Mycobacterium bovis (Bacillus Calmette–Guerin). The preliminary results indicated that most of the tested compounds showed relatively good activity against the test organism. Moreover, antifungal activities of these compounds were evaluated. Finally, their effect was more noticeable on Mycobacterium bovis (BCG).
    Keywords: Antifungal, Anti-mycobacterium, 4H-Pyran, N-Methylmorpholine, Schiff bases
  • Ahmadreza Amraei, Ali Niazi *, Mohammad Alimoradi, Bahram Delfan Pages 1240-1248
    Thirty-one Cephalosporin compounds were modeled using the multivariate image analysis and applied to the quantitative structure activity relationship (MIA-QSAR) approach. The acid dissociation constants (pKa) of cephalosporins play a fundamental role in the mechanism of activity of cephalosporins. The antimicrobial activity of cephalosporins was related to their first pKa by different models. Bidimensional molecular structures (images) were used to calculate some pixel descriptors. The selection of pixels by successive projections algorithm (SPA) was done to achieve simple MIA-QSAR models; based on a small subset of pixels. In the present study, we evaluated the performance of pixel selection technique using SPA for partial least squares (PLS) model. The obtained model showed nice prediction ability with root mean square error of prediction (RMSEP) values of 0.402, 0.315, and 0.160 for principal component regression (PCR), PLS and SPA-PLS models respectively. Among the three methods, SPA-PLS was potentially useful in predicting the pKa of cephalosporins. The study showed the maximum structural efficacy is on pKa in a, b and c regions.
    Keywords: Cephalosporin, QSAR, Partial least squares, Multivariate image analysis, Successive projections algorithm, pixels of selection, Acid dissociation constant
  • Rmain Miri, Fatemeh Bohlooli, Nima Razzaghi, Asl, Ahmad Ebadi * Pages 1249-1262
    Deoxyribonucleic acid (DNA) is an important molecular target for anti-cancer agents due to its involvement in gene expression and protein synthesis which are fundamental steps in cell division and growth. A number of antineoplastic agents interfere with DNA and hence disturb the cell cycle. Compounds including planar aromatic rings are privileged scaffolds in binding to the DNA. This characteristic is mainly arisen from the fact that such structural feature may be appropriate to insert between the base pairs of the DNA double helix and produce relatively stable non-covalent complexes. Besides π-π stacking interactions, binding to the DNA molecule might be intensified through H-bond interactions due to the presence of heterocyclic rings. In the present contribution, a series of experimentally validated cytotoxic indeno [1,2-b] quinoline-9,11-diones (1-12) and their aromatized analogues (13-21) developed in our group were subjected to docking and molecular dynamics simulations to elucidate their most probable binding modes with DNA.
  • Fataneh Jafari, Amin Nowroozi, Mohsen Shahlaei * Pages 1263-1287
    Glucagon and the glucagon receptor are most important molecules control over blood glucose concentrations. These two molecules are very important to studies of type 2 diabetic patients. In literature, several classes of small molecule antagonists of the human glucagon receptor have been reported. Glucagon receptor antagonist could decrease hepatic glucose output and improve glucose control in diabetic patients. In this research, to identify novel and diverse leads for use in potent glucagon receptor antagonist design, a ligand-based pharmacophore modeling , was developed using the best conformations of training set compounds. The best five features pharmacophore model, called Hypo1, includes, hydrogen bond acceptors, two hydrophobic and positive ionizable features, which has the highest correlation coefficient (0.805), cost difference (64.38), low RMS (2.148), as well as it shows a high goodness of fit and enrichment factor. The generated pharmacophore model has been validated by using a series of similar structures with varying affinities for the glucagon receptor. Then, the developed model has been applied as a search query in different database searching with the main objective of finding novel molecules which have the potential to be modified into novel lead compounds. As a result, some hit molecules were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. The results from pharmacophore modeling and molecular docking are complementary to each other and could serve as a useful way for the discovery of potent small molecules as glucagon receptor antagonist.
    Keywords: Glucagon Receptor Antagonist, Ligand-Based Pharmacophore Modeling, Computer Aided Drug Design, Docking, Virtual Screening
  • Mahsa Shahrasbi, Mahsa Azami Movahed, Orkideh Ghorban Dadras, Bahram Daraei, Afshin Zarghi * Pages 1288-1296
    A new series of imidazo[2,1-b]thiazole analogs containing a methyl sulfonyl COX-2 pharmacophore was synthesized and evaluated for their COX-2 inhibitory activity. According to in-vitro COX-1/COX-2 inhibition data, all compounds (6a-g) were selective inhibitors of COX-2 isoenzyme with IC50 values in the highly potent 0.08-0.16 mM range. These results indicated that both potency and selectivity of COX-2 inhibitory activity were affected by the type and size of amine on C-5 of imidazo[2,1-b]thiazole ring. Our data identified N,N-dimethyl-1-(6-(4-(methylsulfonyl)phenyl)imidazo[2,1-b]thiazol-5-yl)methanamine (6a)as a potent and selective COX-2 inhibitor (IC50 COX-1 >100 µM; IC50 COX-2 = 0.08 µM; selectivity index = 313.7). Our results indicated that both potency and selectivity of COX-2 inhibitory activity were affected by the type and size of amine on C-5 of imidazo[2,1-b]thiazole ring.
    Keywords: Design, Synthesis, Cyclooxygenase-2 inhibition, Imidazo[2-1-B]Thiazole, Molecular modeling
  • Bahareh Shokri, Afshin Zarghi, Soraya Shahhosseini, Reza Mohammadi, Farzad Kobarfard * Pages 1297-1305
    It is well known that Arginine-Glycine-Aspartic acid (RGD) and Asparagine-Glycine- Arginine (NGR) peptides preferentially bind to integrin receptors and aminopeptidase N respectively and these two receptors play important roles in angiogenesis. Therefore ketoprofen as a non-selective cox Inhibitor was conjugated with linear RGD and NGR to take advantage of targeting capability of these two motifs and delivering ketoprofen to these cancer cells with overexpression of integrin and aminopeptidase N. In order to investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six carbon (hexanoic acid) linker was also used as a spacer. Cytotoxic effect of the synthesized compounds was evaluated against a group of cancer cell lines, including MCF-7, A2780 (αvβ3 positive), OVCAR3 (high αvβ3), HT-1-80 (high CD13) and SKOV-3 (CD13 positive). Both NGR and RGD conjugated forms of ketoprofen showed higher cytotoxic activity against OVCAR3 and HT-1-80 respectively.
    Keywords: RGD, NGR, Tumour targeting, Integrin, Aminopeptidase N
  • Daniele Souza, Valterl, Uacute, Cio Sales, Cristina Kelly Rodrigues, Larissa De Oliveira, Izabel Lemos, Gyllyandeson Delmondes, Aacute, Lefe Monteiro, Emmily Do Nascimento, Francisco Rodolpho De Figu, Ecirc, Iredo, Jos, Eacute, Galberto Da Costa Pages 1306-1317
    Annona muricata Linnaeus (Annonaceae), popularly known as graviola, is used in folk medicine as both sedative and anticonvulsant. This study correlates the neurochemical profile with the behavioral effects of the hydroalcoholic extract from the leaves of Annona muricata (HLEAM) in mice, proposing to elucidate their mechanism of action on the central nervous system. Flavonoids and phenolic compounds were identified and quantified by High Performance Liquid Chromatography (HPLC) method. The acute toxicity (median lethal dose - LD50) was determined by probitos method using the percentage of mortality based on the Hippocratic screen. HLEAM (25, 50 and 100 mg/kg) was tested, intraperitoneally (i.p.), in models of sedation, anxiety, motor coordination and seizures. The endogenous levels of dopamine, norepinephrine and DOPAC were assayed by reverse-phase HPLC with electrochemical detection. The HPLC analysis of extract revealed the presence of flavonoids (quercetin, isoquercitrin, quercitrin, rutin and kaempferol) and phenolics acids (gallic, chlorogenic, ellagic and caffeic acids). The LD50 was 1091.7 mg/kg and Hippocratic screening indicated central nervous system depressant effect. HLEAM presented sedatives effects at doses 25, 50 and 100 mg/kg, and anxiolytic and anticonvulsant effects at a dose of 100 mg/kg. In addition, these effects were partially reversed by flumazenil. The monoamines analysis by HPLC showed that HLEAM decreased the level of norepinefrine and dopamine in the mouse brain striatum. Thus, the results indicate a possible interaction of HLEAM with the GABAergic and monoaminergic systems, adding medicinal value to the popular use of the plant for the treatment of behavioral and neurological disorders.
    Keywords: Annona muricata, sedative, anxiolytic, anticonvulsant, GABAergic system, monoaminergic system, Phenolic compounds
  • Hae, Yong Noh, Jing Lu, Muhammad Hanif Siddiqi, Sathishkumar Natatajan, Sera Kang, Sungeun Ahn, Yeon, Ju Kim, Deok Chun Yang * Pages 1318-1327
    Ginsenoside F1 is a biologically active compound identified potential from Korean Panax ginseng Meyer. In the present study, the potential targets of ginsenoside F1 were investigated by computational target fishing approaches including ADMET prediction, biological activity prediction from chemical structure, molecular docking, and molecular dynamics methods. Results were suggested to express the biological activity of ginsenoside F1 against p38 MAP kinase protein. The p38 MAP kinase protein is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Numerous studies are shown that an abnormal activation of p38 MAP kinase leads to variety of diseases. The pharmacokinetic result proves that ginsenoside F1 can act like drug like molecule and non-toxic. In addition, molecular level interaction result of ginsenoside F1 with p38 MAP kinase active (binding) sites residues clearly defines inhibitory action of p38 MAP kinase. Further, molecular dynamics study also supported p38 MAP kinase and ginsenoside F1 structural stability. Findings from out study will assist to discover the active drug like molecules from Panax ginseng with help of molecular modeling techniques.
    Keywords: Panax ginseng, p38 MAP kinase inhibitor, G-F1, ADMET, docking
  • Nada Eisa *, Heba S. Said, Nehal M. Elsherbiny, Laila A. Eissa, Mamdouh El, Shishtawy Pages 1328-1338
    The aim of this study is to investigate the antitumor activity and possible molecular mechanism of Phenethyl isothiocyanate (PEITC) against Ehrlich ascites carcinoma in-vivo and in-vitro.
    In-vivo, ascetic fluid volume, body weight, serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined using Ehrlich ascites carcinoma (EAC) bearing mice. In-vitro, MTT assay was used. RT-PCR was used to investigate role of PEITC in apoptosis by analyzing the expression of Bax, caspase-9, and Bcl-2 genes. The effect of PEITC on caspase-9 enzyme activity was also tested.
    PEITC and/or Doxorubicin (Dox) treatment significantly suppressed EAC growth as compared to EAC/oil control mice. PEITC treatment showed a dose-dependent inhibition of EAC cells as indicated by MTT assay. We found that significant increase in MDA level and decrease in TAC caused by Dox treatment were significantly reduced by combination with PEITC treatment. Bax, caspase-9 genes’ expression and caspase-9 enzymatic activity were significantly increased, while Bcl-2 gene expression was significantly decreased in PEITC treated mice.
    PEITC may act as a promising anticancer agent either alone or more effectively in combination with Dox through apoptotic cell death induction.
    Keywords: Apoptosis, Bax, Bcl-2, Caspase-9, Ehrlich ascites carcinoma, Phenethyl isothiocyanate
  • Bin Gong *, Shuang Chen, Wenwen Lan, Yanmin Huang, Xiangcheng Zhu Pages 1339-1346
    Mangroves are the tidal forest existing in the intertidal zone and usually considered as the special marine ecosystem. In the present study, 452 actinomycetes were recovered from nine diferent sites at Maowei Sea Mangrove Reserve in Qinzhou (Guangxi province, China). Among them, Seventy-four strains were purified for 16s RNA gene sequencing and further characterization. The results indicated that the majority of isolates belonged to the genera Streptomyces, including 17 species. Streptomyces sanyensis was the dominant species (31.1%), followed by Streptomyces griseorubens (17.5%), Streptomyces viridobrunneus (10.8%) and other Streptomyces species. Only one rare actinomycetes, Stenotrophomonas was discovered. The isolation of actinomycetes was obviously related to the type of soil and edaphic conditions. Rhizosphere-associated soils gave almost 62.2% actinomycete isolates, nearly twice as many as the non-rhizosphere-associated soils. In addition, 20 actinomycete strains (27%) presented varied antibacterial activities towards four tested organisms, including two drug-resistant clinical strains (MRSA and VRE), while some species of Streptomyces like S.sanyensis, S.viridobrunneus, S.tanashiensis, S.parvus, S.flavotricini and S.parvulus exhibited remarkable cytotoxic activities. Further bioinformatical analysis of these 29 bioactive strains for secondary metabolites biosynthetic machineries revealed that nonribosomal peptide synthetase (NRPS) was detected in 20 isolates (68.9%), whereas type-I polyketide synthase (PKS-I) and type-II polyketide synthase (PKS-II) were detected in 16 and all of the 29 strains, respectively. Hence, our work demonstrated that actinomycetes from mangroves in Maowei Sea Mangrove Reservewere fascinating reservoirs for antibacterial and antitumor natural products discovery.
    Keywords: Antibacterial, antitumor, Actinomycetes, Mangrove, China
  • Imron Meechai, Worrapong Phupong *, Warangkana Chunglok, Puttinan Meepowpan Pages 1347-1352
    Garcinia schomburgkiana, locally known in Thailand as an edible fruit “Ma-dan”, is a plant species of the Clusiaceae family which has been reported as sources of a variety of compounds with biological activities. In the phytochemical studies of Ma-dan, four xanthones were, for the very first time, isolated from the branch acetone extract of G. schomburgkiana. Their structures were determined through the analysis of spectroscopic data (1H, 13C-NMR, IR and MS) and the comparison with those previously reported. Dihydroosajaxanthone (1), an original synthetic xanthone, is reported herein for the first time as a naturally occurring xanthone, together with three known xanthones: xanthochymone A (2), 1,3,7-trihydroxy-2-(3-hydroxy-3-methylbutyl) xanthone (3) and 1,3,5,6-tetrahydroxyxanthone (4). These compounds, especially dihydroosajaxanthone (1), might be considered as chemotaxonomic markers of the Garcinia genus.
    Keywords: Dihydroosajaxanthone, Garcinia schomburgkiana, Clusiaceae, Xanthone, Phytochemical
  • Padma Laxmikant Ladda *, Chandrakant Shripal Magdum Pages 1353-1360
    Tuberculosis still remains a leading cause of death in the world. Currently considerable interest in natural products and their derivatives in the area of drug research for multidrug resistant tuberculosis (MDR-TB). The present investigation focused on identification, isolation, characterization of lead constituents and to determine the antitubercular activity of their enriched fractions and isolated compounds by Nitrate reductase assay (NRA) method. Leaves extracted with ethanol by soxhlet extraction and ethanol extract separated in petroleum ether, chloroform and methanol by separating funnel and fractionated by column chromatography. Ethanol extract, petroleum ether and chloroform fraction showed antitubercular activity at 150 µg/ml. Isolated HEA-2, CM-20 and CM-24 showed MIC at 100 while PE-34 at 50 and 100 µg/ml. β-sitosterol content in chloroform and petroleum ether fractions was calculated by using HPTLC. Pet. ether and chloroform fractions of ethanol extract which contains betulinic acid, ursolic acid and β -sitosterol shows anti- TB activity. HPTLC, IR, 1 H NMR and GC-MS study of isolated PE-34 gave satisfactory results for confirmation of the structure as ursolic acid with significant antitubercular potential.
    Keywords: Mycobacterium tuberculosis, Vitex negundo, NRA, HPTLC, ursolic acid
  • Omid Cheraghi, Mina Abdollahpourasl, Aysa Rezabakhsh *, Reza Rahbarghazi Pages 1361-1370
    To assess different effects of royal Jelly in protecting the human endothelial cells from high glucose level, human umbilical vein endothelial cells were exposed to various concentrations of royal jelly, from 0.625 to 10 mg/ml, at the presence of 5 and 30 mM glucose contents over a course of 72 h. In addition to cell viability assessment by conventional MTT assay, we also analyzed the feature of stemness by expression of Sox-2 and CD133 factors. Moreover, fatty acid profile, the expression of autophagy-related factor, namely microtubule-associated protein light chain 3 and activity of metalloproteinase 2 and 9 and were investigated. Royal jelly supplementation at the concentrations lower than 2.5 mg/ml did not influence the survival rate of cells and partially blunted the cytotoxic effects of 30 mM glucose. The expression of CD133 and Sox-2 factors were increased by royal jelly alone. Interestingly, an up-regulated expression of Sox-2 (58.8±4%) coincided with a reduction in the levels of CD133 (15.1±8.3%) in the combined treatment. We notified that the contents of palmitate and trans-palmitate as well as linoleate decreased by 30 mM glucose content while cis-palmitate levels increased when RJ returned them to near-normal levels (p<0.05). The expression of autophagy marker was prominently induced in the presence of royal jelly at both conditions (p<0.05). The glucose-induced activity of metalloproteinases was also reduced. Royal jelly is able to attenuate the abnormal status of 30 mM glucose condition in endothelial cells by different mechanisms.
    Keywords: Royal jelly, HUVECs, Stemness feature, Fatty acids profile, Autophagy, MMPs activity
  • Ali Moghimi *, Naeima Eftekhar Pages 1371-1385
    The effects of Ocimum basilicum (O. basilicum) and its constituent, rosmarinic acid, on total and differential blood WBC, serum levels of NO2, NO3, MDA, thiol, SOD and CAT in sensitized rats were examined. The study was performed in control animals (group C) and eight groups of sensitized rats to ovalbumin which were given drinking water alone (group S), drinking water containing three concentrations of O. basilicum (O; 0.75, 1.5 and 3.0 mg/mL), three concentrations of rosmarinic acid (R; 0.125, 0.25 and 0.5 mg/mL) and dexamethasone (1.25 μg/mL), (n = 6 for R treated and n = 8 for other groups). Total and differential WBC as well as serum concentrations of oxidant and antioxidant biomarkers were measured in all groups. Serum levels of oxidant biomarkers, total WBC count, percentages of eosinophils and neutrophils were significantly increased but other measured parameters except monocytes were significantly decreased in group S compared to group C. Serum levels of oxidant biomarkers, total WBC count, percentages of eosinophils, neutrophils and monocytes were significantly decreased but other measured parameters were significantly increased in treated S groups with dexamethasone, extract and rosmarinic acid compared to group S. The effects of the extract and rosmarinic acid on some measured variables were significantly higher than the effect of dexamethasone treatment. These results showed the effect of O. basilicum and its constituent, rosmarinic acid on inflammatory and oxidant parameters in sensitized rats which was comparable or even more potent than dexamethasone at used concentrations.
    Keywords: Ocimum basilicum, Rosmarinic acid, White blood cells, Oxidant, antioxidant markers, Sensitized rats
  • Mahsa Sabernavaei, Farzad Kobarfard, Abbas Hadjiakhoondi Hadjiakhoondi, Majid Aghaahmadi, Mohsen Amin, Narguess Yassa * Pages 1386-1391
    Leutea avicenniae Mozaff. belongs to Apiaceae family is an endemic species distributed in the west of Iran. The aim of this study was to investigate the antioxidant activity and acetylcholinestrase (AchE) inhibition of the crude extract, fractions and isolated compounds from methanolic fraction of L. avicenniae. Five compounds were detected from methanol fraction, three phenolic compounds as p-coumric acid, caffeic acid, salicylic acid and two flavonoids as quercetin and astragalin. These structures were identified by spectroscopic techniques such as 1H-NMR, 13C-NMR and UV.
    Antioxidant activity was evaluated by the free radical scavenging assay using 2,2-diphenyl-1-picryl- hydrazyl (DPPH) method. Ellman colorimetric method was used to determine acetylcholinestrase (AChE) inhibition. In the DPPH assay, Quercetin exerted the highest antioxidant activity (IC50=10.24±1.3 µg/ml). Caffeic acid inhibited AChE with IC50 of 12.06±2.01µg/ml which were comparable to Galanthamine as positive control (IC50=62.44±2.2µg/ml).
    In conclusion methanol extract of L. avicenniae contains bioactive components with antioxidant and AchE inhibitory effects.
    Keywords: Leutea avicennia, Apiaceae, AChE, DPPH, Phenolic compounds
  • Nika Khoshnevis, Shahla Rezaei, Amene Samaei, Nouroozi, Mohsen Amin, Mahsa Moshfegh, Mohammad Reza Khoshayand, Mohammad Ali Faramarzi * Pages 1392-1412
    Owing to their superior catalytic activity in the extreme conditions, extremozymes have found the potential biotechnological applications for industrial purposes. A robust extracellular protease activity was detected in the culture broth of Salicola marasensis, an extreme halophilic bacterium, after a 48 h-incubation. The effect of different media ingredients in a liquid state fermentation was followed with the aim of improving the enzyme production yield. Fractional factorial and Box-Behnken designs were applied to get a 3.4 fold (from 6.0 to 20.3 U mL−1) improvement of protease production. The distinguishing features of this enzyme were stability at a wide range of pH (5.0–11.0) and temperature (25–60 °C), significant compatibility towards organic solvents, metal ions, chemicals, and surfactants, and hydrolysis of a variety of substrates. The properties of this enzyme can be of tremendous help in terms of the halophilic proteolytic extract’s industrial applications.
    Keywords: Salicola marasensis, Halophile, Proteolytic extract, Protease activity, Optimization, Characterization
  • Esrafil Mansouri *, Mohammad, Ali Assarehzadegan, Fereshteh Nejad, Dehbashi, Wesam Kooti Pages 1413-1419
    The aim of this study is to evaluate the effects of pravastatin on Adriamycin (ADR)-induced nephropathy and the mechanisms involved. Forty rats were divided into the following 4 groups: control, ADR (15 mg.kg-1, IP), ADR plus pravastatin (20 mg.kg-1 which was started 5 days prior to ADR injection), and ADR plus pravastatin (20 mg.kg-1 which was started 5 days after ADR injection). On day 20 after ADR injection, the animals were sacrificed. The results showed that administration of pravastatin decreased the levels of 24-h urinary protein (24-h UP), blood urea nitrogen (BUN), and creatinine (p < 0.05) which had increased after the injection of ADR; in addition, pravastatin reversed structural changes seen in ADR group. Furthermore, pravastatin elevated mRNA and protein expression of nephrin (p < 0.05) which had been reduced in ADR group. We conclude that pravastatin protects and treats renal injury induced by ADR.
    Keywords: Nephropathy, Adriamycin, Pravastatin, Nephroprotective, Rat
  • Omnia Ahmemd Mohamed Abed El, Gaphar, Amira Mourad Abo, Youssef *, Ali Ahmad Abo, Saif Pages 1420-1430
    Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by joint infiltration and bone damage. The aim of the present study was to evaluate the beneficial effects of losartan in adjuvant-induced arthritis (AIA). Arthritis was induced in rats by subcutaneous injection of 0.2ml of Complete Freund’s adjuvant (CFA) in the planter surface of the hind paw. Arthritic rats were allocated into three groups (n=10), the first group (arthritis control), received 1% of tween 80, the second and the third groups received prednisolone (10 mg/kg/day; p.o) and losartan (20 mg/kg/day; p.o) respectively for two weeks. A fourth group (vehicle control) received 1% tween 80. At the end of the experiment, blood samples were collected for biochemical, oxidative stress and hematological analysis. Histopathological and macroscopical examinations on joints were also performed.
    Our results revealed that losartan significantly reduced serum levels of tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) , rheumatoid factor (RF) and erythrocytes sedimentation rate (ESR).It significantly decreased serum malondialdehyde and increased blood glutathione .Losartan exhibited significant decrease in serum level of total cholesterol (TC),triglycerides (TG) and low density lipoprotein (LDL) coupled with marked increase in high density lipoprotein (HDL).Furthermore losartan decreased white blood cell cells (WBC’s) count and increased red blood cells (RBC’s) ,hemoglobin (Hb) ,platelets and hematocrit (Hct) counts. These findings were further supported by histopathological and macroscopical examinations. It could be concluded that losartan was able to repress biochemical, oxidative and hematological changes associated with AIA. These effects could be attributed to anti-arthritic, hypolipidemic, antioxidant and anti-anemic properties.
    Keywords: Complete Freund?s adjuvant, Losartan, Prednisolone, Rats, Rheumatoid Arthritis
  • Deniz Abedinoghli, Mohammad Charkhpour, Karim Osouli, Bostanabad, Sevil Selselehjonban, Shahram Emami, Mohammad Barzegar, Jalali *, Khosro Adibkia Pages 1431-1443
    This study was conducted to enhance the pharmacologic effect of carbamazepine (CBZ) (as a poorly water-soluble drug) by fabricating CBZ-PVP K30 nanobeads using an electrospraying technique. CBZ-PVP K30 nanosystems with various ratios (1:3 and 1:5) at total solution concentrations of 3% and 5% w/v were prepared. The solution concentration extremely affected the size of the samples; where, the nanobeads (mean diameter of 457.65 ± 113.72 nm and 1.16 ± 0.46 µm) were developed at low and high solution concentrations, respectively. DSC thermographs and PXRD patterns precisely showed CBZ amorphization in the electrosprayed nanosystems. Based on the FTIR spectrum of the electrosprayed samples, a feasible interaction between N–H/O–H group of CBZ and PVP carbonyl group was detected. The in-vitro release studies revealed that the electrosprayed nanosystems represent a comparable rapid dissolution rate with respect to the physical mixtures (PMs) and the pure drug. The in-vivo results in NMRI mice indicated that the electrosprayed nanoformulation (with the drug: polymer ratio of 1:5 at a total solution concentration of 5% (w/v)) prolonged seizure latency time and decreased mortality percent in strychnine (STR) induced seizure mice more efficiently than the PM. Our finding revealed that the electrospraying as a cost-benefit and one step technique could be effectively applied for improving the physicochemical characteristics and pharmacologic effect of CBZ.
    Keywords: Carbamazepine, PVP K30, Electrospray, Nanobeads, In-vivo evaluation
  • Azadeh Yazdi, Akram Mokhtarzadeh Khanghahi, Hossein Baharvand, Mohammad Javan * Pages 1444-1457
    Multiple sclerosis (MS) is an autoimmune disease which affects myelin in the central nervous system (CNS) and leads to serious disability. Currently available treatments for MS mainly suppress the immune system. Regenerative medicine-based approaches attempt to increase myelin repair by targeting endogenous progenitors or transplanting stem cells or their derivatives. Fingolimod exerts anti-inflammatory effects and directly affects neural cells. In this study we assessed the effect of fingolimod on transplanted human induced pluripotent stem cell derived neural progenitors (hiPSC-NPs). hiPSC-NPs were labeled by green fluorescence protein (GFP) and transplanted into the corpus callosum of mice which were chronically demyelinated after cuprizone (CPZ) feedings for 10 weeks. The animals received fingolimod from 1 day prior to NPs transplantation via gavage as well as daily intraperitoneal cyclosporine A from 2 days before cell transplantation until the time of sampling. At either 7 or 21 days after NPs transplantation, the animals were sacrificed and their brains were histologically evaluated for the number of transplanted cells and their fate. In the animals treated with fingolimod, we observed higher numbers of NPs within the injection site compared to the animals who did not receive fingolimod showing that hiPSC- NPs were more efficiently differentiated to the oligodendrocyte lineage. These data have suggested that repetitive treatment with fingolimod, beside its anti-inflammatory effect, may enhance the survival and differentiation of transplanted NPs to oligodendrocyte lineage cells to participate in myelin repair.
    Keywords: Fingolimod (FTY720), Cell therapy, Neural progenitor cell, Cuprizone, Oligodendrocyte, Mouse
  • Shadi Baniasadi, Maryam Alehashem, Masud Yunesian, Noushin Rastkari * Pages 1458-1464
    Exposure of health care workers to antineoplastic drugs and subsequent adverse health effects is still an open issue. Very little has been studied on the extent of occupational exposure and handling conditions of antineoplastic drugs in Iran. We aimed to determine cyclophosphamide and ifosfamide concentrations in the urine samples of oncology healthcare workers. In addition, we assessed workplace safety controls that are important to decrease occupational exposure.Urinary samples of subject and control groups were collected to measure pre and post-shift cyclophosphamide and ifosfamide concentrations. Prior to sample collection, an occupational toxicologist observed and recorded working safety conditions for the healthcare workers during an eight-week period. Heath care workers were also asked about occurrence of acute adverse health effects. A total number of 425 chemotherapeutic drugs (389.83 g) were prepared during the study. Cyclophosphamide was detected in five pre-shift and nine post-shift urine samples. One pre-shift and four post-shift urine samples were positive for Ifosfamide. The urine samples of control group had no detectable concentrations of cyclophosphamide and ifosfamide. Personal protective equipment usage was not adequate for handling activities. Some adverse health effects reported by oncology personnel confirmed exposure to antineoplastic drugs. High percentage of oncology personnel was exposed to antineoplastic drugs that could be related to the large amount of drug preparations and inadequate safety controls. We recommend training of oncology personnel, implementation of safety controls, and periodic surveillance in order to minimize workplace contamination and occupational exposure to antineoplastic drugs.
    Keywords: Antineoplastic drugs, Cyclophosphamide, Healthcare worker, Ifosfamide, Occupational exposure, Oncology
  • Aziz Eftekhari, Elham Ahmadian, Yadollah Azarmi, Alireza Parvizpur, Javad Khalili Fard, Mohammad Ali Eghbal * Pages 1465-1475
    Thioridazine (TZ) is used mainly in the treatment of schizophrenia. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. In this context, we examined the cytotoxic mechanisms of TZ on freshly isolated rat hepatocytes to better understanding of the pathogenesis of TZ-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. The level of parameters such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosomal membrane integrity and cellular glutathione (GSH) content in TZ-treated and non-treated hepatocytes were determined and the mentioned markers were assessed in the presence of Coenzyme Q10 and/or melatonin.
    Results showed that TZ caused an increase in ROS formation as well as induction of LPO and GSH depletion. Moreover, mitochondria and lysosomes seem to be targets of TZ-induced toxicity. The administration of Coenzyme Q10 and/or melatonin efficiently decreased the rate of ROS formation, LPO and improved cell viability, MMP, GSH level and lysosome membrane integrity. This study proposes the possible protective role of Coenzyme Q10 and/or melatonin against TZ-induced cellular injury probably through their radical scavenging properties and their effects on mitochondria and lysosomes.
    Keywords: Thioridazine, hepatotoxicity, ROS formation, Oxidative stress, mitochondrial-lysosomal dysfunction
  • Marjan Aghvami, Peyman Eshghi, Mohammad Hadi Zarei, Hadi Arefi, Fatemeh Sattari, Afshin Zarghi *, Jalal Pourahmad Pages 1476-1487
    B-acute lymphoblastic leukemia (B-ALL) is the frequent pediatric malignity. Chemotherapy is the most practical approaches to deal with such malignancies. Microtubule-targeted agents are one of the most strategic drugs which formerly use in chemotherapy.Although,colchicine-binding anti-tubulin agents exhibited promising effects in clinical trials, their exact mechanism of action is not fully understood.In this study, the effects of two newly synthesized of colchicine derivatives were investigated on cell viability of cancerous and normal lymphocytes. The viability test was carried out by MTT assay. Apoptosis vs. necrosis was measured by double staining with annexin V/PI, and caspase-3 as the ultimate mediator of apoptotic measured through the colorimetric assay. Parameters of mitochondrial damage (ROS formation, MMP decline, mitochondrial swelling, and cytochrome c release following treatment by colchicine derivatives.
    By focusing on mitochondrial parameters, we showed that following treatment by two newly synthetized colchicine derivatives, apoptosis are triggered in cancerous B-lymphocytes. We demonstrated these compounds could activate apoptosis in cancerous lymphocytes by augmentation of reactive oxygen species (ROS), a decline in mitochondrial membrane potential (MMP), mitochondrial swelling, release of cytochrome c and also caspase-3 activation.
    Considering the obtained evidences, these inhibitorscould be the new therapeutic strategies in ALL treatment.
    Keywords: B-acute lymphoblastic leukemia, Microtubules inhibitors, Mitochondria, VDAC, Caspase cascade, Apoptosis
  • Masoumeh Baradaran, Amir Jalali *, Maryam Naderi Soorki, Maumoud Jokar, Hamid Galehdari Pages 1488-1502
    Scorpions are generally an important source of bioactive components, including toxins and other small peptides as attractive molecules for new drug development. Mesobuthus eupeus, from medically important and widely distributed Buthidae family, is the most abundant species in Iran. Researchers are interesting on the gland of this scorpion due to the complexity of its venom. Here, we have analyzed the transcriptome based on expressed sequence tag (EST) database from the venom tissue of Iranian M. eupeus by constructing a cDNA library and subsequent Sanger sequencing of obtained inserts. Sixty-three unique transcripts were identified, which were grouped in different categories, including Toxins (44 transcripts), Cell Proteins (9 transcripts), Antimicrobial Peptides (4 transcripts) and Unknown Peptides (3 transcripts). The analysis of the ESTs revealed several new components categorized among various toxin families with effect on ion channels. Sequence analysis of a new precursor provides evidence to validate the first CaTxs from M. eupeus. The results are exploration of the diversity of precursors expressed of Iranian M. eupeus venom gland. We further described comparative analysis of venom components of Iranian M. eupeus with other sibling species.
    Keywords: cDNA library, Mesobuthus eupeus, transcriptome analysis, Chlorotoxin-like peptide, homology modeling, Molecular dynamics flexible fitting (MDFF)
  • Tahereh Babaee, Ahmad Fazeli, Sameereh Hashemi, Najafabadi, Hosein Rastegar, Ali Mohammadi, Mohammad Reza Khoshayand, Mahmoud Alebouyeh, Mohammad Reza Fazeli* Pages 1503-1508
    Recombinant plasminogen activator (reteplase) is a third generation thrombolytic agent which has been used on coronary artery thrombosis and acute myocardial infarction. Clot lysis assay is usually considered as a unique method to evaluate biological activity of reteplase. In this study biological activity of reteplase was determined by APTT (activated partial thromboplastin time) lysis method. Validity of this method was evaluated in comparison with reference method, clot lysis time assay. Results of APTT lysis test showed good reproducibility (relative standard deviation (RSD) 3-5% for within day analysis and 4-7% for between day analysis), and accuracy (101.3-102.7%). APTT lysis responses were linear in range of 0.001-0.1 mg/mL reteplase. Therefore, APTT lysis method is applicable for biological activity determination of reteplase. Although more comprehensive studies are required to approve this test as a reference method, APTT lysis method seems to be valuable to receive more attention due to advantages of technical simplicity, sensitivity, applicability, and cost efficiency.
    Keywords: Recombinant reteplase, Clot lysis, APTT lysis test, Validation, Biological activity
  • Mahdie Ameri Shah Reza *, Hossein Vahidi, Farzad Kobarfard Pages 1509-1522
    Lentinus edodes (L. edodes) is one of the most famous traditional Chinese medicines and high producer of various bioactive compounds such as polysaccharides. Modern pharmaceutical research shows that the Polysaccharides (LEPLS) of this mushroom is a kind of bioactive compound with clinical significance in medicine and several physiological effects. Up to now, fermentation system has been widely used successfully for the production of various biologically active compounds. Solid-sate fermentation techniques (fungal fermentation strategy) was carried out to produce LEPLs in L. edodes. Hence, the major objective of this study is the production of LEPLs through a developed process by using effective factors in order to achieve the optimal fermentation conditions for significant increase in the yields biomass and LEPLs. In this study, the optimal fermentation conditions of L. edodes polysaccharide using Walnut shell by-products as a substrate were investigated. RSM design of experiments method was used as the statistical method.
    Based on the optimum experimental conditions of SSF, the inoculum size, the incubation time, and the C/N ratio were optimized by RSM. The RSM model estimated that a maximal yield of biomass and polysaccharides (0.045 mg/g and 47.62 mg/g respectively) could be obtained when inoculum size, incubation time, C/N ratio was set at 20, 11.14, 25.66 respectively. As a result, the goodness of the quadratic model was determined by analysis of variance (ANOVA) and coefficient (R2). These values also verified by validation experiments. Finally, the optimal fermentation conditions resulted in a significant increase in the yields of biomass and LEPLs.
    Keywords: Biomass, Polysaccharides, Lentinus edodes, Solid- state fermentation, RSM design of experiments, Optimization
  • Nasrin Amiri Dashatan, Mehdi Koushki, Hojjat, Allah Abbaszadehorcid, Mohammad Rostami, Nejad, Mostafa Rezaei, Tavirany * Pages 1523-1536
    Advancing in genome sequencing has greatly propelled the understanding of the living world, however, it is insufficient for full description of a biological system. Focusing on, proteomics has emerged as another large-scale platform for improving the understanding of biology. Proteomic experiments can be used for different aspects of clinical and health sciences such as food technology, biomarker discovery and drug target identification. Since proteins are main constituents of foods, proteomic technology can monitor and characterize protein content of foods and their change during production process. The proteomic biomarker discovery is advanced in various diseases such as cancer, cardiovascular diseases, AIDS and renal diseases which provide non-invasive methods by the use of body fluids such as urine and serum. Proteomics is also used in drug target identification using different approaches such as chemical proteomics and protein interaction networks. The development and application of proteomics has increased tremendously over the last decade. Advances in proteomics methods offer many promising new directions of studying in clinical fields. In this regard, we want to discuss proteomics technology application in food investigations, drug and biomarker discovery will be discussed.
    Keywords: Proteomics, Proteome profiling, Foodomics, Biomarker, Drug discovery
  • Puyan Daei, Mahsa Ramezanpour, Korosh Khanaki, Maryam Tabarzad *, Iraj Nikokar, Mojtaba Hedayati Ch, Ali Elmi Pages 1537-1549
    miRNAs as one of the potential therapeutic agents have been recently considered for cancer treatment. AS1411 (aptNCL) is a DNA aptamer specifically binding to nucleolin protein on the cancer cell surface with antiproliferative effect. The aim of the study was to develop a conjugate consisted of aptNCL (as targeted delivery of therapeutic agent) and miRNA let-7d (as a tumor suppressor) using two different linking methods and also to evaluate the potential effect of the conjugates on the proliferation of gastric cancer (MKN-45) cell line compared to negative control cell line of human dermal fibroblast (HDF). Conjugation was performed covalently by SM(PEG)2 as a bifunctional crosslinker (conjugate-1) and noncovalently using 19bp complementary sticky end sequences (conjugate-2), respectively. Nucleolin positive MKN-45 and nucleolin negative HDF cells were cultured and treated with the conjugates. Then, the changes in let-7d expression and cell proliferation were determined using Real-time PCR and MTT methods, respectively. In MKN-45 cells, the conjugates caused significantly increase in let7-d uptake compared with HDF cells (p=0.0001). The conjugate-1, likely due to its higher stability compared with the conjugate-2, led to significantly more increase in intracellular let-7d in MKN-45 cells (30 fold versus 15 fold, respectively, p=0.0001). The conjugates revealed more potent antiproliferative effect against gastric cancer cells compared with aptNCL alone (p=0.0001). It was found that the aptNCL-let-7d conjugate efficiently carried let-7d into the cancer cells. Also, it appears that in the setting of aptNCL-let-7d conjugate, let-7d and aptNCL moieties could cooperate and synergistically exhibit the antiproliferative effect on cancer cells.
    Keywords: Nucleolin specific aptamer (aptNCL), miRNA let-7d, Gastric Cancer, Conjugate, Targeted delivery
  • Ashish Gorle *, Dinesh Khairnar Pages 1550-1562
    A number of ways have been investigated for administration of antibacterial agents in dealing of plaque-initiated periodontal disease. These include prolonged release intrapocket devices which are inserted at diseased sites. Intrapocket drug delivery system was designed which contain Doxycycline Hyclate an antibacterial agent. The formulations were so developed with an aim to reduce the dose of a drug, to target the drug to the specific site and to maintain dosage at its absorption site for an extended period of time thereby improves the patient compliance. The study was aim towards by formulating the periodontal in situ gels by temperature induced gelation technique with the utilization of polymer Pluronic F127 which is synthetically prepared. The Pluronic F127 showed the sol-gel transition phenomenon in between 27-37ºC. In situ gels so prepared and characterized for its physico-chemical properties, pH, gelation properties, rheology, gel strength, mucoadhesion, drug content, in vitro & ex-vivo drug release rate, texture analysis and DSC. The formulation found to be solution at room temperature and forms gel after installation into periodontal pocket hence leads to increase in retention time and slowly releases the drug into pocket. The results of characterization of formulation were found to be satisfactory and hence significant bioavailability can be increased these in situ gelling systems would be definitely useful for improving therapeutic efficacy of doxycycline hyclate in periodontitis. Owing to these properties it can be used as an effective delivery system for the intrapocket route.
    Keywords: DH, Pluronic, Situ-Gel, Evaluation, In-vitro study
  • Hamideh Pakniat, Atyeh Bahman, Farideh Movahed *, Niloofar Mohammadi Pages 1563-1570
    Episiotomy is the most prevalent obstetrical procedure with the purpose of either widening vaginal outlet or helping the fetus to deliver as soon as possible with the most feto-maternal safety. The aim of this study is to find out the effects of topical phenytoin cream on wound repair in primiparous women. One-hundred-thirty primiparous mothers were referred to Kowsar Hospital in Qazvin province participated in this clinical trial. Sixty-five participants were assigned in each of intervention and control groups. The intervention group was treated with topical 1% Phenytoin cream and 10% povidone-iodine (betadine) solution and the control group received placebo and betadine solution.
    Wound irrigation with betadine was performed as the routine order in the hospital, three times daily and two centimeters of topical phenytoin or placebo cream, were applied to the wound twice daily. The rate of episiotomy repair was measured by REEDA index in the first 24 h, the fifth and the tenth puerperal day. Data analyses were done t-test and chi-square test and Mann-Whitney. In the first 24 h, it was 6.43 ± 2.15 in the intervention group versus 6.52 ± 5.09 in the control group with no significant difference. However on The 5th day, it appeared 4.56 ± 3.01 in the intervention group versus 6.54 ± 2.98 in the control group (p < 0.001), likewise it was 5.82 ± 2.83 in the control group on the tenth day (p < 0.001). Significant difference was detected both in the 5th and 10th postpartum days. The result of this trial suggested that 1% phenytoin cream speeds-up the wound healing process; therefore it could be applied for accelerating episiotomy repair.
    Keywords: Episiotomy, Phenytoin, Betadine, Primiparity
  • Saeed Abbasi, Shadi Farsaei *, Dorsa Ghasemi, Marjan Mansourian Pages 1571-1580
    Critically ill patients often suffer from disturbance of sleep-wake cycle and consequently delirium development, in intensive care units (ICU). In this study, we aimed to evaluate the effect of exogenous melatonin on delirium development and its related adverse sequelae in the subgroup of medical and surgical ICU patients. We performed a double-blind placebo-controlled randomized pilot study in adult patients admitted to the ICU. Recruited patients according to the considered inclusion criteria were randomized into treatment or placebo groups. Melatonin or placebo was administered in the first 24 h after admission, for 5 consecutive days. Incidence of delirium within 8 days of admission was reported as primary outcome in the different subgroups, and other pertinent clinical characteristics were evaluated as secondary outcomes. Out of the total of 172 patients assigned for the 2 study groups, 70 patients in placebo group and also 67 in melatonin group completed the study. We observed no therapeutic effect of melatonin on delirium prevention in ICU patients (percent of delirium in melatonin versus placebo group were 4.5% and 1.4% respectively). However, our findings indicated that melatonin might be more useful in preventing delirium development in medical ICU patients as compared to the surgical ICU patients. There were no intergroup differences in secondary outcomes with the follow-up ending on May 2016. Our findings suggested melatonin might be a potential option for prevention of delirium in medical ICU patients.
    Keywords: Melatonin, Delirium, Critical care, Clinical trial
  • Narges Pourghahreman *, Ali Rajabzadeh Ghatari, Asiye Moosivand Pages 1581-1592
    Agent based modeling and simulation consider the behavior of agents acting in a system. The agents' interactions result in changing the agent’s behavior, the whole agent based system, and its environment. In this study, the manufacturing, sale, and receiving orders behaviors pertinent to manufacturing and sale agents acting across a pharmaceutical supply chain of an Iranian manufacturing medicine (as a case) are simulated. The departments related to these two agents have some problems affecting the entire supply chain; the results are interpreted based on agile, lean, and green paradigms. During the research, three medicines were selected and the related data were gathered. Then, mathematical modeling and regression analysis (in some parts) were applied. Next, a computer model was composed on matrix library environment (MATLAB). Finally, four scenarios were simulated. According to the information resulted from simulating the first scenario, none of supply chains pertaining to each medicine is agile. Based on the findings of simulating the second scenario, decreasing waste leads the non-antibiotic medicine supply chain to move toward the lean and green paradigms more. According to the third scenario, although more order requests can be fulfilled by increasing production capacity, the supply chain will not become agile. The last scenario’s goal is checking the possibility of receiving 145000 units’ orders for the non-antibiotic medicine which should be prepared during next 70 days while the company confronts lack of raw material and the suppliers are domestic; based on the results, the order will be rejected due to lack of time.
    Keywords: Agent based simulation, Case study, Mathematical modeling, Regression analysis, Pharmaceutical industry, Iran
  • Hossein Safari, Mohammad Arab *, Arash Rashidian, Abbas Kebriaee, Zadeh, Hasan Abolghasem Gorji Pages 1593-1603
    Medication is known as the main and the most effective factor in improving public health. On the other hand, having a strong and effective pharmaceutical industry will, to a very large extent, guarantee people's health. Therefore, this study was prospected to review the different pharmaceutical industries around the world and propose a model for the context of Iran.
    This is a qualitative as well as a comparative study which was carried out in 2015. At the first stage, using the World Bank website, countries were divided into four groups of low-income, lower-middle-income, upper-middle-income, and high-income economies. Then, four countries of Afghanistan, India, Brazil, and Canada were chosen from these four groups, respectively. Secondly, data gathered from these countries were given to two 12-member expert panels. Finally, using the articles and the results of expert panel groups, useful and effective policies were extracted for the growth and development of Iran's pharmaceutical industry.
    Findings of the study indicated that the following seven items are the essential policies for the context of Iran: establishment of high academic centers as well as research institutes, using weak patent law, supporting research and development centers at universities and pharmaceutical companies, backing national pharmaceutical companies up, implementing generic rules, gradual economic liberalization, and membership in world trade organization. Since, pharmaceutical industry is an effective and inseparable part of every health system, proper and evidence-based policies should be taken into account in order to develop this industry and, ultimately, meet the public needs.
    Keywords: Pharmaceutical industry, Growth, development policies, Health, Qualitative study, Iran