Asadi, P.,
Taymouri, S.,
Khodarahmi, G.,
Jalali, H.,
Zaker, H.,
Sadeghi, H.,
Dinari, M. Polymers for Advanced Technologies (10427147)(4)pp. 1358-1366
Abbasi, M.,
Mahboubi-rabbani, M.,
Kashfi, K.,
Sadeghi, H. Journal of Biomolecular Structure and Dynamics (07391102)(23)pp. 14164-14178
Multiple lines of evidence indicate that the NF-κB signaling pathway plays a pivotal role in carcinogenesis; activation of NF-κB in cancer increases cell proliferation and suppresses apoptosis, both of which define tumor mass development. Inhibiting NF-κB leads to tumor suppression by blocking the IKK-α/β enzymes, thus inhibiting its translocation. Furthermore, protecting p65 from acetylation and phosphorylation inhibits NF-κB through its active site. Some small molecules are assumed to inhibit NF-κB and IκB function separately. This study took one of the previously reported NF-κB inhibitors (compound D4) as a promising lead and predicted some dual NF-κB and IκB inhibitors. We performed a virtual screening (VS) workflow on a library with 186,146 compounds with 75% similarity to compound D4 on both NF-κB and IκB proteins. A total of 186 compounds were extracted from three steps of VS 36 were common in both proteins. These compounds were subjected to the quantum polarized ligand docking to elect potent compounds with the highest binding affinity for NF-κB and IκB proteins. The MM-GBSA method calculates the lowest binding free energy for eight selected compounds. These analyses found three top-ranked compounds for each protein with suitable pharmacokinetics properties and higher in-silico inhibitory ability. In the last screening, compound CID_4969 was introduced to a molecular dynamics (MDs) simulation study as a common inhibitor for both proteins. The MDs confirmed the main interactions between the final elected compound and NF-κB/IκB proteins. Consequently, the presented computational approaches could be used for designing promising anti-cancer agents. Communicated by Ramaswamy H. Sarma. © 2023 Informa UK Limited, trading as Taylor & Francis Group.
Khorsandi, Z.,
Afshinpour, M.,
Molaei, F.,
Askandar, R.H.,
Keshavarzipour, F.,
Abbasi, M.,
Sadeghi, H. Journal of Biomolecular Structure and Dynamics (07391102)(17)pp. 7940-7948
In response to the current pandemic caused by the novel SARS-CoV-2, we design new compounds based on Lopinavir structure as an FDA-approved antiviral agent which is currently under more evaluation in clinical trials for COVID-19 patients. This is the first example of the preparation of Lopinavir isosteres from the main core of Lopinavir conducted to various heterocyclic fragments. It is proposed that main protease inhibitors play an important role in the cycle life of coronavirus. Thus, the protease inhibition effect of synthesized compounds was studied by molecular docking method. All of these 10 molecules, showing a good docking score compared. Molecular dynamics (MD) simulations also confirmed the stability of the best-designed compound in Mpro active site. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Ardestani, M.,
Khorsandi, Z.,
Keshavarzipour, F.,
Iravani, S.,
Sadeghi, H.,
Varma, R.S. Pharmaceutics (19994923)(10)
Heat shock proteins (Hsps) have garnered special attention in cancer therapy as molecular chaperones with regulatory/mediatory effects on folding, maintenance/stability, maturation, and conformation of proteins as well as their effects on prevention of protein aggregation. Hsp90 ensures the stability of various client proteins needed for the growth of cells or the survival of tumor cells; therefore, they are overexpressed in tumor cells and play key roles in carcinogenesis. Accordingly, Hsp90 inhibitors are recognized as attractive therapeutic agents for investigations pertaining to tumor suppression. Natural Hsp90 inhibitors comprising geldanamycin (GM), reclaimed analogs of GM including 17-AAG and DMAG, and radicicol, a natural macrocyclic antifungal, are among the first potent Hsp90 inhibitors. Herein, recently synthesized heterocyclic compounds recognized as potent Hsp90 inhibitors are reviewed along with the anticancer effects of heterocyclic compounds, comprising purine, pyrazole, triazine, quinolines, coumarin, and isoxazoles molecules. © 2022 by the authors.
Khorsandi, Z.,
Keshavarzipour, F.,
Varma, R.S.,
Hajipour, A.R.,
Sadeghi, H. Molecular Catalysis (24688231)
Herein, chitosan as an inexpensive, abundant, and biodegradable bio-material, produced from a key constituent of the exoskeletons of crustaceans, was used to generate the cobalt-based magnetic silica nanocomposite for the performance of the C-N cross-coupling reaction as the main step of the synthesis of Abemaciclib and Fedratinibs. Several derivatives of these recently FDA-approved anti-cancer drugs were synthesized for the first time by using Pd/Cu-free co-catalyzed under both, the conventional heating and microwave (MW) irradiation conditions. The potential anticancer activity of synthesized compounds was investigated by molecular docking study. © 2021
Hacettepe University Journal of the Faculty of Pharmacy (13000608)(4)pp. 228-237
Cancer is the second leading cause of death in the world. Due to toxicity and resistance to common therapies, the attempt to develop new anticancer agents has become a major challenge. Oxadiazole and thiadiazole are of interest building blocks used in drug design. Hybrids of thiadiazole-oxadiazole have been synthesized with significant cytotoxic effects. Considering importance of mentioned scaffolds some of the thiadiazole-oxadiazole derivatives were synthesized by three steps in this study. Firstly, thiol function of 2-amino-5-mercapto-1, 3, 4-thiadiazole was alkylated by benzyl chloride derivatives to give compounds (1a-c). The reaction of chloroacetyl chloride with amine group of compounds (1a–c) terminates to amide derivatives (2a-c). Definitive products were produced by treatment of corresponding amide derivatives with 5-(4-chlorophenyl)-1, 3, 4-oxadiazole-2-thiol. Synthesized compounds were evaluated by MTT assay against three cell lines. The final molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to assay the possible interactions. Final products showed range of cytotoxic activity of moderate to good against tested cell lines. Compound (3a) demonstrated a higher cytotoxic activity against MCF-7 (IC50: 26 µM) and Lncap (IC50: 37 µM) cell lines in comparison with other compounds. The highest docking score was-10.55 kcal/mol for compound 3a. © 2022, Hacettepe University, Faculty of Pharmacy. All rights reserved.
Iranian Journal Of Pharmaceutical Research (17350328)(4)pp. 125-136
The coronavirus disease-2019 (COVID-19) was first recognized in Wuhan, China, and quickly spread worldwide. Between all proposed research guidelines, inhibition of the main protease (Mpro) protein of the virus will be one of the main strategies for COVID-19 treatment. The present work was aimed to perform a computational study on FDA-approved drugs, similar to piperine scaffold, to find possible Mpro inhibitors. Firstly, virtual screening studies were performed on a library of FDA-approved drugs (43 medicinal compounds, similar to piperine scaffold). Among imported 43 drugs to virtual screening, 34 compounds were extracted. Four top-ranked drugs in terms of the highest interactions and the lowest binding energy were selected for the IFD study. Among these selections, lasofoxifene showed the lowest IFD score (-691.743 kcal mol-1). The stability of lasofoxifene in the COVID-19 Mpro protein active site was confirmed with 100 ns MD simulation. Lasofoxifene binding free energy was obtained-107.09 and-173.97 kcal mol-1, using Prime MM-GBSA and g_mmpbsa methods, respectively. The identified lasofoxifene by the presented computational approaches could be a suitable lead for inhibiting Mpro protein and COVID-19 treatment. © 2021, Briefland. All rights reserved.
Ramezani-aliakbari, M.,
Varshosaz, J.,
Sadeghi, H.,
Hassanzadeh, F.,
Rostami, M. Langmuir (15205827)(21)pp. 6475-6489
This study is aimed at developing a micellar carrier for an Anderson-type manganese polyoxomolybdate (TRIS-MnPOMo) to improve the potency and reduce the general toxicity. The biotin-targeted stearic acid-polyethylene glycol (SPB) polymeric conjugate was selected for the first time as a micelle-forming basis for the delivery of TRIS-MnPOMo to breast cancer cells. The cytotoxicity of TRIS-MnPOMo and its nanomicellar form (TRIS-MnPOMo@SPB) was evaluated against MCF-7, MDA-MB-231 (breast cancer cell lines), and HUVEC (normal cell line) in vitro using the MTT assay. The quantity of cellular uptake and apoptosis level were studied properly using standard methods. The hydrodynamic size, zeta potential, and polydispersity index of the prepared micelles were 140 nm,-15.6 mV, and 0.16, respectively. The critical micelle concentration was about 30 μg/mL, which supports the colloidal stability of the micellar dispersion. The entrapment efficiency was interestingly high (about 82%), and a pH-responsive release of TRIS-MnPOMo was successfully achieved. The micellar form showed better cytotoxicity than the free TRIS-MnPOMo on cancer cells without any significant heme and normal cell toxicity. Biotin-targeted nanomicelles internalized into the MDA-MB-231 cells interestingly better than nontargeted micelles and TRIS-MnPOMo, most probably via the endocytosis pathway. Furthermore, at the same concentration, micelles remarkably increased the level of induced apoptosis in MDA-MB-231 cells. In conclusion, TRIS-MnPOMo@SPB could profoundly improve potency, safety, and cellular uptake; these results are promising for further evaluations in vivo. © 2021 American Chemical Society.
Azimi, F.,
Ghasemi, J.B.,
Azizian, H.,
Najafi, M.,
Ali faramarzi, M.,
Saghaei, L.,
Sadeghi, H.,
Larijani, B.,
Hassanzadeh, F.,
Mahdavi, M. International Journal of Biological Macromolecules (01418130)pp. 1082-1095
A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC50 values in the range of 65.1–695.0 μM) even much more potent than standard drug acarbose (IC50 = 750.0 μM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC50 = 65.1 ± 0.3 μM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 μM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). © 2020
Azimi, F.,
Azizian, H.,
Najafi, M.,
Hassanzadeh, F.,
Sadeghi, H.,
Ghasemi, J.B.,
Ali faramarzi, M.,
Mojtabavi, S.,
Larijani, B.,
Saghaei, L. Bioorganic Chemistry (00452068)
In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme. © 2021
Ramezani-aliakbari, M.,
Soltanabadi, A.,
Sadeghi, H.,
Varshosaz, J.,
Yadollahi, B.,
Hassanzadeh, F.,
Rostami, M. Journal of Molecular Structure (00222860)1240
In this work, trimethylated gallic acid (Eudesmic acid, EU) was selected for the synthesis of an organo-conjugate (EU2POMo) from TRIS modified Anderson-type manganese polyoxomolybdate (POMo) for the first time. EU2POMo was synthesized through amide bonding between POMo and EU using carbodiimide coupling strategy. Some of the quantum chemical properties of POMo and EU2POMo beside the DFT and TD-DFT calculations were done using the Gaussian program. The cytotoxicity was studied on breast cancer cell lines (MCF-7 and MDA-MB-231) comparing the Human Umbilical Vein Endothelial Cell line (HUVEC) using the MTT method. The cellular uptake was determined using the ICP-MS method, and the apoptosis value was checked by the flow cytometry technique on the MDA-MB-231 cell line. The structure was approved by FTIR, NMR spectroscopy as well as elemental analysis. Quantum chemical calculations proposed better stability and lower chemical potential for EU2POMo, and internal energy and dipole moment were higher in the EU2POMo. Both POMo and EU2POMo showed reasonable anti-cancer effects on breast cancer cell lines (MCF-7 and MDA-MB-231), and the results were somewhat in favor of POMo. Interestingly, EU2POMo showed no significant cytotoxicity on the HUVEC and was safer than POMo. Cellular uptake (33.5% versus 29.2%) and apoptosis value (28% versus 15%) in the case of EU2POMo were slightly better than POMo. In conclusion, this study aimed to introduce a novel, potent and safe anti-cancer Anderson type polyoxometalate to cancer studies. Based on results, this conjugate has sufficient potential for further cancer chemotherapy assessments, specifically breast cancer. © 2021 Elsevier B.V.
Abbasi, M.,
Amanlou, M.,
Aghaei, M.,
Hassanzadeh, F.,
Sadeghi, H. Anti-Cancer Agents In Medicinal Chemistry (18715206)(18)pp. 2583-2591
Background: Heat shock protein90 (Hsp90) is overexpressed in tumor cells, thus the inhibition of the Hsp90 ATPase activity would be a meaningfully effective strategy in cancer therapy. Objective: The present work was aimed at four steps: designing new Hsp90 inhibitors as anti-cancer by a virtual screening study; synthesize designed compounds; biological evaluation of them and finally molecular dynamic (MD) simulations of best compounds. Methods: A virtual screening study was performed on a library (100 compounds) of the ZINC database with benzimidazole scaffold; then an extracted compound and two derivatives were synthesized. The anti-proliferative and ATPase inhibitory activities of these compounds were evaluated by MTT and ATPase inhibition assays, respectively. The western blot analysis was performed to the evaluation of the expression level of Hsp70 and Her2 proteins. Finally, 200 ns molecular dynamic simulation was carried out to confirm the stability of the strongest synthesized compound in Hsp90 active site. Results: ZINC00173501 compound with an aminobenzimidazole scaffold was chosen by the virtual screening study. ZINC00173501 compound and two of its derivatives were synthesized. ATPase inhibitory activity of three synthesized compounds shown that ZINC00173501 compound was the most potent inhibitor (IC50= 8.6 μM) with the anti-proliferative activity 14.41 μM, 19.07 μM and more than 100 μM against MCF-7, HeLa and HUVEC cell lines, respectively. The high level of Hsp70 expression and low level of Her2 expression confirmed ZINC00173501 as an Hsp90 inhibitor. Finally, molecular dynamics simulation showed that ZINC00173501 was stable in Hsp90 active site during 200 ns simulation. Conclusion: The biological evaluation results show that 2-aminobenzimidazole scaffold could be suggested as a lead for inhibition of Hsp90. © 2021 Bentham Science Publishers.
Hassanzadeh, F.,
Jafari e., E.,
Shojaei, F.,
Sadeghi, H. Research In Pharmaceutical Sciences (17355362)(6)pp. 634-642
Background and purpose: In the last few decades, nitrogen-rich heterocyclic compounds such as 1, 3, 4-thiadiazoles, 1, 2, 4-triazoles and 1, 3, 4-oxadiazoles have received considerable attention because of their notable biological properties, especially cytotoxic effects. The small molecules of mentioned azole derivatives revealed very intensive antitumor activity. In addition, phthalimide-thiadiazole and naphthalimide-triazole hybrid derivatives have shown remarkable cytotoxic effects. According to these observations, some of the hybrid derivatives containing the phthalimide-five-membered azoles were prepared in three steps in this research. Experimental approach: The thiol group of azoles was treated with ethyl chloroacetate which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. Subsequently, the corresponding acid hydrazides were utilized to prepare the final derivatives through the reaction with phthalic anhydride. Cytotoxic activity of final compounds was evaluated against MCF-7 and HeLa cell lines using MTT assay. Findings/Results: Compound 3d containing two phthalimide moieties in its structure showed a significant improvement in cytotoxic activity with an IC 50 value of 29 μM against HeLa cell line. Compounds 3a-3c showed less cytotoxic effects against both cell lines. Conclusion and implications: The combination of the thiadiazole nucleus with two phthalimide structures increased the cytotoxic activity against the HeLa cell line. This increase in cytotoxic activity is probably due to its being more lipophilic characteristic and interaction of this derivative with the biological targets of two directions. © 2021 Wolters Kluwer Medknow Publications. All rights reserved.
Fattahpour, S.,
Shamanian, M.,
Tavakoli, N.,
Fathi, M.,
Sadeghi, H.,
Sheykhi, S.R.,
Fesharaki, M.,
Fattahpour, S. International Journal of Biological Macromolecules (01418130)pp. 220-229
Hydrogel scaffolds have been frequently utilized due to their ability to absorb water and develop similar body cell conditions. Specific drug delivery to the tissues ensures less adverse side effects and more efficiency. In the present study, carboxymethyl chitosan (CMC)-methylcellulose (MC)-pluronic (P) and zinc chloride hydrogels containing meloxicam loaded into nanoparticles were developed and characterized. Nanoparticles were incorporated at 3.5, 4.5 and 5.5% (w/v). Hydrogels containing the same amounts of the meloxicam solution were also prepared. Gelation time, swelling and degradation of the hydrogels were investigated. Hydrogels were characterized by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, and rheological analysis. Meloxicam release, chondrocytes attachment and growth on the hydrogels were also studied. Gelation time, swelling and the degradation rate of the hydrogels were found to be decreased by nanoparticles and increased with the addition of the meloxicam solution. SEM images also showed three-dimensional networks. The ATR-FTIR bands were shifted to the lower wave numbers in the hydrogels containing nanoparticles and shifted to the upper ones in the hydrogels containing meloxicam solution. Storage (G′) and loss (G″) modulus were increased by the nanoparticles and reduced by the meloxicam solution. 100% of meloxicam was released from the hydrogels containing the meloxicam solution within 20 days, but it was released slowly from the hydrogels containing nanoparticles in 37days. Chondrocytes metabolic activity was increased on the 6th and 10th days for all hydrogels. Hydrogel containing nanoparticles showed good biocompatibility, bioadhesion, cell growth and expansion. The hydrogel could be, therefore, suitable as a new composite biomaterial for the regeneration of articular cartilage and meloxicam delivery to control the pain and inflammation in osteoarthritis. © 2020 Elsevier B.V.
Hajhashemi, V.,
Ghanadian, M.,
Palizaban, A.,
Mahnam, K.,
Eshaghi, H.,
Gheisari, B.,
Sadeghi, H. Prostaglandins and Other Lipid Mediators (10988823)
Background and aims: Euphorbia is a large genus of flowering plants. In Iran, some plants of this family have been used in the treatment of inflammatory disorders and also to relieve back pain. Euphorbia spinidens is a rich source of Cycloarta-23-ene-3beta,25-diol. Cycloartane structures are the starting material for the synthesis of plant steroids, and the aim of this study is to demonstrate COX inhibitory activity, molecular docking and in vivo approach of anti-inflammatory activity of cycloartane compound isolated from Euphorbia spinidens. Material and Methods: Plant material was extracted with acetone-chloroform and submitted to column chromatography for fractionation. Based on preliminary 1H-NMR spectra, cycloartane fraction was selected and purified by repeated recycle HPLC system. The structure and purity of compound were determined by 1H and 13C-NMR, HPTLC, and mass spectra. Inhibitory activities of the tested compounds on COX-1 and COX-2 were evaluated by a colorimetric COX (ovine) inhibitor screening method. Vero cells were used to assess the toxicity against the normal cells, and calculate the selectivity index. COX inhibitory activity results were evaluated and confirmed by molecular docking experiments. In the in vivo approach, analgesic activity was assessed by acetic acid-induced abdominal writhing and formalin tests. Croton oil-induced ear edema in mice and carrageenan-induced rat paw edema in rats were used to evaluate anti-inflammatory activity. Pain tests were carried out on male Swiss mice (25–35 g). Male Wistar rats (160–200 g) were used for the carrageenan test. Results: Cycloart-23-ene-3β,25-diol showedin vitro cyclooxygenase 1 and 2 inhibitory activities with more selectivity for COX-2. Molecular docking by predicting binding energies in COX protein receptors confirmed in vitro COX inhibitory results, and determined the best position for ligand in COX receptors along with its residue interactions in receptor pockets, which must be considered for designing of their inhibitors. In the in vivo studies, cycloartane inhibited significantly acetic acid-induced abdominal contractions and formalin-induced licking behavior at a dose of 200 mg/kg. The same dose reduced croton oil ear edema in mice and carrageenan-induced paw edema in rats. Conclusion: Therefore, according to these findings, cycloart-23-ene-3beta,25-diol showed promising analgesic and anti-inflammatory effects with low toxicity against normal cells and can be suggested as a template lead for designing anti-inflammatory compounds with good selectivity index, and potency for COX-2 inhibitory activity. © 2020 Elsevier Inc.
Najafipour, A.,
Mahdavian, A.R.,
Sadeghi, H.,
Fassihi, A. Polymer Bulletin (14362449)(6)pp. 3129-3142
Stimulus-responsive nanoparticles have been widely used for many applications in biotechnology and medicine. In this study, dual thermo- and pH-responsive P(NIPAM-co-DMAEMA)-g-PEG nanoparticles has been synthesized by emulsion polymerization. The obtained nanoparticles were characterized by TEM, DLS, UV–Vis, 1HNMR and GPC analytical methods. The P(NIPAM-co-DMAEMA)-g-PEG nanoparticles showed higher LCST than poly(N-isopropylacrylamide) nanoparticles at 45 °C. Swelling and drug release measurements were taken under different conditions. The released amount of methotrexate (MTX) at normal physiological pH and temperature was limited (24%), while an accumulation drug release of about 70% was obtained after 48 h at pH = 5.5 under hyperthermia conditions (45 °C). MTX release data from the prepared nanoparticles were applied to the various conventional kinetic equations. The model with the highest R2 was considered as the best one. MCF-7 cell line was used to evaluate the cytotoxicity of the unloaded and MTX-loaded nanoparticles alone or in combination with hyperthermia. The results showed that the MTX-loaded nanoparticles in combination with hyperthermia suppressed tumor growth efficiently. According to the results, it can be concluded that the prepared nanoparticles might be regarded as promising agents in controlled drug delivery and multimodal cancer therapy to achieve a more effective treatment. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
Iranian Journal Of Basic Medical Sciences (20083874)(7)pp. 945-953
Objective(s): Controversial results have been reported regarding the anti-tumor properties of extracellular vesicles derived from mesenchymal stem cells (MSCs). The present study was conducted to evaluate whether secretome derived from Human Wharton's jelly mesenchymal stem cells (hWJMSCs) may stimulate or inhibit breast cancer growth in vitro and in vivo. Materials and Methods: MTT assays was performed to determine anti-tumor effects of hWJMSCs-secretome on both MCF-7 and 4T1 tumor cells in vitro. Afterward, 4T1 breast tumors were established in different groups of Balb/C mice (12 mice/group). The tumor sizes were monitored in different treatment groups and at day 30 post-tumor inoculation (PTI), blood samples were obtained and 6 mice of each group were sacrificed for hematological and histopathological assays. The rest of the mice in each group (n=6) were left alive up to day 120 PTI to determine survival rate. Results: We found that hWJMSCs-secretome can inhibit growth of MCF-7 and 4T1 tumor cell lines in vitro. Moreover, intratumoral administration of hWJMSCs-secretome resulted in significant tumor growth inhibition and improvement of hematological indices in vivo and prolonged survival rate of tumor bearing mice. Conclusion: According to our findings, hWJMSCs-secretome could be considered a potent anti-tumor agent, however, further investigation should be done on other cancer models. © 2020 Mashhad University of Medical Sciences. All rights reserved.
Abbasi, M.,
Amanlou, M.,
Aghaei, M.,
Bakherad, M.,
Doosti, R.,
Sadeghi, H. Journal of Biomolecular Structure and Dynamics (07391102)(12)pp. 3462-3473
Inhibition of heat shock protein 90 (Hsp90) is known to be a significantly effective strategy in cancer therapy. Here, pyrazolopyranopyrimidine derivatives were characterized as new Hsp90 inhibitors. The molecules’ key structure (ZINC02819805) was determined by utilizing a pharmacophore model virtual screening workflow. Structural optimization was then carried out on compound ZINC02819805, pyrazolopyranopyrimidine derivatives were designed and six chosen derivatives were synthesized. The inhibition of Hsp90 ATPase activity of synthesized compounds revealed that para methylphenyl derivative of pyrazolopyranopyrimidine (HM3) was the most potent inhibitor (IC50 = 5.5 µM). The anti-proliferative activity of this compound was evaluated against a panel of cell lines including MCF-7, HeLa and HUVEC (IC50 = 1.28 µM, IC50 = 1.74 µM and IC50 = 61.48 µM respectively) by MTT method. The western blot analysis of treated MCF-7 cells with compound HM3 showed that the expression level of Hsp70 and Her2 proteins changed. The high level of Hsp70 expression and low level of Her2 expression suggest that compound HM3 exhibits inhibitory effect on Hsp90. Finally, the key interactions between HM3 and Hsp90 protein were studied by molecular dynamics simulation and showed that compound HM3 was stable in Hsp90 active cite during 200 ns simulation. AbbreviationsHsp90 Heat shock protein 90MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideATP adenosine triphosphateMD molecular dynamics simulationRMSD root-mean-square deviationRMSF root-mean-square fluctuationRg gyration radiusm-SABNPs boehmite nanoparticles-supported sulfamic acid Communicated by Ramaswamy H. Sarma. © 2019 Informa UK Limited, trading as Taylor & Francis Group.
Cell and Tissue Banking (15736814)(3)pp. 423-434
Nowadays, Mesenchymal stem cells (MSCs) have become one of the most attractive tools for treating tumors, due to their specific characteristics, the most prominent of which are tropism toward tumor. These cells will exert their effects through their secretion. In this study, our aim was to evaluate the anti-cancer effect of umbilical cord-derived mesenchymal cells (UCMSC) secretome, on MCF-7 tumor cells. MSCs were extracted from the umbilical cord of mothers, having normal delivery or cesarean section. After culture, the supernatants of these cells were collected and freeze-dried. The cytotoxic effect of freeze-dried secretome was examined at different concentrations on MCF-7 and the optimum concentrations (IC50) were calculated, using MTT assay. These results were confirmed by BrdU assay. The effect of induction of apoptosis of the MSC secretome on MCF-7 was determined, using annexin V/PI method by flow cytometry. The results of our study indicate that the isolation and growth time of UCMSCs of mothers who were naturally delivered was lower than those who received cesarean section. Co-culture studies showed that MSCs had cytotoxic effects on MCF-7 cells. The MSC secretome also showed cytotoxic effects on the MCF-7 cell line, this effect was mediated by induction of apoptosis, which was dose-dependent with an IC50 of 10 mg/mL. © 2019, Springer Nature B.V.
Bakherad, Z.,
Bakherad, Z.,
Safavi, M.,
Safavi, M.,
Fassihi, A.,
Fassihi, A.,
Sadeghi, H.,
Sadeghi, H.,
Bakherad, M.,
Bakherad, M.,
Rastegar, H.,
Rastegar, H.,
Ghasemi, J.B.,
Ghasemi, J.B.,
Sepehri, S.,
Sepehri, S.,
Saghaei, L.,
Saghaei, L.,
Mahdavi, M.,
Mahdavi, M. Research on Chemical Intermediates (09226168)(5)pp. 2827-2854
Based on the structural elements of bioactive 3-substituted indoles, a new series of indole–thiosemicarbazone hybrid derivatives were designed, synthesized, and well-characterized using different spectral techniques. The intended scaffolds were screened for their in vitro anti-proliferative activities against breast cancer (MCF-7), lung cancer (A-549), and liver cancer (Hep-G2) cell lines, as well as their anti-oxidant properties. Cytotoxicity studies revealed that compound 6n was the most potent, at least threefold more potent than the commercially available reference drug etoposide, against A-549. In addition, morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis confirmed induction of apoptosis in the A-549 cells by compound 6n. In order to validate the experimental results, molecular studies were performed to achieve the possible binding interactions of the most potent compound (6n) and colchicine with tubulin as well as ANP with ATPase domain of topoisomerase IIα active sites. Moreover, the radical scavenging potential of the final derivatives was found to be excellent with the range of 0.015–0.630 µM, comparable to the standard ascorbic acid (0.655 µM). © 2019, Springer Nature B.V.
Bakherad, Z.,
Bakherad, Z.,
Safavi, M.,
Safavi, M.,
Fassihi, A.,
Fassihi, A.,
Sadeghi, H.,
Sadeghi, H.,
Bakherad, M.,
Bakherad, M.,
Rastegar, H.,
Rastegar, H.,
Saeedi, M.,
Saeedi, M.,
Ghasemi, J.B.,
Ghasemi, J.B.,
Saghaei, L.,
Saghaei, L.,
Mahdavi, M.,
Mahdavi, M. Chemistry and Biodiversity (16121872)(4)
In this work, two novel series of indole-thiosemicarbazone derivatives were designed, synthesized, and evaluated for their cytotoxic activity against MCF-7, A-549, and Hep-G2 cell lines in comparison to etoposide and colchicine as the reference drugs. Generally, the synthesized compounds showed better cytotoxicity towards A-549 and Hep-G2 than MCF-7. Among them, (2E)-2-{[2-(4-chlorophenyl)-1H-indol-3-yl]methylidene}-N-(4-methoxyphenyl)hydrazinecarbothioamide (8l) was found to be the most potent compound against A-549 and Hep-G2, at least three times more potent than etoposide. The morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that compound 8l induced apoptosis in A-549 cells. Moreover, molecular docking methodology was exploited to elucidate the details of molecular interactions of the studied compounds with putative targets. © 2019 Wiley-VHCA AG, Zurich, Switzerland
Pharmaceutical Chemistry Journal (15739031)(5)pp. 388-391
According to the literature, iron chelators have been used to inhibit tumor cell proliferation. Hydroxypyridinones, due to easy derivatization and high affinity for iron, have been suggested as an attractive target for the development of iron scavenging ligands. N-arylhydroxypyridinone derivatives as iron chelators have been previously designed and synthesized, and the present study is performed in order to evaluate the antitumor efficacy of these compounds,. Four derivatives of hydroxypyridinone were tested against HCT116 and SW480 colon cancer cell lines for 48 h using MTT assay. One compound (3-hydroxy-2-methyl-1-phenylpyridin-4(1H)-one, PMPO) showed the maximum cytotoxic activity on both HCT116 and SW480 cancer cells with IC50 = 243 and 180 μmol, respectively, for 48 h treatment. The obtained results demonstrated that various concentrations of test compounds exhibited significant reduction of the cell viability (P < 0.05) in a concentration dependent manner. Our findings indicate that the proposed hydroxypyridinone derivatives can be considered as a new option for the treatment of colon cancer. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
Azimi, F.,
Azimi, F.,
Ghasemi, J.B.,
Ghasemi, J.B.,
Saghaei, L.,
Saghaei, L.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Mahdavi, M.,
Mahdavi, M.,
Sadeghi, H.,
Sadeghi, H.,
Scotti, M.T.,
Scotti, M.T.,
Scotti, L.,
Scotti, L. Current Topics In Medicinal Chemistry (15680266)(13)pp. 1092-1120
Background: Tubulin polymerization inhibitors interfere with microtubule assembly and their functions lead to mitotic arrest, therefore they are attractive target for design and development of novel anticancer compounds. Objective: The proposed novel and effective structures following the use of three-dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly demonstrate the high efficiency of this method in modern drug discovery. Methods: Combined computational approach was applied to extract the essential 2D and 3D features requirements for higher activity as well as identify new anti-tubulin agents. Results: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943 (RMSD=1.019) and excellent predictive power in the training set compounds. Generated model AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features were in good agreement with the vital interactions in the active site. Total prediction accuracy (0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set) and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model. Conclusion: Developed computational platform provided a better understanding of requirement features for colchicine site inhibitors and we believe the results of this study might be useful for the rational design and optimization of new inhibitors. © 2019 Bentham Science Publishers.
Mirabdollahi, M.,
Mirabdollahi, M.,
Javanmard, S.H.,
Javanmard, S.H.,
Sadeghi, H.,
Sadeghi, H. Advanced Pharmaceutical Bulletin (22517308)(4)pp. 649-654
Purpose: Several attempts have been made to identify the mechanisms by which mesenchymal stem cells (MSCs)-derived secretome exert anti-tumor or tumorigenic effects, but still further investigations are needed to explore this subject. Thus, in this study we want to examine the expression of different cytokines in secretome of hWJ-MSCs and their effects on cytokine expression profile of the MCF-7 tumor cells. Methods: The hWJ-MSCs were isolated and characterized according to the International Society for Cellular Therapy criteria. Then, secretome of hWJ-MSCs was collected and freeze-dried, and 20 mg/mL of the freeze-dried secretome was used to treat MCF-7 cancer cells for 48 hours. Afterwards, the expression levels of 12 cytokines including IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, TNFα, IFNγ and GM-CSF in secretome of hWJ-MSCs alone as well as in supernatant of tumor cells before and after treatment with hWJ-MSCs secretome were evaluated. Results: Our results indicate that MCF-7 cells express significant amount of IL-6 and IL-8. Moreover, significant amounts of IL-1a, IL-1b, IL-8, IL-6 and GM-CSF were detected in secretome of hWJ-MSCs. Furthermore, IL-1a, IL-2 and IL-4 were expressed significantly by MCF-7 cells after their treatment with hWJ-MSCs-derived secretome. Conclusion: According to our findings, the hWJ-MSCs derived secretome contains different cytokines which can exert either anti-tumor or tumorigenic effects. © 2019 The Author (s).
Bakherad, Z.,
Mohammadi-khanaposhtani, M.,
Sadeghi, H.,
Rezaei, S.,
Fassihi, A.,
Bakherad, M.,
Rastegar, H.,
Biglar, M.,
Saghaei, L.,
Larijani, B. Journal of Molecular Structure (00222860)pp. 192-200
A new series of thiosemicarbazide-1,2,3-triazole hybrids 10a-o has been synthesized, characterized by 1H NMR, 13C NMR, and screened for their in vitro α-glucosidase inhibitory activity. All of the synthesized compounds displayed excellent α-glucosidase inhibitory activity with IC50 values in the range of 75.0 ± 0.5 to 253.0 ± 0.5 μM, as compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). Among the synthesized compounds, compound 10h (IC50 = 75.0 ± 0.5)with 4-methoxy group at phenyl part of thiosemicarbazide moiety and 2,6-dichloro substituents at benzyl moiety was found to be the most potent compound. Kinetic analysis revealed that compound 10h is a competitive inhibitor for α-glucosidase. Docking study of compound 10h in the active site of α-glucosidase showed that this compound interacted with residues His239, His279, Glu304, Gly306, and Arg312. © 2019 Elsevier B.V.
Jahanian-najafabadi, A.,
Mirian, M.,
Rohani, F.,
Karami, K.,
Kharat, M.H.,
Sadeghi, H. Iranian Journal Of Pharmaceutical Research (17350328)(3)pp. 1323-1331
Today, development of resistance to anticancer drugs (including cisplatin) is noticed as a major problem. Recently several studies demonstrated that palladium complexes showed remarkable cytotoxic effects against K562 cell line and could be used efficiently for treatment of many human cancers including leukemia. Hereof, K562 cells were made resistant to cisplatin using increasing concentration of cisplatin up to 4.5 mM and then cytotoxic effect of synthesized palladium complex was evaluated on this sub-line using MTT assay. Annexin V/ PI staining using flow cytometry and scanning electron microscopy (SEM) were performed to find out the mechanism of the observed cytotoxicity. Results indicated that tested compounds had a noticeable cytotoxic effect on K562 cells 80 times more than cisplatin. Palladium complex also showed significant cytotoxicity on resistant K562 sub-line. Flow cytometry and SEM results revealed that these compounds exert their cytotoxic effect via apoptosis and it could be concluded that the novel synthesized palladium complex might be a good candidate for replacing cisplatin in case of treatment of cisplatin resistant tumors. © 2019, Iranian Journal of Pharmaceutical Research. All rights reserved.
Bakherad, Z.,
Safavi, M.,
Sepehri, S.,
Fassihi, A.,
Sadeghi, H.,
Bakherad, M.,
Rastegar, H.,
Larijani, B.,
Saghaei, L.,
Mahdavi, M. Research on Chemical Intermediates (09226168)(10)pp. 5261-5290
A series of novel imidazopyridine derivatives of indole has been synthesized. All the synthesized derivatives were evaluated for their antiproliferative activity against A-549, T-47D, Hep-G2 and MCF-7 human cancer cell lines. The results demonstrated that some of these derivatives exhibited moderate to excellent cytotoxic activities. Compounds 7a having a cyclohexyl ring substituted to the second amine of imidazopyridyl moiety and phenyl ring of the C-2 indole ring and 7f with a para-methylphenyl ring at the same position exhibited the highest activity against the A-594 cell line with IC50 of 11.48 μM and 10.66 μM, respectively. The results indicate that compounds 7a and 7f are more cytotoxic towards cancer cell lines compared with etoposide in vitro. In addition, compounds, 7d and 7j showed the most potent activity against Hep-G2, equal to etoposide as the standard drug. Also, most of the compounds were inactive against the T-47D and MCF-7 cell lines. The morphological analysis by the acridine orange/ethidium bromide double-staining test and flow cytometry analysis indicated that compounds 7a and 7f induced apoptosis in A-549 cells. Furthermore, in silico and in vitro results of the synthesized compounds showed good correlation with each other. Molecular docking results of the compounds of the 7a–k series with the cyclohexyl ring substituted to the second amine of the imidazopyridyl moiety compared with the 7l–t members with the t-butyl group at the same position confirmed the effect of the higher lipophilicity on hydrophobic interactions with the studied enzymes. Moreover, all the compounds showed higher affinity to tubulin than topoisomerase IIα enzyme. © 2019, Springer Nature B.V.
Mohamad reza nazifi s., ,
Mohamad reza nazifi s., ,
Sadeghi, H.,
Sadeghi, H.,
Fassihi, A.,
Fassihi, A.,
Saghaei, L.,
Saghaei, L. Structural Chemistry (15729001)(1)pp. 175-184
High toxicity of anticancer drugs led to development of targeted drug delivery directly to the specific organs. Polyamine transport system (PTS) of mammalian cells is one of the targets for a cell-selective drug delivery of polyamine–drug conjugates into specific organs. Even without having a 3D structure for mammalian PTS, synthesis of polyamine derivatives and evaluation of their cytotoxic effects are potential practical approaches to find optimal polyamine moieties to be transported from the PTSs. Chinese hamster ovary (CHO) and its mutant cell line (CHO-MG) are two important cells for evaluation of polyamine transportation by polyamine transporters (PAT). If a polyamine conjugate ligand demonstrates a high IC50 ratio on CHO-MG/CHO cells, this indicates a high selectivity of such compound toward PAT. This study discussed the structural requirements (charge, linker, vector, cargo) of polyamine conjugates in order to be transported into the cells by the mean of PTS. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Nikooei, S.,
Nikooei, S.,
Jafari e., E.,
Jafari e., E.,
Vaseghi, G.,
Vaseghi, G. Research In Pharmaceutical Sciences (17355362)(2)pp. 130-137
Triazoles and quinazolinones are important heterocyclic structures with diverse biological properties including cytotoxic, antibacterial, antifungal and anticonvulsant activities. Due to valuable cytotoxic effects of both triazole and quinazoline derivatives, in this study a series of quinazolinone-triazole hybrids were synthesized in a multiple-step reaction procedure. 3-Amino-quinazolinone derivatives were treated with chloroacetyl chloride in the presence of dichloromethane/triethylamine to afford 2-chloro-N-(4-oxo-2-quinazolin3 (3H)-yl) acetamide derivatives. The reaction of resultants with 4-mehyl-4-H-1, 2, 4-triazole-3-thiol in dry acetone and potassium carbonate led to the formation of final products. Synthesized compounds were evaluated for their cytotoxic effects against MCF-7 and Hela cell lines using MTT colorimetric assay. Amongst tested compounds, 6a showed the highest cytotoxic activity against MCF7 cell line at all tested concentrations while compounds 6b and 6c indicated mild cytotoxic effects against Hela cell line at highest tested concentration reducing cell viability about 40%. The IC50 values of tested compounds revealed that the MCF-7 is more susceptible to the compound 6a. © 2019 Medknow Publications.All rights reserved.
Hassanzadeh, F.,
Sadeghi, H.,
Jafari e., E.,
Sharifzadeh, A.,
Dana, N. Research In Pharmaceutical Sciences (17355362)(5)pp. 408-413
1, 3, 4- Oxadiazoles and quinazolinones are privileged structures with extensive biological activities. On account of reported anticancer activity of them, in this study, a multi-step reaction procedure has been developed for the synthesis of some quinazolinone-1, 3, 4-oxadiazole derivatives. Reaction of the synthesized 3-amino-4(3H) quinazolinone derivatives with chloroacetyl chloride in the presence of dichloromethane/triethylamine yielded 2-chloro -N-(4-oxo-2-quinazolin3 (3H)-yl) acetamide derivatives as intermediate. Treatment of the resultants with 5- (4-chlorophenyl) 1, 3, 4-oxadiazole-2-thiol in dry acetone and potassium carbonate gave coupled derivatives of quinazolinone-1, 3, 4-oxadiazole. The cytotoxic effect of final compounds was tested against MCF-7 and HeLa cell lines using MTT assay. Compound 2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio) N-(4-oxo-2-propylquinazolin)3(4H)acatamide 6a exhibited remarkable cytotoxic activity at 10 and 100 μM against HeLa cell line. The alteration of substituents on C2 of quinazolinone ring revealed that the introduction of propyl moeity improved cytotoxic activity against HeLa cell line. © 2019 Medknow Publications. All rights reserved.
Biological Trace Element Research (15590720)(2)pp. 319-329
The purpose of this research was to optimize a new method for preconcentration and determination of trace iron concentrations in aqueous solutions. For this purpose, a newly synthesized ligand, 3-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl) benzoic acid (3-OH-3-MOPBA), was used in the dispersive liquid-liquid microextraction (DLLME) method coupled with UV–vis spectroscopy. The experiments considering input variables of extractant volume, disperser volume, salt concentration, and pH were designed with the aid of central composite design (CCD). The results were analyzed using response surface methodology (RSM). The limit of detection (LOD) was found to be 4.0 μg L−1 under the optimized conditions. A calibration curve with a good linearity (R2 = 0.9986) was obtained over the concentration range of 15–800 μg L−1. The relative standard deviations (RSD) were found to be around 2.1% (n = 7). The main advantages of the developed method are simple application, environment friendly, short time, and low cost which makes this method to be applied routinely for measuring iron in various water samples. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
Abbasi, M.,
Abbasi, M.,
Sadeghi, H.,
Sadeghi, H.,
Amanlou, M.,
Amanlou, M. Journal of Biomolecular Structure and Dynamics (07391102)(6)pp. 1463-1478
Heat shock protein 90(Hsp90), as a molecular chaperone, play a crucial role in folding and proper function of many proteins. Hsp90 inhibitors containing isoxazole scaffold are currently being used in the treatment of cancer as tumor suppressers. Here in the present studies, new compounds based on isoxazole scaffold were predicted using a combination of molecular modeling techniques including three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamic (MD) simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were also done. The steric and electrostatic contour map of CoMFA and CoMSIA were created. Hydrophobic, hydrogen bond donor and acceptor of CoMSIA model also were generated, and new compounds were predicted by CoMFA and CoMSIA contour maps. To investigate the binding modes of the predicted compounds in the active site of Hsp90, a molecular docking simulation was carried out. MD simulations were also conducted to evaluate the obtained results on the best predicted compound and the best reported Hsp90 inhibitors in the 3D-QSAR model. Findings indicate that the predicted ligands were stable in the active site of Hsp90. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
Borzoei, M.,
Borzoei, M.,
Zanjanchi, M.A.,
Zanjanchi, M.A.,
Sadeghi, H.,
Sadeghi, H.,
Saghaei, L.,
Saghaei, L. Food Chemistry (18737072)pp. 9-15
The aim of this study was to establish a new dispersive liquid-liquid microextraction (DLLME) technique for the determination of iron concentration in aqueous solutions and fruit juices based on the reaction between iron and 3-hydroxy-1-(3-hydroxyphenyl)-2-methylpyridin-4(1H)-one (3-OH-PMPO) as a chelating agent. A central composite design (CCD) was applied to optimize the effects of independent parameters (pH, volume of disperser solvent and extractant solvent and chelating agent concentration) on extraction efficiency. Under the optimized conditions, the analytical curve is linear in a concentration range of 10–750 μgL−1 with a detection limit of 5 μgL−1. The relative standard deviation (RSD) for ten repeated determinations of iron concentrations at 40 and 200 μgL−1 was calculated to be 4.2% and 1.2%, respectively. Relative recovery of iron in several water samples was investigated and the average was obtained in the range of 91–108%. © 2018 Elsevier Ltd
Emami, J.,
Emami, J.,
Maghzi, P.,
Maghzi, P.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Mirian, M.,
Mirian, M.,
Rostami, M.,
Rostami, M. Pharmaceutical Development and Technology (10837450)(1)pp. 41-54
To develop an effective therapeutic treatment, the potential of poly (lactic-co-glycolic acid)-polyethylene glycol-retinoic acid (PLGA-PEG-RA) polymeric micelles for targeted delivery of irinotecan to hepatocellular carcinoma (HepG2) and colorectal cancer cell lines (HT-29) was evaluated. PLGA-PEG-RA was synthesized by amide reaction of PLGA with NH2–PEG–NH2 and then PLGA-PEG-NH2 with RA and confirmed by FTIR and 1H NMR spectroscopy. Irinotecan-loaded nanomicelles were prepared using thin-film hydration method and the impact of various formulation variables on their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), and mean release time (MRT) were assessed using a Taguchi design. TEM was used to observe morphology of the nanomicelles and the CMC was determined by fluorescence spectroscopy. Adopted PLGA-PEG-RA nanomicelle exhibited PS of 160 ± 9.13 nm, PDI of 0.20 ± 0.05, ZP of −24.9 ± 4.03 mV, EE of 83.9 ± 3.61%, MRT of 3.28 ± 0.35 h, and CMC value of 25.7 μg/mL. Cytotoxicity of the targeted nanomicelles on HepG2 and HT-29 cell lines was significantly higher than that of non-targeted nanomicelles and the free drug. These results suggest that PLGA-PEG-RA nanomicelles could be an efficient delivery system of irinotecan for targeted therapy of colorectal cancer and hepatocellular carcinoma. © 2017 Informa UK Limited, trading as Taylor & Francis Group.
Maleknia, L.,
Maleknia, L.,
Dilamian, M.,
Dilamian, M.,
Pilehrood, M.,
Pilehrood, M.,
Sadeghi, H.,
Sadeghi, H.,
Hekmati, A.,
Hekmati, A. Research In Pharmaceutical Sciences (17355362)(3)pp. 273-282
In this paper, polyurethane (PU), chitosan (Cs)/polyethylene oxide (PEO), and core-shell PU/Cs nanofibers were produced at the optimal processing conditions using electrospinning technique. Several methods including SEM, TEM, FTIR, XRD, DSC, TGA and image analysis were utilized to characterize these nanofibrous structures. SEM images exhibited that the core-shell PU/Cs nanofibers were spun without any structural imperfections at the optimized processing conditions. TEM image confirmed the PU/Cs core-shell nanofibers were formed apparently. It that seems the inclusion of Cs/PEO to the shell, did not induce the significant variations in the crystallinity in the core-shell nanofibers. DSC analysis showed that the inclusion of Cs/PEO led to the glass temperature of the composition increased significantly compared to those of neat PU nanofibers. The thermal degradation of core-shell PU/Cs was similar to PU nanofibers degradation due to the higher PU concentration compared to other components. It was hypothesized that the core-shell PU/Cs nanofibers can be used as a potential platform for the bioactive scaffolds in tissue engineering. Further biological tests should be conducted to evaluate this platform as a three dimensional scaffold with the capabilities of releasing the bioactive molecules in a sustained manner. © 2018 Herpetologist's League Inc. All rights reserved.
Emami, J.,
Emami, J.,
Yousefian, H.,
Yousefian, H.,
Sadeghi, H.,
Sadeghi, H. Journal Of Pharmacy And Pharmaceutical Sciences (14821826)(1S)
In the present study, a transferrin-conjugated nanostructured lipid carrier (TF-NLCs) for brain delivery of artemisinin (ART) was developed. ART-loaded NLCs (ART-NLCs) were prepared using solvent evaporation method and the impact of various formulation or process variables on the responses were assessed using a Taguchi design. Optimized ART-NLC was then coupled with transferrin as targeting ligand and its in vitro cytotoxicity was investigated against U-87MG brain cancer cell line. As a result, the following values are suggested by the software to prepare the optimized formulation: 20 mg Compritol®, 0.25% Tween 80, 5 mg oleic acid, 2.5 mL dichloromethane and 4 min sonication. Mean particle size (PS), zeta potential (ZP), polydispersity index (PDI), entrapment efficiency (EE), mean release time (MRT) of adopted formulation were confirmed to be 145 ± 12.5 nm, 24.3 ± 1.5 mV, 0.513 ± 0.021, 82.3 ± 7.3 % and 24.0 ± 1.1 h, respectively. Following conjugation of optimized ART-NLCs with TF, PS and MRT were increased, while ZP, and EE were decreased significantly. TF-ART-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the TF-ART-NLCs could potentially be exploited as a delivery system for anticancer and antimalarial drug ART in brain tumors and malaria. © 2018, Canadian Society for Pharmaceutical Sciences. All rights reserved.
Varshosaz, J.,
Varshosaz, J.,
Sadeghi, H.,
Sadeghi, H.,
Asheghali, F.,
Asheghali, F. IET Nanobiotechnology (1751875X)(2)pp. 164-172
Chondroitin (Chn) sulphate composed of N-acetyl galactoseamine units was chosen to target doxorubicin (DOX) to asialoglycoprotein receptors (ASGPRs) overexpressed in HepG2 cells of hepatocellular carcinoma (HCC). Two different ways of targeting the drug to the receptors were compared with each other; (i) by polyelectrolyte complex formation of DOX and Chn (DC), (ii) by loading the drug in gelatin nanoparticles (NPs) and then coating them by Chn. The characteristics of DC complexes were determined by Fourier transform infrared spectroscopy, differential scanning calorimetry and CHN analysis. The complexes and Chn coated NPs were characterised for their particles size, zeta potential, drug loading and release efficiency. The morphology of NPs was studied by transmission electron microscopy. The cytotoxicity of DC complex and Chn coated NPs were compared on HepG2 cells by MTT assay. The results showed that the cytotoxicity of both Chn coated gelatin NPs and DC complexes were significantly increased in comparison with free DOX. However, the presence of Chn did not have significant effect on the cytotoxicity of DOX loaded NPs. It was concluded that polyelectrolyte complex of DC could successfully target the drug to the hepatic ASGPRs and may be a simple promising way for targeted drug delivery in HCC. © The Institution of Engineering and Technology 2016.
Momtazi-borojeni, A.,
Momtazi-borojeni, A.,
Sadeghi, H.,
Sadeghi, H.,
Rabbani, M.,
Rabbani, M.,
Ghannadi, A.,
Ghannadi, A.,
Abdollahi, E.,
Abdollahi, E. Research In Pharmaceutical Sciences (17355362)(3)pp. 257-264
The objective of the present study was to evaluate the cognitive enhancing of pineapple juice and ethanolic extract in scopolamine-induced cognitive deficit mice. The ethanolic extract of pineapple (Ananas comosus (L.) Merr.) was prepared by maceration method and its juice was obtained by a homogenizer. Object recognition task was used to evaluate the mice memory. Exploration time in the first and second trial was recorded. The differences in exploration time between a familiar and a novel object in the second trial were taken as a memory index. Animals were randomly assigned into 15 groups of 6 each including: control group (normal saline + vehicle), positive control group (scopolamine + rivastigmine), seven experimental groups (received scopolamine alone or scopolamine + ethanolic extract of pineapple in different doses), six other experimental groups were treated by ethanolic extract or juice of pineapple in different doses. Scopolamine (100 μL, 1 mg/kg, i.p.) and pineapple juice or extract (50, 75 and 100 mg/kg, i.p.) were administered 40 and 30 min before starting the second trial in the experimental groups. Object discrimination was impaired after scopolamine administration. Results showed that juice and ethanolic extract of pineapple significantly restored object recognition ability in mice treated with scopolamine. These finding suggested that pineapple had a protective role against scopolamine-induced amnesia, indicating its ability in management of cognitive disorders.
Emami, J.,
Emami, J.,
Rezazadeh, M.,
Rezazadeh, M.,
Sadeghi, H.,
Sadeghi, H.,
Khadivar, K.,
Khadivar, K. Pharmaceutical Development and Technology (10837450)(3)pp. 370-382
The treatment of brain cancer remains one of the most difficult challenges in oncology. The purpose of this study was to develop transferrin-conjugated nanostructured lipid carriers (Tf-NLCs) for brain delivery of paclitaxel (PTX). PTX-loaded NLCs (PTX-NLCs) were prepared using solvent evaporation method and the impact of various formulation variables were assessed using Box–Behnken design. Optimized PTX-NLC was coupled with transferrin as targeting ligand and in vitro cytotoxicity of it was investigated against U-87 brain cancer cell line. As a result, 14.1 mg of cholesterol, 18.5 mg of triolein, and 0.5% poloxamer were used to prepare the optimal formulation. Mean particle size (PS), zeta potential (ZP), entrapment efficiency (EE), drug loading (DL), mean release time (MRT) of adopted formulation were confirmed to be 205.4 ± 11 nm, 25.7 ± 6.22 mV, 91.8 ± 0.5%, 5.38 ± 0.03% and 29.3 h, respectively. Following conjugation of optimized PTX-NLCs with transferrin, coupling efficiency was 21.3 mg transferrin per mmol of stearylamine; PS and MRT were increased while ZP, EE and DL decreased non-significantly. Tf-PTX-NLCs showed higher cytotoxic activity compared to non-targeted NLCs and free drug. These results indicated that the Tf-PTX-NLCs could potentially be exploited as a delivery system in brain cancer cells. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
Shahsavari-alavijeh, S.,
Shahsavari-alavijeh, S.,
Sadeghi, H.,
Sadeghi, H.,
Jahanian-najafabadi, A.,
Jahanian-najafabadi, A.,
Mirian, M.,
Mirian, M. Journal Of Reports In Pharmaceutical Sciences (23225106)(2)pp. 115-122
Previous studies showed that palladacycle complexes with three phenyl phosphine ligands and piperidine or biphosphinic based palladacycle complexes were cytotoxic on K562, HT29, and Hela cell lines. In the present study, in order to evaluate the efficacy of the compound on cisplatin resistant cells, first we made HT-29 cells resistant to cisplatin, and then evaluated the potential cytotoxicity of the mentioned plladacylce complex on them. In addition, it was evaluated whether cytotoxic effect of the compound is mediated via apoptosis or necrosis death mechanisms. In this regard, Annexin V/PI by staining followed by flow cytometric analysis was performed. Results showed that palladacycle complexes were 45 times more cytotoxic than cisplatin (P<0.05) on the resistant HT-29 cells. Flow cytometry results also revealed that apoptosis induction was the major cell death mechanism of these compounds. Therefore, it could be concluded that these compounds might be effectively cytotoxic for cisplatin resistant cells. However, further in vitro and in vivo preclinical studies on evaluation of specific and non-specific cytotoxic characteristics of these complexes are necessary. © 2017 by Kermanshah University of Medical Sciences.
Mirian, M.,
Mirian, M.,
Khanahmad, H.,
Khanahmad, H.,
Darzi, L.,
Darzi, L.,
Salehi, M.,
Salehi, M.,
Sadeghi, H.,
Sadeghi, H. Research In Pharmaceutical Sciences (17355362)(2)pp. 88-98
Viral hepatitis, as an international public health concern, seriously affects communities and health system. In recent years, great strides have been taken for development of new potential tools against viral hepatitis. Among these efforts, a valuable strategy introduced new molecules called "aptamers". Aptamers as potential alternatives for antibodies could be directed against any protein in infected cells and any components of viral particles. In this review, we will focus on recent advances in the diagnosis and treatment of viral hepatitis based on aptamer technology. In recent years, various types of aptamers including RNA and DNA were introduced against viral hepatitis. Some of these aptamers can be utilized for early and precise diagnosis of hepatitis infections and other group selected as therapeutic tools against viral targets. Designing diagnostic and therapeutic platforms based on aptamer technology is a promising approach in viral infections. The obtained aptamers in the recent years showed obvious potential for use as diagnostic and therapeutic tools against viral hepatitis. Although some modifications to increase the biostability and half-life of aptamers are underway, it seems these molecules will be a favorable substitute for monoclonal antibody in near future.
Momtazi-borojeni, A.,
Momtazi-borojeni, A.,
Askari-khorasgani, O.,
Askari-khorasgani, O.,
Abdollahi, E.,
Abdollahi, E.,
Sadeghi, H.,
Sadeghi, H.,
Mortazaeinezhad, F.,
Mortazaeinezhad, F.,
Sahebkar, A.,
Sahebkar, A. JAMS Journal of Acupuncture and Meridian Studies (20938152)(3)pp. 180-186
Background Kelussia odoratissima Mozaff. (Apiaceae) is an edible, indigenous, and ethnomedicinal plant that grows only in Iran. Although antioxidant and anti-inflammatory properties of K. odoratissima have been reported, cytotoxic activity of this plant has not been investigated previously. Objective This study aims to evaluate the cytotoxicity of K. odoratissima leaf extract against a panel of human cancer cell lines. A secondary aim was to perform a phytochemical analysis of the plant's leaf oil. Methods To extract the plant oil, dried leaves were subjected to hydrodistillation using a Clevenger-type apparatus for up to 3 hours. For the phytochemical analysis, essential oil was subjected to gas chromatography/mass spectrometry. Plant extraction was performed by macerating leaf powder of K. odoratissima (50 g) in 70% methanol (500 mL) at room temperature (25–28°C) for 24 hours. To perform cytotoxicity assays, methanolic extract of K. odoratissima was tested against a panel of cell lines including MDA-MB468 (human breast cancer cell line), K562 (human leukemia cell line), SKOV3 (human ovarian cancer cell line), Y79 (human eye cancer cell line), A549 (lung cancer cell line), and HEK 293 (normal human embryonic kidney cell line). Results Gas chromatography/mass spectrometry analysis revealed that sesquiterpens are dominant volatile components of the plant, followed by phthalides comprising 3-butyldine phthalide and 3-n-butyl phthalide, the latter compound being the major component of the leaf oil (25.1%). The leaf extract showed selective and dose-dependent cytotoxicity against MDA-MB468, K562, SKOV3, Y79, and A549 cancer cell lines with IC50 values (concentration that inhibits cell growth by 50%) of 85 μg/mL, 70 μg/mL, 120 μg/mL, 82 μg/mL, and145 μg/mL, respectively. Conclusions The present results suggest a direct cytotoxic activity of K. odoratissima leaf extract against human cancer cell lines. This activity of K. odoratissima may find application in combination with traditional herbal medicines to develop a new anticancer pharmacopuncture therapy. © 2017
Abbasi, M.,
Abbasi, M.,
Sadeghi, H.,
Sadeghi, H.,
Amanlou, M.,
Amanlou, M. Daru Journal Of Pharmaceutical Sciences (15608115)(1)
Background: Heat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy. Methods: In the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models' validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein. Results: The made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound. Conclusion: The QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites. © 2017 The Author(s).
Safari, M.,
Safari, M.,
Kamari, Y.,
Kamari, Y.,
Ghiaci, M.,
Ghiaci, M.,
Sadeghi, H.,
Sadeghi, H.,
Mirian, M.,
Mirian, M. Drug Development and Industrial Pharmacy (03639045)(5)pp. 862-870
In this work, a series of composites of insulin (Ins)/zirconium phosphate (ZrP) were synthesized by intercalation method, then, these composites were coated with TiO2 by sol-gel method to prepare Ins/ZrP@TiO2 hybrid composites and the drug release of the composites was investigated by using UV-Vis spectroscopy. Ins/ZrP (10, 30, 60 wt%) composites were prepared by intercalation of insulin into the ZrP layers in water. Then Ins/ZrP composites were coated with different amounts of TiO2 (30, 50, 100 wt %) by using titanium tetra n-butoxide, as precursor. Formation of intercalated Ins/ZrP and Ins/ZrP@TiO2 hybrid composites was characterized by FT-IR, FE-SEM, BET and XRD analysis. Zeta potential of the optimized Ins/ZrP@TiO2 hybrid composite was determined −27.2 mV. Cytotoxic effects of the optimized Ins/ZrP@TiO2 hybrid composite against HeLa and Hek293T cell lines were evaluated using MTT assay and the results showed that designed drug delivery system was not toxic in biological environment. Compared to the Ins/ZrP composites, incorporation of TiO2 coating enhanced the drug entrapment considerably, and reduced the drug release. The Ins/ZrP composites without TiO2 coating released the whole drug after 30 min in pH 7.4 (phosphate buffer solution) while the TiO2-coated composites released the entrapped drug after 20 h. In addition to increasing the shelf life of hormone, this nanoencapsulation and nanocoating method can convert the insulin utilization from injection to oral and present a painless and more comfortable treatment for diabetics. © 2016 Informa UK Limited, trading as Taylor & Francis Group.
Varshosaz, J.,
Varshosaz, J.,
Khabbazian, E.,
Khabbazian, E.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Rostami, M.,
Rostami, M.,
Taymouri, S.,
Taymouri, S. IET Nanobiotechnology (1751875X)(7)pp. 843-851
Biotinylated chitosan/poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) copolymer was synthesised by an amide reaction in two steps. Structural characterisation was performed using 1HNMR and Fourier transform infra-red (FTIR) spectra. Critical micelle concentration (CMC) of the copolymer was determined by pyrene as a fluorescent probe. Doxorubicin (DOX) was loaded in the micelles by the direct dissolution method. The effects of different variables including type of copolymer, copolymer concentration, stirring rate and stirring time were studied on the physicochemical properties of the micelles including: particle size, zeta potential, release efficiency and loading efficiency of nanoparticles using an irregular factorial design. The in vitro cytotoxicity of DOX-loaded biotin-targeted micelles was studied in HepG2 cells which over express biotin receptors by 3, 5-[dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay. The successful synthesis of the biotinylated copolymer of chitosan/PMVEMA was confirmed by FTIR and 1HNMR. The optimised micelles showed the CMC of 33 μg/ml, particle size of 247 ± 2 nm, zeta potential of +9.46 mV, polydispersity index of 0.22, drug-loading efficiency of 71% and release efficiency of 84.5 ± 1.6%. The synthesised copolymer was not cytotoxic. The cytotoxicity of DOX-loaded in targeted micelles on HepG2 cell line was about 2.2-fold compared with free drug. © The Institution of Engineering and Technology 2017.
Rezazadeh, M.,
Rezazadeh, M.,
Emami, J.,
Emami, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Rostami, M.,
Rostami, M.,
Mohammadkhani, H.,
Mohammadkhani, H. Current Drug Delivery (15672018)(8)pp. 1189-1200
Objective: Low water solubility, high systemic toxicity and insignificant cellular uptake have limited efficient clinical applications of the anti-tumor agent Paclitaxel (PTX). To overcome these limitations, a Novel Nanostructured Lipid Carrier (NLC) modified with Folic Acid (FA) and polyethylene glycol (PEG) was prepared by emulsion solvent evaporation method using cholesterol, α-tocopherol, lecithin and Poloxamer. A partial factorial design was applied to determine the appropriate levels of variables for optimized formulation. Formulations were evaluated for Particle Size (PS), Zeta Potential (ZP), Entrapment Efficiency (EE), and release efficiency (RE72%). FA- and PEGconjugated octadecylamine (FA-ODA and PEG-ODA) were synthesized and confirmed by FTIR and H-NMR and incorporated either alone or in combination with the optimized formulation whose properties were also evaluated. PTX-loaded optimized, targeted, pegylated, targeted/pegylated NLCs, pure PTX, and Anzatax® along with their respective controls were selected for toxicity evaluation on human breast cancer cell line, MCF-7, using MTT assay. Methods: PS, ZP, EE%, and RE72% of the optimized formulation were 154.6 nm, -16.5 mv, 79.1% and 49.3%, respectively. Incorporation of α-tocopherol as the liquid lipid allowed for more efficient drug encapsulation, PS reduction, enhanced stability and sustained-release of the drug. Cytotoxicity of PTX-loaded NLCs modified with both FA-ODA and PEG-ODA was significantly enhanced compared to that of free PTX and other drug-loaded modified NLCs. Results and Conclusion: The results suggest that preparation of NLCs with synthesized conjugates might be a promising candidate for drug delivery of PTX to the cancerous cells and has a great potential as a carrier for tumor targeting in breast cancer. © 2017 Bentham Science Publishers.
Sadeghi, H.,
Sadeghi, H.,
Seidaiy, S.S.,
Seidaiy, S.S.,
Rezvani, M.R.,
Rezvani, M.R. Human Geographies (18436587)(2)pp. 213-229
Aiming to explain the socio-economic effects of reservoir dams on the sustainable development of rural areas, this paper, as a case study on Iran focuses on Karun 3 Dam, the largest arch dam of the Middle East. 350 rural household were studied through survey data collection. The households settled in 38 villages where questionnaires were distributed accordingly. The results showed that the dam has been effective in improving agriculture and boosting local economic indices, but has not affected on tourism, industrial development and employment. Also, it seems that the indices of quality of life, welfare and social capital correlate with inefficient dam performance in rural sustainable economic development. Evaluation of the effective social and economic variables of the dam in relation to the sustainable development of rural settlements shows that there is a duality in management based sustainable development that has prevented the positive effects of the dam on villages. © 2017 Human Geographies; The authors.
Pilehrood, M.,
Pilehrood, M.,
Atashi, A.,
Atashi, A.,
Sadeghi, H.,
Sadeghi, H.,
Nousiainen, P.,
Nousiainen, P.,
Harlin, A.,
Harlin, A. Journal of Nanoscience and Nanotechnology (discontinued) (15334899)(9)pp. 9000-9007
The introduction of a three dimensional scaffold providing the closest analogies to extracellular matrix (ECM) is currently a key strategy for tackling many challenges in tissue repair. Here, we present a new hybrid scaffold constructed by coating electrospun chitosan/polyethylene oxide (PEO) nanofibers on commercial BioTek polystyrene (PS) scaffold obtained from Sigma Aldrich. The viability and proliferation rate of mesenchymal stem cells (MSCs) seeded on micro-nano structured hybrid scaffold (MNHS) and commercial PS scaffolds were analyzed by MTT assay. The results of the MTT assay revealed a higher degree of viability and proliferation rate in MSCs seeded on MNHS compared with the commercial PS scaffold. DAPI images also confirmed the higher degree of attachment and viability of MSCs seeded on MNHS. Moreover, MSCs on both scaffolds differentiated to osteoblasts and adipocytes cells, as reflected by the images obtained from Alizarin Red and Oil Red-O staining. Alkaline phosphatase activity (ALP) and calcium content assays revealed that the MNHS has a higher potential for osteogenic differentiation than the commercial scaffold. To quantify the osteoblast and adipocyte gene expression, quantitative RT-PCR was carried out for MNHS, commercial scaffold and Tissue culture polystyrene (TCPS). It was found that MNHS can express a higher level of Runt-related transcription factor 2 (Runx2), osteonectin and osteocalcin in osteogenic differentiation as well as increased expression of PPARγ and UCP-1 in adipogenic differentiation. The enhancement of the attachment, viability and proliferation as well as bi-lineage differentiation may result from the biochemical and structural analogies of MNHS to native ECM. Furthermore, it was observed that biocompatible MNHS scaffold can potentially be utilized as a suitable scaffold for bone and connective tissue engineering. Copyright © 2016 American Scientific Publishers. All rights reserved. Printed in the United States of America.
Daneshfaraz, R.,
Daneshfaraz, R.,
Sadeghi, H.,
Sadeghi, H.,
Joudi, A.R.,
Joudi, A.R. Advances and Applications in Fluid Mechanics (discontinued) (09734686)(4)pp. 851-866
Hydraulic jump is one of the most important phenomena in a rapidly varying flow. This phenomenon occurs in free surface flow and transforms the flow from supercritical into subcritical. The transformation causes the depth to increase within a short distance. In the present study, characteristics of a hydraulic jump in contractions and expansions with straight and curved walls were investigated for five Froude numbers in the range of 5.8-9.1. The values of depth and velocity were measured in different sections of the hydraulic jump that occurred in the transitions. The values of energy dissipation in the expansions with straight and curved walls averaged 24.95% and 21.23%, relatively. In the contractions, the energy dissipation averaged 15.93% and 12.49%. Also, the results showed that the Reynolds stresses in the contraction and the expansion increased and decreased relatively by increasing the longitude distance from the beginning of the jump. © 2016 Pushpa Publishing House, Allahabad, India.
Mirian, M.,
Mirian, M.,
Taghizadeh, R.,
Taghizadeh, R.,
Khanahmad, H.,
Khanahmad, H.,
Salehi, M.,
Salehi, M.,
Jahanian-najafabadi, A.,
Jahanian-najafabadi, A.,
Sadeghi, H.,
Sadeghi, H.,
Kouhpayeh, S.,
Kouhpayeh, S. Research In Pharmaceutical Sciences (17355362)(5)pp. 366-373
Hepatitis B virus (HBV) is considered as a global health concern and hepatitis B surface antigen (HBsAg) is the most immunogenic protein of HBV. The purpose of this study was to evaluate the expression of HBsAg on the cell surface of human embryonic kidney cell line (HEK293T). After transformation of expression vector pcDNA/HBsAg to E.coli TOP10F', plasmid was extracted and digested with BglII. Afterwards, the linearized vector was transfected to cells and treated with hygromycin B for 5 weeks to expand the resulted clonies. The permanent expression of HBsAg followed by flow cytometry uptill now about one year. Genomic DNA was extracted from transfected cells and the existence of HBsAg gene was assessed by PCR. Real-time RT-PCR was utilized to measure the expression at the RNA level and flow cytometery was carried out to assess protein expression. Insertion of HBsAg cDNA in HEK293T genome was confirmed by PCR. The results of real-time RT-PCR illustrated that each cell expresses 2275 copies of mRNA molecule. Flow cytometry showed that compared with negative control cells, 99.9% of transfected cells express HBsAg on their surface. In conclusion, stable expression of hepatitis B surface antigen on the membrane of HEK293T provides an accurate post-translational modification, proper structure, and native folding in contrast with purified protein from prokaryotic expression systems. Therefore, these exposing HBsAg cells are practical in therapeutic, pharmaceutical, and biological sets of research.
Rezazadeh, M.,
Rezazadeh, M.,
Emami, J.,
Emami, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Minaiyan, M.,
Minaiyan, M.,
Mostafavi, A.,
Mostafavi, A.,
Rostami, M.,
Rostami, M.,
Lavasanifar, A.,
Lavasanifar, A. Drug Delivery (10717544)(5)pp. 1707-1717
A water-insoluble anti-tumor agent, paclitaxel (PTX) was successfully incorporated into novel-targeted polymeric micelles based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (PTX/TS-CS-PEG-FA). The aim of the present study was to evaluate the pharmacokinetics, tissue distribution and efficacy of PTX/TS-CS-PEG-FA in comparison to Anzatax® in tumor bearing mice. The micellar formulation showed higher in vitro cytotoxicity against mice breast cancer cell line, 4T1, due to the folate receptor-mediated endocytosis. The IC50 value of PTX, a concentration at which 50% cells are killed, was 1.17 and 0.93 µM for Anzatax® and PTX/TS-CS-PEG-FA micelles, respectively. The in vivo anti-tumor efficacy of PTX/TS-CS-PEG-FA, as measured by reduction in tumor volume of 4T1 mouse breast cancer injected in Balb/c mice was significantly greater than that of Anzatax®. Pharmacokinetic study in tumor bearing mice revealed that the micellar formulation prolonged the systemic circulation time of PTX and the AUC of PTX/TS-CS-PEG-FA was obtained 0.83-fold lower than Anzatax®. Compared with Anzatax®, the Vd, T1/2ß and MRT of PTX/TS-CS-PEG-FA was increased by 2.76, 2.05 and 1.68-fold, respectively. As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Taken together, our evaluations show that PTX/TS-CS-PEG-FA micelle is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for intravenous administration of PTX. © 2014 Informa UK Limited, trading as Taylor & Francis Group.
Dormiani, K.,
Dormiani, K.,
Sadeghi, H.M.M.,
Sadeghi, H.M.M.,
Sadeghi, H.,
Sadeghi, H.,
Forouzanfar, M.,
Forouzanfar, M.,
Baharvand, H.,
Baharvand, H.,
Ghaedi, K.,
Ghaedi, K.,
Nasr-esfahani, M.H.,
Nasr-esfahani, M.H. Cell Journal (Yakhteh) (22285806)(4)pp. 565-581
Objective: Induced pluripotent stem cells are generated from somatic cells by direct reprogramming. These reprogrammed pluripotent cells have different applications in biomedical fields such as regenerative medicine. Although viral vectors are widely used for efficient reprogramming, they have limited applications in the clinic due to the risk for immunogenicity and insertional mutagenesis. Accordingly, we designed and developed a small, non-integrating plasmid named pLENSO/Zeo as a 2A-mediated polycistronic expression vector. Materials and Methods: In this experimental study, we developed a single plasmid which includes a single expression cassette containing open reading frames of human LIN28, NANOG, SOX2 and OCT4 along with an EGFP reporter gene. Each reprogramming factor is separated by an intervening sequence that encodes a 2A self-processing peptide. The reprogramming cassette is located downstream of a CMV promoter. The vector is easily propagated in the E. coli GT115 strain through a CpG-depleted vector backbone. We evaluated the stability of the constructed vector bioinformatically, and its ability to stoichiometric expression of the reprogramming factors using quantitative molecular methods analysis after transient transfection into HEK293 cells. Results: In the present study, we developed a nonviral episomal vector named pLENSO/Zeo. Our results demonstrated the general structural stability of the plasmid DNA. This relatively small vector showed concomitant, high-level expression of the four reprogramming factors with similar titers, which are considered as the critical parameters for efficient and consistent reprogramming. Conclusion: According to our experimental results, this stable extrachromosomal plasmid expresses reliable amounts of four reprogramming factors simultaneously. Consequently, these promising results encouraged us to evaluate the capability of pLENSO/Zeo as a simple and feasible tool for generation of induced pluripotent stem cells from primary cells in the future.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Khoraskani, F.R.,
Khoraskani, F.R.,
Mirian, M.,
Mirian, M.,
Behdadfar, B.,
Behdadfar, B. International Journal of Biological Macromolecules (01418130)pp. 1192-1205
The novel dual targeted nanoparticles loaded with doxorubicin (DOX) and magnetic nanoparticles (MNPs) were prepared for treatment of breast cancer. Nanoparticles were produced by a layer-by-layer technique and functionalized with a bioconjugate of chitosan-poly(methyl vinyl ether maleic acid)(PMVMA)-LHRH to target LHRH receptors. The successful production of chitosan-PMVMA copolymer and its conjugation to LHRH was confirmed by FTIR and 1HNMR spectroscopy. Capillary electrophoresis analysis showed 72.51% LHRH conjugation efficiency. Transmission electron microscopy and thermogravimetric analysis showed the entrapment of the MNPs in the core of the nanoparticles and vibrating sample magnetometery confirmed their paramagnetic properties. The iron content of nanoparticles determined by inductively coupled plasma optical emission spectrometry showed to be between 3.5–84%. Particle size, zeta potential, drug entrapment and release efficiency of the nanoparticles were 88.1–182.6 nm, 10–30 mV, 62.3–87.6% and 79.8–83.4%, respectively. No significant protein binding was seen by nanoparticles. The MTT assay showed in LHRH positive cells of MCF-7 the IC50 of the drug reduced to about 2 fold compared to the free drug. By saturation of LHRH receptors the viable MCF7 cells increased significantly after exposure with the targeted nanoparticles. Therefore, the cellular uptake of the nanoparticles might be done by active endocytosis through the LHRH receptors. © 2016 Elsevier B.V.
Soleimani, M.,
Soleimani, M.,
Mahnam, K.,
Mahnam, K.,
Sadeghi, H.M.M.,
Sadeghi, H.M.M.,
Sadeghi, H.,
Sadeghi, H.,
Jahanian-najafabadi, A.,
Jahanian-najafabadi, A. Research In Pharmaceutical Sciences (17355362)(3)pp. 187-199
p28 and NRC peptides are two anticancer peptides with various mechanisms have shown to be effective against breast cancer. Therefore, it seems that construction of a chimeric protein containing the two peptides might cause synergistic cytotoxic effects. However, since the two peptides bear opposite charges, production of a chimeric protein in which the two moieties do not intervene each other is difficult. In this study, our goal was to find a suitable peptide linker for the new chimeric protein in a manner that none of the peptides intervene the other's function. We selected some linkers with different characteristics and lengths and created a small library of the chimeric proteins harboring these linkers. Homology modeling and molecular dynamic simulation revealed that (PA)5 P and (EAAAK)3 linkers can separate the p28 and NRC peptides effectively. Thus, the chimeric protein linked with (PA)5 P or (EAAAK)3 linkers might show synergistic and stronger anticancer effects than the separate peptide moieties because they could exert their cytotoxic effects freely which is not influenced by the other part.
Rezazadeh, M.,
Rezazadeh, M.,
Emami, J.,
Emami, J.,
Mostafavi, A.,
Mostafavi, A.,
Rostami, M.,
Rostami, M.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Minaiyan, M.,
Minaiyan, M.,
Lavasanifar, A.,
Lavasanifar, A. Journal Of Pharmacy And Pharmaceutical Sciences (14821826)(5)pp. 647-660
A simple, rapid, and sensitive reversed-phase HPLC method was developed and validated for determination of paclitaxel (PTX) in plasma, various organs and tumor tissues of tumor-bearing mice. Tissue specimens of liver, kidneys, spleen, lungs, heart and tumor were separately homogenized in normal saline. Plasma or tissue homogenate (250 μl) containing PTX and internal standard (diazepam) were extracted by diethyl ether (6 ml). The separation was achieved on a μ-Bondapak C18 HPLC column using sodium acetate buffer solution (0.01 M)/acetonitrile (58/42 v/v) at pH 5 ± 0.1 and flow rate of 1.9 mL/min. The effluent was monitored at 227 nm and column temperature was adjusted at 58ºC. The internal standard and PTX were eluted at 4.2 and 5.2 min, respectively and no interfering peaks were observed. Calibration curves were linear over the concentration range of 0.25-10 μg/ml of PTX in plasma and 0.3-20 μg/ml PTX in tissue homogenates with acceptable precision and accuracy (<15%). The mean recoveries of the drug after plasma extraction was 87.4% ± 3.6 while those of tissue homogenates ranged from 62.1± 4.5 to 75.5± 3.2 depending on the type of tissues studied. PTX was stable in samples with no evidence of degradation during 3 freeze–thaw cycles and 3 months storage at −70 °C. The developed HPLC method was applied to quantify PTX in the mouse plasma and tissues after intravenous administration of 10 mg equivalent PTX/Kg dose of PTX-loaded tocopherol succinate-chitosan-polyethylene glycol-folate (TS-CS-PEG-FA) micelles formulation or Anzatax® (Cremophor® EL- based formulation of PTX) to female Balb/c mice. © 2015, Canadian Society for Pharmaceutical Sciences. All rights reserved.
Abbasi, M.,
Abbasi, M.,
Ramezani, F.,
Ramezani, F.,
Elyasi, M.,
Elyasi, M.,
Sadeghi, H.,
Sadeghi, H.,
Amanlou, M.,
Amanlou, M. Daru Journal Of Pharmaceutical Sciences (15608115)(1)
Background: MMP-2 enzyme is a kind of matrix metalloproteinases that digests the denatured collagens and gelatins. It is highly involved in the process of tumor invasion and has been considered as a promising target for cancer therapy. The structural requirements of an MMP-2 inhibitor are: (1) a functional group that binds the zinc ion, and (2) a functional group which interacts with the enzyme backbone and the side chains which undergo effective interactions with the enzyme subsites. Methods: In the present study, a QSAR model was generated to screen new inhibitors of MMP-2 based on L-hydroxy tyrosine scaffold. Descriptors generation were done by Hyperchem 8, DRAGON and Gaussian98W programs. SPSS and MATLAB programs have been used for multiple linear regression (MLR) and genetic algorithm partial least squares (GA-PLS) analyses and for theoretical validation. Applicability domain of the model was performed to screen new compounds. The binding site potential of all inhibitors was verified by structure-based docking according to their binding energy and then the best inhibitors were selected. Results: The best QSAR models in MLR and GA-PLS were reported, with the square correlation coefficient for leave-one-out cross-validation (Q2LOO) larger than 0.921 and 0.900 respectively. The created MLR and GA-PLS models indicated the importance of molecular size, degree of branching, flexibility, shape, three-dimensional coordination of different atoms in a molecule in inhibitory activities against MMP-2. The docking study indicated that lipophilic and hydrogen bonding interactions among the inhibitors and the receptor are involved in a ligand-receptor interaction. The oxygen of carbonyl and sulfonyl groups is important for hydrogen bonds of ligand with Leu82 and Ala83. R2 and R3 substituents play a main role in hydrogen bonding interactions. R1 is sited in the hydrophobic pocket. Methylene group can help a ligand to be fitted in the lipophilic pocket, so two methylene groups are better than one. The Phenyl group can create a π-π interaction with Phe86. Conclusions: The QSAR and docking analyses demonstrated to be helpful tools in the prediction of anti-cancer activities and a guide to the synthesis of new metalloproteinase inhibitors based on L-tyrosine scaffold. © 2015 Abbasi et al.; licensee BioMed Central.
Emami, J.,
Emami, J.,
Rezazadeh, M.,
Rezazadeh, M.,
Rostami, M.,
Rostami, M.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Mostafavi, A.,
Mostafavi, A.,
Minaiyan, M.,
Minaiyan, M.,
Lavasanifar, A.,
Lavasanifar, A. Drug Development and Industrial Pharmacy (03639045)(7)pp. 1137-1147
The aim of this study was to develop chitosan derivative polymeric micelles for co-delivery of paclitaxel (PTX) and α-tocopherol succinate (α-TS) to the cancer cells to improve the therapeutic efficiency and reduce side effects of PTX. In this study, amphiphilic tocopheryl succinate-grafted chitosan oligosaccharide was synthesized and physically loaded by PTX and α-TS with entrapment efficiency of 67.9% and 73.2%, respectively. Physical incorporation of α-TS into the micelles increased the hydrophobic interaction between PTX and the micelles core, which improved micelle stability, reduced the micelle size and also sustained the PTX release from the micelles. The mean particle size and zeta potential of αTS/PTX-loaded micelles were about 133 nm and 25.2 mV, respectively, and PTX release was completed during 6-9 d from the micelles. Furthermore, the cytotoxicity of α-TS/PTX-loaded micelles against human ovarian cancer cell line cancer cell in vitro was higher than that of PTX-loaded micelles and the free drug solution. Half maximal inhibitory concentration values of PTX after 48-h exposure of the cells to the PTX-loaded micelles modified and unmodified with α-TS were 110 and 188 ng/ml, respectively. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.
Mirian, M.,
Mirian, M.,
Behrooeian m., ,
Behrooeian m., ,
Ghanadian, M.,
Ghanadian, M.,
Dana, N.,
Dana, N.,
Sadeghi, H.,
Sadeghi, H. Research In Pharmaceutical Sciences (17355362)(3)pp. 233-240
Angiogenesis, formation of new blood vessels, play an important role in some diseases such as cancer and its metastasis. Using angiogenesis inhibitors, therefore, is one of the ways for cancer treatment and prevention of metastasis. Medicinal plants have been shown to play a major role in the treatment of a variety of cancers. In this direction, cytotoxic and angiogenic effects of oleo gum resin extracts of Rhus coriaria, Pistacia vera and Pistacia khinjuk from Anacardiaceae family were studied. For IC50 values, cytotoxic effects of the plant extracts were evaluated at different concentrations (1, 10, 20, 40, 80,100 μg/ml) against human umbilical vein endothelial normal cell (HUVEC) and Y79 cell lines using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In vitro tube formation on matrigel base was used to evaluate angiogenic effects in the presence of increasing concentrations (50, 100, 250 μg/ml) of the extracts. Vascular endothelium growth factor was used as angiogenesis stimulator. Gas chromatography results showed that α-pinene and β-pinene were the major essential oils constituents of all plant extracts. According to the MTT assay results, the R. coriaria resin extract was more cytotoxic than those of P. vera and P. khinjuk extracts (IC50, 9.1 ± 1.6 vs 9.8 ± 2.1 and 12.0 ± 1.9, respectively;P<0.05). Cytotoxic effects of all extracts against Y79 cell line was significantly higher than those of HUVEC used as a normal cell line (P<0.05). Tube formation assay also showed that extract of R. coriaria resin inhibited angiogenesis more significantly than other tested extracts (P<0.05). It could be concluded that R. coriaria resin extract possess cytotoxic effect and antiangiogenesis against cancer cells and as an anticancer natural product has a good potential for future studies.
Emami, J.,
Emami, J.,
Rezazadeh, M.,
Rezazadeh, M.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Mostafavi, A.,
Mostafavi, A.,
Minaiyan, M.,
Minaiyan, M.,
Rostami, M.,
Rostami, M.,
Davies, N.,
Davies, N. International Journal of Biological Macromolecules (01418130)pp. 29-40
In this study a novel receptor-targeted micelle delivery system based on tocopherol succinate-chitosan-polyethylene glycol-folic acid (TS-CS-PEG-FA) was synthesized and loaded with paclitaxel (PTX). Physicochemical properties of the micelles such as critical micelle concentration, micelle size, entrapment efficiency, stability, release properties, cellular uptake and in vitro cytotoxicity were investigated in detail. Furthermore, the pharmacokinetics and tissue distributions of PTX-loaded micelles were evaluated in Balb/c mice and compared with Anzatax® (PTX in Cremophor EL®). Particle sizes and zeta potentials of the micelles were in the range of 162.3-277.1nm and 18.5-28.3mV, respectively. The drug entrapment efficiencies of the micelles were within 53.6-82.5% (w/w). Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded TS-CS-PEG-FA micelles compared to free PTX. The Vd and t1/2β of PTX-loaded TS-CS-PEG-FA were increased by 2.76- and 2.05-fold, respectively, while the plasma AUC of the micelles was only 0.76-fold lower than those of Anzatax® As demonstrated by tissue distribution, the PTX/TS-CS-PEG-FA micelles increased accumulation of PTX in tumor tissue. Therefore, the targeted chitosan derived micelle offered a stable and effective delivery system for PTX cancer chemotherapy. © 2015 Elsevier B.V..
Hendijani, F.,
Hendijani, F.,
Javanmard, S.H.,
Javanmard, S.H.,
Rafiee l., L.,
Rafiee l., L.,
Sadeghi, H.,
Sadeghi, H. Research In Pharmaceutical Sciences (17355362)(2)pp. 134-142
Multipotent mesenchymal stem cells (MSCs) are recently found to alter the tumor condition. However their exact role in tumor development is not yet fully unraveled. MSCs were established to perform many of their actions through paracrine effect. Thus investigation of MSC secretome interaction with tumor cells may provide important information for scientists who are attempting to apply stem cells in the treatment of the disease. In this study we investigated the effect of human Wharton's jelly derived MSC (WJ-MSCs) secretome on proliferation, apoptotic potential of A549 lung cancer cells, and their response to the chemotherapeutic agent doxorubicin. WJ-MSCs were isolated from human umbilical cord and then characterized according to the International Society for Cellular Therapy criteria and WJ-MSC secretome was collected. BrdU cell proliferation assay and Annexin V-PI staining were used for the evaluation of cytotoxic and proapoptotic effects of WJ-MSC secretome on A549 cells. WJ-MSC secretome neither induced proliferation of lung cancer cells nor affected the apoptotic potential of the tumor cells. We also studied the combinatorial effect of WJ-MSC secretome and the anticancer drug doxorubicinwhich showed no induction of drug resistance when A549 cells was treated with combination of WJ-MSC secretome and doxorubicin. Although MSCs did not show antitumor properties, our in vitro results showed that MSC secretome was not tumorigenic and also did not make lung cancer cells resistant to doxorubicin. Thus MSC secretome could be considered safe for other medical purposes such as cardiovascular, neurodegenerative, and autoimmune diseases which may exist or occur in cancer patients.
Emami, J.,
Emami, J.,
Pourmashhadi, A.,
Pourmashhadi, A.,
Sadeghi, H.,
Sadeghi, H.,
Varshosaz, J.,
Varshosaz, J.,
Hamishehkar, H.,
Hamishehkar, H. Pharmaceutical Development and Technology (10837450)(7)pp. 791-800
The objective of the present study was to develop, evaluate and optimize a polymeric nanoparticle (NP) system containing Cxb for pulmonary delivery of Cxb in the treatment of lung cancer. NPs were prepared by the emulsion solvent diffusion and evaporation method using poly(D, Llactideglycolide)(PLGA). The size of NPs ranged from 153 to 192nm and was affected by PLGA content, surfactant concentration and organic phase volume. Zeta potential of NPs (-4.5 to -8.6 mV) was more affected by PLGA content and organic phase volume. PLGA content was also the most effective factor on the entrapment efficiency and release rate of Cxb from NPs. The optimum formulation which obtained with 5 mg Cxb, 25 mg PLGA, 0.5% surfactant, 2.5% organic volume and 15 000 rpm showed release of Cxb within 30 h. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass medium aerodynamic diameter, geometric standard deviation of 70.3%, 1.46% and 3.38%, respectively. Our results provide evidence for the potential of PLGA NPs for delivery of Cxb through inhalation as means to alleviate the cardiovascular risk of Cxb administration. © 2015 Informa Healthcare USA, Inc.
Hendijani, F.,
Hendijani, F.,
Javanmard, S.H.,
Javanmard, S.H.,
Sadeghi, H.,
Sadeghi, H. Tissue and Cell (00408166)(3)pp. 229-234
Mesenchymal stem cell (MSC) therapy moves toward clinic progressively. Recent evidences establish anticancer effect of mesenchymal stem cells. However multiple factors including type of cancer, MSC source, study design, and animal model play role in final outcome. Wharton's jelly - a newly approved source of MSCs - possesses superiorities to bone marrow as the conventional source; therefore investigation of its medical effects can produce beneficial results. In this survey we examined cytotoxic and proapoptotic effect of human Wharton's jelly MSC secretome on K562 human leukemia cells.MSCs were isolated from human Wharton's jelly of umbilical cord by explant culture method, then characterized according to ISCT criteria (morphology and plastic adherence, surface antigenicity and differentiation potential). MSC secretome was collected and its cytotoxic and proapoptotic effects on K562 cells in combination with doxorubicin were evaluated using BrdU cell proliferation assay and Annexin V-PI staining.Our results showed antiproliferative effect of mesenchymal stem cell secretome on K562 cancer cells, the effect was also added to cytotoxic effect of doxorubicin without induction of drug resistance. Human Wharton's jelly derived mesenchymal stem cells exerted cytotoxic effect on leukemia cells. Addition of that effect to anticancer effect of chemotherapeutic agents can leads to cytotoxic drug dose reduction and diminished side effects. © 2015 Elsevier Ltd.
Dormiani, K.,
Dormiani, K.,
Sadeghi, H.M.M.,
Sadeghi, H.M.M.,
Sadeghi, H.,
Sadeghi, H.,
Ghaedi, K.,
Ghaedi, K.,
Forouzanfar, M.,
Forouzanfar, M.,
Baharvand, H.,
Baharvand, H.,
Nasr-esfahani, M.H.,
Nasr-esfahani, M.H. Gene Therapy (09697128)(8)pp. 663-674
Targeted integration of a therapeutic gene at specific loci in safe genomic regions by a non-viral vector can restore the function of the damaged gene. This approach also minimizes the potential genotoxic effects of transferred DNA. In this study, we have developed a non-viral vector that functions according to site-specific recombination (SSR). The vector contained a bacterial backbone and puromycin resistance gene (pur r), a β-globin expressing cassette and an attB recombination site. We used phiC31 integrase to insert a copy of the vector into specific genomic locations of a human hematopoietic cell line. Site-specific integration of the vector with one or two copies in the transcriptionally active regions of the genome was confirmed. After genomic integration, we used Cre recombinase to remove the bacterial backbone and pur r. This removal was verified by negative selection and genomic PCR screening. Following deletion of these sequences, the stable β-chain expression was continued for several months in the absence of selective pressure. Consequently, this vector may potentially be a powerful tool for ex vivo correction of β-globinopathies such as β-thalassemia through successful genomic integration of a functional copy of the globin gene into the patient's target cells. © 2015 Macmillan Publishers Limited All rights reserved.
Fattahi, A.,
Fattahi, A.,
Asgarshamsi, M.,
Asgarshamsi, M.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Varshosaz, J.,
Varshosaz, J.,
Rostami, M.,
Rostami, M.,
Mirian, M.,
Mirian, M.,
Sadeghi, H.,
Sadeghi, H. Journal of Materials Science: Materials in Medicine (15734838)(2)
The novel amphiphilic derivatives of Methotrexate–chitosan oligosaccharide (MTX–CHO) with different molar feeding ratios of MTX were synthesized. The degree of MTX substitution ranged from 4.47 to 13.5 %. MTX–CHO copolymer formed micelles with an average size of 134.6 ± 14.52 to 236.6 ± 30.01 nm, and zeta potential of 20 ± 5 to 16.8 ± 7.74 mV. The critical micelle concentration was found to range from 125 to 0.56 mg/l. Analysis of micelles with different degree of substitutions (DSs) revealed that the size of micelles decreased by increasing DS while zeta potential was reduced. Release study indicated that drug content had effect on the release rate. With increasing amount of loaded drug in the micelle, release rate was decreased. Drug loaded and unloaded MTX–CHO micelles showed significant cytotoxicity on MDA-MB-231. Loaded micelle was more effective than unloaded one which indicated that conjugation could reduce efficacy of MTX. The viability of MDA-MB-231 in presence of drug loaded micelles was significantly decreased and cell viability at 1 µg/ml was 45.17 ± 9 % while the viability of unloaded micelles was 91.86 ± 9.88. These phenomena make MTX–CHO micelles as a good candidate for hydrophobic anticancer drug carrier. © 2015, Springer Science+Business Media New York.
Abbasi, M.,
Abbasi, M.,
Sadeghi, H.,
Sadeghi, H.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Amanlou, M.,
Amanlou, M. Journal of Molecular Graphics and Modelling (10933263)pp. 186-195
Abstract Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold. © 2015 Published by Elsevier Inc.
Akbari, V.,
Akbari, V.,
Abedi, D.,
Abedi, D.,
Pardakhty, A.,
Pardakhty, A.,
Sadeghi, H.,
Sadeghi, H. Avicenna Journal Of Medical Biotechnology (20084625)(2)pp. 69-75
Background: Development of new drug carriers would be an interesting approach if it allowed increased efficacy of antibiotics and a reduction in doses, thus reducing the risk of developing resistance. As with most drug carriers, niosomes have been used to improve the selective delivery and the therapeutic index of antimicrobial agents. Methods: In this study, different formulation of niosomes containing ciprofloxacin (CPFX), Span (20, 60 or 80), Tween (20, 60 or 80) and cholesterol were prepared by film hydration method. The release of the drug from different formulations was studied by using Franz diffusion cell. The niosomes were further characterized by optical microscopy and particle size analysis, and their antimicrobial activity was evaluated. Results: Size of the niosomes was significantly dependent on the amount of cholesterol and surfactant type and varied from 8.56 to 61.3 μm. The entrapment efficiency of CPFX niosomes prepared by remote loading was more than 74%. Niosomes composed of Span/Tween 60 provided a higher CPFX release rate than other formulations. The obtained results indicated a diffusion-based mechanism for drug leakage through bilayers. All formulations presented more antibacterial activity as compared to free CPFX solution. Conclusion: Niosomal CPFX appears to be a promising approach in the management of bacterial infections, especially ophthalmic ones, and should be further evaluated by in vivo experiments. © 2015, Avicenna Journal of Medical Biotechnology. All rights reserved.
Hendijani, F.,
Hendijani, F.,
Sadeghi, H.,
Sadeghi, H.,
Javanmard, S.H.,
Javanmard, S.H. Cell and Tissue Banking (15736814)(4)pp. 555-565
Adult stem cells are of particular importance for applications in regenerative medicine. Umbilical cord was established recently as an alternative source of mesenchymal stem cell (MSC) instead of bone marrow (BM) and is superior to BM and other adult tissues according to several MSC properties. Additionally, for the purpose of cell therapy in clinical scale, steps of cell isolation, expansion and culture required to be precisely adjusted in order to obtain the most cost-effective, least time-consuming, and least labor-intensive method. Therefore, in this study, we are going to compare two simple and cost-effective explant culture methods for isolation of MSCs from human umbilical cord. One of the methods isolates cells from entire cord and the other from Wharton’s jelly matrix. Isolated cells then cultured in simple medium without addition of any growth factor. MSCs obtained via both methods display proper and similar characteristics according to morphology, population doubling time, post-thaw survival, surface antigenicity and differentiation into adipocytes, osteocytes, and chondrocytes. MSCs can easily be obtained from the entire cord and Wharton’s jelly, and it seems that both tissues are appropriate sources of stem cells for potential use in regenerative medicine. However, from technical largescale preview, MSC isolation from entire cord piece is less labor-intensive and time-consuming than from Wharton’s jelly part of the cord. © 2014, Springer Science+Business Media Dordrecht.
Sadeghi, H.,
Sadeghi, H.,
Mohammadi, F.,
Mohammadi, F.,
Fazeli, H.,
Fazeli, H.,
Mirlohi, M.,
Mirlohi, M. Iranian Journal Of Basic Medical Sciences (20083874)(10)pp. 815-819
Objective(s): Several beneficial effects have been attributed to the probiotic lactic acid bacteria. It was determined that lactobacilli can exert antiproliferative effects on the various cancer cell lines including colon cancer. Effects of lactic acid bacteria on colon cancer may vary from strain to strain and there is a need to find the new probiotic strains with tumor suppressing properties through in vitro studies.
Karami, K.,
Karami, K.,
Hosseini-kharat, M.,
Hosseini-kharat, M.,
Sadeghi, H.,
Sadeghi, H.,
Lipkowski, J.,
Lipkowski, J.,
Mirian, M.,
Mirian, M. European Journal of Medicinal Chemistry (02235234)pp. 8-17
The reactions between [Pd2{(C,N)-C6H 4CH2NH(Et)}2(μ-X)2] (X = Cl or Br) and 1,2-bis(diphenylphosphino)ethane (dppe) in the 1:1 molar ratio resulted in the dppe-bridged Pd(II) complexes, [Pd2{(C,N)-C6H 4CH2NH(Et)}2(μ-dppe)(Cl)2] (1) and [Pd2{(C,N)-C6H4CH2NH(Et)} 2(μ-dppe)(Br)2] (2), respectively, which were characterized by elemental analyses, infrared (IR), 1H- and 31P{1H} NMR spectroscopy. The molecular structure of 1 was determined by single-crystal X-ray diffraction. In vitro cytotoxicity of 1, 2, dppe, PhCH2NH(Et) and cisplatin were carried out against four human tumor cell lines. The interactions of complexes towards DNA and protein are investigated. The results suggested that both complexes could interact with FS-DNA through the intercalation mode. Moreover, the reactivity towards BSA revealed that the microenvironment and the secondary structure of BSA were changed in the presence of Pd(II) complexes.© 2013 Elsevier Masson SAS. All rights reserved.
Pilehrood, M.,
Pilehrood, M.,
Dilamian, M.,
Dilamian, M.,
Mirian, M.,
Mirian, M.,
Sadeghi, H.,
Sadeghi, H.,
Maleknia, L.,
Maleknia, L.,
Nousiainen, P.,
Nousiainen, P.,
Harlin, A.,
Harlin, A. BioMed Research International (23146141)
3D nanofibrous chitosan-polyethylene oxide (PEO) scaffolds were fabricated by electrospinning at different processing parameters. The structural characteristics, such as pore size, overall porosity, pore interconnectivity, and scaffold percolative efficiency (SPE), were simulated by a robust image analysis. Mouse fibroblast cells (L929) were cultured in RPMI for 2 days in the presence of various samples of nanofibrous chitosan/PEO scaffolds. Cell attachments and corresponding mean viability were enhanced from 50% to 110% compared to that belonging to a control even at packed morphologies of scaffolds constituted from pores with nanoscale diameter. To elucidate the correlation between structural characteristics within the depth of the scaffolds' profile and cell viability, a comparative analysis was proposed. This analysis revealed that larger fiber diameters and pore sizes can enhance cell viability. On the contrary, increasing the other structural elements such as overall porosity and interconnectivity due to a simultaneous reduction in fiber diameter and pore size through the electrospinning process can reduce the viability of cells. In addition, it was found that manipulation of the processing parameters in electrospinning can compensate for the effects of packed morphologies of nanofibrous scaffolds and can thus potentially improve the infiltration and viability of cells. © 2014 Mohammad Kazemi Pilehrood et al.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Banitalebi m., ,
Banitalebi m., ,
Rostami, M.,
Rostami, M.,
Nayebsadrian m., ,
Nayebsadrian m., Colloid and Polymer Science (0303402X)(10)pp. 2647-2662
Folate-targeted cyclodextrin/retinoic acid (CD/RA) conjugate was synthesized using carbonyldiimidazole (CDI) and dimethylaminopyridine (DMAP). The structure of the produced macromolecule was studied by FTIR and 1HNMR. The developed macromolecule could self-aggregate to form micelles. Critical micelle concentration (CMC) of the macromolecule was determined by pyrene as a fluorescent probe. Doxorubicin (DOX)-loaded micelles were prepared by direct dissolution method. To optimize the effect of cyclodextrin type (α or β), the molar ratio of RA to CD and the drug content, a full factorial design was used and their effects on particle size, polydispersity index, zeta potential, loading efficiency (LE%), and release efficiency (RE24%) in 24 h were studied. Orientation of folate ligand on the surface of the micelles was studied by X-ray photoelectron spectroscopy (XPS) technique. The cytotoxicity of DOX-loaded micelles was studied on KG-1 cells which overexpressed folate receptor (FR) and FR-negative HepG2 cells using MTT assay. FTIR and 1HNMR spectra confirmed successful production of the micelles and XPS spectra showed surface orientation of folate. The best results obtained from β-cyclodextrin with molar ratio of 4 to RA and 15 % drug content. The optimized micelles showed the particle size of 103 ± 4 nm, zeta potential of -36 mV, polydispersity index of 0.28 ± 0.05, LE% of 100 %, and RE24% of 69.88 ± 1.6 %. The IC50of targeted micelles was half of non-targeted micelles and free DOX. © 2014 Springer-Verlag Berlin Heidelberg.
Varshosaz, J.,
Hassanzadeh, F.,
Sadeghi, H.,
Nayebsadrian m., ,
Banitalebi m., ,
Rostami, M. BioMed Research International (23146141)
Folate and retinoic acid grafted/dextran (FA-RA/DEX) copolymers with different molecular weight of DEX were synthesized using carbonyldiimidazole and dimethylaminopyridine for targeted delivery of doxorubicin (DOX) in acute myelogenous leukemia (AML). The copolymers structure was confirmed by 1H NMR and FTIR. Critical micelle concentration (CMC) of each copolymer was determined using pyrene as a fluorescent probe. DOX was loaded in micelles by the direct dissolution method. Physical properties of micelles, including particle size, zeta potential, drug loading efficiency, and drug release profiles, were examined. The orientation of the folate ligand on the surface of the micelles was studied by X-ray photoelectron spectroscopy (XPS) technique. The cytotoxicity of micelles loaded with DOX at different concentrations was studied in KG1 cells using MTT assay and their cellular uptake by flow cytometry technique. FTIR and 1H NMR spectra confirmed successful production of the targeted micelles and XPS spectra showed the surface orientation of folate. R15D10F7 copolymer produced micelles with particle size of 82.86 nm, polydispersity index of 0.3, zeta potential of -4.68 mV, drug loading efficiency of 96%, and release efficiency of 63%. DOX loaded in folate-targeted micelles of RA/DEX was more toxic than that in nontargeted micelles and free drug and seems promising in reducing drug resistance in AML. © 2014 J. Varshosaz et al.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Larian z., ,
Larian z., ,
Rostami, M.,
Rostami, M. Chemical Engineering Journal (13858947)pp. 133-146
Pluronic® F127 grafted poly (methyl vinyl ether-alt-maleic acid) copolymer was synthesized using dicyclohexylcarbodiimide and dimethylaminopyridine to prepare a suitable micellar carrier for delivery of doxorubicin (DOX) in breast cancer. The copolymer structure was confirmed by 1H NMR and FTIR. Critical micelle concentration (CMC) of the copolymer was determined by pyrene as a fluorescent probe. DOX was loaded in micelles by direct dissolution method, and the physical properties of micelles; including particle size, zeta potential, drug loading efficiency and drug release profiles were studied. The cytotoxicity of micelles loaded with DOX in different concentrations was studied in MCF-7 cells using MTT assay. FTIR and 1H NMR spectra confirmed successful production of the copolymeric micelles with CMC of 390μg/ml. Optimized micelles were obtained using 6mg of DOX per 24mg of copolymer, a temperature of 45.7°C, stirring time of 1h and stirring rate of 400RPM. This produced micelles with a particle size of 419.1±38.2nm, zeta potential of -13.3±1.2mV, an acceptable drug loading efficiency of 93.5±2.7% and the release efficiency of 29.0±3.1%. The release test at 4h showed a sustained release property. The drug release from copolymer was pH dependent and was faster in pH 5.5 compared to 7.4. The synthesized copolymer was not cytotoxic. Its micelles, when loaded with 0.21μM of DOX could kill about 48.9±1.7% of MCF-7 cells compared to free DOX; which killed 36.4±1.1% of these cells at the same concentration. This significant difference in cytotoxicity (p<0.05) seems promising in reducing drug resistance in breast cancer. © 2013 Elsevier B.V.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Firozian, F.,
Firozian, F. BioMed Research International (23146141)
Targeted drug delivery using folate receptors is one of the most interesting chemotherapeutic research areas over the past few years. A novel folate targeted copolymer was synthesized using dextran stearate coupled to folic acid. FT-IR and NMR spectroscopy were used to confirm successful conjugation. Micelles prepared using this copolymer were characterized for their particle size, zeta potential, critical micelle concentration (CMC), drug loading capacity, and release efficiency. Cytotoxicity and cellular uptake of the micelles were estimated using CT-26 colorectal carcinoma cell line. FT-IR and NMR spectroscopy confirmed production of folate grafted dextran stearate copolymer. Low CMC value indicates that the copolymers are suitable for preparation of stable micelles useful in parenteral dosage forms. Particle size and zeta potential of the targeted nanoparticles were 105.5 ± 2.0 nm and -21.2 mV, respectively. IC50 of etoposide loaded in folate grafted dextran stearate enhanced about 20-fold compared to the pure drug (0.49 ± 0.11 μg/mL versus 9.41 ± 0.52 μg/mL). It seems that etoposide loaded in micelles of folate grafted dextran stearate copolymer is promising in reducing drug resistance of colorectal cancer by boosting etoposide cellular uptake. © 2014 Jaleh Varshosaz et al.
Iranian Journal Of Basic Medical Sciences (20083874)16(11)pp. 1203-1208
Objective(s): Regarding the presence of many active biological constituents in Avicennia marina, the present investigation was carried out to study cytotoxic activity of crude methanol leave extract and column chromatographic fractions of A. marina against MDA-MB 231 cell line (human breast cancer cell) and HEK (Human embryonic kidney cell) line. Materials and Methods: The anticancer activity of crude methanol extract and sub-fractions were evaluated, using MTT assay. The induction of apoptosis was determined by analyzing DNA fragmentation in breast cancer cells treated with active fraction of crude methanol extract using agarose gel electrophoresis. To investigate molecular mechanism of apoptosis, gene expression levels of p53 and Bcl-2 were measured using quantitative real time PCR. Results: Fraction 10 was the most active fraction and was detected with HPLC as luteolin. The 50% cell cytotoxic concentration (CC50) of crude methanol extract and luteolin was 250 and 28 μg/ml, respectively. This fraction was found to be an apoptotic agent against MDA-MB 231 cells, which leads to causing DNA fragmentation. The mRNA expression level of Bcl-2 and p53 was significantly decreased and increased respectively in cancer cells treated by luteolin. Conclusion: The results suggested that Luteolin isolated from Avicennia marina could probably induce apoptosis on breast cancer cell line by the regulation of p53 and Bcl-2 pathways.
Sadeghi, H.,
Sadeghi, H.,
Karimimanesh, A.,
Karimimanesh, A.,
Varshosaz, J.,
Varshosaz, J. Journal of Isfahan Medical School (10277595)(217)pp. 2169-2177
Background: Aromatase inhibitors such as letrozole inhibit the synthesis of estrogens and help in the treatment of estrogen-dependent breast cancer. Using letrozole-loaded lipid nanocapsules (LNCs) as site directed drugs may help in the treatment of these tumors. Methods: LNCs were prepared by triglycerides, lecithin and polyethylene glycol in water phase inversion method. Prepared LNCs had particle size of less than 100 nm and were characterized with their particle size, zeta potential, and polydispersity index by Malvern Zeta-Sizer. LNCs were tested against MCF-7 cells (human breast adenocarcinoma cell line). They were compared with free letrozole in terms of cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Findings: S17O20L1.5W3.5, with particle size of 100 ± 3.4 nm, zeta potential of -3.6 ± 0.4, polydispersity of 0.283 ± 0.08, and loading efficiency of 96.6 ± 1.5, was the optimum formulation. Cytotoxicity of the prepared LNCs was 80% of that of free letrozole. This effect was concentrationdependent, i.e. cell survivals in stock solutions of 50 μg/ml, 10 μg/ml, and 5 μg/ml were 20%, 40%, and 60%, respectively. Conclusion: LNCS can be used as a selective formulation against cancer cells. Their cytotoxic effect is comparable to free letrozole.
Akbari, V.,
Akbari, V.,
Abedi, D.,
Abedi, D.,
Pardakhty, A.,
Pardakhty, A.,
Sadeghi, H.,
Sadeghi, H. Journal of Nanoparticle Research (13880764)(4)
In order to propose non-ionic surfactant vesicles (niosomes) for the treatment of intracellular infections, a remote loading method (active drug encapsulation) followed by sonication was used to prepare nano-niosome formulations containing ciprofloxacin (CPFX). Size analysis, size distribution and zeta potentials of niosomes were evaluated and then their antimicrobial activity, cellular uptake, cytotoxicity, intracellular distribution, and antibacterial activity against intracellular Staphylococcus aureus infection of murine macrophage-like, J774, cells were investigated in comparison to free drug. Our findings reveal that size and composition of the niosome formula can influence their in vitro biological properties. Vesicles in the 300-600 nm size range were phagocytosed to a greater degree by macrophages in comparison to other size vesicles. The minimum inhibitory concentrations (MICs) of CPFX-loaded niosomes were two to eightfold lower than MICs of free CPFX. In addition, niosome encapsulation of CPFX provided high intracellular antimicrobial activities while free CPFX is ineffective for eradicating intracellular forms of S. aureus. Encapsulation of CPFX in niosomes generally decreased its in vitro cytotoxicity. Our results show that niosomes are suitable drug delivery systems with good efficacy and safety properties to be proposed for drug targeting against intracellular infections. © 2013 Springer Science+Business Media Dordrecht.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Ghelich khan, Z.,
Ghelich khan, Z. Journal of Isfahan Medical School (10277595)(218)pp. 2206-2216
Background: Anthracyclines are used to treat different types of cancer including hepatocellular carcinoma. However, they have various side effects such as cardiotoxicity. Designing a drug delivery system which targets retinoic acid receptors in hepatocellular carcinoma can reduce these side effects. Methods: Chitosan/retinoic acid/albumin nanoparticles were prepared using a coacervation method. Nanoparticles which were optimized according to their particle size, zeta potential, polydispersity index, loading efficiency and release of doxorubicin, were used for further tests of cytotoxicity on HepG2 cells [by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] and cellular uptake tests (by fluorescent microscopy). Findings: The optimum targeted nanoparticles (with particle size of 286 ± 50.0 nm, zeta potential of 30.5 ± 3.6 mv, polydispersity index of 0.50 ± 0.06, loading efficiency of 43.6 ± 13.5%, and drug release of 56.17 ± 6.00%) in a concentration of 0.5 mg/ml were two to three times more cytotoxic than non-targeted nanoparticles and free drug. Their cellular uptake was also more. Conclusion: Chitosan/retinoic acid/albumin targeted nanoparticles loaded with doxorubicin could affect HepG2 cells more effectively than non-targeted nanoparticles and free drug.
Sadeghi, H.,
Sadeghi, H.,
Alavi, M.,
Alavi, M.,
Asghari, G.,
Asghari, G.,
Mirian, M.,
Mirian, M. Journal of Isfahan Medical School (10277595)(253)pp. 1508-1517
Background: Taxus baccata is known as a source of anticancer drug called taxol. This study was performed to confirm the consistency of results obtained by extraction of Taxanes by optimal solvent system using biological assessment. Methods: Three cell lines including MDA-MB-468, Hela and K562 were cultured in PRMI-1640 medium with 10% fetal bovine serum. Powder of aerial parts of Taxus baccata was extracted using 8 different solvent by maceration method. High performance thin layer chromatography (HPTLC) was used to standardize the extracts according to taxol content. Cytotoxicity of different concentrations of extracts (acetone 20, 50 and 100%, ethanol 20, 50 and 100%, acetone dichloromethane (1-1), and pure methanol) was evaluated against cultured cells, using MTT assay. Findings: Acetone-dichloromrthane (1-1) then pure acetone extract were the most cytotoxic extracts. Meanwhile, between the three cell lines tested, the highest cytotoxic effect of the extracts was observed on K562 cells. Conclusion: The results of this study showed that among evaluated extracts, more cytotoxic effect wsa in acetone-dichloromethane (1-1) followed by pure acetone extract. Analysis of extracts showed that the highest amount of taxans has been extracted by acetone-dichloromethane or pure acetone solvent system. We can conclude that there is a direct correlation between the cytotoxic effect and amount of taxans.
Karami, K.,
Karami, K.,
Kharat, M.H.,
Kharat, M.H.,
Sadeghi, H.,
Sadeghi, H.,
Lipkowski, J.,
Lipkowski, J.,
Mirian, M.,
Mirian, M. Polyhedron (02775387)(1)pp. 187-192
Reaction of chloro-bridged dinuclear palladacycles, [Pd2{(C,N)- C6H4CH2NH(R)}2(μ-Cl) 2] (R = Et (1a); R = t-Bu (1b)) with pyridine and PPh3 in the 1:2 M ratio at room temperature was used to prepare the mononuclear complexes, [Pd(C,N)-C6H4CH2NH(R)Cl(L)] (R = Et and L = Py (2a); R = t-Bu and L = PPh3 (2b)). Bridged biphosphinic palladacycle, [Pd2(C,N-dmba)2(μ-dppe)(Cl)2] (2c), (where dmba = N,N-dimethylbenzylamine and dppe = 1,2- bis(diphenylphosphino)ethane) has been also synthesized. The complexes were fully characterized by elemental analysis, IR and NMR spectroscopies. In addition, the solid structures of palladacycles 2a and 2c were studied by single-crystal X-ray crystallography. In vitro cytotoxicity assays of the cyclopalladated complexes, (2a-2c) and cisplatin were evaluated against the Hela (human cervix carcinoma), HT-29 (colon cancer cell line), K562 (leukemia cancer cell line) and MDA-MB-468 (human breast carcinoma). The complexes 2a-2c display IC50 values in a μM range better than that of the antitumor drug cisplatin. © 2012 Elsevier Ltd. All rights reserved.
Sadeghi, H.,
Sadeghi, H.,
Saghaei, L.,
Saghaei, L.,
Tadayonnia, N.,
Tadayonnia, N.,
Mirian, M.,
Mirian, M. Journal Of Reports In Pharmaceutical Sciences (23225106)(1)pp. 5-15
A series of 3-hydroxypyridin-4-one derivatives (HPOs) as bidentate iron (III) chelating agents were synthesized from 3-hydroxypyran-4-ones (maltol and ethyl maltol) in three steps through protection of hydroxyl group. The protected compounds were then reacted with suitable primary amines to give benzylated pyridinones. Finally, the benzyl group was removed by catalytic hydrogenation to produce the desired products. The partition coefficient of the free ligands and their iron (III) complexes were determined in an aqueous/octanol system using shakeflask method. The cytotoxic effects of these iron chelators against MCF-7 and MDA-MB-231 cancer cells were also evaluated using MTT assay. The results revealed that cytotoxicity of synthesized compounds were closely related to the lipophilycity of them so that the most lipophilic compound (4f) showed the highest activity; whereas compound 4a as a more hydrophilic agent showed the lowest cytotoxic effect; Although these compounds were cytotoxic at high concentration (≥ 0.1 mM). © 2013 by Kermanshah University of Medical Sciences.
Sadeghi, H.,
Sadeghi, H.,
Aliasgharluo m., ,
Aliasgharluo m., ,
Fattahi, A.,
Fattahi, A.,
Mirian, M.,
Mirian, M.,
Ghanadian, M.,
Ghanadian, M. Research In Pharmaceutical Sciences (17355362)(4)pp. 299-304
Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) developed as a selective inhibitor of cyclooxygenase-2 (COX-2) for the treatment of rheumatoid arthritis disease. Recently some other mechanisms have been identified for anti cancer activity of these agents including induction of apoptosis, inhibition of tumor vascularization, stimulation of antitumor immune responses and inhibition of cellular protein synthesis. The cytotoxic effects of four synthesisized analogues of celecoxib (coded as D, E, F and G) were evaluated against Hela , MDA-MB-231, A-2780-s and HT-29 cancer cells, using MTT assay; Also their induction of apoptosis using DNA fragmentation analysis were studied. MTT assay showed that cell survival percent of COX-2 positive cell lines (HT-29, MDA-MB-231 and Hela; p≤0.05) were decreased significantly after exposure to the tested COX-2 inhibitors while little effect was observed on the COX-2 negative cell line (A-2780-s). Results also showed that A-2780-s and Hela were the most resistant and the most sensitive cell lines to these compounds, respectively. Moreover, in DNA fragmentation assay, induction of apoptosis was confirmed by electrophoretic pattern of separated DNA fragments in Hela cell line. Compounds E and G in comparison with D and F exerted more cytotoxic effect on COX-2 positive cell lines (Hela, HT-29 and MDA-MB-231). This could be due to the hydrophobic substituent (Cl, CH3) located at the para position of phenyl ring leading to more lipophilicity and cell uptake. In addition, these COX-2 inhibitors induced apoptosis on Hela cell-line, which could be considered as one of the cytotoxic mechanisms of these compounds as potential anti cancer agents.
Rismanchian, M.,
Rismanchian, M.,
Khodaeian, N.,
Khodaeian, N.,
Bahramian, L.,
Bahramian, L.,
Fathi, M.,
Fathi, M.,
Sadeghi, H.,
Sadeghi, H. Iranian Journal Of Pharmaceutical Research (17350328)(3)pp. 437-443
The cytotoxicity of the biomaterials is a key issue that should be addressed prior to pre-clinical applications. This study was designed to evaluate and compare the cytotoxixity of two forms of bioactive glasses: nanopowder and micropowder. Human HGF1-PI53 gingival fibroblast cells were used to evaluate the cytotoxicity of 0.5, 1, 1.5, 2, 5, 10, 15 and 20 mg/ mL concentrations of the two bioactive glasses via MTT assay. The results were statistically analyzed using analysis of variance and Tukey's test. A p-value less than 0.05 was considered statistically signifcant. Results showed that two bioactive glasses had statistically signifcant differences at 5, 10, 15 and 20 mg/mL concentrations (p-value < 0.05) and there was no correlation between time and cell cytotoxicity of bioactive glasses (p-value > 0.05), using t-test and Spearman's correlation coefficient. We conclude that that cytotoxicity of nanopowder bioactive glass at concentrations ≤ 2 mg/mL was similar to micropowder bioactive glass at 24 and 48 h, however, it is more cytotoxic at concentrations ≥ 5 mg/mL in the first 48 h of applications. © 2013 by School of Pharmacy.
Avicenna Journal Of Medical Biotechnology (20084625)5(2)pp. 96-103
Background: Magnetic nanoparticles in a variable magnetic field are able to produce heat. This heat (42-45°C) has more selective effect on fast dividing cancer cells than normal tissues. Methods: In this work magnetite nanoparticles have been prepared via coprecipitation and phase identification was performed by powder x-ray diffraction (XRD). Magnetic parameters of the prepared nanoparticles were measured by a Vibrating Sample Magnetometer (VSM). A sensitive thermometer has been used to measure the increase of temperature in the presence of an alternating magnetic field. To evaluate the cytotoxicity of nanoparticles, the suspended magnetite nanoparticles in liquid paraffin, doxorubicin and a mixture of both were added to the MDA-MB-468 cells in separate 15 ml tubes and left either in the RT or in the magnetic field for 30 min. Cell survival was measured by trypan blue exclusion assay and flow cytometer. Particle size distribution of the nanoparticles was homogeneous with a mean particles size of 10 nm. A 15°C temperature increase was achieved in presence of an AC magnetic field after 15 min irradiation. Results: Biological results showed that magnetite nanoparticles alone were not cytotoxic at RT, while in the alternative magnetic filed more than 50% of cells were dead. Doxorubicin alone was not cytotoxic during 30 min, but in combination with magnetite more than 80% of the cells were killed. Conclusion: It could be concluded that doxorubicin and magnetite nanoparticles in an AC magnetic field had combinatory effects against cells. © 2013, Avicenna Journal of Medical Biotechnology. All rights reserved.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Ghelich khan, Z.,
Ghelich khan, Z.,
Rostami, M.,
Rostami, M. Journal of Nanomaterials (16874129)
Retinoic acid (R) grafted chitosan (C) copolymers with different degree of substitution of retinoic acid on the chitosan were synthesized. Retinoic acid targeted chitosan-albumin nanoparticles were prepared for targeted delivery of doxorubicin in hepatocellular carcinoma by coacervation method. Physical properties of nanoparticles including particle size, zeta potential, drug loading efficiency, and drug release profiles were studied. TEM micrographs were taken to see the morphology of nanoparticles. The cytotoxicity of doxorubicin-loaded nanoparticles was studied on HepG2 cells using MTT assay and their cellular uptake by fluorescence microscopy. FTIR and 1HNMR spectra confirmed successful production of RC conjugate which was used in production of the targeted RC-albumin nanoparticles. ICof drug loaded in these nanoparticles reduced to half and one-third compared to nontargeted nanoparticles and free drug, respectively. © 2013 Jaleh Varshosaz et al.
Saghaei, L.,
Saghaei, L.,
Sadeghi, H.,
Sadeghi, H.,
Ashaehshoar m., ,
Ashaehshoar m., Research In Pharmaceutical Sciences (17355362)(3)pp. 185-195
range of iron bidentae ligands containing the chelating moiety 3-hydroxypyridin-4-ones (HPOs) have been synthesized via a single or a three-step synthetic pathway. In the single-step reaction, maltol was directly reacted by suitable primary amine and in the second synthetic method; benzylated maltol was reacted with related amines to give 1-substuted-2-methyl-3- benzyloxypyridin-4-one derivatives. Finally, removal of the benzyl group under acidic conditions was performed by catalytic hydrogenation to yield the favored bidentate chelators as HCl salt. The partition coefficient of the free ligands and their iron (III) complexes between an aqueous phase buffered at pH 7.4 and 1-octanol were also determined. The cytotoxic effects of these iron chelators against HeLa and K562 cell lines were evaluated using MTT assay and the results showed that cytotoxicity was closely related to the lipophilicity of compounds so that the most lipophilic compound (4g) revealed the highest activity and compound 4e as a more hydrophilic agent (Kpart; 0.05) showed the lowest cytotoxic effect.
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in the US National Cancer Institute program in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia, and named it taxol. When it was developed commercially, the generic name was changed to paclitaxel. Paclitaxel is now used to treat patients with ovarian, breast, and advanced forms of Kaposi’s sarcoma. Paclitaxel stabilizes microtubules and, as a result, interferes with the normal breakdown of microtubules during cell division. Together with docetaxel, it forms the drug category of the taxanes. While offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug. There was originally concern because of the environmental impact of its original sourcing, no longer used, from the Pacific yew. So in recent years, extensive research has been done to find a way to produce it from alternative resources including related compounds and also to lessen the side effects of paclitaxel. © Springer-Verlag Berlin Heidelberg 2013.
Varshosaz, J.,
Varshosaz, J.,
Sadeghi, H.,
Sadeghi, H.,
Ghasemi s., ,
Ghasemi s., ,
Behdadfar, B.,
Behdadfar, B. BioMed Research International (23146141)
Amphiphilic copolymer of folate-conjugated dextran/retinoic acid (FA/DEX-RA) was self-assembled into micelles by direct dissolution method. Magnetic iron oxide nanoparticles (MNPs) coated with oleic acid (OA) were prepared by hydrothermal method and encapsulated within the micelles. Doxorubicin HCl was loaded in the magnetic micelles. The characteristics of the magnetic micelles were determined by Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and vibrating sample magnetometer (VSM). The crystalline state of OA-coated MNPs and their heat capacity were analyzed by X-ray diffraction (XRD) and differential scanning calorimetry (DSC) methods, respectively. The iron content of magnetic micelles was determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Bovine serum albumin (BSA) was used to test the protein binding of magnetic micelles. The cytotoxicity of doxorubicin loaded magnetic micelles was studied on MCF-7 and MDA-MB-468 cells using MTT assay and their quantitative cellular uptake by fluorimetry method. TEM results showed the MNPs in the hydrophobic core of the micelles. TGA results confirmed the presence of OA and FA/DEX-RA copolymer on the surface of MNPs and micelles, respectively. The magnetic micelles showed no significant protein bonding and reduced the ICof the drug to about 10 times lower than the free drug. © 2013 J. Varshosaz et al.
Varshosaz, J.,
Varshosaz, J.,
Sadeghi, H.,
Sadeghi, H.,
Shafipour, F.,
Shafipour, F. Farmacia (00148237)(1)pp. 64-79
The aim of this study was to prepare stealth solid lipid nanoparticles (SLN S) of risperidone, for controlled delivery through the intravenous (i.v.) route to reduce the frequency of administration, dose and adverse effects during the short-term management of manifestation of psychotic disorders. Stealth SLNs were prepared by emulsification-solvent diffusion and sonication method by adding acetone/ethanol containing drug, lipid and stabilizer to aqueous phase, containing surfactant, under homogenization. The effect of lipid type, lipid percentage, stabilizer type and stabilizer percentage were evaluated on the particle size, zeta potential, drug loading efficiency and drug release for optimization of SLNs. Dialysis bag membrane was used to determine drug release, the Rose Bengal binding constant for surface hydrophobicity and serum protein adsorption. The cytotoxicity of SLNs on macrophages and red blood cells were also assessed in order to evaluate the impact of surface modifications on toxicity of the different formulations. The optimized formulation was composed of 0.05% stearyl alcohol (relative to the total volume of dispersion) and 25% PEG 40 stearate (relative to the weight of lipid) using a homogenization speed of 1000 rpm and 4 minutes sonication. The results showed that the in vitro specifications of stealth SLN S of risperidone are suitable for i.v. administration.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Firozian, F.,
Firozian, F.,
Mirian, M.,
Mirian, M. Journal of Nanomaterials (16874129)
Amphiphilic polymer surfactants are composed of hydrophilic and hydrophobic polymers and are widely used in targeted drug delivery. The purpose of this study was the evaluation of the effect of molecular weight and molar ratio of dextran on physicochemical properties of dextran stearate polymeric micelles. Dextran stearate was synthesized by acylation of dextran with stearoyl chloride. Etoposide loaded polymeric micelles were prepared by dialysis method. The resulting micelles were evaluated for particle size, zeta potential, critical micelle concentration (CMC), drug loading capacity, and release efficiency. Cytotoxicity and cellular uptake of micelles were studied in CT-26 colorectal carcinoma cell line. Molecular weight and molar ratio of dextran-stearate were impressive on zeta potential, CMC, drug loading capacity, and release efficiency. Unlike polymer molecular weight, molar ratio of stearate had a significant effect on cytotoxicity and particle size of etoposide loaded micelles. Although molecular weight of dextran had no significant effect on cytotoxicity of micelles on CT-26 cells, it had drastic attributes for stability of polymeric micelles. Consequently, both variables of molecular weight of dextran and molar ratio of stearate should be taken into account to have a stable and effective micelle of dextran-stearate. © 2012 Jaleh Varshosaz et al.
Asghari, G.,
Asghari, G.,
Mostajeran a., A.,
Mostajeran a., A.,
Sadeghi, H.,
Sadeghi, H.,
Nakhai a., ,
Nakhai a., Journal Of Medicinal Plants (27172058)(SUPPL. 8)pp. 74-82
Background: Taxol is an effective anticancer drug used widely in the treatment of a variety of cancers, including carcinomas of the ovary and breast. Taxol was originally isolated from the bark of Pacific yew tree Taxus bervifolia L.. Increasing demand for taxol and resource paucity of Pacific yew trees has driven several research groups to advance the taxol production methodologies, including using elicitors in suspension cultures of Taxus spp. cells. Elicitors are often used to improve taxol production incultured cells. Objectives: The aim of this work is to inject the Taxus baccata tree a single and combination of salaicylic acid and silver nitrate to improve taxol production. Methods: Salicylic acid and silver nitrate solution in different concentration were prepared and injected to tree. After 30 days of elicitors' injection the leave for aerial parts of the tree was collected. The dried powder of the leave was extracted by maceration with ethanol 96%. To detect taxol, a high-performance liquid chromatography (HPLC) system was employed. Results: The treated cells with salaicylic acid and silver nitrate displayed a significant decrease in taxol. Increasing concentration of elicitors resulted lower content of taxol. Conclusion: The injection of single and combine of salaicylic acid and silver nitrate on the Taxus baccata tree showed negative effect on taxol production. It seems that more researchs need to be done in order to understand the acting mechanisms of used elicitors.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Shakery m., ,
Shakery m., Current Nanoscience (18756786)(2)pp. 249-258
Statins can inhibit growth of malignant cells. Aims: The aim of the present work was to increase efficacy of simvastatin on chronic meyloid leukemia K562 cells by folate targeted solid lipid nanoparticles (SLN). Methodology: Folate targeting agent was prepared by chemical reaction between folic acid and dodecylamine. Folate targeted SLNs of simvastatin were prepared by an emulsification- solvent evaporation method. Then cytotoxicity of SLNs was studied on K562 cell line by Trypan blue and cellular uptake by flow cytometry method. Different concentrations of doxorubicin were used in combination to SLNs of simvastatin to study their possible synergistic effect in reducing the required cytotoxic dose of doxorubicin. Results: Simvastatin loaded SLNs were more cytotoxic than free simvastatin. The targeting property of glyceryl monostearate (GMS) SLNs was more efficient than other studied lipids. SLNs of simvastatin could reduce the cytotoxic dose of doxorubicin particularly when the dose of doxorubicin was low. Conclusion: Folate targeted SLNs can significantly enhance cytotoxic effect of simvastatin on K562 cell line and show synergistic effect with doxorubicin in reducing its dose. This may be of great value from clinical point of view in reduction of the cardiac toxicity of doxorubicin. © 2012 Bentham Science Publishers.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Khadem, M.,
Khadem, M. Journal of Liposome Research (08982104)(3)pp. 224-236
The aim of the present study was to design a targeted delivery system of 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). Lactobionic acid (LB) was conjugated to stearyl amine (SA) by a chemical reaction. The nanostructured lipid carriers (NLCs), containing LB conjugate, lecithin, glyceryl monostearate, oil [oleic acid (OA) or Labrafac 5 or 10%], and 5-FU, were dissolved in alcohol/acetone, the oil phase was added to the aqueous phase containing Tween 80 or Solutol® HS15 (0.25 or 0.5%), and NLCs were prepared by an emulsification-solvent diffusion method. Physical properties and drug release were studied in NLCs. The thiazolyl blue tetrazolium bromide assay was used to study the cytotoxicity of NLCs on HepG2 cells, and the cellular uptake of NLCs was determined by flow cytometry. Fourier transform infrared spectroscopy and H-NMR spectra confirmed the successful conjugation of LB and SA. The optimized NLCs consisted of 0.5% Solutol HS15 and 10% OA oil. The particle size of these nanoparticles was 139.2 nm, with a zeta potential of 18 mV, loading efficiency of 34.2%, release efficiency after 2 hours of the release test was 72.6%, and crystallinity was 0.63%. The galactosylated NLCs of 5-FU were cytotoxic on the HepG2 cell line in a half concentration of 5-FU and seems promising in reducing 5-FU dose in HCC. © 2012 Informa Healthcare USA, Inc.
Nayebsadrian m., ,
Nayebsadrian m., ,
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Banitalebi m., ,
Banitalebi m., ,
Rostami, M.,
Rostami, M. Journal of Nanomaterials (16874129)
Amphiphilic copolymers with self-assembling properties produce micelles in aqueous solutions and are made of two hydrophilic and hydrophobic segments. The objective of this study was optimization of the production of folate-conjugated dextran/retinoic acid (DEX/RA) micelles of doxorubicin. Micelles were prepared by direct dissolution method, and different effective parameters on their production were studied by a Taguchi design. The studied variables included CMC of the copolymer, polymer and drug contents, DEX Mw, stirring time, and rate and temperature. The effects of variables on responses of particle size, polydispersity index, zeta potential, drug loading, and release efficiency were studied. The most effective factors on particle size were DEX Mw, CMC of the copolymer, and stirring rate. Zeta potential and drug loading were more affected by the polymer content, DEX Mw, stirring time, and drug concentration. Stirring time and rate and also temperature of water were more effective variables on drug release rate. The optimum processing situation for micelles formation was obtained by copolymers with CMC <17 g/mL and prepared from 20.1 mg copolymers of DEX Mw of 10000 and drug concentration of 15.9%. The optimized temperature for micelles formation was 40.7°C, and stirring time was 1 hr at a rate of 560 rpm. © 2012 M. Nayebsadrian et al.
Journal of Magnetism and Magnetic Materials (03048853)324(14)pp. 2211-2217
Superparamagnetic and monodispersed aqueous ferrofluids of Zn substituted magnetite nanoparticles (Zn xFe 3-xO 4, x=0, 0.25, 0.3, 0.37 and 0.4) were synthesized via hydrothermal-reduction route in the presence of citric acid, which is a facile, low energy and environmental friendly method. The synthesized nanoparticles were characterized by X ray diffraction (XRD) analysis, Fourier transform infrared (FTIR) spectroscopy, scanning and transmission electron microscopy (SEM and TEM) and the dynamic light scattering (DLS) method. The results showed that a certain amount of citric acid was required to obtain single phase Zn substituted magnetite nanoparticles. Citric acid acted as a modulator and reducing agent in the formation of spinel structure and controlled nanoparticle size and crystallinity. Mean particle sizes of the prepared nanoparticles were around 10 nm. The results that are obtained from XRD, magnetic and power loss measurements showed that the crystallinity, saturation magnetization (M S) and loss power of the synthesized ferrofluids were all influenced by the substitution of Zn in the structure of magnetite. The Zn substituted magnetite nanoparticles obtained by this route showed a good stability in aqueous medium (pH 7) and hydrodynamic sizes below 100 nm and polydispersity indexes below 0.2. The calculated intrinsic loss power (ILP) for the sample x=0.3 (e.g. 2.36 nH m 2/kg) was comparable to ILP of commercial ferrofluids with similar hydrodynamic sizes. © 2012 Elsevier B.V. All rights reserved.
Journal of Solid State Chemistry (1095726X)187pp. 20-26
Monodispersed aqueous ferrofluids of iron oxide nanoparticle were synthesized by hydrothermal-reduction route. They were characterized by X-ray diffraction analysis, Fourier transform infrared spectroscopy, scanning and transmission electron microscopy and dynamic light scattering. The results showed that certain concentrations of citric acid (CA) are required to obtain only magnetic iron oxides with mean particle sizes around 8 nm. CA acts as a modulator and reducing agent in iron oxide formation which controls nanoparticle size. The XRD, magnetic and heating measurements showed that the temperature and time of hydrothermal reaction can affect the magnetic properties of obtained ferrofluids. The synthesized ferrofluids were stable at pH 7. Their mean hydrodynamic size was around 80 nm with polydispersity index (PDI) of 0.158. The calculated intrinsic loss power (ILP) was 9.4 nHm 2/kg. So this clean and cheap route is an efficient way to synthesize high ILP aqueous ferrofluids applicable in magnetic hyperthermia. © 2012 Elsevier Inc. All rights reserved.
Varshosaz, J.,
Varshosaz, J.,
Hassanzadeh, F.,
Hassanzadeh, F.,
Sadeghi, H.,
Sadeghi, H.,
Andalib, S.,
Andalib, S. European Journal of Medicinal Chemistry (02235234)pp. 429-438
The aim of the present study was to reduce 5-FU side effects by targeted nanostructured lipid carriers (NLCs) to LDL receptors that are over expressed in colorectal carcinoma and also use of a new synthesized conjugate of retinoic acid as a cytotoxic agent. Fatty acyl amide derivative of retinoic acid was synthesized by its conjugation to octadecylamine with the expectation to improve its loading capacity in NLCs of 5-FU. The NLCs were prepared by an emulsification-solvent evaporation method using cholesterol and cholesteryl stearate. Physical properties and drug release were studied in NLCs. The cytotoxicity of NLCs loaded with 5-FU and retinoic acid conjugate was studied on colon cancer cells (HT29) using MTT assay. To confirm that drug targeting has been done through LDL receptors, APO-E was omitted from the cell culture and the MTT assay was repeated. FTIR and 1H NMR spectra confirmed successful production of the conjugate. Results showed the IC50 of free 5-FU was about 7.6 μM while in comparable concentration, the cytotoxicity of 5-FU loaded in NLCs containing the retinoic acid conjugate was nearly 2 fold of NLCs just loaded with 5-FU and more than 5 fold of free 5-FU. The retinoic acid conjugate loaded NLCs prepared by cholesterol can target LDL receptors of HT29 cells and seems promising in reducing 5-FU dose in colorectal cancer. © 2012 Elsevier Masson SAS. All rights reserved.
Fassihi, A.,
Fassihi, A.,
Mahnam, K.,
Mahnam, K.,
Moeinifard, B.,
Moeinifard, B.,
Bahmanziari, M.,
Bahmanziari, M.,
Sadeghi, H.,
Sadeghi, H.,
Zarghi, A.,
Zarghi, A.,
Sabet, R.,
Sabet, R.,
Salimi, M.,
Salimi, M.,
Mansourian, M.,
Mansourian, M. Medicinal Chemistry Research (10542523)(10)pp. 2749-2761
Novel 1,4-dihydropyridines were synthesized and subjected to calcium-channel blocking evaluation and conformational analysis using semi-empirical (PM3) and density functional theory (DFT) as computational methods. All molecules had a boat-like 1,4-dihydropyridine ring in both the methods. In PM3 method almost 54% of the molecules were deviated from planarity, but in DFT method all the molecules had perfect flattened-boat conformation. Using both the methods, the C-4 substituent was pseudoaxial with its phenylamino substitution in sp orientation in 82.14% of the molecules. Trans-trans and cis-cis conformation had the greatest and lowest proportion in the molecules, respectively. Trans-trans conformers which possessed sp conformation for the substituted group on the imidazole ring were active calcium-channel blocking agents. © Springer Science+Business Media, LLC 2011.
Pharmaceutical Sciences (23832886)16(4)pp. 229-238
Objectives: The medicinal plant of Avicennia marina has been used widely in traditional medicine for treatment of skin disease and rheumatoid in Iran. The present investigation was carried out to study the anticancer effects of different crude extracts of A. marina's leaves against breast cancer cell line (MDA-MB 231). Methods: MDA-MB 231 and L929 healthy cells were separately cultured in RPMI-1640 medium completed with 10% fetal calf serum and penicillin / streptomycin (50 IU/ml and 50 μg/ ml respectively). Collected leaves were dried and powdered, then were soaked in five solvents with different lipophilicity. The cytotoxic effects of different concentration of crude extracts on cultured cells were measured using the MTT assay. Chromosomal DNA was extracted, isolated and resolved using agarose gel electrophoresis. Result: Methanolic extract exerted higher anti-cancer activity on human breast cancer cells compared with other extracts. IC50 of the methanolic extract was measured at 480 μg/ml. Furthermore, the methanol extract induced a significant growth inhibition and apoptosis in a dose-dependent manner on MDA-MB 231 as human cancer cells but there was no significant effect against L929 as normal cells. Methanolic extract showed time dependent growth inhibition effect so that, after 24, 48, and 72 h treatment cell growth was inhibited by 40%, 44%, and 59%, respectively. Conclusion: The present results suggest that valuable cytotoxic components could be isolated from this plant by partitioning methanol crude extract. Further investigations are underway in this regard.
Saghaei, L.,
Saghaei, L.,
Sadeghi, H.,
Sadeghi, H.,
Kafiri m., ,
Kafiri m., Research In Pharmaceutical Sciences (17355362)(2)
A series of 3-hydroxypyridin-4-one derivatives (HPOs) were synthesized and their partition coefficient values (Kpart) were determined. The cytotoxic effects of these iron chelators against Hela cancer cells were also evaluated. The IC50 of HPOs was determined using MTT assay. Among these ligands, compound 4e (Kpart=5.02) with an IC50 of 30 μM and 4f (Kpart=0.1) with an IC50 of 700 μM showed the lowest and highest IC50s, respectively. In conclusion, the introduction of a more hydrophobic functional group (such as butyl in compound 4e) on the nitrogen of pyridinone ring resulted in higher cytotoxic activity of ligands.
Mirian, M.,
Mirian, M.,
Zarghi, A.,
Zarghi, A.,
Sadeghi, S.,
Sadeghi, S.,
Tabaraki, P.,
Tabaraki, P.,
Tavallaee, M.,
Tavallaee, M.,
Dadrass, O.,
Dadrass, O.,
Sadeghi, H.,
Sadeghi, H. Iranian Journal Of Pharmaceutical Research (17350328)(4)pp. 741-748
Sulfonamides are the first effective chemotherapeutic agents used for several years to cure or prevent systemic bacterial infections. In addition, this agents showed anti-carbonic anhydrase and cause cell cycle perturbation in the G1 phase, disruption of microtubule assembly, suppression of the transcription activator Nf-Y, angiogenesis and matrix metalloproteinase (MMP). In recent years, novel synthesized sulfonamides have been introduced as antitumor, antiviral and anti-inflammatory agents. In this paper, the cytotoxic effects of 8 synthesized sulfonamides were investigated by MTT assay on HeLa, MDA-MD-468 and MCF-7 cancer cell lines. Human cancer cells were cultured and passaged in RPMI-1640 medium. Cells incubated in 96-well plates in a concentration of 1 × 105 cells/mL for 24 h, and then logarithmic concentrations (0.1 μm, 1 μm, 10 μm, 100 μm, 1mM) of each drug were prepared, added to the plates and incubated for 72 h. Cell survival was then determined using ELISA plate reader in 540 nm applying MTT assay. All tested sulfonamides showed cytotoxic effect on HeLa and MCF-7 cells in the concentration range of 100-1000 μm. These sulfonamides were cytotoxic against MDA-MB-468 cell line at a concentration of 10-100 μm and reduced the cell survival less than 50%. According to the results calculated IC50's were as following: MDA-MB-468 < 30 μm; MCF-7 < 128 μm and HeLa < 360 μm. In conclusion, some tested sulfonamides had good cytotoxic effects against breast cancer cells, MDA-MB-468 and further investigations are needed to confirm their effects against other cells. © 2011 by School of Pharmacy.
The metabolically active tumor cells may be characterized by a pronounced adenosine release that regulates the growth and development of the tumor. Consequently, the expression pattern of defined receptor subtypes will be an important determinant for specific effects of adenosine on the control of tumor cell growth. In recent studies, the expression profile, signal transduction, molecular function and cell growth modulation of adenosine receptors in the human breast cancer cell lines has been reported. To investigate the possible roles of adenosine receptors in other types of human cancers, in this study, we characterized the expression profile of adenosine receptors in two different human cancer cell lines: prostate carcinoma cell line (Du-145) and lung adenocarcinoma cell line (Calu-6). Our purpose is to test the hypothesis that diverse human cancer cell lines, according to their adenosine receptor subclass status, would show differential growth modulation. Methods: RNA was extracted and reverse transcribed to cDNA. PCR primers were synthesized from human adenosine receptor cDNA sequences. PCR was performed under optimized condition for each receptor subtype. The PCR products were separated on agarose gels. Results: All two human cancer cell lines studied contained detectable amounts of mRNA specific for adenosine receptor except A3 subtypes. Conclusion: In conclusion the differentially expressed genes identified in this study might provide new insights into the possible roles of adenosine receptors on cell growth and development.
Palizaban, A.,
Palizaban, A.,
Sadeghi, H.,
Sadeghi, H.,
Abdollahpour f., ,
Abdollahpour f., Research In Pharmaceutical Sciences (17355362)(2)pp. 119-125
The anti-cancer activity of metal ions in the lanthanide group is being considered recently. It has been reported that cerium salts might stimulate the metabolism and therefore, produce anti-cancer effects. However, little is known about the effects of protein-cerium complex in controlling cancer cell growth. The aim of the present study was to elucidate the possible pathways for the cytotoxic effect of cerium in the presence of apo-transferrin on two cancer cell lines (Hela and MCF-7), that express transferrin receptors 3-4 fold higher than normal cells. The effect of different concentrations of cerium (0.1, 1, 10, 100 μM) in the presence and absence of transferrin for 48 h and 72 h incubation periods (37°C, 5% CO2 and 95 humidity) was studied using the MTT assay. The results showed that cerium has a cell-proliferation inhibitory activity which is significantly increased by transferrin protein. Compared with the direct treatment of cancer cells with cerium, the presence of transferrin assisted inhibition of cell proliferation by 20% and 40% in Hela and MCF-7 cells, respectively. Though apo-transferrin could lightly induce cell growth particularly in MCF-7 cells by itself, this phenomenon could not overcome the cerium-protein cell-proliferation inhibition activity. In conclusion, our results indicate that at a certain concentration, the cerium compounds could be possibly involved in the control of cell proliferation and inhibiting the growth of cancer cells.
Heidarkhan tehrani, A.,
Heidarkhan tehrani, A.,
Zadhoush, A.,
Zadhoush, A.,
Karbasi, S.,
Karbasi, S.,
Sadeghi, H.,
Sadeghi, H. Journal of Materials Science: Materials in Medicine (15734838)(11)pp. 2989-2998
Fibrous scaffolds of engineered structures can be chosen as promising porous environments when an approved criterion validates their applicability for a specific medical purpose. For such biomaterials, this paper sought to investigate various structural characteristics in order to determine whether they are appropriate descriptors. A number of poly(3-hydroxybutyrate) scaffolds were electrospun; each of which possessed a distinguished architecture when their material and processing conditions were altered. Subsequent culture of mouse fibroblast cells (L929) was carried out to evaluate the cells viability on each scaffold after their attachment for 24 h and proliferation for 48 and 72 h. The scaffolds' porosity, pores number, pores size and distribution were quantified and none could establish a relationship with the viability results. Virtual reconstruction of the mats introduced an authentic criterion, "Scaffold Percolative Efficiency" (SPE), with which the above descriptors were addressed collectively. It was hypothesized to be able to quantify the efficacy of fibrous scaffolds by considering the integration of porosity and interconnectivity of the pores. There was a correlation of 80% as a good agreement between the SPE values and the spectrophotometer absorbance of viable cells; a viability of more than 350% in comparison to that of the controls. © 2010 Springer Science+Business Media, LLC.
Sadeghi, H.,
Sadeghi, H.,
Emami, A.,
Emami, A.,
Saidi, M.,
Saidi, M.,
Sadeghi, B.,
Sadeghi, B.,
Jafarian, A.,
Jafarian, A. Iranian Journal Of Pharmaceutical Research (17350328)(4)pp. 281-286
Isolation of some potent anti-tumor compounds from medicinal plants has motivated researchers to screen different parts of plant for their anti-tumor effects. It has been reported that several species of conifers posses' cytotoxic activities on some tumor cell lines. Here branchlets and berries of Juniperus foetidissima and J. sabina were collected, dried and ethanol extracts of them obtained using percolation. Extracts were dried in reduced pressure and cytotoxic effects of different concentrations (5, 10, 20 μg/ml) were evaluated by MTT assay against three tumor cell lines (Hela, KB, MDA-MB-468), using ELISA at 540 nm. The extracts of the branchlets of male and female of J.foetidissima and berries extract of J. sabina showed inhibitory activities against KB cells. Extracts of male branchlets of J. foetidissima and berries extract of J. sabina were cytotoxic (cell survival less than 50%) against Hela cell line. Regarding to MDA-MB-468, only the extract of male branchlets of J. foetidissima was cytotoxic. Extracts of J. sabina were not cytotoxic at tested concentrations. According to the results obtained by MTT assay, KB cells seem to be much more sensitive than the other cell lines. Copyright © 2009 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services.
Sagha, M.,
Sagha, M.,
Karbalaie, K.,
Karbalaie, K.,
Tanhaee, S.,
Tanhaee, S.,
Esfandiari, E.,
Esfandiari, E.,
Salehi, H.,
Salehi, H.,
Sadeghi, H.,
Sadeghi, H.,
Razavi, S.,
Razavi, S.,
Nasr-esfahani, M.H.,
Nasr-esfahani, M.H.,
Baharvand, H.,
Baharvand, H. Stem Cells and Development (15473287)(9)pp. 1351-1359
The role of paraxial mesoderm or the somites in decision of ectoderm to acquire the neuroepithelial fate and its subsequent diversification to functional neural subtypes especially in mammalians is obscure. Here we report, for the first time, the influence of the co-culture of alginate bead-encapsulated somites isolated from chick embryos on neural differentiation in mouse embryonic stem cells-derived embryoid bodies (EBs). Using a combination of morphology, immunofluorescence, flow cytometry, semiquantitative, and conventional RT-PCR techniques, we show that the somites induce rosette structures and weakly enhance neural differentiation and neural markers in a dose-dependent manner in comparison to the control group, but its effect is lower than retinoic acid treatment of EBs. By liquid chromatography-mass spectrometry, it was revealed that somitic cells synthesized and released retinoids into the medium. However, no effective influence of somitic co-culture on rostrocaudal or dorsoventral patterning is seen. Therefore, like amphibians, somites have a modest neural-inducing activity in amniotes. © 2009 Mary Ann Liebert, Inc.
Sadeghi, H.,
Sadeghi, H.,
Asghari, G.,
Asghari, G.,
Mostafavi, A.,
Mostafavi, A.,
Esmaeili a., ,
Esmaeili a., Daru Journal Of Pharmaceutical Sciences (15608115)(3)pp. 192-198
Background and the purpose of the study: Taxol, a natural antitumor agent, was first isolated from the extract of the bark of Taxus brevifolia Nutt., which is potentially a limited source for Taxol. In the search of an alternative source, optimum and cost benefit extracting solvents, various solvents with different percentage were utilized to extract Taxol from needles of Taxus baccata. Methods: One g of the dried needles of Taxus baccata, collected from Torkaman and Noor cities of Iran, was extracted with pure ethanol or acetone and 50% and 20% of ethanol or acetone in water. Solvents were evaporated to dryness and the residues were dissolved in 5 ml of methanol and filtered. To one ml of the filtrate was added 50 μl of cinamyl acetate as the internal standard and 20 μl of the resulting solution was subjected to the HPLC to determine the extraction efficiencies of tested solvents. Five μl of filtrate was also subjected to the LC-MS using water/acetonitrile (10/90) as mobile phase and applying positive electrospray ionization (ESI) to identify the authenticity of Taxol. Results: Results of this study indicated that Taxol extraction efficiency was enhanced as the percentage of ethanol or acetone was increased. HPLC analysis showed that Taxol could be quantified by UV detection using standard curve. The standard curve covering the concentration ranges of 7.8 - 500 μg/ml was linear (r2= 0.9992) and CV% ranged from 0.52 to 15.36. LC-MS analysis using ESI in positive-ion mode confirmed the authenticity of Taxol (m/z 854; M+H), as well as some adduct ions such as M+Na (m/z 876), M+K (m/z 892) and M+CH3CN+H2O (m/z 913). Conclusions: The results suggest that 100% acetone is the best solvent for the extraction of Taxol from Taxus baccata needles.
Sadeghi, H.,
Sadeghi, H.,
Chan, K.,
Chan, K.,
Lehmler, H.,
Lehmler, H.,
Robertson, L.W.,
Robertson, L.W.,
O'brien, P.J.,
O'brien, P.J. Chemico-Biological Interactions (00092797)(3)pp. 184-192
Polychlorinated biphenyl (PCB) and PCB metabolites are highly lipophilic and accumulate easily in the lipid bilayer and fat deposits of the body. The molecular cytotoxic mechanisms of these metabolites are still not understood. The aim of the present study was to compare the cytotoxicity and toxicological properties of six dihydroxylated metabolites using isolated rat hepatocytes. All of the metabolites were more cytotoxic than 4-chlorobiphenyl (4-ClBP) and less cytotoxic than phenyl hydroquinone (PHQ). The order of cytotoxic effectiveness of catecholic metabolites expressed as LC50 (2 h) was 3′,4′-diCl-2,3-diOH-biphenyl > PHQ > 4′-Cl-2,5-diOH-biphenyl, 4′-Cl-2,3-diOH-biphenyl > 2′,5′-diCl-3,4-diOH-biphenyl > 2′,3′-diCl-3,4-diOH-biphenyl > 3′,4′-diCl-3,4-diOH-biphenyl > 4′Cl-3,4-diOH-biphenyl > 4′-Cl-biphenyl; showing that the positions of hydroxyl and chlorine groups were important for their hepatotoxicity and that the two 2,3-diOH congeners were the most cytotoxic. Cytotoxicity for 3,4-diOH metabolites correlated with the number and position of chlorine atoms with the more chlorine atoms being more cytotoxic. The cytotoxic order of metabolites with two chlorine atoms being 2′,5′ > 2′,3′ > 3′,4′. Borneol, an uridine diphosphate glucuronosyltransferases (UGT) inhibitor, increased the cytotoxicity of all tested metabolites; suggesting that glucuronidation was a major mechanism of elimination of these compounds. On the other hand entacapone, a catechol-O-methyl transferase (COMT) inhibitor, only increased the cytotoxicity of 3′,4′-diCl-3,4-diOH-biphenyl, 3′,4′-diCl-2,3-diOH-biphenyl and 4′-Cl-2,3-diOH-biphenyl. Hepatocyte GSH was depleted (oxidized and conjugated) by these metabolites before cytotoxicity ensued in a similar order of effectiveness to their cytotoxicity with PHQ being the most effective. Hepatocyte mitochondrial membrane potential also decreased before cytotoxicity ensued with a similar order of effectiveness as their cytotoxicity. These results suggest that catecholic cytotoxicity can be attributed to mitochondrial toxicity and oxidative stress. Semiquinone or benzoquinone species were also important in the cytotoxicity of catecholic metabolites. © 2007 Elsevier Ireland Ltd. All rights reserved.
Movahedian a., A.,
Movahedian a., A.,
Sadeghi, H.,
Sadeghi, H.,
Ghannadi, A.,
Ghannadi, A.,
Gharavi, M.,
Gharavi, M.,
Azarpajooh, S.,
Azarpajooh, S. Journal of Medicinal Food (15577600)(1)pp. 98-101
Allium porrum L. is a herbaceous plant from the Liliaceae family and has been widely used in Persian foods as a flavor component and in Iranian traditional medicine as an anti-atherogenic remedy. The present investigation was undertaken to evaluate the antihypercholesterolemic effect of a hydroalcoholic extract of A. porrum L. bulbs. Rabbits were divided into five groups-control, hypercholesterolemic control, and three treatment groups (hypercholesterolemic diet + 250, 500, or 1,000 mg/kg of body weight of extract, respectively)-and were fed for 12 weeks. Blood samples were obtained to analyze plasma cholesterol, triglycerides, and low-density lipoprotein (LDL), very LDL, and high-density lipoprotein (HDL) cholesterol. Body weight increased in all groups throughout the treatment without significant differences among them. Plasma total cholesterol increased with respect to the control in the positive control group at the end of the treatment. Plasma total cholesterol decreased in all groups treated with A. porrum extract in a dose-dependent fashion. Changes in the distribution of cholesterol in HDL or LDL were found, and LDL cholesterol decreased significantly in all of the groups treated with A. porrum extract with respect to the hypercholesterolemic group. Thus, these findings indicate that this plant may be useful for the treatment of hypercholesterolemia. © Mary Ann Liebert, Inc.
Emami, A.,
Emami, A.,
Sadeghi, H.,
Sadeghi, H.,
Saeidi, M.,
Saeidi, M.,
Jafarian, A.,
Jafarian, A. Pharmaceutical Biology (13880209)(4)pp. 299-304
In this study, branchlets, fruit, or bark of Taxus baccata L. as well as branchlets or fruits of two other species of Iranian conifers, namely, Platycladus orientalis France and Cupressus sempervirens L. var. horizentalis (Mill) Gunde were collected, identified, and the cytotoxic effects of hydroalcoholic extracts on three human tumor cell lines were determined. Different concentrations of extracts were added to cultured cells and incubated for 72 h. Cell survival was evaluated using the MTT assay. Extracts from bark of female Taxus baccata showed inhibitory activities against Hela cells. The extracts of the branchlets of male and female T. baccata as well as obtained extract from fruits of P. orientalis showed inhibitory activities against MDA-MB-468 cells, whereas the extracts of branchlets of female T. baccata showed inhibitory activities against KB cells. In conclusion, obtained extract from bark of T. baccata showed comparable cytotoxic effect to doxorubicin against Hela cells. © 2005 Taylor & Francis Ltd.
Sadeghi, H.,
Sadeghi, H.,
Tabarzadi, M.,
Tabarzadi, M.,
Zarghi, A.,
Zarghi, A. Farmaco (0014827X)(8)pp. 645-649
The antitumor activity of dihydroxyanthracenediones such as mitoxantrone on a panel of cancer cell lines during the last 30 years, led investigators to synthesize thousands of anthracycline analogs and test their cytotoxicity to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. To achieve this, new synthesized congeners either have different side arms or have extra rings on their skeletons. Following these studies, we proposed total synthesis of 2-amino-N-[4-(2-amino-3-hydroxy-propionylamino)-9,10-dioxo-9, 10-dihydroanthracene-1-yl]-3-hydroxy-propionamide (V) and 6-amino-hexanoic acid [4-(5-amino-pentanoylamino)-9,10-dioxo-9,10-dihydro-anthracen-1-yl]-amide (VI). Acetylation of 1,4-diaminobenzene using acetyl chloride and reaction with phthalic anhydride under a Friedel-Crafts reaction and then cyclization gave 1, 4-diamino-anthraquinone. This compound was reacted with two amino acids (L-serine and 6-amino hexanoic acid) in their ester forms, using ethyl chloroformate as a coupling agent. Hydrolyzing esterified compounds gave their amino substituted derivatives. These compounds with diamine side arms are supposed to provide better intercalation with DNA. Synthesized novel ametantrone derivatives were tested against a panel of cancer cells (KB, Hela, MDA-MB-468 and K562), using MTT assay. The results showed that tested compounds inhibited the growth of cancer cells at micromolar concentrations. However, compound (VI) was more cytotoxic than compound (V) probably because of its longer side chains and better intercalation with DNA. © 2004 Elsevier SAS. All rights reserved.
Pharmaceutical Biology (13880209)(4-5)pp. 367-373
Breast cancer is the most prevalent type of cancer in pre- and postmenopausal women in most Western countries. In the treatment of metastatic breast cancer, doxorubicin has the broadest spectrum of antitumor activity of any drug currently available but produces a dose-dependent cardiomyopathy that limits its clinical usefulness. The aim of this research project was to target the affected tissues, which contain estrogen receptors (ERs). Initially, a series of estrogen derivatives with side chains linked at the 3- and 17-positions of estrone were synthesized, and then novel anticancer prodrugs were obtained from these by further linking these compounds to doxorubicin by means of various alkyl spacer groups. These estrogenic prodrugs were designed to target tumor cells containing ERs, found in human breast cancer cells, and to release the active anticancer moiety when internalized. The estrogenic prodrugs were then biologically evaluated using in vitro chemosensitivity assays against human ER-positive (MCF-7) and ER-negative (MCF-7ADR and MT-1) breast tumor cells and a leukemia (K562) cell line. The results showed that estrone derivatives with substituted aminoalcohol side chains of various lengths (2-6 carbons) linked to the 17-position of estrone were mostly inactive. Estronedoxorubicin prodrugs containing doxorubicin at the 3-position of estrone (CCRL 1042 and CCRL 1036) were relatively inactive and nonselective against all cell lines tested. However, when doxorubicin was linked to the 17-position of estrone, these prodrugs had at least an order greater activity than their 3-linked counterparts. Using a short aminoxyspacer group (2 carbons) at this position produced CCRL 1035, which had a lower activity against all cell lines tested compared to doxorubicin. In contrast, the prodrug incorporating doxorubicin at the 17-position of estrone via a long spacer group (12 carbons, CCRL 1033) was both potent and selective against ER-positive cells MCF-7. These studies have shown that linking doxorubicin to the 17-position of estrone via a long alkyl spacer group conferred selectivity of cytotoxic action against ER-positive breast cancer tumor cells.
Sadeghi, H.,
Sadeghi, H.,
Emami, A.,
Emami, A.,
Saeidi, M.,
Saeidi, M.,
Jafarian, A.,
Jafarian, A. Iranian Journal Of Pharmaceutical Research (17350328)(2)pp. 107-110
It has been reported that several conifers possess cytotoxic activities on some human tumor cell lines. Taxol as a natural cytotoxic compound has been extracted from this family. In a program to screen the cytotoxic effects of natural resources, male and female branchlets, fruit or bark of two different species of Iranian conifers were collected, identified and the cytotoxic effects of their hydroalcoholic extracts on three human tumor cell lines were determined. Different concentrations of extracts were added to cultured cells and incubated for 72 h. Cell survival was evaluated using MTT assay. Extracts from bark of female Taxus baccata showed inhibitory activities against Hela cells. The extracts of the branchlets of male and female T. baccata and branchlets of Cupressus horizentalis showed inhibitory activities against MDA-MB-468 cells, whereas the extracts of branchlets of female T. baccata showed inhibitory activities against KB cells. In conclusion, extract obtained from the bark of Iranian T. baccata showed a comparable cytotoxic effect to doxorubicin against Hela cells. © 2003, Iranian Journal of Pharmaceutical Research. All rights reserved.
Daru Journal Of Pharmaceutical Sciences (15608115)(3)pp. 82-87
Majority of the currently available anticancer drugs are designed to have selective toxicity to rapidly dividing cells. Among these agents the focus of many studies are compounds obtained from natural products with high therapeutic index. In this study the cytotoxicity of HESA-A, a marine compound, on cancer and normal cells was evaluated. HESA-A was prepared in normal saline as a stock solution (0.8 mg/ml, pH=7.4), sterilized and further diluted to final concentrations of 0.4, 0.2, 0.1 and 0.05 mg/ml. Cells (MDA-MB-468, Hep-2, Hela as cancer cells; L929 and McCoy as normal cells) were grown in completed RPMI 1640 and seeded in 96 well micro plates at a concentration of 1-5 × 104 cells/ml. After incubation for 24 h, different concentrations of HESA-A were added and cells were further incubated for 72 h. Using MTT assay, percent cell survival was determined by ELISA at 540 nm. Doxorubicin was used as a positive control (20 μg /ml). HESA-A (0.4 mg/ml) reduced the number of viable MDA-MB-468 and Hela cells to less than 50%. For Hep-2 cells the IC 50 was 0.8 mg/ml. In normal cells IC50 could not be obtained at any given concentrations. These results suggest that HESA-A in therapeutic doses and in a concentration dependent manner inhibits the growth of cancer cells more selectively than normal cells.
Zarghi, A.,
Zarghi, A.,
Sadeghi, H.,
Sadeghi, H.,
Fassihi, A.,
Fassihi, A.,
Faizi m., ,
Faizi m., ,
Shafiee a., ,
Shafiee a., Farmaco (0014827X)(11)pp. 1077-1081
Alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-methylthio-1-phenylamino-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that in the series of alkyl esters increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units decreases activity. In the phenylalkyl ester series increasing the length of methylene chain also decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. In addition, two compounds, 5b and 5f were more active than the nifedipine. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.
