Publications by authors named "Ali Mohammad Sharifi"

28 Publications

  • Page 1 of 1

In vitro and in vivo evaluation of a nanofiber wound dressing loaded with melatonin.

Int J Pharm 2021 Mar 23;596:120213. Epub 2021 Jan 23.

Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran; Razi Drug Research Center, Department of Pharmacology, Iran University of Medical Sciences, Tehran, Iran; Tissue Engineering Group (NOCERAL), Department of Orthopedics Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address:

Wound healing is a complicated process that takes a long time to complete. The three-layer nanofiber wound dressing containing melatonin is highly expected to show remarkable wound repair by reducing the wound healing time. In this study, chitosan (Cs)-polycaprolactone (PCL)/ polyvinylalcohol (PVA)-melatonin (MEL)/ chitosan-polycaprolactone three-layer nanofiber wound dressing was prepared by electrospinning for melatonin sustained release. The characteristics of the wound dressing were further evaluated. The wound dressing had a high water uptake after 24 h (401%), and the water contact angle results showed that it had hydrophilicity effect that supported the cell attachment. The wound healing effect of wound dressing was examined using a full-thickness excisional model of rat skin by the local administration of MEL. The gene expressions of transforming growth factor-beta (TGF-β1), alpha-smooth muscle actin (α-SMA), collagen type I (COL1A1), and collagen type III (COL3A1) were further studied. The histopathological evaluation showed the complete regeneration of the epithelial layer, remodeling of wounds, collagen synthesis, and reduction in inflammatory cells. The NF + 20% MEL significantly increased TGF-β1, COL1A1, COL3A1, and α-SMA mRNA expressions. This wound dressing may have a considerable potential as a wound dressing to accelerate the wound healing.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120213DOI Listing
March 2021

Role of organic and ceramic biomaterials on bone healing and regeneration: An experimental study with significant value in translational tissue engineering and regenerative medicine.

Iran J Basic Med Sci 2020 Nov;23(11):1426-1438

Razi Drug Research Center, and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Objectives: We investigated the role of various biomaterials on cell viability and in healing of an experimentally induced femoral bone hole model in rats.

Materials And Methods: Cell viability and cytotoxicity of gelatin (Gel; 50 µg/µl), chitosan (Chi; 20 µg/µl), hydroxyapatite (HA; 50 µg/µl), nanohydroxyapatite (nHA; 10 µg/µl), three-calcium phosphate (TCP; 50 µg/µl) and strontium carbonate (Sr; 10 µg/µl) were evaluated on hADSCs via MTT assay. femoral drill-bone hole model was produced in rats that were either left untreated or treated with autograft, Gel, Chi, HA, nHA, TCP and Sr, respectively. The animals were euthanized after 30 days. Their bone holes were evaluated by gross-pathology, histopathology, SEM and radiography. Also, their dry matter, bone ash and mineral density were measured.

Results: Both the Gel and Chi showed cytotoxicity, while nHA had no role on cytotoxicity and cell-viability. All the HA, TCP and Sr significantly improved cell viability when compared to controls (0.05). Both the Gel and Chi had no role on osteoconduction and osteoinduction. Compared to HA, nHA showed superior role in increasing new bone formation, mineral density and ash (0.05). In contrast to HA and nHA, both the TCP and Sr showed superior morphological, radiographical and biochemical properties on bone healing (0.05). TCP and Sr showed the most effective osteoconduction and osteoinduction, respectively. In the Sr group, the most mature type of osteons formed.

Conclusion: Various biomaterials have different efficacy during bone regeneration. TCP was found to be the best material for osteoconduction and Sr for osteoinduction.
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http://dx.doi.org/10.22038/ijbms.2020.46228.10707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671416PMC
November 2020

Skin wound healing assisted by angiogenic targeted tissue engineering: A comprehensive review of bioengineered approaches.

J Biomed Mater Res A 2021 Apr 10;109(4):453-478. Epub 2020 Oct 10.

Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran.

Skin injuries and in particular, chronic wounds, are one of the major prevalent medical problems, worldwide. Due to the pivotal role of angiogenesis in tissue regeneration, impaired angiogenesis can cause several complications during the wound healing process and skin regeneration. Therefore, induction or promotion of angiogenesis can be considered as a promising approach to accelerate wound healing. This article presents a comprehensive overview of current and emerging angiogenesis induction methods applied in several studies for skin regeneration, which are classified into the cell, growth factor, scaffold, and biological/chemical compound-based strategies. In addition, the advantages and disadvantages of these angiogenic strategies along with related research examples are discussed in order to demonstrate their potential in the treatment of wounds.
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http://dx.doi.org/10.1002/jbm.a.37105DOI Listing
April 2021

Investigating The Alterations of Oxidative Stress Status, Antioxidant Defense Mechanisms, MAP Kinase and Mitochondrial Apoptotic Pathway in Adipose-Derived Mesenchymal Stem Cells from STZ Diabetic Rats.

Cell J 2020 Jul 18;22(Suppl 1):38-48. Epub 2020 Jul 18.

Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Objective: This study aimed to investigate the reliability of diabetic adipose-derived stem cells (ADSCs) for autologous cell-based therapies by exploring the functionality of signalling pathways involved in regulating oxidative stress and apoptosis.

Materials And Methods: In this experimental study, ADSCs were isolated from streptozotocin (STZ)-induced diabetic rats (dADSCs) and normal rats (nADSCs). The colonies derived from dADSCs and nADSCs were compared by colony-forming unit (CFU) assay. Reactive oxygen species (ROS) formation and total antioxidant power (TAP) were also measured. Furthermore, the expression of antioxidant enzymes, including catalase (), superoxide dismutase (Sod)-1 and -3, glutathione peroxidase , -3 and -4 was measured at mRNA level by semi-quantitative reverse transcriptase polymerase chain reaction assay. The expression of Bax, Bcl2, caspase-3, total and phosphorylated c-Jun N-terminal kinase (JNK) and P38 Mitogen-Activated Protein Kinase (MAPK) at protein level was analyzed by western blotting.

Results: The results of this study indicated that viability and plating efficiency of dADSCs were significantly lower than those of nADSCs. ROS generation and TAP level were respectively higher and lower in dADSCs. The gene expression of antioxidant enzymes, including Cat, and in dADSCs was significantly greater than that in nADSCs. However, and mRNA levels were decreased in dADSCs. Moreover, Bax/Bcl-2 protein ratio, caspase-3 protein expression and phosphorylation of JNK and P38 proteins were increased in dADSCs compared to nADSCs.

Conclusion: Taken together, diabetes might impair the cellular functions of dADSCs as candidates for autologous cellbased therapies. This impairment seems to be mediated by JNK, P38 MAPKs, and mitochondria pathway of apoptosis and partly by disruption of antioxidant capacity.
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http://dx.doi.org/10.22074/cellj.2020.6958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481893PMC
July 2020

Control of Hyperglycemia Using Differentiated and Undifferentiated Mesenchymal Stem Cells in Rats with Type 1 Diabetes.

Cells Tissues Organs 2020 7;209(1):13-25. Epub 2020 Jul 7.

Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran,

Due to their ability in self-renewing and differentiation into a wide variety of tissues, mesenchymal stem cells (MSCs) exhibit outstanding potential for regenerative medicine. This study was aimed at investigating different aspects of MSC therapy in controlling hyperglycemia in streptozotocin-induced diabetes rats. Using an islet cell differentiation protocol, bone marrow (BM) MSCs were differentiated into insulin-producing cells (IPCs). The differentiation process was evaluated by immunocytochemistry, reverse transcriptase PCR, and dithizone staining. Diabetic animals in 4 diabetic individual groups received normal saline, BM-MSCs, coadministration of BM-MSCs with supernatant, and IPCs. Blood glucose and insulin levels were monitored during the experiment. Immunohistochemical analysis of the pancreas was performed at the end of the experiment. Administration of BM-MSCs could not reverse glucose and insulin levels in experimental animals as efficiently as cotransplantation of BM-MSCs with supernatant. The effect of coadministration of BM-MSCs with supernatant and transplantation of IPCs on controlling hyperglycemia is comparable. Immunohistochemical analysis showed that number and size of islets per section were significantly increased in groups receiving IPCs and BM-MSC-supernatant compared to the MSC group of animals. In conclusion, coadministration of BM-MSCs with supernatant could be used as efficiently as IPC transplantation in controlling hyperglycemia in diabetic rats.
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http://dx.doi.org/10.1159/000507790DOI Listing
July 2020

Design, fabrication, and optimization of a dual function three-layer scaffold for controlled release of metformin hydrochloride to alleviate fibrosis and accelerate wound healing.

Acta Biomater 2020 09 23;113:144-163. Epub 2020 Jun 23.

Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, P.O. Box 14395-1561, Tehran, Iran.

Abnormal wound healing caused by the over-expression of collagen and fibronectin leads to fibrosis, the major complication of all treatment modalities. A three-layer nanofiber scaffold was designed, optimized, and fabricated. This scaffold comprised two supportive polycaprolactone (PCL)-chitosan layers on the sides and a polyvinyl alcohol (PVA)-metformin hydrochloride (metformin-HCl) in the middle. The physico-chemical properties of scaffold, such as mechanical characteristics, degradation, swelling, and in-vitro drug release, were evaluated. The biological tests, including cell viability in response to metformin-HCl and Tween 80, scaffold biocompatibility, cell attachment, and antibacterial activity, were further conducted. The wound healing effect of scaffold loaded with metformin-HCl (MSc+Met) was assessed in donut-shaped silicone splints in rats. Histopathological and immunohistochemical evaluation as well as mRNA expression levels of fibrosis markers were also studied. SEM images indicated a uniform, bead-less morphology and high porosity. Surface modification of scaffold by Tween 80 improved the surface hydrophilicity and enhanced the adhesion and proliferation of fibroblasts. The scar area on day 15 in MSc+Met was significantly lower than that of other groups. Histopathological and immunohistochemical evaluation revealed that group MSc+Met was the best, having significantly lower inflammation, higher angiogenesis, the smallest scar width and depth, maximum epitheliogenesis score, and the most optimal modulation of collagen density. Local administration of metformin-HCl substantially down-regulated the expression of fibrosis-involved genes: transforming growth factor (TGF-β1), collagen type 1 (Col-I), fibronectin, collagen type 3 (Col-III), and alpha-smooth muscle actin (α-SMA). Inhibiting these genes alleviates scar formation but delays wound healing; thus, an engineered scaffold was used to prevent delay in wound healing. These results provided evidence for the first time to introduce an anti-fibrogenic slow-releasing scaffold, which acts in a dual role, both alleviating fibrosis and accelerating wound healing.
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http://dx.doi.org/10.1016/j.actbio.2020.06.031DOI Listing
September 2020

Protective effect of hydralazine on a cellular model of Parkinson's disease: a possible role of hypoxia-inducible factor (HIF)-1α.

Biochem Cell Biol 2020 06 14;98(3):405-414. Epub 2020 May 14.

School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.

Parkinson's disease (PD) is a neurodegenerative disease accompanied by a low expression level of cerebral hypoxia-inducible factor (HIF-1α). Hence, activating the hypoxia-signaling pathway may be a favorable therapeutic approach for curing PD. This study explored the efficacy of hydralazine, a well-known antihypertensive agent, for restoring the impaired HIF-1 signaling in PD, with the aid of 6-hydroxydopamine (6-OHDA)-exposed SH-SY5Y cells. The cytotoxicity of hydralazine and 6-OHDA on the SH-SY5Y cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and apoptosis detection assays. The activities of malondialdehyde, nitric oxide (NO), ferric reducing antioxidant power (FRAP), and superoxide dismutase (SOD) were also measured. Expression levels of HIF-1α and its downstream genes at the protein level were assessed by Western blotting. Hydralazine showed no toxic effects on SH-SY5Y cells, at the concentration of ≤50 μmol/L. Hydralazine decreased the levels of apoptosis, malondialdehyde, and NO, and increased the activities of FRAP and SOD in cells exposed to 6-OHDA. Furthermore, hydralazine up-regulated the protein expression levels of HIF-1α, vascular endothelial growth factor, tyrosine hydroxylase, and dopamine transporter in the cells also exposed to 6-OHDA, by comparison with the cells exposed to 6-OHDA alone. In summary, hydralazine priming could attenuate the deleterious effects of 6-OHDA on SH-SY5Y cells by increasing cellular antioxidant capacity, as well as the protein levels of HIF-1α and its downstream target genes.
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http://dx.doi.org/10.1139/bcb-2019-0117DOI Listing
June 2020

Protective effects of atorvastatin against high glucose-induced nuclear factor-κB activation in cultured C28I2 chondrocytes.

J Recept Signal Transduct Res 2019 Feb 25;39(1):1-8. Epub 2019 Jun 25.

b Razi Drug Research Center, Iran University of Medical Sciences , Tehran , Iran.

A number of epidemiological and experimental documents emphasizes a close relation between type 2 diabetes mellitus (T2DM) and the progression of osteoarthritis (OA). In order to understand the underlying mechanisms of atorvastatin (ATO) in OA, we sought to explore the effect of ATO on high glucose (HG)-mediated NF-κB activation in cultured C28I2 chondrocytes. The effects of various concentrations of ATO on C28I2 human chondrocytes viability were assessed to obtain the non-cytotoxic concentrations of drug by MTT-assay. The cells were pretreated with 0.01 and 0.1 μM ATO for 6 h, followed by incubation with HG (75 mM) for 72 h. The protein expressions of IκBα (np), IκBα (p), NF-κB (p), and NF-κB (np) were analyzed by western blotting. The effects of ATO on the mRNA expressions of chondrogenic specific markers including SOX9, aggrecan, collagen type 2, and COMP were evaluated by reverse transcription-polymerase chain reaction. ATO in determined concentrations had no cytotoxic effect on C28I2 cells after 72 h. ATO pretreatment exerted remarkable protective effects against HG-induced cytotoxicity. Moreover, ATO decreased IκBα phosphorylation and NF-κB nuclear translocation. It was also able to improve the gene expression of chondrogenic-specific markers in C28I2 cells compared to the control group. ATO could significantly decrease HG-induced inflammation in the cultured C28I2 chondrocytes through the activation of canonical NF-κB signaling pathway. These beneficial effects of ATO may be owing to its anti-inflammatory properties. Therefore, treatment with ATO may provide an effective approach to prevent HG-induced cartilage destruction in clinical setting.
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http://dx.doi.org/10.1080/10799893.2018.1557206DOI Listing
February 2019

Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes.

J Physiol Biochem 2019 Jun 22;75(2):153-162. Epub 2019 Feb 22.

Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.

The high glucose concentration is able to disturb chondrocyte homeostasis and contribute to OA pathogenesis. This study was designed to investigate the protective effects of atorvastatin (ATO) on high glucose (HG)-mediated oxidative stress and mitochondrial apoptosis in C28I2 human chondrocytes. The protective effect of ATO (0.01 and 0.1 μM) on HG (75 mM)-induced oxidative stress and apoptosis was evaluated in C28I2 cells. The effects of ATO on HG-induced intracellular ROS production and lipid peroxidation were detected and the protein expression levels of Bax, Bcl-2, caspase-3, total and phosphorylated JNK and P38 MAPKs were analyzed by Western blotting. The mRNA expression levels of antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. Pretreatment with ATO remarkably increased the gene expression levels of antioxidant enzymes and reduced HG-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. Atorvastatin could considerably reduce HG-induced oxidative stress and mitochondrial apoptosis through increasing the expression of antioxidant enzymes. Atorvastatin may be considered as a promising agent to prevent high glucose-induced cartilage degradation in OA patients.
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http://dx.doi.org/10.1007/s13105-019-00666-8DOI Listing
June 2019

Distinct Tie2 tyrosine phosphorylation sites dictate phenotypic switching in endothelial progenitor cells.

J Cell Physiol 2019 05 24;234(5):6209-6219. Epub 2018 Sep 24.

Department of Pharmacology, Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.

Angiogenesis is a regulated process involving the proliferation, migration, and remodeling of different cell types particularly mature endothelial and their progenitor cells, nominated as endothelial progenitor cells (EPCs). Tie2/Tek is a tyrosine kinase receptor expressed by endothelial cells that induces signal transduction pathways involved in endothelial biology. To address the potential importance of the various tyrosine residues of Tie2 in EPC development, we generated a series of Tie2 tyrosine mutated (Y1106F, Y1100F, and Y1111F) EPCs and then assess the biological features of these cells. Clonogenic, tubulogenic, proliferative, migratory, and functional properties of these cells were analyzed. Next, GFP-positive EPCs containing Tie2 tyrosine mutations were systemically transplanted into sublethaly irradiated mice to analyze the potency of these cells for marrow reconstitution. We found that mutation in the Tie2 tyrosine 1106 residue directed EPCs toward a mature endothelial phenotype, which was associated with augmented tubulogenic and migratory properties, and increased phosphorylation of the active site (tyrosine 992) as well as increased vascular perfusion in the in vivo Matrigel plug assay. Moreover, transplantation of 1106 Tie2 mutant EPCs failed to reconstitute the bone marrow after myeloablation, whereas transplantation of EPCs with the 1100 or 1111 Tie2 tyrosine mutation resulted in bone marrow engraftment, leading to improved survival of recipient mice. Our findings demonstrate that the tyrosine 1106 residue in Tie2 plays a key role to maintain the stemness features of EPCs.
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http://dx.doi.org/10.1002/jcp.27349DOI Listing
May 2019

Restoring the IL-1β/NF-κB-induced impaired chondrogenesis by diallyl disulfide in human adipose-derived mesenchymal stem cells via attenuation of reactive oxygen species and elevation of antioxidant enzymes.

Cell Tissue Res 2018 08 26;373(2):407-419. Epub 2018 Mar 26.

Department of Pharmacology and Razi Drug Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Strategies based on mesenchymal stem cell (MSC) therapy for restoring injured articular cartilage are not effective enough in osteoarthritis (OA). Due to the enhanced inflammation and oxidative stress in OA microenvironment, differentiation of MSCs into chondrocytes would be impaired. This study aims to explore the effects of diallyl disulfide (DADS) on IL-1β-mediated inflammation and oxidative stress in human adipose derived mesenchymal stem cells (hADSCs) during chondrogenesis. MTT assay was employed to examine the effects of various concentrations of DADS on the viability of hADSCs at different time scales to obtain non-cytotoxic concentration range of DADS. The effects of DADS on IL-1β-induced intracellular ROS generation and lipid peroxidation were evaluated in hADSCs. Western blotting was used to analyze the protein expression levels of IκBα (np), IκBα (p), NF-κB (np) and NF-κB (p). Furthermore, the gene expression levels of antioxidant enzymes in hADSCs and chondrogenic markers at days 7, 14 and 21 of differentiation were measured using qRT-PCR. The results showed that addition of DADS significantly enhanced the mRNA expression levels of antioxidant enzymes as well as reduced ROS elevation, lipid peroxidation, IκBα activation and NF-κB nuclear translocation in hADSCs treated with IL-1β. In addition, DADS could significantly increase the expression levels of IL-1β-induced impaired chondrogenic marker genes in differentiated hADSCs. Treatment with DADS may provide an effective approach to prevent the pro-inflammatory cytokines and oxidative stress as catabolic causes of chondrocyte cell death and enhance the protective anabolic effects by promoting chondrogenesis associated gene expressions in hADSCs exposed to OA condition.
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http://dx.doi.org/10.1007/s00441-018-2825-yDOI Listing
August 2018

Long term treatment by mesenchymal stem cells conditioned medium modulates cellular, molecular and behavioral aspects of adjuvant-induced arthritis.

Cell Mol Biol (Noisy-le-grand) 2018 Jan 31;64(1):19-26. Epub 2018 Jan 31.

Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Neuroinflammation plays a crucial role in expression of symptoms of numerous autoimmune and neurodegenerative diseases such as pain during rheumatoid arthritis. Overproduction of pro-inflammatory cytokines and activation of intracellular signaling pathways have been strongly implicated in the generation of pathological pain states, particularly at central nervous system sites and induction of spinal neuroinflammatory symptoms. The wide ranges of research to define new therapeutic approaches, including neuroimmune-modulators like stem cells are in progress. Mesenchymal stem cells conditioned medium (MSC-CM) has anti-inflammatory factors which can regulate the immune responses. The aim of this study was to investigate the effect of administration of MSC-CM on behavioral, cellular and molecular aspects of adjuvant-induced arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by single subcutaneous injection of CFA into the rat's hind paw on day 0. MSC-CM was administered daily (i.p.) and during the 21 days of the study after injection. Hyperalgesia, Edema, Serum TNF-α levels and p38MAPK and NF-κB activities were assessed on days 0,7,14 and 21 of the study. The results of this study indicated the role of MSC-CM in reducing inflammatory symptoms, serum TNF-α levels and activity of intracellular signaling pathway factors during different phases of inflammation caused by CFA. It seems that MSC-CM treatment due to its direct effects on inhibition of intracellular signaling pathways and pro-inflammatory cytokines can alleviate inflammatory symptoms and pain during CFA-induced arthritis.
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http://dx.doi.org/10.14715/cmb/2018.64.2.5DOI Listing
January 2018

Protective Effect of Ginger (Zingiber officinale Roscoe) Extract against Oxidative Stress and Mitochondrial Apoptosis Induced by Interleukin-1β in Cultured Chondrocytes.

Cells Tissues Organs 2017 7;204(5-6):241-250. Epub 2017 Sep 7.

RAZI Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.

Aims: The protective effects of ginger (Zingiber officinale Roscoe) extract on IL-1β-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes.

Methods: The effects of various concentrations of ginger extract on C28I2 human chondrocyte viability were evaluated in order to obtain noncytotoxic concentrations of the drug by methylthiotetrazole assay. The cells were pretreated with 5 and 25 μg/mL ginger extract for 24 h, followed by incubation with IL-1β (10 ng/mL) for 24 h. The effects of ginger extract on IL-1β-induced intracellular reactive oxygen species (ROS) production and lipid peroxidation were examined. The mRNA expressions of antioxidant enzymes including catalase, superoxide dismutase-1, glutathione peroxidase-1, glutathione peroxidase-3, and glutathione peroxidase-4 were evaluated by reverse transcription polymerase chain reaction. The protein expressions of Bax, Bcl-2, and caspase-3 were analyzed by Western blotting.

Results: No cytotoxicity was observed at any concentration of ginger extract in C28I2 cells. Ginger extract pretreatment remarkably increased the gene expression of antioxidant enzymes and reduced the IL-1β-induced elevation of ROS, lipid peroxidation, the Bax/Bcl-2 ratio, and caspase-3 activity.

Conclusions: Ginger extract could considerably reduce IL-1β-induced oxidative stress and consequent mitochondrial apoptosis as the major mechanisms of chondrocyte cell death. These beneficial effects of ginger extract may be due to its antioxidant properties. It may be considered as a natural herbal product to prevent OA-induced cartilage destruction in the clinical setting.
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http://dx.doi.org/10.1159/000479789DOI Listing
July 2018

Evaluation of fibrin-gelatin hydrogel as biopaper for application in skin bioprinting: An in-vitro study.

Biomed Mater Eng 2016 ;27(6):669-682

Department of Pharmacology, Iran University of Medical Science, Tehran, Iran.

Background: Recent advances in tissue engineering have led to the development of the concept of bioprinting as an interesting alternative to traditional tissue engineering approaches. Biopaper, a biomimetic hydrogel, is an essential component of the bioprinting process.

Objective: The aim of this work was to synthesize a biopaper made of fibrin-gelatin hybrid hydrogel for application in skin bioprinting.

Methods: Different composition percentages of the two biopolymer hydrogels, fibrin-gelatin, have been studied for the construction of the biopaper and were examined in terms of water absorption, biodegradability, glucose absorption, mechanical properties and water vapor transmission. Subsequently, tissue fusion study was performed on prepared 3T3 fibroblast cell line pellets embedded into the hydrogel.

Results: Based on the obtained results, fibrin-gelatin blend hydrogel with the same proportion of two components provides a natural scaffold for fibroblast-based bioink embedding and culture.

Conclusions: The suggested optimized hydrogel was a suitable candidate as a biopaper for skin bioprinting technology.
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http://dx.doi.org/10.3233/BME-161617DOI Listing
March 2017

The effect of nitrazepam on depression and curiosity in behavioral tests in mice: The role of potassium channels.

Eur J Pharmacol 2016 Nov 9;791:369-376. Epub 2016 Sep 9.

Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Evidence show that gamma-aminobutyric acid (GABA) receptors are involved in depression, so the aim of this study was to investigate the effect of nitrazepam as agonist of GABA receptors on depression and curiosity in male mice and the role of potassium channel in antidepressant-like response. For this purpose, we studied the antidepressant-like properties of fluoxetine, nitrazepam, glibenclamide, and cromakalim by both forced swimming test (FST) and tail suspension test (TST). Animals were injected by various doses of nitrazepam (0.05, 0.1, and 0.5mg/kg). Nitrazepam at dose of 0.5mg/kg significantly decreased the immobility time compared to control group in both FST and TST. Fluoxetine also showed such a response. Co-administration of nitrazepam (0.05mg/kg) with glibenclamide in TST (1mg/kg) and in FST (0.3, 1mg/kg) also showed antidepressant-like response. Beside, cromakalim (0.1mg/kg) could reverse the antidepressant-like effect of nitrazepam (0.5mg/kg) in both FST and TST, while cromakalim and glibenclamide alone could not change the immobility time compared to control group (P>0.05). The hole-board test revealed that nitrazepam at doses of 0.5 and 0.1mg/kg could increase the activity of the animal's head-dipping and boost the curiosity and exploration behavior of mice. The results of this study revealed that nitrazepam may possess antidepressant-like properties and this effect is dependent to potassium channels in both FST and TST.
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http://dx.doi.org/10.1016/j.ejphar.2016.09.017DOI Listing
November 2016

Studying neuroprotective effect of Atorvastatin as a small molecule drug on high glucose-induced neurotoxicity in undifferentiated PC12 cells: role of NADPH oxidase.

Metab Brain Dis 2017 02 1;32(1):41-49. Epub 2016 Aug 1.

Razi Drug Research Center and Dept. of Pharmacology, Iran University of Medical Sciences, Tehran, Iran.

Overproduction of reactive oxygen species (ROS) by NADPH oxidase (NOX) activation has been considered the essential mechanism induced by hyperglycemia in various tissues. However, there is no comprehensive study on the role of NOXs in high glucose (HG)-induced toxic effect in neural tissues. Recently, a therapeutic strategy in oxidative related pathologies has been introduced by blocking the undesirable actions of NOX enzymes by small molecules. The protective roles of Statins in ameliorating oxidative stress by NOX inhibition have been shown in some tissues except neural. We hypothesized then, that different NOXs may have role in HG-induced neural cell injury. Furthermore, we postulate that Atorvastatin as a small molecule may modulate this NOXs activity to protect neural cells. Undifferentiated PC12 cells were treated with HG (140 mM/24 h) in the presence and absence of Atorvastatin (1 μM/96 h). The cell viability was measured by MTT assay and the gene and protein expressions profile of NOX (1-4) were determined by RT-PCR and western blotting, respectively. Levels of ROS and malondialdehyde (MDA) were also evaluated. Gene and protein expression levels of NOX (1-4) and consequently ROS and MDA levels were elevated in HG-treated PC12 cells. Atorvastatin could significantly decrease HG-induced NOXs, ROS and MDA elevation and improve impaired cell viability. It can be concluded that HG could elevate NOXs activity, ROS and MDA levels in neural tissues and Atorvastatin as a small molecule NOX inhibitor drug may prevent and delay diabetic complications, particularly neuropathy.
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http://dx.doi.org/10.1007/s11011-016-9883-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102122PMC
February 2017

Utilizing the micron sized non-thermal atmospheric pressure plasma inside the animal body for the tumor treatment application.

Sci Rep 2016 07 7;6:29048. Epub 2016 Jul 7.

Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

This study aimed to evaluate the effects of micron sized non-thermal atmospheric pressure plasma inside the animal body on breast cancer tumor. The μ-plasma jet consists of micron sized hollow tube in which pure helium gas is ionized by high voltage (4 kV) and high frequency (6 kHz). The efficiency of the plasma treatment in killing cancer cells was first investigated by cell viability measurements of treated 4T1 cells using flow cytometry and cell cycle analysis. For exploration of the in vivo effects of the plasma treatment, the BALB/c mice inoculated by 4T1 cell lines were exposed subcutaneously to plasma for 3 minutes. In addition, H&E staining, TUNEL and Western blotting assays were performed in order to observed the effects of the non-thermal plasma on the tumor cells. The results showed that the efficiency of the plasma in suppression of the tumor growth is comparable to that of a typical chemotherapy drug. Moreover, the results indicated that the plasma induces apoptosis in the tumor tissue and increases the ratio of the apoptotic to anti-apoptotic protein expression. We believe that these findings presented herein may extend our knowledge of the mechanisms by which the plasma exerts its promising anti-cancer effects.
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http://dx.doi.org/10.1038/srep29048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935881PMC
July 2016

Role of Simvastatin on fracture healing and osteoporosis: a systematic review on in vivo investigations.

Clin Exp Pharmacol Physiol 2016 07;43(7):659-84

Department of Pathology, School of Veterinary Medicine, Shiraz, Iran.

Simvastatin is a lipid lowering drug whose beneficial role on bone metabolism was discovered in 1999. Several in vivo studies evaluated its role on osteoporosis and fracture healing, however, controversial results are seen in the literature. For this reason, Simvastatin has not been the focus of any clinical trials as yet. This systematic review clears the mechanisms of action of Simvastatin on bone metabolism and focuses on in vivo investigations that have evaluated its role on osteoporosis and fracture repair to find out (i) whether Simvastatin is effective on treatment of osteoporosis and fracture repair, and (ii) which of the many available protocols may have the ability to be translated in the clinical setting. Simvastatin induces osteoinduction by increasing osteoblast activity and differentiation and inhibiting their apoptosis. It also reduces osteoclastogenesis by decreasing both the number and activity of osteoclasts and their differentiation. Controversial results between the in vivo studies are mostly due to the differences in the route of administration, dose, dosage and carrier type. Local delivery of Simvastatin through controlled drug delivery systems with much lower doses and dosages than the systemic route seems to be the most valuable option in fracture healing. However, systemic delivery of Simvastatin with much higher doses and dosages than the clinical ones seems to be effective in managing osteoporosis. Simvastatin, in a particular range of doses and dosages, may be beneficial in managing osteoporosis and fracture injuries. This review showed that Simvastatin is effective in the treatment of osteoporosis and fracture healing.
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http://dx.doi.org/10.1111/1440-1681.12577DOI Listing
July 2016

Combination of ultrasound and newly synthesized magnetic nanocapsules affects the temperature profile of CT26 tumors in BALB/c mice.

J Med Ultrason (2001) 2015 Jan 18;42(1):9-16. Epub 2014 Jul 18.

Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), PO Box 14155-5983, Tehran, Iran.

Purpose: To investigate the effects of a combination of 3-MHz ultrasound waves with a new magnetic nanocapsule containing 5-fluorouracil (5-Fu) on the temperature profile of a mouse colon tumor (CT26) in BALB/c mice.

Methods: Firstly, 5-Fu-loaded magnetic nanocapsules were synthesized using a multiple emulsion solvent evaporation procedure. Magnetic resonance imaging (MRI) was performed to evaluate the efficiency of nanocapsule localization in the tumor during magnetic drug targeting (MDT). Tumors were separately exposed to 3-MHz ultrasound waves at the intensities of 0.1, 0.3, 0.5, and 1 W/cm(2) for 10 min in the absence and presence of nanocapsules. The temperature of the tumor was recorded at 1-min intervals.

Results: The effective diameter of the nanocapsules was approximately 70 nm, and it was demonstrated that magnetic nanoparticles were well dispersed inside the nanocapsules. MRI confirmed that the magnetic nanocapsules were successfully targeted to the tumor after accomplishing MDT. Temperature change due to sonication of the tumor was strongly intensity dependent. Moreover, temperature-time curves revealed that the magnetic nanocapsules significantly affected the temperature rise profile of a sonicated tumor.

Conclusion: Data presented in this study would be helpful to develop an ultrasound-mediated MDT procedure so that temperature changes of the tumor and its surrounding normal tissues may be controllable.
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http://dx.doi.org/10.1007/s10396-014-0558-4DOI Listing
January 2015

Deferoxamine Preconditioning of Neural-Like Cells Derived from Human Wharton's Jelly Mesenchymal Stem Cells as a Strategy to Promote Their Tolerance and Therapeutic Potential: An In Vitro Study.

Cell Mol Neurobiol 2016 Jul 5;36(5):689-700. Epub 2015 Aug 5.

Razi Drug Research Center, Department of Pharmacology, School of Medicine, Iran University of Medical Science, Tehran, Iran.

Transplantation of neural-like cells is considered as a promising therapeutic strategy developed for neurodegenerative disease in particular for ischemic stroke. Since cell survival is a major concern following cell implantation, a number of studies have underlined the protective effects of preconditioning with hypoxia or hypoxia mimetic pharmacological agents such as deferoxamine (DFO), induced by activation of hypoxia inducible factor-1 (HIF-1) and its target genes. The present study has investigated the effects of DFO preconditioning on some factors involved in cell survival, angiogenesis, and neurogenesis of neural-like cells derived from human Wharton's jelly mesenchymal stem cells (HWJ-MSCs) in presence of hydrogen peroxide (H2O2). HWJ-MSCs were differentiated toward neural-like cells for 14 days and neural cell markers were identified using immunocytochemistry. HWJ-MSC-derived neural-like cells were then treated with 100 µM DFO, as a known hypoxia mimetic agent for 48 h. mRNA and protein expression of HIF-1 target genes including brain-derived neurotrophic factors (BDNF) and vascular endothelial growth factor (VEGF) significantly increased using RT-PCR and Western blotting which were reversed by HIF-1α inhibitor, while, gene expression of Akt-1, Bcl-2, and Bax did not change significantly but pAkt-1 was up-regulated as compared to poor DFO group. However, addition of H2O2 to DFO-treated cells resulted in higher resistance to H2O2-induced cell death. Western blotting analysis also showed significant up-regulation of HIF-1α, BDNF, VEGF, and pAkt-1, and decrease of Bax/Bcl-2 ratio as compared to poor DFO. These results may suggest that DFO preconditioning of HWJ-MSC-derived neural-like cells improves their tolerance and therapeutic potential and might be considered as a valuable strategy to improve cell therapy.
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http://dx.doi.org/10.1007/s10571-015-0249-8DOI Listing
July 2016

Synergistic effects of magnetic drug targeting using a newly developed nanocapsule and tumor irradiation by ultrasound on CT26 tumors in BALB/c mice.

J Mater Chem B 2015 Mar 28;3(9):1879-1887. Epub 2015 Jan 28.

Medical Physics Department, School of Medicine, Iran University of Medical Sciences (IUMS), Associate Professor of Biophysics, Razi Drug Research Centre, P.O. Box: 14155-5983, Tehran, Iran.

The aim of the current study was to magnetically target the 5-fluorouracil (5-Fu) loaded magnetic poly lactic-co-glycolic acid (PLGA) nanocapsules towards CT26 colon tumor model in BALB/c mice. In addition, we ultrasonicated the tumors impregnated by nanocapsules with the goal of aiding them in magnetic drug targeting (MDT) procedure. Newly synthesized 5-Fu-loaded PLGA magnetic nanocapsules were characterized. Various treatment modalities with the use of nanocapsules, magnetic fields, and ultrasound were applied to the tumors and appropriate controls were considered. Magnetic resonance imaging (MRI) and Prussian blue (PB) staining were performed to analyze the distribution of nanocapsules within the CT26 tumor. Finally, anti-tumor and pro-apoptotic effects of each treatment modality on CT26 tumors were investigated. The effective diameter of nanocapsules was approximately 70 nm. The histological staining of the tumor tissue with PB as well as MRI revealed a broad distribution of magnetic nanocapsules within the tumor and confirmed the targeting of nanocapsules to the tumors. Anti-tumor studies demonstrated that the combination of nanocapsules-MDT-ultrasound effectively inhibits the growth of CT26 tumors compared with injection of 5-Fu alone (P < 0.01). The present study exhibits potentials of the newly synthesized magnetic nanocapsule and suggests that the combination of MDT and ultrasound might help this new nanotechnology-based cancer chemotherapy agent in vivo.
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http://dx.doi.org/10.1039/c4tb01708kDOI Listing
March 2015

Feasibility of clinoptilolite application as a microporous carrier for pH-controlled oral delivery of aspirin.

Acta Chim Slov 2014 ;61(4):688-93

Clinoptilolite is a natural zeolite which due to high surface area/volume ratio has found many applications in industries and medicine. Aspirin is a non-steroidal anti-inflammatory drug which is currently used as an anticoagulant, antinociceptive, antipyretic, and anti-inflammatory drug. It is an acidic drug which induces gastric irritation due to inhibition of cyclooxygenase I located in gastric mucosa. In the present work, adsorption and desorption of aspirin on Iranian clinoptilolite micronized particles were studied in acidic and relatively alkaline pHs. Effect of particle size of clinoptilolite was also investigated on adsorption and desorption of aspirin. Specific surfaces, particle sizes, and zeta potentials of clinoptilolite particles were also determined. Scanning electron micrograph was used to study the morphology and crystallinity of clinoptilolite particles. The results showed that adsorption and desorption of aspirin on clinoptilolite are particle size- and pH-dependent. The present work proposes clinoptilolite as an inexpensive, efficient, and non-toxic natural available microporous material for aspirin oral delivery.
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May 2015

Cerium and yttrium oxide nanoparticles against lead-induced oxidative stress and apoptosis in rat hippocampus.

Biol Trace Elem Res 2015 Mar 18;164(1):80-9. Epub 2014 Dec 18.

Razi Drug Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Iran,

Due to numerous industrial applications, lead has caused widespread pollution in the environment; it seems that the central nervous system (CNS) is the main target for lead in the human body. Oxidative stress and programmed cell death in the CNS have been assumed as two mechanisms related to neurotoxicity of lead. Cerium oxide (CeO2) and yttrium oxide (Y2O3) nanoparticles have recently shown antioxidant effects, particularly when used together, through scavenging the amount of reactive oxygen species (ROS) required for cell apoptosis. We looked into the neuroprotective effects of the combinations of these nanoparticles against acute lead-induced neurotoxicity in rat hippocampus. We used five groups in this study: control, lead, CeO2 nanoparticles + lead, Y2O3 nanoparticles + lead, and CeO2 and Y2O3 nanoparticles + lead. Nanoparticles of CeO2 (1000 mg/kg) and Y2O3 (230 mg/kg) were administered intraperitoneally during 2 days prior to intraperitoneal injection of the lead (25 mg/kg for 3 days). At the end of the treatments, oxidative stress markers, antioxidant enzymes activity, and apoptosis indexes were investigated. The results demonstrated that pretreatments with CeO2 and/or Y2O3 nanoparticles recovered lead-caused oxidative stress markers (ROS, lipid peroxidation, and total thiol molecules) and apoptosis indexes (Bax/Bcl-2 and caspase-3 protein expression). Besides, these nanoparticles reduced the activities of lead-induced superoxide dismutase and catalase as well as the ADP/ATP ratio. Interestingly, the best recovery resulted from the compound of these nanoparticles. Based on these outcomes, it appears that this combination may potentially be beneficial for protection against lead-caused acute toxicity in the brain through improving the oxidative stress-mediated programmed cell death pathway.
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http://dx.doi.org/10.1007/s12011-014-0197-zDOI Listing
March 2015

Effect of 17β-estradiol on mediators involved in mesenchymal stromal cell trafficking in cell therapy of diabetes.

Cytotherapy 2015 Jan 20;17(1):46-57. Epub 2014 Nov 20.

Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Background Aims: Mesenchymal stromal cells (MSCs) have shown great promise for cell therapy of a wide range of diseases such as diabetes. However, insufficient viability of transplanted cells reaching to damaged tissues has limited their potential therapeutic effects. Expression of estrogen receptors on stem cells may suggest a role for 17β-estradiol (E2) in regulating some functions in these cells. There is evidence that E2 enhances homing of stem cells. Induction of hypoxia-inducible factor-1α (HIF-1α) by E2 and the profound effect of HIF-1α on migration of cells have previously been demonstrated. We investigated the effect of E2 on major mediators involved in trafficking and subsequent homing of MSCs both in vitro and in vivo in diabetic rats.

Methods: E2 has been selected to improve the poor migration capacity of MSCs toward sites of injury. MSCs were incubated with different concentrations of E2 for varying periods of time to investigate whether estradiol treatment could be effective to enhance the efficiency of MSC transplantation.

Results: E2 significantly enhanced the viability of the cells that were blocked by ICI 182,780 (estrogen receptor antagonist). E2 also increased HIF-1α, CXC chemokine receptor 4 and C-C chemokine receptor 2 protein and messenger RNA levels measured by Western blot and reverse transcription-polymerase chain reaction. The enzymatic activity of matrix metalloproteinase 2 and metalloproteinase 9 was elevated in E2-treated cells through the use of gelatin zymography. Finally, the improved migration capacity of E2-treated MSCs was evaluated with the use of a Boyden chamber and in vivo migration assays.

Conclusions: Our data support that conditioning of MSCs with E2 promotes migration of cells in cultured MSCs in vitro and in a diabetic rat model in vivo through regulation of major mediators of cell trafficking.
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http://dx.doi.org/10.1016/j.jcyt.2014.06.009DOI Listing
January 2015

Protective effects of alpha lipoic acid on high glucose-induced neurotoxicity in PC12 cells.

Metab Brain Dis 2015 Jun 18;30(3):731-8. Epub 2014 Nov 18.

Razi Drug Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Iran.

Hyperglycemia plays an important role in the development of diabetic neuropathy. In this study, we investigated the protective effects of alpha lipoic acid (ALA) against high glucose-induced neurotoxicity in PC12 cells as a suitable in vitro model for studying neuronal functions. PC12 cells were treated with high glucose (25 mg/ml for 24 h) in the absence and presence of ALA (100 μM for 24 h). The viability of PC12 cells was estimated by using MTT assay. The expression of pro- apoptotic Bax, anti- apoptotic Bcl-2 and caspase 3 protein were evaluated by western blotting. The reactive oxygen species (ROS) levels were determined with 2,7-dichlorodihydro- fluorescein diacetate (H2DCFDA). Biochemical markers of oxidative stress were assessed by using the total antioxidant power (TAP), lipid peroxidation (LPO), ADP/ATP ratio, activity of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Pretreatment of PC12 cells with ALA, significantly improved high glucose-induced toxicity by increasing activity of antioxidant enzymes CAT and SOD in the PC12 cell. It also increased the concentrations of TAP. An elevated level of cell death and ROS in high glucose conditions, diminished with ALA treatment. Over expression of Bax and caspase 3 protein, elevation of ADP/ATP ratio and LPO level in high glucose- treated PC12 cells, were significantly reduced by ALA. It was concluded that ALA attenuates neurotoxicity induced by high glucose in PC12 cells.
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http://dx.doi.org/10.1007/s11011-014-9625-1DOI Listing
June 2015

A new magnetic nanocapsule containing 5-fluorouracil: in vivo drug release, anti-tumor, and pro-apoptotic effects on CT26 cells allograft model.

J Biomater Appl 2014 Oct 9;29(4):548-56. Epub 2014 Jun 9.

Medical Physics Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Razi Drug Research Centre, Iran University of Medical Sciences, Tehran, Iran

The purpose of this study was to create an optimized method for preparation of 5-fluorouracil-loaded magnetic poly lactic-co-glycolic acid nanocapsules and to investigate its potential as multifunctional carriers to deliver therapeutic agents for tumor-targeted therapies. The in vitro release of the newly synthesized 5-fluorouracil-loaded poly lactic-co-glycolic acid magnetic nanocapsules was investigated in phosphate-buffered saline medium using the dialysis method. In vivo release studies of the magnetic nanocapsules were performed in rabbits. Finally, the targeting properties, anti-tumor, and pro-apoptotic effects of this new magnetic nanocapsule on CT26 cells allograft model were studied. The effective diameter of nanocapsules was 67.2 nm. In vivo release investigations showed that 5-fluorouracil has a sustained release profile, prolonged lifetime in the rabbit plasma, and increased tissue appetency when loaded into the magnetic nanocapsule. Magnetic resonance imaging confirmed that the magnetic nanocapsules were successfully targeted to the tumor. Additionally, the anti-tumor studies revealed that the targeted therapy with magnetic nanocapsules containing 5-fluorouracil effectively inhibits the growth of tumors compared with 5-fluorouracil alone (P < 0.01). The present study demonstrates that this new magnetic nanocapsule can be considered a new nanotechnology-based cancer chemotherapy agent in vivo.
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http://dx.doi.org/10.1177/0885328214536940DOI Listing
October 2014

The effect of fetal liver-derived cell suspension allotransplantation on patients with diabetes: first year of follow-up.

Acta Med Iran 2012 ;50(8):541-6

Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Stem cell-based therapies have recently opened up new horizons for treatment of various types of diseases including diabetes mellitus. However, long-term efficacy and safety of these novel modalities still remain a serious question. Hereby, we aim to report the one-year follow-up results in the diabetic patients who underwent fetal liver-derived hematopoietic stem cell allotransplantation. Fifty six patients with type one (n=30) and type two (n=26) diabetes, aged 10-58 years old (32.8 ± 16.3) were divided into the intervention and placebo group. The patients in the intervention group underwent fetal liver-derived hematopoietic stem cell transplantation while the patients in the placebo group received 5 ml of normal saline both via an intravenous route. The patients were visited at regular intervals to evaluate the efficacy of transplantation in glycemic control as well as possible complications. In the 6th month of the follow-up, there was a significant decrease in HbA1c levels in all groups without any rise in the fasting c-peptide. However, none of the precipitants transiently or continuously became insulin free in the first year after transplantation. It can be concluded that, in this study, fetal liver-derived hematopoietic stem cell transplantation had no significant effects on glycemic control. The heterogeneity of our patients might account for the negative results. Hence, longer follow-up results will be reported in the near future.
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April 2013

CD44+ cancer cells express higher levels of the anti-apoptotic protein Bcl-2 in breast tumours.

Cancer Immun 2009 Apr 23;9. Epub 2009 Apr 23.

Department of Pathology, Iran University of Medical Sciences, Tehran, Iran.

Breast tumours consist of phenotypically diverse populations of breast cancer cells of which only a minority has the ability to form new tumours. The capacity for breast tumour development has been shown to be restricted to breast cancer stem cells with the CD44+/CD24(-/low) phenotype. These cells can resist apoptosis through mechanisms such as the regulation of Bcl-2. Identification of this population of cells is important because of its implication in the development of new therapeutic strategies. One hundred and forty-six primary operable breast cancer patients were investigated in order to identify the population of CD44+ and Bcl-2+ cells in paraffin-embedded tissues by immunohistochemistry. The prevalence of these phenotypes was then correlated with clinicopathological features. CD44 and Bcl-2 expression was detected in 86% and 82% of breast tumours, respectively. There was no significant correlation between CD44+ tumour cell prevalence and tumour characteristics, whereas the prevalence of CD44+ cells was associated with higher levels of Bcl-2 expression (P = 0.004). In univariate analysis, Bcl-2 expression was correlated with breast tumours of lower grade (P < 0.001) and fewer lymphatic metastases (P < 0.05). Our findings suggest that the prevalence of CD44+ tumour cells as a subpopulation of breast cancer stem cells was of no clinicopathological significance, but was correlated with higher Bcl-2 expression. This population of tumour cells may thus be more resistant to apoptosis. Targeting these cells in combination with current treatments may be more effective in treating breast cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935767PMC
April 2009