Publications by authors named "Hamid Reza Sadeghnia"

105 Publications

Association between serum Vitamin E concentrations and the presence of Metabolic Syndrome: A population-based cohort study.

Acta Biomed 2021 07 1;92(3):e2021047. Epub 2021 Jul 1.

a:1:{s:5:"en_US";s:92:"c. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran";}.

Background: Metabolic syndrome (MetS) is a cluster of clinical and metabolic features that include central obesity, dyslipidemia, hypertension and impaired glucose tolerance. These features are accompanied by increased oxidative stress and impaired antioxidant defenses. Vitamin E is a major factor in the non-enzymatic antioxidant defenses. The aim of present study was to investigate the association between serum levels of vitamin E and the presence of MetS and its components in a sample population of Mashhad stroke and heart atherosclerotic disorder (MASHAD) cohort study.

Methods: This cross-sectional study was carried out in 128 subjects with MetS and 235 subjects without MetS. MetS was defined according to the International-Diabetes-Federation criteria. Serum levels of vitamin E were measured using the HPLC method. Anthropometric and biochemical parameters were measured using standard protocols.  Results. MetS patients had significantly lower serum levels of vitamin E (Vit E), Vit E/Total cholesterol (TC), and Vit E/ (TC+triglyceride(TG)) compared to the control group (P < 0.05).  Vit E/ (TG+TC) was also significantly lower in diabetics or those with elevated levels of high sensitive C-reactive protein (hs-CRP). Additionally, there was a significant association between Vit E/ (TG + Total Cho) and the number of components of the metabolic syndrome (p= 0.02) Conclusions. There is a significant inverse association between indices of Vit E status and the presence of MetS. Moreover, a significantly lower Vit E/ (TC+TG) was observed along with individuals with increasing numbers of components of the MetS.
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http://dx.doi.org/10.23750/abm.v92i3.9173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343740PMC
July 2021

The effect of RGD-targeted and non-targeted liposomal Galbanic acid on the therapeutic efficacy of pegylated liposomal doxorubicin: From liposomal preparation to in-vivo studies.

Int J Pharm 2021 Jul 19;604:120710. Epub 2021 May 19.

Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

The anti-cancer therapeutic application of Galbanic acid (Gba) as a strong antiangiogenic sesquiterpene coumarin has been limited due to its low water solubility. This issue necessitates developing new liposomal formulations for the efficient delivery of Gba in vivo. In this study, various liposomal formulations were prepared by a thin-film hydration method, and Gba was incorporated into the liposomal bilayers, which consequently increased its release profile compared to formulations in our previous study prepared by remote loading methods. The most stable formulation with desired properties was selected and decorated with RGD peptide (cyclo [Arg-Gly-Asp-D-Tyr-Cys]) to target tumor vasculature actively. The fluorescently-labeled model liposomes showed that the targeting could improve the receptor-mediated endocytosis of the liposomes higher than those prepared in our previous study in vitro in human umbilical vein endothelial cells (HUVECs), which was confirmed by chicken chorioallantoic membrane angiogenesis (CAM) model in vivo. Although not significant, it also could increase the accumulation of liposomes in colon tumors. In BALB/c mice bearing colon cancer, not only non-targeted Gba liposomes but also even RGD-targeted ones combinatorial therapy with pegylated liposomal doxorubicin could improve the anti-tumor efficacy as compared to their monotherapy. These outcomes have strong consequences for cancer therapy.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120710DOI Listing
July 2021

Effect of rutin on oxidative DNA damage in PC12 neurons cultured in nutrients deprivation condition.

Iran J Basic Med Sci 2020 Mar;23(3):390-395

Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Rutin is a flavonoid with potent antioxidant property, which exhibited cytoprotective effects in several models of neuronal injury. This work aimed to examine whether rutin can protect neurons against oxidative DNA damage caused by serum/glucose deprivation (SGD) as an in vitro model of neurodegeneration and ischemia.

Materials And Methods: The PC12 cells were cultured for 2 hr in normal culture medium containing different concentrations of rutin or α-tocopherol (positive control) and then further incubated for 12 hr in SGD condition. Then, cell viability, DNA fragmentation, lipid peroxidation, generation of reactive oxygen species (ROS), and the expression of proteins involved in apoptosis were determined.

Results: The SGD condition significantly decreased viability of the cells, which was accompanied by a significant rise in the generation of ROS and lipid peroxidation. Rutin enhanced the viability of PC12 cells in SGD condition and reduced the production of ROS and lipid peroxidation. In addition, rutin decreased DNA damage and inhibited apoptotic cell death by decreasing the levels of proapoptotic proteins (Bax, caspase-3, caspase-9) and increasing the level of anti-apoptotic protein Bcl-2.

Conclusion: This study demonstrated that rutin inhibits oxidative DNA damage and neuronal death induced by nutrients deprivation condition. Further studies may warrant the use of rutin as an appropriate neuroprotective agent for ischemic attacks and other neurodegenerative disorders.
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http://dx.doi.org/10.22038/IJBMS.2020.31832.7657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229504PMC
March 2020

The effects of acetyl-11-keto-β-boswellic acid on brain cytokines and memory impairment induced by lipopolysaccharide in rats.

Cytokine 2020 07 4;131:155107. Epub 2020 May 4.

Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

The therapeutic effects of the olibanum, the resin of Boswellia serrata on inflammatory diseases have been reported. There are more than 200 active ingredients in this resin including acetyl-11-keto-β-boswellic acid (AKBA). We proposed that AKBA can improve memory impairment induced by cerebral inflammation following the administration of lipopolysaccharide (LPS). Forty male rats were grouped and received the following treatments: Control (diluted DMSO + saline), LPS (diluted DMSO + 1 mg/kg LPS), LPS- AKBA 5 and LPS- AKBA 10 (5 or 10 mg/ kg AKBA before LPS). Morris water maze (MWM), passive avoidance (PA) and biochemical tests were carried out. Pre-treatment with both doses of AKBA improved memory performance in MWM and PA tests (P < 0.05 to P < 0.001). Pre-treatment by AKBA improved the levels of hippocampal IL-10 (P < 0.001), BDNF (P < 0.001), CAT (P < 0.05 and P < 0.001), SOD P < 0.001 and thiols (P < 0.01 and P < 0.001) while reduced IL-6 (P < 0.001), TNF-α (P < 0.001), NO (P < 0.05 and P < 0.001), GFAP (P < 0.001) and MDA (P < 0.001) levels. AKBA effectively ameliorated LPS-induced learning and memory impairments and improved BDNF in a neuroinflammation animal model. The effects seem to be due to setting a positive balance between pro-inflammatory to inflammatory cytokines and reinvigorate the antioxidant system.
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http://dx.doi.org/10.1016/j.cyto.2020.155107DOI Listing
July 2020

Author Correction: Liposomal formulation of Galbanic acid improved therapeutic efficacy of pegylated liposomal Doxorubicin in mouse colon carcinoma.

Sci Rep 2020 Feb 27;10(1):3965. Epub 2020 Feb 27.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-60918-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044310PMC
February 2020

Rosmarinic Acid Protects Adipose Tissue-Derived Mesenchymal Stem Cells in Nutrient-Deficient Conditions.

Prev Nutr Food Sci 2019 Dec 31;24(4):449-455. Epub 2019 Dec 31.

Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad 91779-44553, Iran.

One of the major challenges for stem cell therapy of ischemic organs is that the transplanted cells are confronted with nutrient deficiency and oxidative stress. Previous studies have indicated that pretreatment of stem cells with cytoprotective phytochemicals improves their therapeutic potential. This study was aimed to investigate whether rosmarinic acid can enhance survival of adipose tissue-derived stem cells (ASCs) in nutrient-deficient culture as an model of ischemia. The ASCs were isolated from subcutaneous adipose tissue of male adult Wistar rats and incubated for 24 h with rosmarinic acid in nutrient-deficient (glucose- and serum-deprived, GSD) culture medium. In a separate experiment, ASCs were pre-incubated for 4 h with rosmarinic acid and then exposed to GSD conditions for 24 h. The viability of ASCs was determined using thiazolyl blue tetrazolium bromide assays. The effect of rosmarinic acid on the cell cycle was evaluated using propidium iodide staining. GSD conditions significantly decreased the viability of ASCs and enhanced the generation of reactive oxygen species (ROS), lipid peroxidation, sub-G1 cell populations, and necrosis. Both pre-incubation and incubation of ASCs with 0.75~6 μM rosmarinic acid significantly increased cell viability in GSD conditions. Rosmarinic acid further decreased the level of ROS, lipid peroxidation, the percent of cells in sub-G1 stage, and necrosis in GSD conditions. These findings suggest that rosmarinic acid enhances survival of ASCs cultured in nutrient-deficient conditions through promoting antioxidant effects. Therefore, rosmarinic acid may help preserve ASCs survival after they are transplanted into ischemic organs.
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http://dx.doi.org/10.3746/pnf.2019.24.4.449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941722PMC
December 2019

A Review of Potential Efficacy of Saffron ( L.) in Cognitive Dysfunction and Seizures.

Prev Nutr Food Sci 2019 Dec 31;24(4):363-372. Epub 2019 Dec 31.

Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad 9177944553, Iran.

(saffron) is traditionally used to relieve several ailments. Experimental researches have also investigated applications of saffron and its active constituents for the treatment of a wide spectrum of disorders. This review discusses pharmacological/therapeutic properties of saffron and its main components on memory function, learning ability and seizures, to highlight their merit for alleviating these disorders. An extensive literature review was carried out using various databases including ISI Web of Knowledge, Medline/PubMed, Science Direct, Scopus, Google Scholar, Embase, Biological Abstracts, and Chemical Abstracts. The growing body of evidence showed the value of saffron and its' components, alone, or in combination with the other pharmaceuticals, for improving learning and memory abilities and controlling seizures. These findings may provide pharmacological basis for the use of saffron in cognitive disturbance and epilepsy. However, further preclinical and clinical studies are necessary.
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http://dx.doi.org/10.3746/pnf.2019.24.4.363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941716PMC
December 2019

Menstrual problems in adolescence: relationship to serum vitamins A and E, and systemic inflammation.

Arch Gynecol Obstet 2020 01 16;301(1):189-197. Epub 2019 Nov 16.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Vitamin status and inflammatory mechanisms may be related to menstrual cycle abnormalities. We investigated the associations between serum fat soluble vitamin (vitamins A and E) concentrations and biomarkers of inflammation and antioxidant status with menstrual characteristics, primary dysmenorrhea (PD) and premenstrual syndrome (PMS) in healthy adolescents.

Methods: A total of 897 adolescent girls either suffering from PMS (n = 134), PD (n = 322), PMS and PD (n = 293) or healthy adolescents (n = 148) were recruited. Serum vitamin A and E, high-sensitivity C-reactive protein (hs-CRP), antibody titers to Hsp27 (anti-Hsp27), serum prooxidant-antioxidant balance (PAB), WBC, mean platelet volume (MPV), and platelet distribution width (PDW) and RBC distribution width (RDW) were measured. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and RDW-to-platelet ratio (RPR) were calculated.

Results: Girls with long bleeding periods had lower concentrations of serum vitamin E compared to those who reported a normal period duration. There were significantly differences between the groups reporting oligomenorrhea, regular menses and polymenorrhea with respect to NLR, RPR, MPV and PDW. Logistic regression demonstrated that the presence of both PMS and PD was positively related to higher serum hs-CRP, PAB and NLR, while serum vitamin A level was inversely related to the presence of PMS.

Conclusions: We found that serum vitamin A, hs-CRP, PAB and NLR are significantly associated with the presence of PMS and PD. Inflammatory processes may contribute to the etiology, symptoms and severity of menstrual disorders. Prospective studies are needed to elucidate the possibility of targeting oxidative stress and inflammatory process for the amelioration of menstrual symptoms.
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http://dx.doi.org/10.1007/s00404-019-05343-1DOI Listing
January 2020

Designing a multifunctional staphylokinase variant (SAK-2RGD-TTI) with appropriate thrombolytic activity in vitro.

Biotechnol Lett 2020 Jan 4;42(1):103-114. Epub 2019 Nov 4.

Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective: Thrombin, platelets, and plasmin are three key factors involved in hemostasis and thrombolysis. Thrombolytic therapy with clinically approved drugs is often followed by recurrent thrombosis caused by thrombin-induced platelet aggregation from the clot debris. In order to minimize these problems, new constructs were designed for the expression of recombinant staphylokinase (rSAK) and also a fusion protein composed of staphylokinase, 20 amino acids containing 2 RGD followed by tsetse thrombin Inhibitor (SAK-2RGD-TTI) in Pichia pastoris.

Result: Modeling the tertiary structure of SAK-2RGD-TTI showed that the linker containing RGD and TTI did not interfere with proper folding of SAK. In laboratory testing, the purified SAK-2RGD-TTI (420 μg/mL) dissolved an average of 45% of the blood clot. The activity of the SAK-2RGD-TTI was also confirmed in various tests including human plasminogen activation assay, fibrin clot lysis assay, well diffusion method, activated partial thromboplastin time and platelet rich clot lysis assay.

Conclusion: Our findings suggest that SAK-2RGD-TTI has improved therapeutic properties preventing reocclussion. It further confirms that it is practicable to assemble and produce a hybrid multifunctional protein that targets hemostatic process at various stages.
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http://dx.doi.org/10.1007/s10529-019-02748-5DOI Listing
January 2020

3-Acetyl-11-keto-β-boswellic acid attenuated oxidative glutamate toxicity in neuron-like cell lines by apoptosis inhibition.

J Cell Biochem 2020 02 23;121(2):1778-1789. Epub 2019 Oct 23.

Pharmacological Research Center of Medicinal Plants, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

3-Acetyl-11-keto-β-boswellic acid (AKBA), a pentacyclic triterpenic acid present in gum resin of Boswellia serrata, has been found to possess antioxidant and neuroprotective properties. In this study, we aimed to examine protective properties of AKBA against glutamate-induced neuronal injury. To investigate the effects of AKBA (2.5-10 µM) on glutamate injury in neuron-like cells PC12 and N2a, two treatment regimens (incubation for 2 or 0 hours before glutamate exposure) were used. Then, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used to determine viability of the cells. Cellular redox status was evaluated using fluorimetry and comet assays. Annexin V/propidium iodide double staining and Western blot analysis of relative apoptotic proteins were conducted. Based on the results, 24 hours incubation with glutamate (8 mM) increased the cell mortality of PC12 and N2a (P < .001). However, AKBA (2.5-10 µM) enhanced the cell viability in both treatment regimens (P < .001). Also co- and pretreatment with AKBA significantly attenuated lipid peroxidation, reactive oxygen species production, and DNA injury (P < .05 and P < .001). AKBA also restored the activity of cellular superoxide dismutase under glutamate toxicity; this effect was seen to be more significant during the pretreatment regimen (P < .001). Moreover, Western blot analysis indicated that AKBA inhibited glutamate-induced programmed cell death through depressing the elevation of the expression ratio of Bax/Bcl-2 and cleaved-caspase-3 proteins, concentration-dependently. Overall, the present findings suggest the neuroprotective activities of AKBA against glutamate-induced cell injury probably by inhibiting oxidative damage and reducing apoptotic cell death.
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http://dx.doi.org/10.1002/jcb.29413DOI Listing
February 2020

The protective effect of vitamin E on rats' ovarian follicles following an administration of diazinon: An experimental study.

Int J Reprod Biomed 2019 Feb 19;17(2). Epub 2019 Mar 19.

Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Diazinon (DZN) is an organophosphate insecticide that has been widely utilized in agriculture all over the world and caused many negative effects on different species such as plants and animal species, especially on a human.

Objective: The aim of the present study was to evaluate the protective effect of vitamin E on rats' ovarian follicles following an administration of diazinon.

Materials And Methods: A total of 30 adult female Wistar rats were divided into five groups: a control group (without any intervention), sham group (received only pure olive oil, as solvent), experimental group I (DZN+olive oil, 60 mg/kg), experimental group II (vitamin E, 200 mg/kg), and experimental group III (DZN: 60 mg/kg+vitamin E: 200 mg/kg). All drugs were injected intraperitoneally, except vitamin E which was administrated by gavage. The animals were scarified after two weeks and left ovary was used to measure proliferation of ovarian follicles. Tissues were analyzed by the PCNA technique and viewed with an optical microscope for evaluating cells proliferation.

Results: The result of the present study revealed that the number of proliferative cells in the experimental group I decreased significantly in contrast to the control group in secondary and Graffian follicles (p 0.001). The administration of vitamin E plus DZN significantly increased proliferative cells compared to the DZN group (p 0.001). Primordial follicles showed that all study groups were lacking PCNA positive cells, which means no expression of PCNA in these follicles. The results of this study showed that primary follicles in all study groups had a few and scattered PCNA positive cells with no significant difference between the groups (p 0.05).

Conclusion: Results showed that DZN reduced proliferation in secondary and Graffian follicles and vitamin E increased it. The results of this study suggested that vitamin E by its antioxidant activity was able to improve the DZN-induced ovarian toxicity.
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http://dx.doi.org/10.18502/ijrm.v17i2.3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693314PMC
February 2019

Common Polymorphisms in Genes Related to Vitamin D Metabolism Affect the Response of Cognitive Abilities to Vitamin D Supplementation.

J Mol Neurosci 2019 Sep 16;69(1):150-156. Epub 2019 Jul 16.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

It is possible that vitamin D acts as a neurosteroid and that vitamin D deficiency may have an adverse impact on brain function and cognitive function. There are a few reports that have demonstrated an association between polymorphisms of genes involved in vitamin D metabolism and neurodegenerative disease. We aimed to evaluate the relationship between common, functional vitamin D-associated gene variants and cognitive abilities and to investigate the effect size of this polymorphism on cognitive capabilities associated with high-dose vitamin D supplementation. A total of 319 healthy adolescents received a high dose of vitamin D (50,000 IU)/week for 9 weeks. A questionnaire was used to assess cognitive abilities at baseline and after treatment. The genotypes of the CYP2R1-rs10766197 and GC-rs4588 variants were determined using TaqMan genotyping techniques. At baseline, total cognitive ability scores were higher in the AA group who were homozygous for the uncommon allele, compared with the other (AG and GG) genotypes of the CYP2R1-rs10766197 polymorphism (104.9 ± 27.8 vs. 79.1 ± 38.8 vs. 73.1 ± 25.6; p < 0.001, respectively). During the supplementation period, cognitive ability scores increased in individuals with the AG and GG genotypes, while individuals with a AA genotype did not show significant change in total score after intervention (p = 0.17). For GC SNP (rs4588), no major differences at baseline and trial-net change of cognitive tasks score were observed between the genotypes under three genetic models (p = 0.67). Vitamin D supplements have trait-dependent effects on cognitive performance that suggests a causal role for vitamin D in cognitive performance. The rs10766197 variant, near the CYP2R1 gene locus, significantly modified the efficacy of high-dose vitamin D3 supplementation for its effects on improving cognitive abilities indicate that some subjects might require a higher dose to benefit from in terms of cognitive performance.
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http://dx.doi.org/10.1007/s12031-019-01344-6DOI Listing
September 2019

Liposomal formulation of Galbanic acid improved therapeutic efficacy of pegylated liposomal Doxorubicin in mouse colon carcinoma.

Sci Rep 2019 07 2;9(1):9527. Epub 2019 Jul 2.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Galbanic acid (Gba), a sesquiterpene coumarin, with strong antiangiogenic activity could serve as an excellent anti-cancer agent. However, Gba is a poor water-solube which hampered its clinical application. In this study, a pegylated liposomal Gba (PLGba) with HSPC/Cholesterol/mPEG-DSPE (56.2, 38.3, 5.3% molar ratio) was developed by the thin film hydration plus extrusion and calcium acetate gradient remote loading method, to address the issue of poor Gba solubility. Moreover, an integrin-targeting ligand (RGD peptide, cyclo[Arg-Gly-Asp-D-Tyr-Cys]) was post-inserted into liposomes in order to increase Gba cell delivery. Using fluorescently-labeled model liposomes, it was found that the targeting could improve the integrin-mediated cellular uptake of the liposomes in vitro in human umbilical vein endothelial cells (HUVECs), and in vivo as evidenced by chicken chorioallantoic membrane angiogenesis (CAM) model. It also could enrich the liposome accumulation in C26 tumor. Interestingly, co-treatment with PLGba and pegylated liposomal doxorubicin (PLD, also known as Doxil) had a synergistic and antagonistic antiproliferative effect on the C26 tumor cell line and the normal HUVEC, respectively. In C26 tumor bearing BALB/c mice, the PLGba and PLD combinatorial therapy improved the antitumor efficacy of the treatment as compared to those of single agents. This results have clear implications for cancer therapy.
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http://dx.doi.org/10.1038/s41598-019-45974-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606580PMC
July 2019

Effects of PPAR-γ agonist, pioglitazone on brain tissues oxidative damage and learning and memory impairment in juvenile hypothyroid rats.

Int J Neurosci 2019 Oct 3;129(10):1024-1038. Epub 2019 Jul 3.

Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences , Mashhad , Iran.

: The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on the brain tissues oxidative damage and learning and memory impairment in the juvenile hypothyroid rats was evaluated. : Rats were classified as: ( 1 ) Control; (2) Propylthiouracil (PTU); (3) PTU-Pio 10 and (4) PTU-Pio 20. PTU was given in drinking water (0.05%) during 6 weeks. Pioglitazone (10 or 20 mg/kg) was daily injected intraperitoneally. Passive avoidance (PA) and Morris water maze (MMW) were conducted. Later, the animals were sacrificed and the brain tissues were removed for biochemical measurements. : The results indicated that in the MWM escape latency as well as traveled path increased in the PTU group as compared to the control group. Also, the time spent in the target quadrant in the probe test of MWM and step-through latency in the PA test were decreased in the PTU group as compared to the control group. Pioglitazone reversed all the negative behavioral effects of hypothyroidism. Administration of PTU attenuated thiol and superoxide dismutase (SOD), and catalase (CAT) activities in the brain tissues, whereas increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. PPARγ agonist improved thiol, SOD and CAT, while diminished MDA concentration. : Our finding in the present study indicated that PPARγ agonist pioglitazone prevented the brain tissues from oxidative damage and learning and memory impairments in juvenile hypothyroid rats.
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http://dx.doi.org/10.1080/00207454.2019.1632843DOI Listing
October 2019

Thymoquinone alleviates renal interstitial fibrosis and kidney dysfunction in rats with unilateral ureteral obstruction.

Phytother Res 2019 Aug 18;33(8):2023-2033. Epub 2019 Jun 18.

Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Unilateral ureteral obstruction (UUO) causes severe renal tubulointerstitial fibrosis. Because of many pharmacologic properties of thymoquinone (TQ), in this study, the effects of TQ against kidney fibrosis and dysfunction were investigated in rats with UUO. Forty male Wistar rats were divided into five groups: Sham operated, UUO, and the animals with UUO treated with losartan, captopril, or TQ. Collagen IV and transforming growth factor (TGF)-β1 expressions, interstitial fibrosis, histological changes, and kidney function were assessed. UUO markedly increased renal expression of TGF-β1 and collagen I and induced interstitial fibrosis (p < .001). Losartan, captopril, or TQ significantly downregulated the expression of these fibrotic markers and interstitial fibrosis (p < .01-p < .001). In UUO group, serum levels of urea and creatinine and protein excretion rate significantly increased, but glomerular filtration rate (GFR) and urine osmolarity showed a significant decrease (p < .001-p < .05). Administration of captopril and TQ caused no significant change in serum urea and protein excretion rate. Unlike losartan and captopril, TQ caused no significant alteration in GFR compared with Day 1. Losartan caused significant increases in serum urea and creatinine but significant decrease in urine osmolarity. TQ could be regarded as a potent therapeutic agent for treatment of UUO-induced kidney fibrosis and dysfunction.
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http://dx.doi.org/10.1002/ptr.6376DOI Listing
August 2019

Trigonella foenum-graceum seed (Fenugreek) hydroalcoholic extract improved the oxidative stress status in a rat model of diabetes-induced memory impairment.

Horm Mol Biol Clin Investig 2019 Jun 6;39(2). Epub 2019 Jun 6.

Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Background The antidiabetic and antioxidant effects of Trigonella foenum-graceum have been suggested. The effects of hydroalcoholic extract of the plant seeds and metformin against the diabetes-induced memory impairment were investigated. Materials and methods The rats were treated: (1) control, (2) diabetic (3-6) and diabetic rats treated by 50, 100 and 200 mg/kg of the plant extract or metformin. The rats were diabetic by streptozotocin (STZ, 55 mg/kg). After the passive avoidance test, malondialdehyde (MDA), nitric oxide (NO) metabolites, total thiol (SH), catalase (CAT) and superoxide dismutase (SOD) were determined in the brain. Results In the diabetic group, at 3, 24 and 48 h after receiving a shock, the latency to enter the dark room was lower than for the controls (p < 0.001). All doses of the extract and metformin increased the latencies to enter the dark at 3 and 24 h after the shock treatment (p < 0.05-p < 0.001). Additionally, the two higher doses of the extract and metformin increased the latency at 48 h after the shock (p < 0.05-p < 0.001). Diabetes also elevated MDA and NO metabolites, while it reduced thiol, SOD and CAT in the hippocampal and cortical tissues (p < 0.001). Treatment of the diabetic animals by the highest dose of the extract and also metformin reduced the MDA and NO metabolites, while it improved thiols, SOD and CAT (p < 0.01-p < 0.001). Conclusions Based on our findings, metformin and the hydro-alcoholic extract from the T. foenum-graceum seed prevented memory deficits resulting from diabetes. Preventing oxidative damage in the brain may at least, in part, be responsible for the positive effects of the extract and metformin.
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http://dx.doi.org/10.1515/hmbci-2018-0074DOI Listing
June 2019

Anticonvulsant Activity of Viola tricolor against Seizures Induced by Pentylenetetrazol and Maximal Electroshock in Mice.

Iran J Med Sci 2019 May;44(3):220-226

Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Recently, there has been much more interest in the use of medicinal plants in search of novel therapies for human neurodegenerative diseases such as epilepsy. In the present study, we investigated the anticonvulsant effects of () on seizure models induced by pentylenetetrazol (PTZ) and maximal electroshock stimulation (MES).

Methods: Totally, 260 mice were divided into 26 groups (n=10). Thirty minutes after treatment with the hydroalcoholic extract of (VHE 100, 200, and 400 mg/kg) and its ethyl acetate (EAF 50, 100, and 200 mg/kg) and n-butanol (NBF 50, 100, and 200 mg/kg) fractions as well as diazepam (3 mg/kg), seizure was induced by PTZ (100 mg/kg) or by MES (50 Hz, 1 s and 50 mA). Analysis was performed via ANOVA with the Tukey-Kramer post-hoc test using GraphPad Prism 6.01 (La Jolla, CA).

Results: The VHE (400 mg/kg) significantly enhanced latency to the first generalized tonic-clonic seizures (GTCs) induced by PTZ in comparison to the control group (P<0.001). All 3 concentrations of the EAF (50, 100, and 200 mg/kg) significantly prolonged the latency of PTZ-induced seizures compared to the control group. Additionally, all the concentrations of the NBF (50, 100, and 200 mg/kg) made a significant increment in GTCs latency induced by PTZ in comparison to the control group. On the other hand, all the concentrations of the VHE, EAF, and NBF significantly reduced the incidence of hind-limb tonic extension (HLTE) induced by MES, when compared to the control group.

Conclusion: The present study showed that and its ethyl acetate and n-butanol fractions possessed anticonvulsant effects as confirmed by the prolongation of latency to the first GTCs induced by PTZ and decrement in the incidence of HLTE induced by MES.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525727PMC
May 2019

Antioxidant and toxicity studies of biosynthesized cerium oxide nanoparticles in rats.

Int J Nanomedicine 2019 26;14:2915-2926. Epub 2019 Apr 26.

Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran,

Purpose: The purpose of this study was to investigate the acute toxic potential of cerium oxide nanoparticles (CNPs) synthesized by pullulan in adult male Wistar rats.

Patients And Methods: Thirty male Wistar rats randomly were divided into five experimental groups of six animals each. The animals were received 50, 100, 200, and 400 mg/kg CNPs for 14 consecutive days. At the end of the experiment, the rats were euthanized and histopathological evaluation of the liver and renal tissues, as well ass, the markers of serum oxidative stress including thiobarbituric acid reactive substances, total sulfhydryl content, and antioxidant capacity (using ferric reducing/antioxidant power assay) were assessed. Hematological parameters and the activity of liver function enzymes were also measured.

Results: The results of this study showed that CNPs caused no significant changes in the activity of liver enzymes, hepatic and renal histopathology and hematological parameters, while significantly improved serum redox status.

Conclusion: Acute administration of pullulan-mediated CNPs is safe and possess antioxidant activity.
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http://dx.doi.org/10.2147/IJN.S194192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487897PMC
July 2019

Role of in the biosynthesis of AgNPs and their antibacterial properties.

IET Nanobiotechnol 2019 Apr;13(2):189-192

Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Silver nanoparticles (AgNPs) have been biosynthesised through the extracts of fruits, which served as the reducing agents and capping agents. Biosynthesised AgNPs have been found to be ultraviolet-visible (UV-vis) absorption spectra since they have displayed one surface plasmon resonance peak at 438 nm, attesting the formation of spherical NPs. These particles have been characterised by UV-vis, field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy analysis. The formation of AgNPs at 1.0 mM concentration of AgNO has resulted in NPs that contained mean diameters in a range of 20-40 nm. The green-synthesised AgNPs have demonstrated high antibacterial effect against pathogenic bacteria (i.e. , , and ). Biosynthesising metal NPs through plant extracts can serve as the facile and eco-friendly alternative for chemical and/or physical methods that are utilised for large-scale nanometal fabrication in various medical and industrial applications.
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http://dx.doi.org/10.1049/iet-nbt.2018.5215DOI Listing
April 2019

The Effect of Diazinon on Cell Proliferation and Apoptosis in Testicular Tissue of Rats and The Protective Effect of Vitamin E.

Int J Fertil Steril 2019 Jul 27;13(2):154-160. Epub 2019 Apr 27.

Research Center for Neuroscience, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.

Background: Diazinon (DZN) is an organophosphate pesticide, and nowadays this pesticide is mostly used in agriculture. In this study, we analyzed the effects of DZN and vitamin E (Vit E) on apoptosis and the proliferation of germ cells in rat testis.

Materials And Methods: In this experimental study, 30 male Wistar rats were divided into five groups (n=6 per group) consisting of control, sham (received olive oil), experimental group i (60 mg/kg DZN), experimental group ii (60 mg/kg DZN and 200 mg/kg Vit E), and experimental group iii (200 mg/kg Vit E). After six weeks, left testis of rats was removed for the detection of proliferative cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase end-labeling (TUNEL).

Results: Compared with the control group, DZN in the experimental group i decreased the number of PCNA-positive cells and increased the number of TUNEL-positive cells (P<0.001). Vit E improved detrimental changes by the decrease in the rate of apoptosis and the increase in the proliferation of testicular germ cells (P<0.001).

Conclusion: Vit E can decrease the number of TUNEL-positive cells and increase the number of PCNA-positive cells by the neutralization of the toxicity caused by DZN in the testicular tissue.
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http://dx.doi.org/10.22074/ijfs.2019.5612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500077PMC
July 2019

Depression in adolescent girls: Relationship to serum vitamins a and E, immune response to heat shock protein 27 and systemic inflammation.

J Affect Disord 2019 06 8;252:68-73. Epub 2019 Apr 8.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: The inflammation and oxidative stress are thought to play an important role in the etiopathogenesis of some psychological disorders. We aimed to assess the potential relationships between serum fat soluble vitamins (Vitamins A and E), antibody titers to Hsp27 (anti-Hsp27) and hematological markers of inflammation, with mood disorders in a population of adolescent girls.

Methods: A total of 563 adolescent girls (Age 12-18 years) were included in the study. The presence and severity of depression, insomnia and sleepiness were assessed using validated questionnaires. Serum vitamins A and E, anti-Hsp27 antibody titers, white blood cell, lymphocyte, neutrophil, platelet counts, and red blood cell distribution width (RDW), were also measured. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and RDW to platelet ratio (RPR) were calculated.

Results: Serum anti-HSP27 antibody titers, PLR, and RPR values was significantly higher in subjects with a high depression score compared to normal individuals (p < 0.05). However, there was no association between serum inflammatory markers concentrations and sleep disorders; although individuals with insomnia had a lower vitamin E/HDL ratio compared to healthy adolescents. In multivariate logistic regression analyses adjusted for potential confounders, anti-HSP was an independent predictor of severe depression (OR = 5.0, 95% CI: 1.6-15.7, p < 0.05).

Limitation: The cross-sectional design of study and the inclusion of only female adolescents participants are limitations.

Conclusion: Our findings suggest that serum anti-HSP27 antibody titers may be useful biological marker in depressive patients. This finding may support a role of oxidative stress in the etiology of depression, and targeting this pathway may be of value in the treatment of depression.
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http://dx.doi.org/10.1016/j.jad.2019.04.048DOI Listing
June 2019

The Association Between Neuropsychological Function with Serum Vitamins A, D, and E and hs-CRP Concentrations.

J Mol Neurosci 2019 Jun 9;68(2):243-250. Epub 2019 Apr 9.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

Vitamin status and the presence of subclinical inflammation may affect cognitive performance and behavior. We have investigated the relationship between serum fat soluble vitamins (vitamins A, D, and E) and inflammatory markers with aggression and cognitive abilities, in a population of healthy adolescents. A cross-sectional study of 940 adolescent girls was performed. Serum concentrations of vitamins A, D, and E, hs-C-reactive protein (hs-CRP), and antibody titers to Hsp27 (anti-Hsp27) were measured. Hematological indices including lymphocyte, neutrophil, platelet counts, and red blood cell distribution width (RDW) were evaluated. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and RDW to platelet ratio (RPR) were calculated. A Cognitive Abilities Questionnaire and the Buss-Perry Aggression Questionnaire were applied to assess cognitive performance and aggression, respectively. There was a positive correlation between serum vitamins A with vitamins D and E, as well as between serum hs-CRP with serum vitamin E. Linear regression analysis showed that serum vitamin D, hs-CRP, anti-Hsp27, and RDW were significantly associated with aggression score. Furthermore, serum vitamin E, hs-CRP, anti-Hsp27, NLR, and RPR were significantly associated with cognitive ability score. Inflammatory processes may affect cognitive performance and behavior. Prospective studies are warranted to determine the potential of targeting antioxidant and inflammatory pathways for the treatment of psychological disorder.
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http://dx.doi.org/10.1007/s12031-019-01288-xDOI Listing
June 2019

Therapeutic Potential of Curcumin in the Treatment of Glioblastoma Multiforme.

Curr Pharm Des 2019 ;25(3):333-342

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Despite standard multimodality treatment, the highly aggressive nature of GBM makes it one of the deadliest human malignancies. The anti-cancer effects of dietary phytochemicals like curcumin provide new insights to cancer treatment. Evaluation of curcumin's efficacy against different malignancies including glioblastoma has been a motivational research topic and widely studied during the recent decade. In this review, we discuss the recent observations on the potential therapeutic effects of curcumin against glioblastoma. Curcumin can target multiple signaling pathways involved in developing aggressive and drug-resistant features of glioblastoma, including pathways associated with glioma stem cell activity. Notably, combination therapy with curcumin and chemotherapeutics like temozolomide, the GBM standard therapy, as well as radiotherapy has shown synergistic response, highlighting curcumin's chemo- and radio-sensitizing effect. There are also multiple reports for curcumin nanoformulations and targeted forms showing enhanced therapeutic efficacy and passage through blood-brain barrier, as compared with natural curcumin. Furthermore, in vivo studies have revealed significant anti-tumor effects, decreased tumor size and increased survival with no notable evidence of systemic toxicity in treated animals. Finally, a pharmacokinetic study in patients with GBM has shown a detectable intratumoral concentration, thereby suggesting a potential for curcumin to exert its therapeutic effects in the brain. Despite all the evidence in support of curcumin's potential therapeutic efficacy in GBM, clinical reports are still scarce. More studies are needed to determine the effects of combination therapies with curcumin and importantly to investigate the potential for alleviating chemotherapy- and radiotherapy-induced adverse effects.
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http://dx.doi.org/10.2174/1381612825666190313123704DOI Listing
February 2020

Adipose tissue-derived mesenchymal stem cells and keratinocytes co-culture on gelatin/chitosan/β-glycerol phosphate nanoscaffold in skin regeneration.

Cell Biol Int 2019 Feb 21. Epub 2019 Feb 21.

Stem Cell and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR), Razavi Khorasan Branch, Mashhad, Iran.

Using cell-based engineered skin is an emerging strategy for treating difficult-to-heal wounds. To date, much endeavor has been devoted to the fabrication of appropriate scaffolds with suitable biomechanical properties to support cell viability and growth in the microenvironment of a wound. The aim of this research was to assess the impact of adipose tissue-derived mesenchymal stem cells (AD-MSCs) and keratinocytes on gelatin/chitosan/β-glycerol phosphate (GCGP) nanoscaffold in full-thickness excisional skin wound healing of rats. For this purpose, AD-MSCs and keratinocytes were isolated from rats and GCGP nanoscaffolds were electrospun. Through an in vivo study, the percentage of wound closure was assessed on days 7, 14, and 21 after wound induction. Samples were taken from the wound sites in order to evaluate the density of collagen fibers and vessels at 7 and 14 days. Moreover, sampling was done on days 7 and 14 from wound sites to assess the density of collagen fibers and vessels. The wound closure rate was significantly increased in the keratinocytes-AD-MSCs-scaffold (KMS) group compared with other groups. The expressions of vascular endothelial growth factor, collagen type 1, and CD34 were also significantly higher in the KMS group compared with the other groups. These results suggest that the combination of AD-MSCs and keratinocytes seeded onto GCGP nanoscaffold provides a promising treatment for wound healing.
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http://dx.doi.org/10.1002/cbin.11119DOI Listing
February 2019

Vitamin C improves liver and renal functions in hypothyroid rats by reducing tissue oxidative injury.

Int J Vitam Nutr Res 2020 Jan 21;90(1-2):84-94. Epub 2019 Feb 21.

Pharmacological Research Center of Medicinal Plants, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

The effects of Vit C on liver and renal function and the tissues oxidative damage was investigated in hypothyroid rats. The pregnant rats were divided into 5 groups (n=6): (1) Control; (2) Propylthiouracil (PTU; 0.005%), (3-5) PTU plus 10, 100 or 500 mg/kg b.w. Vit C. The drugs were added to the drinking water of the dams and their pups during lactation period and then continued for the offspring through the first 8 weeks of their life. Finally, 7 male offspring from each group were randomly selected. Thyroxine, protein and albumin concentrations in the serum and thiol content and superoxide dismutase (SOD) and catalase (CAT) activities in renal and liver tissues of hypothyroid group was lower (all P<0.001) while, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK-P), creatinine and blood urea nitrogen (BUN) concentrations in the serum and malondialdehyde (MDA) in the liver and renal tissues were higher than the control (all P<0.001). All doses of Vit C increased thyroxine, protein and albumin and thiol content in in renal and liver tissues while, decreased AST, ALT and ALK-P concentration and MDA in liver and renal tissues compared to PTU group (P<0.05-P<0.001). Creatinine, BUN and SOD and CAT were improved by both 100 and 500 mg/kg of Vit C in the renal (P<0.05-P<0.001) and by 100 mg/kg in the liver (P<0.05-P<0.001). Vit C improved liver and renal function of hypothyroid rats which might be due to its protective effects against tissues oxidative damage.
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http://dx.doi.org/10.1024/0300-9831/a000495DOI Listing
January 2020

Rheum turkestanicum reduces glutamate toxicity in PC12 and N2a cell lines.

Folia Neuropathol 2018 ;56(4):354-361

Glutamate is considered to be responsible for the pathogenesis of many neurodegenerative diseases. Reactive oxygen species (ROS) production is considered to be involved in the glutamate-induced apoptosis process. In this study, we investigated the neuroprotective effects of Rheum turkestanicum in the glutamate-induced rat pheochromocytoma (PC12 cells) and mouse neuroblastoma (N2a) cell lines. Rutin as an antioxidant was used as positive control. Glutamate cytotoxicity was accompanied by an increment of malondialdehyde (MDA) content, ROS generation and apoptosis induction. However, pretreatment with the root extract of R. turkestanicum significantly reduced MDA content, ROS generation and apoptotic cell death. Also rutin at a dose of 100 µM reduced ROS production and protected against glutamate toxicity. Also the quantification of rutin in R. turkestanicum extract was achieved and was about 0.11% ± 0.01 w/w. All these findings indicated that R. turkestanicum protected PC12 and N2a cells against glutamate-induced oxidative cell death and apoptosis and might raise the possibility of R. turkestanicum usage as a neuroprotective agent.
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http://dx.doi.org/10.5114/fn.2018.80869DOI Listing
May 2019

Serum vitamin E as a significant prognostic factor in patients with dyslipidemia disorders.

Diabetes Metab Syndr 2019 Jan - Feb;13(1):666-671. Epub 2018 Nov 13.

Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Objectives: Obesity and overweight are among the main causes of cardiovascular disease (CVD) mortality. Dyslipidemia, fatty liver index, is strongly related to CVD. Vitamin E as an antioxidant protects the hepatic cells against oxidative stress and prevents fatty liver disease. The aim of the current study is to evaluate the relationship between anthropometric parameters and fasted lipid profile with serum vitamin E levels.

Study Design: A randomized trial was designed based on data from the Mashhad stroke and heart atherosclerotic disorders (MASHAD: 2010-2020).

Methods: 363 CVD subjects (173 males and 190 females) was selected at random, among 9704 subjects in three regions of Mashhad, northeast of Iran to investigate the specific correlations among their serum vitamin E, lipid profile (TG, HDL-C, LDL-C and TC), and anthropometric features (height, weight, BMI, hip and waist circumferences.

Result: The results indicated the significant relationships between vitamin E, and fasting serum lipid profile in subjects. Serum vitamin E was negatively correlated to TC, TG, and LDL-C and positively related to HDL-C. Also, statistically negative correlations were found between vitamin E and anthropometric parameters (weight, waist and hip circumference, middle Arm, and Systolic Blood Pressure). Moreover, vitamin E ratios such as vitamin E/(TC + TG) and vitamin E/TC values as standardized vitamin E, had significant negative correlation with BMI, the whole of anthropometric parameters, and dyslipidemia risk factors including TC, TG and LDL-C.

Conclusion: We found that vitamin E profile was significantly lower in the dyslipidemia subjects. It is generally suggested that vitamin E monitoring might be used as a useful prognostic and therapeutic agent in dyslipidemia disorder.
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http://dx.doi.org/10.1016/j.dsx.2018.11.034DOI Listing
May 2019

Induction of cytotoxicity and apoptosis in FLT3 mutant expressing cells using novel pyrimido cyanoacrylates and quinoline derivatives.

Biomed Pharmacother 2018 Dec 26;108:893-905. Epub 2018 Sep 26.

Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Background: Aberrant activation of FMS-like tyrosine kinase 3 (FLT3) is associated with acute myeloid leukemia (AML). Leukemic cells expressing constitutively active FLT3 mutants are resistance to the current cancer therapies (radiotherapy and chemotherapy); hence, there is an increased interest to identify new agents for the treatment of AML. The main aim of this study was evaluating cytotoxic effects of novel pyrimidocyanoacrylates and quinoline derivatives on FLT3 overexpressing cells.

Materials And Methods: Five novel pyrimidocyanoacrylates & 2-chloro 3-carbaldehyde quinolone derivative compounds, E1QAC1, E1QAC2, E1QAC3, E1QAC4, and E1QAC5 were designed and synthesized at the Department of Chemistry, Faculty of Sciences, Ferdowsi University, Mashhad, Iran. FDC-P1 cells expressing human wild-type FLT3 (FD-FLT3-WT) and internal tandem duplication (ITD) mutants (FD-FLT3-ITD) used in this study. The cells maintained in DMEM medium supplemented with 10% fetal calf serum (FCS) and murine granulocyte-macrophage colony stimulating factor (mGM-CSF). Potency for induction of cytotoxicity (IC value) and apoptosis was determined after treating the cells with concentration of the compounds by resazurin assay. Bax and Bcl2 activation status was also investigated by Western blot analysis.

Results: All the compounds had concentration-dependent effects on inhibition of cell proliferation and induction of apoptosis in both cell lines. E1QAC4 was the most potent compound for inhibition of cell proliferation (with IC50 value of 19 μM) and apoptosis induction in the FLT3-WT cells. However, FD-FLT3-ITD cells were nearly five-times more resistant to all the compounds (except than E1QAC2) that the FLT3-WT expressing cells. Western blotting results also showed that FD-FLT3-ITD cells had lower levels of Bax and higher levels of Bcl2 than the FD-FLT3-WT cells.

Conclusion: The five novel heterocyclic compounds (E1QAC1-5) had cytotoxic effects and induced apoptosis in FD-FLT3 cells. Therefore, it is worthwhile to consider them as potential lead compound for development of new therapeutic agents for AML patients.
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http://dx.doi.org/10.1016/j.biopha.2018.09.001DOI Listing
December 2018

Study of the mechanisms of crocetin-induced differentiation and apoptosis in human acute promyelocytic leukemia cells.

J Cell Biochem 2018 Sep 11. Epub 2018 Sep 11.

Department of New Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Crocetin, the major carotenoid in saffron, exhibits potent anticancer effects. However, the antileukemic effects of crocetin are still unclear, especially in primary acute promyelocytic leukemia (APL) cells. In the current study, the potential antipromyelocytic leukemia activity of crocetin and the underlying molecular mechanisms were investigated. Crocetin (100 µM), like standard anti-APL drugs, all-trans retinoic acid (ATRA, 10 µM) and As O (arsenic trioxide, 50 µM), significantly inhibited proliferation and induced apoptosis in primary APL cells, as well as NB4 and HL60 cells. The effect was associated with the decreased expressions of prosurvival genes Akt and BCL2, the multidrug resistance (MDR) proteins, ABCB1 and ABCC1 and the inhibition of tyrosyl-DNA phosphodiesterase 1 (TDP1), while the expressions of proapoptotic genes CASP3, CASP9, and BAX/BCL2 ratio were significantly increased. In contrast, crocetin at relatively low concentration (10 µM), like ATRA (1 µM) and As O (0.5 µM), induced differentiation of leukemic cells toward granulocytic pattern, and increased the number of differentiated cells expressing CD11b and CD14, while the number of the immature cells expressing CD34 or CD33 was decreased. Furthermore, crocetin suppressed the expression of clinical marker promyelocytic leukemia/retinoic acid receptor-α ( PML/RARα) in NB4 and primary APL cells, and reduced the expression of histone deacetylase 1 ( HDAC1) in all leukemic cells. The results suggested that crocetin can be considered as a candidate for future preclinical and clinical trials of complementary APL treatment.
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http://dx.doi.org/10.1002/jcb.27489DOI Listing
September 2018

Evaluation of anticancer effects of cerium oxide nanoparticles on mouse fibrosarcoma cell line.

J Cell Physiol 2019 04 6;234(4):4987-4996. Epub 2018 Sep 6.

Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Cerium oxide nanoparticles are associated with anticancer effects. While protecting normal cells, these nanoparticles exert their anticancer effects via oxidative stress and apoptosis in the cancer cells. In this study, the anticancer properties of nanoceria on fibrosarcoma cell line are evaluated. Cerium oxide nanoparticles were synthesized by the coprecipitation method and their anticancer effects on mouse fibrosarcoma tumor cells (WEHI164) were investigated. Viability assay was evaluated by MTT, and the DC-FDA assay performed for the detection of reactive oxygen species. For apoptosis assay, the annexin V/PI test was done as well as measuring the mRNA and protein expression levels of Bax and Bcl2 by real-time PCR and western blot method, respectively. Characterization of nanoceria reveals that synthesized nanoceria has cubic floruit structure with a size of about 30 nm. Toxicity assessment results show that nanoceria increases ROS levels and induced apoptosis in a dose-dependent manner in cancer cells (WEHI164), whereas low levels of toxicity were observed in normal cells (L929), even at the concentrations above 250 µg/ml in MTT assay. Real-time PCR and western blot assays showed that nanoceria could significantly increase the Bax expression in cancer cells. The results showed that nanoceria could act as a potential therapeutic agent for the treatment of fibrosarcoma.
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http://dx.doi.org/10.1002/jcp.27303DOI Listing
April 2019
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