Publications by authors named "Hassan Malekinejad"

69 Publications

Prodigiosin induced the caspase-dependent apoptosis in human chronic myelogenous leukemia K562 cell.

Res Pharm Sci 2021 Feb 30;16(1):26-34. Epub 2020 Dec 30.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, I.R. Iran.

Background And Purpose: Chronic myeloid leukemia (CML) as a myeloproliferative disease is characterized by increased cellularity of bone marrow. Implementing the latest treatment protocols is currently accompanied by serious and life-threatening side effects. There are worldwide attempts to find new effective and potent therapeutic agents with minimal side effects on CML patients. This study was carried out to discover the potential antiproliferative and apoptotic effects of naturally produced prodigiosin (PDG) on K562 cells as an accepted model of CML.

Experimental Approach: The anti-proliferative effect of PDG was measured by MTT assay. To highlight the mechanism of cytotoxicity, the apoptotic cell death pathway was investigated by morphological and biochemical assessments. The dual acridine orange/ethidium bromide staining technique and western blotting method were applied to assess the mechanism of the potential apoptotic impact of PDG on K562 cells.

Findings/results: PDG-induced time- and concentration-dependent anti-proliferative effects were revealed with an estimated IC value of 54.06 μM. The highest cell viability reduction (60%) was recorded in cells, which were exposed to 100 μM concentration. Further assays demonstrated that in the dual acridine orange/ethidium bromide staining method the cell population in the late apoptosis phase was increased in a concentration-dependent manner, which was confirmed with remarkable DNA fragmentation.

Conclusion And Implications: We found that the PDG-induced apoptosis in K562 cells is mediated through the caspase-3 activation both in mRNA and protein levels. Our results suggest that PDG could be a potent compound for further pharmacokinetic and pharmacodynamics studies in the model of CML.
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http://dx.doi.org/10.4103/1735-5362.305186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074807PMC
February 2021

The Molecular targets of Cannabinoids in the treatment of Cancer and Inflammation

Curr Pharm Des 2021 04 25. Epub 2021 Apr 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

Objective: In this review we discuss the emerging evidence for the effectiveness of cannabinoids in the treatment of cancer and inflammation. The remarkable effects complete the traditional evidence for their successful application in the treatment of pain and cancer-related side effects.

Methods: we searched Pub Med (132 articles) and Google scholar (9 articles) databases and gathered the clinical (4 articles), preclinical (28 articles) studies, reports on cell culture models (30 articles) and other original and review articles (78 articles) related to inflammation, cancer and cannabinoids.

Results: Cannabinoids are described in three different forms, comprising endo- phyto- and synthetic compounds that exert biological effects. The molecular and cellular pathways of endogenous cannabinoids in the maintenance of homeostasis are well documented. In addition to classical cannabinoid receptors type 1 and 2, Vanilloid receptors and G protein-coupled receptor 55 were identified as common receptors. Subsequently, the effectiveness of phyto- and synthetic cannabinoids mediated by cannabinoid receptors has been demonstrated in the treatment of inflammatory diseases including neurodegenerative diseases as well as gastrointestinal and respiratory inflammations. Another accepted property of cannabinoids is their anti-cancer effects. Cannabinoids were found to be effective in the treatment of lung, colorectal, prostate, breast, pancreas and hepatic cancers. The anticancer effects of cannabinoids were characterized by their anti-proliferative property, inhibition of cancer cells migration, suppression of vascularization and induction of apoptosis.

Conclusion: The current review provides and overview the role of endocannabinoid system in the mediation of physiological functions, the type and expression of cannabinoids receptors under physiological and pathological conditions. In additions, the molecular pathways involved in the effects of cannabinoids and the effectiveness of cannabinoids in the treatment of inflammations and cancers are highlighted.
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http://dx.doi.org/10.2174/1381612827666210426092847DOI Listing
April 2021

Cannabinoids pharmacological effects are beyond the palliative effects: CB2 cannabinoid receptor agonist induced cytotoxicity and apoptosis in human colorectal cancer cells (HT-29).

Mol Cell Biochem 2021 Apr 22. Epub 2021 Apr 22.

School of Pharmacy, Department of Pharmacology and Toxicology, Urmia University of Medical Sciences, Urmia, Iran.

Colorectal cancer (CRC) is between the top three occurring cancers worldwide. The anticancer effects of Cannabinoid receptor 2 (CB) agonist (GW833972A) in the presence and absence of its inverse agonist (SR144528) on Human colorectal adenocarcinoma cells (HT-29) was investigated. Following cell viability assays on HT-29 and HFF cells, the molecular mechanism(s) of cytotoxicity and apoptotic pathways of cell death were analyzed. The anticancer effects of CB agonist were measured with tumor cell migration and colony-forming assays. Real-time PCR and Western blotting techniques were used to examine any alterations in the expression of apoptotic genes. A concentration and time-dependent cytotoxicity of CB agonist with IC50 value of 24.92 ± 6.99 μM was obtained. The rate of lipid peroxidation was elevated, while the TNF-α concentration was declined, significantly (p < 0.05). CB agonist (50 μM) reduced the colony-forming capability by 83% and tumor cell migration by 50%. Apoptotic effects of CB agonist were revealed with the increase of apoptotic cells in Acridine orange/Ethidium bromide staining, clear DNA fragmentation, pro-apoptotic genes and proteins upregulation (Caspase-3 and p53), and significant downregulation of anti-apoptotic Bcl-2. All assessments demonstrated that CB agonist-induced effects were reversed by CB inverse agonist. These data suggest that CB agonists at micro-molar concentrations might be considered in the CRC treatment, and their effectiveness attributes to the apoptosis induction via upregulation of caspase-3 and p53 and downregulation of Bcl-2.
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http://dx.doi.org/10.1007/s11010-021-04158-6DOI Listing
April 2021

Crocetin suppresses the growth and migration in HCT-116 human colorectal cancer cells by activating the p-38 MAPK signaling pathway.

Res Pharm Sci 2020 Dec 27;15(6):592-601. Epub 2020 Nov 27.

Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, I.R. Iran.

Background And Purpose: Crocetin is a natural antioxidant that is found in the crocus flower and (fruit). Previous studies have reported its anticancer activity both and . In addition, crocetin suppresses the growth and migration of human colorectal cancer cells, however, its mechanism of action remains to be elucidated. Therefore, the present study investigated the molecular mechanism of crocetin effect on colorectal cancer cells (HCT-116) .

Experimental Approach: HCT-116 cells were treated with different concentrations (0, 200, 400, 600, and 800 μM) of crocetin for 24 h. The cell survival rate was measured by MTT assay. Cell migration capacity was evaluated using the wound healing assay. The expression levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-9) was monitored by RT-PCR. Phosphorylation of focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) was determined using western blot.

Findings/results: The proliferation of HCT-116 was inhibited by crocetin at 800 μM ( < 0.001). Crocetin prevented migration of HCT-116 cells ( < 0.05) and suppressed VEGF and MMP-9 mRNA expression ( < 0.001) and increased phosphorylation of p38 (MAPK; < 0.001). However, no significant change in the phosphorylation of FAK was observed.

Conclusion And Implication: These data suggested that crocetin-induced growth- and migration- suppressing effects on HCT-116 cells may partially depend on the regulation of the p38 (MAPK) signaling pathway.
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http://dx.doi.org/10.4103/1735-5362.301344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020854PMC
December 2020

Effects of Supplemental Chromium Nanoparticles on IFN-γ expression of Heat Stress Broilers.

Biol Trace Elem Res 2021 Feb 17. Epub 2021 Feb 17.

Department of Animal Science, Agricultural Faculty, Ataturk University, 25240, Erzurum, Turkey.

The aim of present study was to investigate the beneficial effect of chromium (III) picolinate (CrPic) and chromium (III) picolinate nanoparticles (NCrPic) addition on growth performance, stress-related hormonal changes, and serum levels of various immunity biomarkers, as well as the gene expression of IFN-γ in broilers exposed to heat stress conditions. Treatments included T1 which received the basal diet with no feed additive; T2 exposed to heat stress; T3, T4, and T5 containing 500, 1000, and 1500 ppb CrPic; as well as T6, T7, and T8 containing 500, 1000, and 1500 ppb NCrPic, respectively. After 2 weeks from CrPic and NCrPic supplementation, IFN-γ mRNA expression was assayed using the RT-PCR technique. The results showed that the lower body weight, daily weight gain, daily feed intake by heat stress, and the feed conversion ratio were recovered remarkably by CrPic and NCrPic supplements. The stress-elevated levels of cortisol and immunoglobulin were reduced significantly using CrPic and NCrPic supplementation (P ≤ 0.05). The gene expression profile showed that the upregulated expression of IFN-γ was regulated by the addition of CrPic and NCrPic, in particular, to the diet; however, a full downregulation of IFN-γ expression was observed after week 2 of NCrPic supplementation. In conclusion, the results indicated that nanoparticle supplementation could be effective in reducing heat stress-induced detrimental alterations, thereby attributing to substantial changes to the immune system, including IFN-γ expression.
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http://dx.doi.org/10.1007/s12011-021-02634-0DOI Listing
February 2021

Cyclopiazonic acid induced p53-dependent apoptosis in the testis of mice: Another male related risk factor of infertility.

Environ Toxicol 2021 May 5;36(5):903-913. Epub 2021 Jan 5.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

Cyclopiazonic acid (CPA) is an indole tetrameric acid mycotoxin. This study carried out to investigate the potential effects of CPA on male reproductive system. In the current study, 40 adult male mice were divided into five groups (n = 8). The control group did not expose to CPA, while animals in vehicle-received group; received the CPA-solvent (0.05% dimethyl sulfoxide) and the animals of third, fourth, and fifth groups received CPA 0.03, 0.06, and 0.12 mg/kg, body weight, respectively for 28 days. Morphometric and morphological deviations, spermatogenesis indices, malondialdehyde (MDA) content, total thiol molecules (TTM) concentration, total antioxidant capacity (TAC), protein carbonylation rate (CO), and nitric oxide (NO) concentration were examined. The expression changes of apoptotic genes (P53, Bcl-2, and Caspase III) at mRNA level were also evaluated by qPCR technique. Reduction in the Leydig and Sertoli cells population, diameter of seminiferous tubules, and spermatogenesis parameters was significant only in the group that received the highest dose of CPA. An increase in the level of MDA, NO, and CO in testicular tissue and reduction of TAC and TTM were observed in the CPA-exposed groups. Significant up-regulation (p < .05) in the expression of P53 and Caspase III genes and down-regulation of Bcl-2 gene were found in the CPA-received groups. These results are indicating the detrimental effects of CPA on the testicles, which may attribute to the CPA-induced oxidative stress and apoptosis. Moreover, results also help to understand a serious concern about the presence of CPA in foods as a potential risk factor in male-related infertility.
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http://dx.doi.org/10.1002/tox.23092DOI Listing
May 2021

Mycotoxicoses in veterinary medicine: Aspergillosis and penicilliosis.

Vet Res Forum 2020 15;11(2):97-103. Epub 2020 Jun 15.

Department of Veterinary Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands .

Molds and mycotoxins are contaminants of animal feed causing spoilage and clinical intoxication. Animal exposure to mycotoxins reflects diet composition with major differences occurring between animals kept predominantly of pastures, i.e. ruminants and horses, and those consuming formulated feed like pigs and poultry. Mixed feeds are composed of several ingredients, often sourced from different continents. Subsequently, practitioners may confront endemic diseases and signs of toxin exposure related to toxins imported accidentally with contaminated feed materials from other countries and continents. Mycotoxins comprise more than 300 to 400 different chemicals causing a variety of clinical symptoms. Mycotoxin exposure causes major economic losses due to reduced performance, impaired feed conversion and fertility, and increased susceptibility to environmental stress and infectious diseases. In acute cases, clinical symptoms following mycotoxin ingestion are often non-specific, hindering an immediate diagnosis. Furthermore, most mold species produce more than one toxin, and feed commodities are regularly contaminated with various mold species resulting in complex mixtures of toxins in formulated feeds. The effects of these different toxins may be additive, depending on the level and time of exposure, and the intensity of the clinical symptoms based on age, health, and nutritional status of the exposed animal(s). Threshold levels of toxicity are difficult to define and discrepancies between analytical data and clinical symptoms are common in daily practice. This review aims to provide an overview of and toxins that are frequently found in feed commodities and discusses their effects on animal health and productivity.
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http://dx.doi.org/10.30466/vrf.2020.112820.2686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413002PMC
June 2020

Transcellular brain drug delivery: A review on recent advancements.

Int J Pharm 2020 Aug 26;586:119582. Epub 2020 Jun 26.

Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

The blood-brain barrier (BBB) has a pivotal role in maintaining brain homeostasis. It robustly protects the brain parenchyma against the invasion of irrelevant substances, which may interrupt its critical function. From a pharmaceutical point of view, such a barrier may cause central nervous system (CNS) disorders refractory by restricting the therapeutics from accessing to their target sites in cerebral parenchyma. On the other side, the increasing rate of CNS disorders demands novel strategies to be developed for effective transferring the drugs through the BBB. Transcellular pathways seem to be more promising in ferrying across the BBB than paracellular route due to using the regular biological routes and retaining the BBB integrity, as well. The transcellular pathway contains several mechanisms for the transportation of therapeutic molecules, which are alternately applicable based on the physicochemical characteristics of the crossing molecule. In the present article, the most considerable transcellular routes, including the adsorptive mediated transcytosis (AMT), receptor-mediated transcytosis (RMT), cell-mediated transcytosis (CMT), and the efflux pumps-mediated drug delivery approaches were reviewed. Exosome, as a new drug carrier, utilizable in various transcellular routes, was also discussed.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119582DOI Listing
August 2020

Cardioprotective effects of memantine in myocardial ischemia: Ex vivo and in vivo studies.

Eur J Pharmacol 2020 Sep 13;882:173277. Epub 2020 Jun 13.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran. Electronic address:

Myocardial infarction (MI) refers to the loss of cardiomyocytes due to inadequate coronary blood flow and subsequently a reduced oxygen supply. Activation of N-methyl-D-aspartate (NMDA) receptors has been linked to myocardial infarction. The aim of the present study was to determine the cardioprotective effects of memantine, in myocardial infarction both in ex vivo and in vivo models. Effects of memantine on the electrocardiogram (ECG) pattern, cardiodynamic parameters, infarct size and lipid peroxidation were evaluated in the isolated perfused rat heart. Moreover, in in vivo studies in rats, the protective effects of memantine on isoproterenol-induced myocardial infarction model (administration of 100 mg/kg isoproterenol subcutaneously for 2 consecutive days) was evaluated by measuring ECG pattern, mean arterial pressure, malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, cardiac tumor necrosis factor-alpha (TNF-α) level and cardiac remodeling. The results from the ex vivo isolated perfused heart showed that memantine treatment increased heart rate, left ventricular systolic pressure and left ventricular maximal rate of pressure increase, and decreased cardiac arrhythmia, MDA level and infarct size in comparison to ischemia/reperfusion (IR) group. The isoproterenol-induced MI (Iso) as used in the in vivo model demonstrated that MDA levels and MPO activity were decreased in memantine groups. Memantine treatment reduced the expression of cardiac TNF-α in comparison to Iso group. Cardiac fibrosis and hypertrophy were lower in memantine groups. In conclusion, memantine exerts cardioprotective effects in models of myocardial infarction, which may be attributed to reduction of pro-inflammatory and oxidative stress factors and subsequently a decrease in cardiac remodeling.
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http://dx.doi.org/10.1016/j.ejphar.2020.173277DOI Listing
September 2020

Experimental diabetes negatively affects the spermatogonial stem cells' self-renewal by suppressing GDNF network interactions.

Andrologia 2020 Oct 15;52(9):e13710. Epub 2020 Jun 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

The present study was done to analyse the time-dependent effects of diabetes on Sertoli cells-spermatogonial stem cells' (SSCs) network interaction by focusing on glial cell line-derived neurotrophic factor (GDNF) and its special receptors, gfrα1 and c-RET as well as the Bcl-6b. In total, 40 Wistar rats were considered in; control, 20, 45 and 60 days diabetes-induced groups. An experimental diabetes was induced by STZ. The GDNF, gfrα1, c-RET and Bcl-6b expressions were evaluated. The serum level of testosterone, tubular repopulation (RI) and spermiogenesis (SPI) indices, general histological alterations, germ cells, mRNA damage, sperm count and viability were assessed. The diabetes, in a time-dependent manner, diminished mRNA and protein levels of GDNF, gfrα1, c-RET and Bcl-6b versus control group (p < .05), enhanced percentage of seminiferous tubules with negative RI, SPI, and diminished Leydig and Sertoli cells distribution, serum levels of testosterone, sperm count and viability. Finally, the number, percentage of cells and seminiferous tubules with normal mRNA content were significantly (p < .05) diminished. In conclusion, as a new data, we showed that the diabetes by inducing severe mRNA damage and suppressing GDNF, gfrα1, c-RET and Bcl-6b expressions, potentially affects the Sertoli-SSCs' network and consequently inhibits the SSCs' self-renewal process.
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http://dx.doi.org/10.1111/and.13710DOI Listing
October 2020

Effects of rabbit pinna-derived blastema cells on tendon healing.

Iran J Basic Med Sci 2020 Jan;23(1):13-19

Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Objectives: Tendon healing is substantially slow and often associated with suboptimal repair. Cell therapy is one of the promising methods to improve tendon repair. Blastema, a population of undifferentiated cells, represents characteristics of pluripotent mesenchymal stem cells and has the potentials to be used in regenerative medicine. The aim of this study was to investigate the use of blastema allotransplantation in rabbit tendon healing.

Materials And Methods: In this study, one rabbit was used as a blastema donor, and twenty-four rabbits were divided into control and treatment groups. Blastema cells were obtained from ear pinna upon punch hole injury in the donor rabbit. Under general anesthesia, a complete transverse tenotomy was performed on the midsubstance of deep digital flexor tendon followed by suture-repair. In the treatment group, 1 × 10 blastema cells suspended in buffer saline were injected intratendinously at the repair site, while the control group received only the buffer saline. Cast coaptation was maintained for two weeks. Eight weeks after the operation, tendons were harvested, and histopathological, biomechanical, and biochemical assays were performed on samples.

Results: Mechanical testing showed a significant increase in ultimate load, energy absorption, stiffness, yield load, stress, and strain in blastema-treated tendons compared to controls. Also, higher hydroxyproline content and improved collagen alignment along with lower inflammatory cell infiltration and decreased angiogenesis were observed in blastema-treated tendons.

Conclusion: Increased levels of hydroxyproline and improved histopathological and biomechanical parameters in the treatment group suggest that blastema cells could be considered an adjunct to tendon repair in rabbits.
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http://dx.doi.org/10.22038/IJBMS.2019.29102.7045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206831PMC
January 2020

Effects of Securigera Securidaca seed extract in combination with glibenclamide on antioxidant capacity, fibroblast growth factor 21 and insulin resistance in hyperglycemic rats.

J Ethnopharmacol 2020 Feb 23;248:112331. Epub 2019 Oct 23.

Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Ethnopharmacological Relevance: Undesired effects of synthetic antidiabetic agents have made researchers to seek for safer and healthier resources. With this aspect, herbal materials have attracted substantial research interest and are being extensively investigated. Considering that herb-drug interactions can be a double-edged sword presenting both risks and benefits, investigation of such interactions is greatly in demand.

Aim Of The Study: to investigate possible beneficial effects of hydroalcoholic extract of SecurigeraSecuridaca seed (HESS) on antioxidant capacity, fibroblast growth factor 21 (FGF21) and insulin resistance in Streptozotocin (STZ)-induced diabetic rats, alone and in combination with glibenclamide.

Materials And Methods: Forty male Wistar rats were randomly divided in to eight equal groups including healthy and diabetic controls and six treated groups with a various doses of HESS alone and in combination with glibenclamide, for 35 consecutive days. Serum samples were taken and analyzed for biochemical profile, HOMA indexes, FGF21, oxidative/nitrosative stress and inflammatory biomarkers as compared with the controls. Moreover, total phenolic and flavonoid contents of herbal extract were assessed.

Results: The herbal extract was found to be rich in flavonoid and phenolic components. Both of glibenclamide and the HESS decreased glucose and insulin resistance, as well as increased body weight and insulin sensitivity. Moreover, the extract could mitigate oxidative/nitrosative stress and inflammation dose-dependently, however, the standard drug was less effective than HESS. Induction of diabetes increased FGF21 levels and both of the treatments could reduce its contents, however, glibenclamide was more effective than HESS.

Conclusions: The results clearly show that there is no contradiction between HESS and glibenclamide. Moreover, the herbal extract could augment antioxidant and anti-inflammatory properties of the standard drug.
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http://dx.doi.org/10.1016/j.jep.2019.112331DOI Listing
February 2020

Cardioprotective Effects of Atorvastatin Are Mediated Through PPARγ in Paraquat-Exposed Rats.

J Cardiovasc Pharmacol 2019 11;74(5):400-408

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

Background: Paraquat poisoning is one of leading intoxication worldwide without an effective antidote and treatment protocol. Among the other organs, cardiotoxicity of paraquat has been frequently reported.

Aim: The protective effects of atorvastatin (STN) on paraquat-induced cardiotoxicity and the role of peroxisome proliferator-activated receptors γ in the mediation of STN effects were investigated.

Methods: Forty-two male Wistar rats were aliquoted into control or test groups. The animals in test groups in addition of paraquat received saline normal (PQ), pioglitazone (PGT), atorvastatin (STN), PGT + STN, PGT + GW9662, and/or STN + GW9662 for 14 days.

Results: PGT and STN lowered lipid peroxidation rate, nitric oxide concentration, and activity of myeloperoxidase and CK/MB in the heart. PGT and STN protected from thiol molecules reduction and PQ-induced histopathological injuries. STN regulated the PQ-induced upregulation of COX-II expression in the heart. All STN-related protective effects were reversed by GW9662 as PPARγ antagonist.

Conclusions: These data suggest a cardioprotective effect for STN against the PQ-induced inflammation and oxidative stress. The pharmacologic approach of these findings indicates that STN through PPARγ pathway lowered the PQ-induced cardiotoxicity.
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http://dx.doi.org/10.1097/FJC.0000000000000731DOI Listing
November 2019

Deoxynivalenol reduces quality parameters and increases DNA damage in mice spermatozoa.

Andrologia 2019 Jun 31;51(5):e13238. Epub 2019 Jan 31.

Department of Animal Sciences, Faculty of Agriculture, Urmia University, Urmia, Iran.

This study was performed to investigate in vitro effects of deoxynivalenol (DON) on mice sperm quality parameters including viability, motility and DNA damages at various concentrations and exposure times. Mice spermatozoa were exposed to DON at 0, 2.5, 5 and 10 µM for 1, 3 and 6 hr, motility parameters were evaluated by computer-assisted analysis and viability was examined by colorimetric metabolic activity assay and HOS test. DNA damage was examined by acridine orange staining, and sperm damages via lipid peroxidation pathway were determined by malondialdehyde (MDA) content measurement. DON affected sperm parameters in a concentration- and time-dependent manner. In all test groups, the average path velocity and progressive motile spermatozoa were remarkably reduced. In comparison with the controls, after 1, 3 and 6 hr exposure to DON, viability of spermatozoa was reduced 25, 30 and 49% respectively. DON exposure at 10 µM for 6 hr resulted in 15% DNA damage and 2.5-fold more MDA generation, when compared with nonexposed spermatozoa. Our data suggest that DON causes sperm quality parameters decline in concentration- and time-dependent fashion, which attribute to the reduction in sperm metabolic activity and membrane integrity and equally to increase in lipid peroxidation rate and DNA damage.
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http://dx.doi.org/10.1111/and.13238DOI Listing
June 2019

Quercetin alleviates high glucose-induced damage on human umbilical vein endothelial cells by promoting autophagy.

Phytomedicine 2019 Mar 8;56:183-193. Epub 2018 Nov 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Quercetin, a flavonoid antioxidant, has been found to exert therapeutic effects in diabetic condition. Autophagy represents a homeostatic cellular mechanism for the turnover of unfolds proteins and damaged organelles through a lysosome-dependent degradation manner. We speculated that quercetin could protect endothelial cells against high glucose-induced damage by promoting autophagic responses.

Methods: HUVECs viability was evaluated by MTT method. Griess and TBARS assays were used to monitor the levels of NO and MDA, respectively. Intracellular ROS generation was determined in DCFDA-stained cells analyzed by flow cytometry. To investigate the role of quercetin in endothelial cell migratory behavior, we used a scratch test. The level of autophagy proteins LC3, Beclin-1 and P62 were measured by western blotting technique.

Results: Our results showed that quercetin had the potential to increase cell survival after exposure to high glucose (P < 0.05). Total levels of oxidative stress markers were profoundly decreased and the activity of GSH was increased by quercetin (P < 0.05). High glucose suppressed HUVECs migration to the scratched area (P < 0.05). However, a significant stimulation in cell migration was observed after exposure to quercetin (P < 0.05). Based on data, autophagy was blocked at the late stage by high glucose concentration while quercetin enhanced autophagic response by reducing the P62 level coincided with the induction of Beclin-1 and LC3-II to LC3-I ratio (P < 0.05). All these beneficial effects were reversed by 3-methyladenine as an autophagy inhibitor.

Conclusion: Together, our data suggest that quercetin could protect HUVECs from high glucose induced-damage possibly by activation of the autophagy response.
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http://dx.doi.org/10.1016/j.phymed.2018.11.008DOI Listing
March 2019

A molecular basis for the synergy between 17‑allylamino‑17‑demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression.

Gene 2019 Feb 11;684:30-38. Epub 2018 Oct 11.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical sciences, Urmia, Iran.

Anti-proliferative, anti-metastatic and anti-angiogenic effects of 17‑allylamino‑17‑demethoxy geldanamycin (17-AAG) were studied alone and in combination with Capecitabine (Cap) and/or Irinotecan (IR) on HT-29 human colorectal carcinoma cells. Expression of MMP-9 (matrix metalloproteinase‑9) and VEGF (vascular endothelial growth factor) mRNA was analyzed by real-time PCR method. The study was further followed by wound scratch assay for migration assessment. Nitric oxide content, Malondialdehyde generation and total anti-oxidant capacity were also assessed. Results showed significant differences between mono- and double therapy (p < 0.05). Combination of 17-AAG with IR or Cap resulted in synergistic effect (Combination Index < 1). Among double combination groups only Cap/17-AAG showed significant differences in MMP-9 and VEGF genes expression and wound healing assay. Moreover, a significant decrease of wound area in our triple combination group was obtained, indicating the antagonistic effect. IR/17-AAG and IR/Cap double combination groups resulted in down-regulation of MMP-9 and VEGF mRNA expression, respectively. Significant generation of MDA and decrease in TAC values have been observed in all our tested groups, however, the IR/17-AAG combination was the only group that could elevate NO concentration, significantly. Our findings demonstrated potent anti-angiogenesis and anti-metastatic effects for 17-AAG when it is provided in double combination especially with Cap, suggesting a new protocol in colorectal cancer combination therapy. These findings may indicate that down-regulation of VEGF and MMP-9 genes is directly related to angiogenesis and metastasis.
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http://dx.doi.org/10.1016/j.gene.2018.10.016DOI Listing
February 2019

The effect of vitamin C on mice hemolytic anemia induced by phenylhydrazine: an animal model study using histological changes in testis, pre-implantation embryo development, and biochemical changes.

Iran J Basic Med Sci 2018 Jul;21(7):668-677

Department of Anatomy & Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Objectives: The aim of the present study was to assess the effects of vitamin C (Vit C) on hemolytic anemia induced by phenylhydrazine (PHZ).

Materials And Methods: Twenty-four healthy male mice were divided into four groups, randomly: Control group (0.1 ml/day, normal slaine, IP), PHZ group that received only PHZ 8 mg/100 g/48 hr, IP, PHZ+Vit C group that received PHZ 8 mg/100 g/48 hr, IP and Vit C 100 mg/kg BW-1/day by gavage and Vit C group that received 100 mg/kg BW-1/day Vit C by gavage. After 35 days, germinal cells, RNA damage, sperm parameters, testis malondialdehyde (MDA) content, serum total antioxidant capacity (TAC), pre-implantation embryo development and mRNA levels of cyclin D1 and c-myc in two-cell, and morula and blastocyst stages were assessed.

Results: Vit C reduced the RNA damage, enhanced sperm quality, promoted pre-implantation embryo development and improved testicular antioxidant and endocrine status (<0.05). Vit C reduced cyclin D1 expression and up-regulated c-myc mRNA level in two-cell, morula, and blastocyst embryonic cells.

Conclusion: Vit C enhanced the fertilizing potential by ameliorating the endocrine status, antioxidant capacity, and sperm quality. Finally, the cyclin D1 and c-myc gene expressions were regulated in PHZ+Vit C treated group that promoted the embryo development.
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http://dx.doi.org/10.22038/IJBMS.2018.25819.6356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098957PMC
July 2018

Alpha-zearalenol negatively influences ram sperm parameters during liquid storage.

Vet Res Forum 2018 15;9(2):171-178. Epub 2018 Jun 15.

Department Plant Breeding and Biotechnology, Faculty of Agriculture, Urmia University, Urmia, Iran.

This study was aimed to investigate the effects of 17 𝛽-estradiol (E2) and 𝛼-zearalenol (α-ZOL) on motility parameters, plasma membrane integrity, levels of produced nitric oxide (NO) and total antioxidant capacity of Ghezel ram sperm during the liquid storage at 4 ˚C, for various periods of time. Semen samples were collected from four rams and diluted with Tris-egg yolk extender and supplemented with E2 (100 µmol) or different concentrations of α-ZOL (100 pmol, 100 nmol and 100 µmol) at a final concentration of 200 × 10 sperm per mL. We failed to show any significant effect of E2 at 100 µmol concentration on ram's sperm parameters while α-ZOL resulted in a significant decrease of plasma membrane integrity at 100 µmol concentration (55.40% for α-ZOL 62.20% for control) after 96 hr incubation. Alpha-ZOL had decreasing effect on sperm motility parameters including curvilinear velocity and average path velocity at 100 µmol concentration after 96 hr storage. Although remarkable reduction of total antioxidant capacity at high concentration of α-ZOL and long incubation time was found, however no significant changes were recorded in NO level during storage time. It was concluded that the detrimental effect of α-ZOL on ram sperm might be attributed to its induced oxidative stress and damage to the plasma membrane.
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http://dx.doi.org/10.30466/VRF.2018.30823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047571PMC
June 2018

Antioxidant effects of () on cyclophosphamide-induced testicular injury in rats.

Vet Res Forum 2018 15;9(1):35-41. Epub 2018 Mar 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

Cyclophosphamide (CP) is known to reduce fertility. The protective effects of (SP) against CP-induced testicular toxicity were investigated. Male Wistar rats were categorized into eight groups (n = 7). Four groups of rats were administered CP at a dose of 5 mg in 5 mL distilled water kg per day orally. Two of these groups were received SP (500 and 1000 mg kg per day) orally after CP administration. One of these groups was also received vitamin E (100 mg kg per day) intraperitoneally. A vehicle treated control group, two SP control groups (500 and 1000 mg kg per day) and a vitamin E control group were also included. Body and testes weights, sperm count, serum levels of glutathione peroxidase (GPx), malondialdehyde (MDA), histological and histomorphometric alternations in testes were investigated after four weeks. The CP-treated group exhibited significant decreases in the body and testes weights and spermatogenic activities. Several histological alterations were observed in this group. The CP treatment caused a significant reduction in sperm count, in serum level of GPx, as well increased serum concentration of MDA. The SP co-administration caused an increase in GPx serum level, a decrease in MDA serum level and improvements in histological and histomorphometric alternations. Vitamin E co-treatment showed partial recovery in above-mentioned parameters. These results suggest that SP due to a reduction in oxidative stress has more effective protection against CP-induced reproductive damages in rat than vitamin E.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913559PMC
March 2018

Effect of hydroxychloroquine on oxidative/nitrosative status and angiogenesis in endothelial cells under high glucose condition.

Bioimpacts 2017 23;7(4):219-226. Epub 2017 Aug 23.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Under the diabetic condition, sustained production of oxidative/nitrosative stress results in irreversible vascular injuries. A great number of diabetic pathologies, such as inefficient or aberrant neo-angiogenesis emerge following chronic hyperglycemic condition. Lack of enough data exists regarding hydroxychloroquine (HCQ) contribution on angiogenesis during diabetes mellitus. To better address whether HCQ could blunt or exacerbate oxidative status and angiogenesis under high glucose condition (HCG), human umbilical vein endothelial cells (HUVECs) were exposed to 30 µM HCQ in combination with 30 mM glucose over a course of 72 hours. Viability was measured was evaluated by MTT assay. We used Griess method and TBARS assay to monitor changes in the levels of NO and MDA followed by flow cytometric analysis of ROS using DCFDA. To show the impact of HCQ on cell motility and in vitro angiogenic properties, we exploited routine scratch test and in vitro tubulogenesis, respectively. Our data showed that HCQ diminished cell viability under 5 and 30 mM glucose contents. HCQ significantly decreased the total levels of nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) in both sets of environments. Additionally, inhibitory effects were observed on cell migration after exposure to HCQ ( < 0.001). Anti-angiogenic activity of HCQ was confirmed by the reduction of tube areas under a normal or surplus amount of glucose ( < 0.001). In overall, results suggest that HCQ changes the oxidative/nitrosative status of HUVECs both in 5 and 30 mM conditions. HCQ is able to reduce migration and angiogenic activity of HUVECs irrespective of the glucose content.
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http://dx.doi.org/10.15171/bi.2017.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801533PMC
August 2017

Silibinin protects human endothelial cells from high glucose-induced injury by enhancing autophagic response.

J Cell Biochem 2018 11 26;119(10):8084-8094. Epub 2018 Jun 26.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Silibin, a flavonoid from the seeds of Silybum marianum (L.) Gaertn. (Asteraceae) has been reported to produce curative properties in diabetes. Autophagy is generated by a vast array of insults for removal of damaged proteins and organelles from the cell. Inadequate autophagy promotes endothelial cells dysfunction and delays in diabetic ulcers recovery. We hypothesized that silibinin could protect endothelial cells against high glucose-induced damage by engaging autophagic responses. HUVECs viability was evaluated by MTT assay. The Griess method and TBARS assay were used to monitor changes in the levels of nitric oxide and malondialdehyde, respectively. ROS generation was recorded in DCFDA-stained cells analyzed by flow cytometry. To investigate the role of silibinin on migration, we used scratch test. The level of autophagy proteins LC3, Becline-1, and P62 were measured by Western blotting. Our data showed that silibinin had potential to increase cell survival after exposure to high glucose condition. Total levels of oxidative stress markers were profoundly reduced and the activity of GSH was increased by silibinin. High glucose suppressed HUVECs migration to the scratched area. However, a significant increase in cell migration was observed after exposure to silibinin. Autophagy was blocked at the late stage by high glucose concentration and silibinin initiated an autophagic response by reducing P62 and enhancing Beclin-1 and LC3-II-LC3-I ratio. These effects were blocked by autophagy inhibitor of 3-Methyladenine. These observations suggest that silibinin could protect HUVECs from high glucose induced-damage possibly by activation of autophagy pathway.
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http://dx.doi.org/10.1002/jcb.26735DOI Listing
November 2018

Roles of p21, p53, cyclin D1, CDK-4, estrogen receptor α in aflatoxin B1-induced cytotoxicity in testicular tissue of mice.

Environ Toxicol 2018 Apr 23;33(4):385-395. Epub 2017 Dec 23.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran.

This study was done in order to investigate time-dependent effect of AFB1 on expression of genes involving in cell cycle check point machinery at G, S, and M phases. For this purpose, 24 mature male Swiss albino mice were randomly divided into control and test groups. The animals in test group subdivided into three groups, which received the AFB1 at a daily dose of 20 µg/kg body weight, through intraperitoneal (i.p.) route, for 7, 14, and 21 days. The p21, p53, cyclin D1, CDK4, and ERα expressions at both mRNA and protein level were analyzed by using reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. Moreover, the tubular differentiation (TDI) and spermiogenesis (SPI) indices were analyzed. Finally, the testicular DNA fragmentation was assessed by using DNA Ladder test. Observations revealed that the AFB1 remarkably (P < .05) reduced cyclin D1, Cdk4, and ERα expression at both mRNA and protein levels. Up-regulated p21 and p53 expression was revealed in AFB1-received animals, which developed time dependently. Histological examinations exhibited a significant reduction in TDI and SPI indices. Finally, the AFB1 resulted in severe DNA fragmentation. Our data showed that the AFB1 by down-regulating the cyclin D1, Cdk4, and ERα expression adversely affects cyclin D1/Cdk4 and cyclin D1/ERα interactions. Moreover, the AFB1-induced overexpression of p21 (as a kinase inhibitor), in turn results in cell cycle arrest via inhibiting the Cdk4 interaction with cyclin D1. Finally, the AFB1-induced DNA damage triggers the p53-dependent apoptosis pathway independent to p21 overexpression.
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http://dx.doi.org/10.1002/tox.22524DOI Listing
April 2018

Anti-atherosclerotic effect of extract on experimentally induced hypercholesterolemia in rats.

Vet Res Forum 2017 15;8(3):185-193. Epub 2017 Sep 15.

Department of Basic Sciences, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

(Bermuda grass) is a perennial plant traditionally used as an herbal medicine in many countries. In the present study, anti-atherosclerotic property of ethanolic extract of was investigated in the experimentally induced hypercholesterolemia in rats. In this study, 36 male Wistar rats were selected and allocated into six groups (n = 6). The control group received a normal diet, sham group received a high cholesterol diet (HCD; 1.50% cholesterol and 24.00% fat) and other groups received a HCD and ethanolic extract of at low (100 mg kg), moderate (200 mg kg) and maximum (400 mg kg) doses via gavages. The last group received atorvastatin (10 mg kg) through gavage with a HCD. The study period for all groups was six months. At the end of this period, parameters including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were assessed in the blood samples. Additionally, histopathological and immunohistochemical examinations on coronary and aorta arteries sections were performed. The results showed an increase in vessels wall thickness and proliferation of smooth muscle cells in the HCD group, while these pathological changes were not seen in -treated groups. Treatment of HCD animals with positively changed lipid profile by lowering of TC, TG and LDL-C. The results indicate that prevents from early atherosclerotic changes in the vessels wall.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653881PMC
September 2017

Rapamycin inhibits oxidative/nitrosative stress and enhances angiogenesis in high glucose-treated human umbilical vein endothelial cells: Role of autophagy.

Biomed Pharmacother 2017 Sep 13;93:885-894. Epub 2017 Jul 13.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Chronic hyperglycemia is a potent risk factor of abnormal angiogenesis with various tissue diseases. Autophagy, as an alternative cell response, is mostly generated by a vast array of insults. Applying autophagic response contributes to normal cell retrieval circumstance during various insults. We aimed to show whether stimulation/inhibition of autophagy could reduce or exacerbate oxidative status and angiogenic potential in endothelial cells after exposure to 30mM glucose. HUVECs were incubated with the combined regime of 100nM Rapamycin and 30mM glucose over a period of 72h. The effect of rapamycin on cell viability, malondialdehyde levels, and nitric oxide were monitored by convenient assays. Intracellular ROS level was measured by flow cytometric analysis and DCFDA. HUVECs migration and angiogenic properties were assessed using scratch test and tubulogenesis assay. The expression of autophagic modulators LC3, Becline-1 and P62 was measured by using western blotting. Data showed 30mM glucose reduced cell viability, migration and in vitro tubulogenesis and level of ROS and nitric oxide were found to increased (p<0.05). Rapamycin had potential to increase cell survival and significantly decreased the total levels of oxidative stress markers after cell exposure to 30mM glucose (p<0.05). Rapamycin potentially improved the detrimental effect of 30mM glucose on cell migration and tubulogenesis capacity (p<0.05). Effective autophagic response was stimulated by rapamycin by increasing beclin-1, and the LC3-II/I ratio and reducing intracellular P62 level (p<0.05), resulting in the improvement of cell health and function. Together, rapamycin protected HUVECs from damages caused by high glucose concentration. This effect was possibly mediated by autophagy-dependent pathway.
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http://dx.doi.org/10.1016/j.biopha.2017.07.044DOI Listing
September 2017

Co-Administration of Vitamin E and Testosterone Attenuates The Atrazine-Induced Toxic Effects on Sperm Quality and Testes in Rats.

Cell J 2017 Jul-Sep;19(2):292-305. Epub 2017 Feb 22.

Private Veterinary Practitioner, Urmia, Iran.

Objective: Atrazine (ATZ) as a widely used herbicide is considered as a potent endocrine disrupter which adversely affects reproductive systems in both genders. This study aimed to assess the effects of testosterone (T)- and vitamin E (VitE)- alone and their coadministration on testicular function and sperm parameters after exposure to ATZ in rats.

Materials And Methods: In this experimental study, the rats (n=30) are assigned into the following 5 groups: control-sham group (n=6) receiving corn oil, ATZ group (n=6) receiving 200 mg/kg ATZ alone, ATZ+VitE group (n=6) receiving 150 mg/kg ATZ+VitE, ATZ+T group (n=6) receiving 400 µg/kg ATZ+T, and ATZ+VitE+T group (n=6) receiving ATZ+VitE+T for 48 consecutive days. Total antioxidant capacity (TAC), total thiol molecules (TTM), and malondialdehyde (MDA) were analyzed. Serum levels of T, luteinizing hormone (LH), and inhibin-B (IN-B) were also determined. Histological examination and sperm analysis were performed. The data were analyzed using Graph-Pad Prism software version 2.01.

Results: Co-administration of VitE and T significantly (P<0.05) increased ATZ-decreased TAC and TTM levels and reduced ATZ-increased MDA content. T and VitE significantly (P<0.05) increased serum levels of ATZ-reduced T (1.94 ± 0.96), IN-B (122.10 ± 24.33) and LH (0.40 ± 0.10). The T+VitE animals showed a reduction in apoptotic cells and an increase in Leydig cells steroidogenesis. Co-administration of T and VitE significantly (P<0.05) reduced the ATZ-induced DNA disintegrity and chromatin de-condensation. VitE and T protected germinal cells RNA and protein contents against ATZ-induced damages.

Conclusion: T and VitE in simultaneous form of administration were able to normalize the ATZ-induced derangements through promoting antioxidant capacity and endocrine function.
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http://dx.doi.org/10.22074/cellj.2016.490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412788PMC
February 2017

Crosstalk between E2F1 and P53 transcription factors in doxorubicin-induced DNA damage: evidence for preventive/protective effects of silymarin.

J Pharm Pharmacol 2017 Sep 23;69(9):1116-1124. Epub 2017 May 23.

Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Objectives: To study the effects of silymarin in various forms of applications on the molecular mechanism(s) of doxorubicin-induced testicular toxicity in male rats.

Methods: Following DOX administration with or without SMN in male rats, sperm quality assays were conducted. Moreover, total antioxidant capacity and nitric oxide content of testis were determined. Expression profile of p53 and E2F1 was analysed by PCR technique. Ultimately, the rate of DNA fragmentation in the testes was quantitatively measured.

Key Findings: P53 and E2F1 expression in DOX-received animals at mRNA level showed a revers profile of an up- and down-regulation, respectively. Administration of SMN in preventive and protective forms resulted in a significant (P < 0.05) reduction in DOX-induced sperm abnormalities, DNA fragmentation, nitric oxide concentration and a marked increase in total antioxidant power, rate of sperm motility and viability. SMN lowered the DOX-up-regulated expression of p53 at mRNA level.

Conclusions: DOX-induced testicular toxicity was characterized by lowering sperm quality values, induction of oxidative and nitrosative stress and DNA fragmentation. Preventive and protective effects of SMN on DOX-induced testicular toxicity may attribute to its antioxidant property. DOX-induced testicular damages and SMN preventive/protective effects might be mediated via up- and down-regulation of p53 and E2F1 transcription factors.
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http://dx.doi.org/10.1111/jphp.12745DOI Listing
September 2017

Silymarin: A Novel Natural Agent to Restore Defective Pancreatic β Cells in Streptozotocin (STZ)-induced Diabetic Rats.

Iran J Pharm Res 2016 ;15(3):493-500

Department of pharmacology and toxicology, Faculty of Veterinary medicine, Urmia University, Iran.

This study aimed to investigate the potency of silymarin (SMN) and melatonin (MEL) on restoring the pancreatic   cells in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into five groups, including: control (C), untreated diabetic (D), SMN-treated diabetic (50 mg/Kg, orally), MEL-treated diabetic (10 mg/Kg, i.p.), and SMN plus MEL-treated diabetic rats. Diabetes was induced by injection of STZ (50 mg/Kg, i.p.). The blood glucose and insulin levels were measured. After the 28 days treatment period, antioxidant status was analyzed by determination of total antioxidant capacity (TAC) in the liver and serum. The histopathological changes in the pancreatic islets were examined by histochemical staining and enumeration of   cells. Although none of the test compounds reduced the blood glucose level to normal concentration, however SMN alone and in combination with MEL was able to decline it significantly (P<0.05) after 28 days administration. Both SMN and MEL could recover the diabetes-reduced TAC values. Moreover, the diabetes-induced cellular vacuolation and   cells depletion were improved by the SMN treatment. Our data suggest that the SMN and MEL treatment was able to normalize the antioxidant status, while only SMN administration could restore the  cells of Langerhans islets in diabetic rats.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5149036PMC
January 2016

Atorvastatin protected from paraquat-induced cytotoxicity in alveolar macrophages via down-regulation of TLR-4.

Environ Toxicol Pharmacol 2017 Jan 18;49:8-13. Epub 2016 Nov 18.

Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

The current study designed to clarify the mechanism of paraquat-induced cytotoxicity and protective effects of Atorvastatin on freshly isolated alveolar macrophages (AMs). AMs were collected via bronchoalveolar lavage and exposed to various concentrations of paraquat in the presence and absence of atorvastatin for 24h. Cell viability, myeloperoxidase activity; nitric oxide generation and total antioxidant capacity were assessed. Expression of TLR-4 at mRNA and protein levels were studied by using PCR and western blot methods Atorvastatin enhanced the paraquat-reduced cell viability and reduced the paraquat-induced myeloperoxidase activity and nitric oxide production. Moreover, atorvastatin down-regulated by 60% the paraquat up-regulated expression of TLR-4 at protein and mRNA level. Our results suggest that, AMs in vitro model could be a novel cytological tool for studies on paraquat poisoning and therapy regimens. Additionally, atorvastatin cytoprotective effects on paraquat-induced cytotoxicity partly attribute to its anti-myeloperoxidase, antioxidant properties, which might be regulated via TLR-4 expression.
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http://dx.doi.org/10.1016/j.etap.2016.11.011DOI Listing
January 2017

Zearalenone and 17 β-estradiol induced damages in male rats reproduction potential; evidence for ERα and ERβ receptors expression and steroidogenesis.

Toxicon 2016 Sep 12;120:133-46. Epub 2016 Aug 12.

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran; Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, P.O. Box: 1177, Urmia University, Urmia, Iran.

The estrogen receptors (ERs)-dependent effects of Zearalenone (ZEA) on structure and function of the testis as well as sperm parameters were compared with 17-β estradiol as endogenous substance. For this purpose, 30 mature male rats were assigned into five groups as; control (appropriate volume of normal saline, i. p.), ZEA-received (1, 2 and 4 mg/kg, b. w., i. p.) and 17 β-estradiol (E2)-received (appropriate dose of 0.1 mg/kg, i. p.). Following 28 days, the mRNA levels of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in the testis and sperms and the expression of them at protein levels in testicles were estimated. Mitochondrial content of germinal epithelium, Leydig cells steroid foci, sperm quality parameters and serum level of testosterone were assessed. Fluorescent techniques were used for analyzing apoptosis and mRNA damage in necrotic cells. ZEA reduced the mRNA and protein levels of ERα in testicles while up-regulated the ERβ expression. The mRNA level of ERα decreased in sperms of ZEA and E2-received animals. No remarkable changes were found for ERβ expression in sperms from ZEA and E2-received animals. ZEA reduced the Leydig cells steroidogenesis, mitochondrial content of germinal cells and elevated cellular apoptosis and necrosis dose-dependently. E2 reduced the testosterone concentration, enhanced the apoptosis and reduced sperm quality. Our data suggest that ZEA-induced detrimental effects in the structure and function of testis, may attribute to changing the ERs expression at mRNA and translational level.
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http://dx.doi.org/10.1016/j.toxicon.2016.08.009DOI Listing
September 2016

Determination of naturally occurring estrogenic hormones in cow's and river buffalo's meat by HPLC-FLD method.

J Food Drug Anal 2016 07 11;24(3):457-463. Epub 2016 Apr 11.

Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Urmia University, Urmia, Islamic Republic of Iran.

This study was performed to measure and compare the levels of steroid hormones [estrone (E), 17β-estradiol (E), and estriol (E)] and their conjugated metabolites in cow's and river buffalo's meat in two distinct follicular and luteal phases. Moreover, the possible effect of a heating process on steroid hormone concentration was also investigated. The collected meat (biceps femoris muscle) samples were subjected to liquid extraction, enzymatical deconjugation, and C18 solid-phase extraction. Estrogens were analyzed using high performance liquid chromatography equipped with a fluorescence detector. In the follicular phase the levels of steroid hormones (E and E) in either tested species were higher than the luteal phase. Moreover, in the present study, E concentration (free and deconjugated value, 16.2 ± 1.1 ng/L) was found to be the highest phenolic estrogen in beef, while the dominant estrogen in muscle of river buffalo was E (free and deconjucated value, 23.3 ± 1.3 ng/L). The study revealed that animal species influenced the concentration of hormones (E and E) in the samples. The heating process did not significantly change (p > 0.05) the levels of estrogens. The further findings of the present study showed that E (deconjugated form) was only detected in the buffalo's meat (15.8 ± 1.9 ng/L). These data suggest that although meat is one of the valuable nutrient sources for humans, there are, however, increasing concerns about the safety of meat due to the excessive presence of steroid hormones.
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http://dx.doi.org/10.1016/j.jfda.2016.02.014DOI Listing
July 2016