Publications by authors named "Azadeh Mohammadirad"

32 Publications

Biochemical and molecular evidences on the protection by magnesium oxide nanoparticles of chlorpyrifos-induced apoptosis in human lymphocytes.

J Res Med Sci 2015 Nov;20(11):1021-31

Toxicology and Poisoning Research Center, Ahar Branch, Ahar, Iran; Pharmaceutical Sciences Research Center, Ahar Branch, Ahar, Iran; Islamic Azad University, Ahar Branch, Ahar, Iran; Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Background: Chlorpyrifos (CP) is one of the most widely used organophosphate (OP) insecticides in agricultural and residential pest control with its attendant adverse health effect. In the present study, it is proposed to investigate the possible modulatory role of magnesium oxide nanoparticles (MgO NPs) against CP-induced toxicity in human lymphocytes and determine the mechanisms lying behind this protection by viability and biochemical assays.

Materials And Methods: Isolated lymphocytes were exposed to 12 μg/mL CP either alone or in combination with different concentrations of MgO NPs (0.1 μg/mL, 1 μg/mL, 10 μg/mL, and 100 μg/mL). After a 3-day incubation, the viability and oxidative stress markers including cellular mitochondrial activity, caspase-3 and -9 activities, total antioxidant power, lipid peroxidation, and myeloperoxidase (MPO) activity were measured. Also, the levels of tumor necrosis factor-α (TNF-α) as inflammatory index, along with acetylcholinesterase (AChE) activity were measured. Statistical differences were determined using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison tests.

Results: It is indicated that CP-exposed lymphocytes treated with MgO NPs resulted in a substantial reduction in the pace of mortality as well as the stages of oxidative stress in a dose-dependent manner. Also, MgO NPs (100 μg/mL) meaningfully restored CP-induced increase of TNF-α (P < 0.001) and decrease of AChE activity (P < 0.001) and were capable of preventing CP-treated human lymphocytes from apoptosis (P < 0.001).

Conclusion: Our results demonstrate that MgO NPs in approximate 100 nm diameter not only make cells resistant to the toxic properties of CP but also attenuate toxic effects of CP, which is demonstrating the potential of MgO NPs to be applied in future immune deficiency therapeutic strategies.
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http://dx.doi.org/10.4103/1735-1995.172811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755087PMC
November 2015

Protective Effect of Selenium-Based Medicines on Toxicity of Three Common Organophosphorus Compounds in Human Erythrocytes In Vitro.

Cell J 2016 17;17(4):740-747. Epub 2016 Jan 17.

Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Organophosphorus (OP) compounds are used to control pests, however they can reach the food chain and enter the human body causing serious health problems by means of acetylcholinesterase (AChE) inhibition and oxidative stress (OS). Among the OPs, chlorpyrifos (CHP), malathion (MAL), and diazinon (DIA) are commonly used for commercial extermination purposes, in addition to veterinary practices, domestic, agricul- ture and public health applications. Two new recently registered medicines that contain selenium and other antioxidants, IMOD and angipars (ANG), have shown beneficial ef- fects for OS related disorders. This study examines the effect of selenium-based medi- cines on toxicity of three common OP compounds in erythrocytes.

Materials And Methods: In the present experimental study, we determined the ef- ficacy of IMOD and ANG on OS induced by three mentioned OP pesticides in human erythrocytes in vitro. After dose-response studies, AChE, lipid peroxidation (LPO), total antioxidant power (TAP) and total thiol molecules (TTM) were measured in eryth- rocytes after exposure to OPs alone and in combined treatment with IMOD or ANG.

Results: AChE activity, TAP and TTM reduced in erythrocytes exposed to CHP, MAL and DIA while they were restored in the presence of ANG and IMOD. ANG and IMOD reduced the OPs-induced elevation of LPO.

Conclusion: The present study shows the positive effects of IMOD and ANG in re- duction of OS and restoration of AChE inhibition induced by CHP, MAL and DIA in erythrocytes in vitro.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746424PMC
http://dx.doi.org/10.22074/cellj.2016.3846DOI Listing
February 2016

On The Protection by The Combination of CeO2 Nanoparticles and Sodium Selenite on Human Lymphocytes against Chlorpyrifos-Induced Apoptosis In Vitro.

Cell J 2015 11;17(2):361-71. Epub 2015 Jul 11.

Toxicology and Poisoning Research Center, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran ; Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Chlorpyrifos (CP) as an organophosphorus pesticide is thought to induce oxidative stress in human cells via producing reactive oxygen species (ROS) that leads to the presence of pathologic conditions due to apoptosis along with acetylcholinesterase (AChE) inhibition.This study aimed to evaluate the apoptotic effects of CP and to assess the protective potential of CeO2nanoparticle (CNP) and sodium selenite (SSe) by measuring cascades of apoptosis, oxidative stress, inflammation, and AChE inhibition in human isolated lymphocytes.

Materials And Methods: In the present experimental study, we examined the anti-oxidative and AChE activating potential of CNP and SSe in CP-treated human lymphocytes. Therefore, the lymphocytes were isolated and exposed to CP, CP+CNP, CP+SSe, and CP+CNP+SSe after a three-day incubation. Then tumor necrosis factor-alpha (TNF-α) release, myeloperoxidase (MPO) activity, thiobarbituric acid-reactive substances (TBARS) levels as inflammatory/oxidative stress indices along with AChE activity were assessed. In addition, the apoptotic process was measured by flow cytometry.

Results: Results showed a significant reduction in the mortality rate, TNF-α, MPO activity, TBARS, and apoptosis rate in cells treated with CNP, SSe and their combination. Interestingly, both CNP and SSe were able to activate AChE which is inhibited by CP. The results supported the synergistic effect of CNP/SSe combination in the prevention of apoptosis along with oxidative stress and inflammatory cascade.

Conclusion: CP induces apoptosis in isolated human lymphocytes via oxidative stress and inflammatory mediators. CP firstly produces ROS, which leads to membrane phospholipid damage. The beneficial effects of CNP and SSe in reduction of CP-induced apoptosis and restoring AChE inhibition relate to their anti-oxidative potentials.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503850PMC
http://dx.doi.org/10.22074/cellj.2016.3748DOI Listing
July 2015

In vitro protection of human lymphocytes from toxic effects of chlorpyrifos by selenium-enriched medicines.

Iran J Basic Med Sci 2015 Mar;18(3):284-91

Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran ; Toxicology and Poisoning Research Center and Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Objectives: Chlorpyrifos (CP) is a broad-spectrum organophosphorus pesticide used extensively in agricultural and domestic pest control, accounting for 50% of the global insecticidal use. In the present study, protective effects of two selenium-enriched strong antioxidative medicines IMOD and Angipars were examined in human lymphocytes treated with CP in vitro.

Materials And Methods: Isolated lymphocytes were exposed to 12 µg/ml CP either alone or in combination with effective doses (ED50) of IMOD (0.2 µg/ml) and Angipars (1 µg/ml). After 3 days incubation, the viability and oxidative stress markers including cellular lipid peroxidation (LPO), myeloperoxidase (MPO), total thiol molecules (TTM), and total antioxidant power (TAP) were evaluated. Also, the levels of tumor necrosis factor-α (TNF-α), as inflammatory index along with acetylcholinesterase (AChE) activity and cell apoptosis were assessed by flow cytometry.

Results: Results indicated that effective doses of IMOD and Angipars reduced CP-exposed lymphocyte mortality rate along with oxidative stress. Both agents restored CP-induced elevation of TNF-α and protected the lymphocytes from CP-induced apoptosis and necrosis.

Conclusion: Overall, results confirm that IMOD and Angipars reduce the toxic effects associated with CP through free radical scavenging and protection from apoptosis and necrosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414995PMC
March 2015

On the benefit of galls of Quercus brantii Lindl. in murine colitis: the role of free gallic acid.

Arch Med Sci 2014 Dec;10(6):1225-34

Department of Pharmacology and Toxicology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: In this study we investigated the effect of gall of Quercus brantii Lindl., a traditional Iranian medicine, in a murine model of experimental colitis induced in male rats by rectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS).

Material And Methods: Quantification of the main active components was done for estimation of total phenolic content and free gallic acid. Gall of Quercus brantii Lindl. in two forms (gall powder and gall hydro alcoholic extract) was gavaged for 10 days (500 mg/kg). Ten days after induction of colitis, colonic status was examined by macroscopic, microscopic and biochemical analyses. Colonic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were analyzed as biomarkers of inflammatory condition. To determine the role of oxidative stress (OS) in colitis, the levels of cellular lipid peroxidation (LPO), total antioxidant power (TAP) and myeloperoxidase (MPO) were measured in colon tissues.

Results: TNBS-induced colitis exhibited a significant increase in colon MPO activity and concentrations of cellular LPO, TNF-α and IL-1β, while TAP was significantly reduced. Microscopic evaluations of the colonic damage in the colitis group revealed multifocal degenerative changes in the epithelial lining and areas of necrosis, extensive mucosal and sub-mucosal damage with congested blood vessels, edema and hemorrhages along with extensive infiltration of inflammatory cells. Parameters including macroscopic and microscopic scores, TNF-α, IL-1β, LPO, TAP and MPO improved by both gall extract and gall powder of Quercus brantii Lindl. and reached close to normal levels. The level of total phenols (GAE/100 g of sample) and free gallic acid were estimated to be 88.43 ±7.23 (mean ± SD) and 3.74% of dry weight, respectively.

Conclusions: The present study indicates that the gall of Quercus brantii Lindl. is able to exert antioxidative and anti-inflammatory effects on the biochemical and pathological parameters of colitis.
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http://dx.doi.org/10.5114/aoms.2014.47831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296077PMC
December 2014

Zinc oxide nanoparticles reduce apoptosis and oxidative stress values in isolated rat pancreatic islets.

Biol Trace Elem Res 2014 Dec 3;162(1-3):262-9. Epub 2014 Sep 3.

Ahar Branch, Islamic Azad University, Ahar, Iran.

Although toxic effects of zinc oxide nanoparticles (ZnO NPs) have been previously studied, there are still controversies in terms of dose, size, shape, and affecting cells. By such a perspective, in this study, small size of ZnO NPs with a diameter of 10 nm at low concentrations was studied for any effect on the viability and function of isolated rat pancreatic islets. Islets of Langerhans were isolated and assessed for viability, functionality (insulin secretion), cytosolic reactive oxygen species (ROS), and apoptosis by flow cytometry. The LC50 of ZnO NPs was found at 1,400 ng/mL at the first phase of the study. A meaningful increase in viability of islets and insulin secretion in basal and even stimulated concentrations of glucose was found by ZnO NPs (70 ng/mL) with p < 0.001 and p < 0.05, respectively. Likewise, ZnO NPs in 70 ng/mL concentration decreased cytosolic ROS generation (p < 0.05). In the meantime, the percentage of early stage of apoptotic cells dropped down to 17 % (from 29 % of control). These results for the first time confirm that ZnO NPs are not only safe when used at dose of 70 ng/mL but also improve viability and function of pancreatic islets and meanwhile reduce oxidative stress and prevent cells from entering the apoptotic phase.
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http://dx.doi.org/10.1007/s12011-014-0113-6DOI Listing
December 2014

Improvement in The Function of Isolated Rat Pancreatic Islets through Reduction of Oxidative Stress Using Traditional Iranian Medicine.

Cell J 2014 25;16(2):147-163. Epub 2014 May 25.

Faculty of Pharmacy and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran.

Objective: Pancreatic islets have fewer antioxidant enzymes than other tissues and thus are vulnerable to oxidative stress. In the present study, the effects of nine specifically selected Iranian medical plants on the mitochondria function and survival of isolated rat islets were examined.

Materials And Methods: In this experimental study, following laparotomy, pancreases of rats were removed and the islets isolated and incubated in vitro for 24 hours. Logarithmic doses of plant materials were added to the islets and incubated for an additional 24 hours after which the viability of the cells and production of reactive oxygen species (ROS) were measured. Levels of insulin production in relation to static and stimulated glucose concen- trations were also determined.

Results: The tested compounds markedly increased survival of the islet cells, their mi- tochondrial activity, and insulin levels at the same time as reducing production of ROS. Greatest effects were observed in the following order: Peganum harmala, Glycyrrhiza glabra, Satureja hortensis, Rosmarinus officinalis, Teucrium scordium, Aloe vera, Zingiber officinale, Silybum marianum, and Hypericum perforatum at doses of 10, 10(3), 10(4), 10, 10(2), 10(2), 10(-1), 10 and 10(3)μgmL(-1), respectively.

Conclusion: Based on these results, we suggest that pretreatment with these select- ed Iranian medical plants can improve the outcomes of pancreas transplants and grafts through the control of oxidative stress damage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071980PMC
January 2015

Anti-aging effects of some selected Iranian folk medicinal herbs-biochemical evidences.

Iran J Basic Med Sci 2013 Nov;16(11):1170-80

Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

Objective(s): In the current study, the effects of selected folk medicinal herbs were evaluated in D-galactose-induced aging in male mice.

Materials And Methods: Male BALB/c mice were randomly divided into 12 groups composing sham, control, and treated groups. Aging was induced by administration of D-galactose (500 mg/kg/day for 6 weeks). A positive control group was assigned that received vitamin E (200 mg/kg/day). The extract of herbs was prepared, lyophilized, and used in this study. The herbs were administered by gavage for 4 weeks to D-galactose-aged animals at the selected doses (mg/kg/day) as follows: Zingiber officinale (250), Glycyrrhiza glabra (150), Rosmarinus officinalis (300), Peganum harmala (50), Aloe vera (150), Satureja hortensis (200), Teucrium scordium (200), Hypericum perforatum (135) and Silybum marianum (150). One group of animals was assigned as sham and not given D-galactose.

Results: At the end of treatment, pro-inflammatory markers including tumor necrosis factor-α (TNF-α), interlukine-1β (IL-β), interlukine-6 (IL-6), NF-kappaB (NF-κb), total antioxidant power (TAP), thiobarbituric acid reactive substances (TBARS) as lipid peroxidation (LPO) marker and male sex hormones i.e. testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured in the blood.

Conclusion: These data for the first time indicate significant anti-aging potential of examined herbs. RESULTS showed that D-galactose induces a significant oxidative stress and promotes proinflammatory cascade of aging while all herbs more or less recovered these changes. Among 9 herbal extracts, Silybum marianum showed the best effect in restoring aging changes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909629PMC
November 2013

Effects of IMOD™ and Angipars™ on mouse D-galactose-induced model of aging.

Daru 2012 Oct 27;20(1):68. Epub 2012 Oct 27.

Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran, 1417614411, Iran.

The aim of this study was to evaluate the effects of two registered herbal drugs called IMOD and Angipars on mouse model. Aging was induced by D-galactose (500 mg/kg) administered to animals for 6 weeks through drinking water. Male BALB/c mice were randomly divided into 5 groups receiving D-galactose (D-galactose, 500 mg/kg) for 6 weeks; positive control (D-galactose [500 mg/kg] for 6 weeks + Vitamin E [200 mg/kg/day] intraperitoneally for 4 weeks); IMOD (D-galactose [500 mg/kg] for 6 weeks + IMOD [20 mg/kg/day] intraperitoneally for 4 weeks), Angipars (D-galactose [500 mg/kg] for 6 weeks + Angipars [2.1 mg/kg/day] by gavage for 4 weeks); and the fifth group that was sham and not given D-galactose. At the end of treatment, pro-inflammatory markers including tumor necrosis factor-α (TNF-α), interlukine-1β (IL-β), interlukine-6 (IL-6), Nuclear Factor-kappaB (NF-κb), total antioxidant power (TAP), lipid peroxides (LPO) and male sex hormones i.e. testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured in the blood.Results showed that D-Galactose induces a significant oxidative stress and proinflammatory cascade of aging while both IMOD and Angipars recovered all of them. Interestingly, IMOD and Angipars were better than Vitamin E in improving male sex hormones in aged mice. This effect is so important and should be considered as an advantage although it cannot be explained with current knowledge. The conclusion is that IMOD and Angipars have marked anti-aging effect on D-galactose-induced model of aging.
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http://dx.doi.org/10.1186/2008-2231-20-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555951PMC
October 2012

Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles.

Toxicol Appl Pharmacol 2013 Feb 19;266(3):356-65. Epub 2012 Dec 19.

Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Cisplatin (CIS), an anticancer alkylating agent, induces DNA adducts and effectively cross links the DNA strands and so affects spermatozoa as a male reproductive toxicant. The present study investigated the cellular/biochemical mechanisms underlying possible protective effect of selenium nano-particles (Nano-Se) as an established strong antioxidant with more bioavailability and less toxicity, on reproductive toxicity of CIS by assessment of sperm characteristics, sperm DNA integrity, chromatin quality and spermatogenic disorders. To determine the role of oxidative stress (OS) in the pathogenesis of CIS gonadotoxicity, the level of lipid peroxidation (LPO), antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) and peroxynitrite (ONOO) as a marker of nitrosative stress (NS) and testosterone (T) concentration as a biomarker of testicular function were measured in the blood and testes. Thirty-two male Wistar rats were equally divided into four groups. A single IP dose of CIS (7 mg/kg) and protective dose of Nano-Se (2 mg/kg/day) were administered alone or in combination. The CIS-exposed rats showed a significant increase in testicular and serum LPO and ONOO level, along with a significant decrease in enzymatic antioxidants levels, diminished serum T concentration and abnormal histologic findings with impaired sperm quality associated with increased DNA damage and decreased chromatin quality. Coadministration of Nano-Se significantly improved the serum T, sperm quality, and spermatogenesis and reduced CIS-induced free radical toxic stress and spermatic DNA damage. In conclusion, the current study demonstrated that Nano-Se may be useful to prevent CIS-induced gonadotoxicity through its antioxidant potential.
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http://dx.doi.org/10.1016/j.taap.2012.11.025DOI Listing
February 2013

Biochemical and cellular evidence of the benefit of a combination of cerium oxide nanoparticles and selenium to diabetic rats.

World J Diabetes 2011 Nov;2(11):204-10

Nazila Pourkhalili, Amir Nili-Ahmadabadi, Shokoufeh Hassani, Mohsen Pakzad, Maryam Baeeri, Azadeh Mohammadirad, Mohammad Abdollahi, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Tehran University of Medical sciences, Tehran 1417614411, Iran.

Aim: To study the combinative effects of nanocerium and selenium in a murine model of diabetes.

Methods: Cerium oxide (CeO(2)) nanoparticles (60 mg/kg per day) and sodium selenite (5 μmol/kg per day) alone or in combination, or the metal form of CeO(2) (60 mg/kg) were administered for 2 wk by intraperitoneal injection to streptozotocin-induced diabetic rats. At the end of treatment blood was collected, liver tissue dissected and then oxidative stress markers, extent of energy depletion and lipid profile were evaluated.

Results: Antioxidant enzymes and high density lipoprotein decreased whereas oxidative stress, adenosine diphosphate/adenosine triphospahte levels, cholesterol, triglyceride and low density lipoprotein increased on induction of diabetes. All were improved by a combination of nanocerium and sodium selenite. There was a relative amelioration by CeO(2) nanoparticles or sodium selenite alone, but the metal form of CeO(2) showed no significant improvement.

Conclusion: The combination of nanocerium and sodium selenite is more effective than either alone in improving diabetes-induced oxidative stress.
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http://dx.doi.org/10.4239/wjd.v2.i11.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215770PMC
November 2011

On the benefit of magnetic magnesium nanocarrier in cardiovascular toxicity of aluminum phosphide.

Toxicol Ind Health 2013 Mar 10;29(2):126-35. Epub 2011 Nov 10.

Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

The present study was designed to determine the effect of a new (25)Mg(2+)-carrying nanoparticle ((25)MgPMC16) on energy depletion, oxidative stress, and electrocardiographic (ECG) parameters on heart tissue of the rats poisoned by aluminum phosphide (AlP). (25)MgPMC16 at doses of 0.025, 0.05, and 0.1 median lethal dose (LD50 = 896 mg/kg) was administered intravenously (iv) 30 min after a single intragastric administration of AlP (0.25 LD50). Sodium bicarbonate (Bicarb; 2 mEq/kg, iv) was used as the standard therapy. After anesthesia, the animals were rapidly connected to an electronic cardiovascular monitoring device for monitoring of ECG, blood pressure (BP), and heart rate (HR). Later lipid peroxidation, antioxidant power, ATP/ADP ratio, and Mg concentration in the heart were evaluated. Results indicated that after AlP administration, BP and HR decreased while R-R duration increased. (25)MgPMC16 significantly increased the BP and HR at all doses used. We found a considerable increase in antioxidant power, Mg level in the plasma and the heart and a reduction in lipid peroxidation and ADP/ATP ratio at various doses of (25)MgPMC16, but (25)MgPMC16-0.025 + Bicarb was the most effective combination therapy. The results of this study support that (25)MgPMC16 can increase heart energy by active transport of Mg inside the cardiac cells.(25)MgPMC16 seems ameliorating AlP-induced toxicity and cardiac failure necessitating further studies.
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http://dx.doi.org/10.1177/0748233711425074DOI Listing
March 2013

Biochemical and pathological evidences on the benefit of a new biodegradable nanoparticles of probiotic extract in murine colitis.

Fundam Clin Pharmacol 2012 Oct 19;26(5):589-98. Epub 2011 Jul 19.

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

Efficacy of probiotics in the management of human inflammatory bowel disease (IBD) has been approved in the recent years. In the present work, the efficacy of a new biodegradable nanoparticles (NPs) of encapsulated and lyophilized probiotic extract (LPE) was examined in murine colitis. Colitis was induced by rectal instillation of trinitrobenzen sulfonic acid to male Wistar rats. The safety and effective dose of LPE was determined in a pilot study. To ease delivery into colon, LPE was encapsulated in chitosan-coated-poly (lactide co glycolide acid) NPs. After induction of colitis, animals in different groups received test compound in three doses by gavage for 10 days. Groups of sham, control (saline), and standard (dexamethasone) were also assigned. Colonic pathological examination, tumor necrosis factor alpha, interlukin (IL)-1β, myeloperoxidase (MPO), and lipid peroxidation (LPO) were performed. LPE at all doses (273, 545, and 1100 mg/kg) had positive effects in reduction of pro-inflammatory cytokines, LPO, and MPO in a dose-dependent manner. The formulated compound containing medium dose of LPE was more efficient in mitigating the experimental colitis in comparison with that of high-dose LPE. It is concluded that LPE and its nanoparticle-encapsulated form are very much effective in control of colitis. Regarding safety of this compound, further studies can be conducted in patients with IBD.
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http://dx.doi.org/10.1111/j.1472-8206.2011.00966.xDOI Listing
October 2012

Effect of Phlomis persica on glucose levels and hepatic enzymatic antioxidants in streptozotocin-induced diabetic rats.

Pharmacogn Mag 2010 Jul;6(23):219-24

Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Methanol extract of the aerial parts of Phlomis persica Boiss. (Lamiaceae) (PPE) was studied to evaluate the effects of antidiabetic potential, by measuring fasting blood glucose, insulin, total antioxidant power (TAP), using ferric reducing antioxidant power (FRAP), lipid peroxidation (using thiobarbituric acid reactive substances, TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) on streptozotocin-induced diabetes in rats. Male Wistar rats were randomly divided into five groups of six animals each. Oral administration of PPE at doses of 100 and 200 mg/kg once a day for 10 days resulted in a significant reduction in fasting blood glucose and an increase in serum insulin levels, in comparison with diabetic control group. It also prevented diabetes-induced loss in body weight. Hepatic TAP increased and TBARS decreased following PPE treatments. The extract at 100 and 200 mg/kg increased the activity of hepatic SOD, CAT, and GPx in diabetic rats. It is concluded that PPE has antidiabetic potential that is comparable with glibenclamide. In conclusion, the results of the present study show positive effects of P. persica on experimental diabetes and thus the antidiabetic effect of PPE is related to its potential to inhibit hepatocellular oxidative stress.
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http://dx.doi.org/10.4103/0973-1296.66940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950386PMC
July 2010

Prevention of malathion-induced depletion of cardiac cells mitochondrial energy and free radical damage by a magnetic magnesium-carrying nanoparticle.

Toxicol Mech Methods 2010 Nov 4;20(9):538-43. Epub 2010 Oct 4.

Pharmaceutical Sciences Branch, Islamic Azad University.

The present work was designed to examine the effect of a new (25)Mg(2+)-carrying nanoparticle (PMC16) on energy and oxidative stress parameters inside the heart of the rats exposed to acute mild toxic dose of malathion, a widely used organophosphate. Post a single intraperitoneal (ip) injection of malathion (0.25 of LD50), PMC16 at different doses (0.05, 0.1, and 0.2 of LD50) was administered intravenously (iv) as a supplement to standard therapy of atropine and pralidoxime. MgSO(4) was used as another supplement for comparison with PMC16. Oxidative stress biomarkers including lipid peroxidation (LPO) and reactive oxygen species (ROS), antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), ATP/ADP ratio, and Mg in the cardiac cells were determined. Results indicated a significant increase in LPO, ROS, ADP/ATP ratio, and a decrease in Mg post-malathion poisoning in comparison to controls. All of these parameters were improved by use of standard therapy either with MgSO4 or various doses of PMC16. The activities of SOD, CAT, and GPx did not change significantly in the present acute malathion poisoning model and neither MgSO(4) or PMC16 had no considerable improvement on these parameters. Comparing groups that received normal Mg and those of various doses of PMC16, a significant difference was found with the PMC16 (0.2 LD50) group. PMC16 0.2 reduced cardiac cells LPO and ROS of Mal-exposed animals rather than that of MgSO4. PMC16 0.2 was also significantly better than MgSO(4) in improving MAL-induced changes in ADP/ATP ratio and also intracellular Mg levels. This study illustrates that malathion-induced cardiac cells toxicity is improved by administration of Mg as a result of increasing cardiac ATP through active transport of Mg inside the cells. Finally, the results of this study support positive effects of this magnetic Mg nanoparticle carrier but do not confirm its absolute efficacy that remains to be explored by further tests in different animal models and organs before moving to a phase I human trial.
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http://dx.doi.org/10.3109/15376516.2010.518173DOI Listing
November 2010

Inhibition of tumor necrosis factor and nitrosative/oxidative stresses by Ziziphora clinopoides (Kahlioti); a molecular mechanism of protection against dextran sodium sulfate-induced colitis in mice.

Toxicol Mech Methods 2009 Feb;19(2):183-9

Laboratory of Toxicology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Inflammatory bowel disease (IBD) is a chronic condition of the intestine with unknown etiology involving multiple immune genetic and environmental factors. The authors were interested in examining the protective effect of Ziziphora clinopoides methanolic extract, an Iranian folk herbal medicine, on inflammatory mediators in experimental colitis. Colitis in NMRI mice was induced by oral administration of dextran sodium sulfate (DSS, 3%). Z. clinopoides was administrated orally at doses of 75, 150, and 300 mg/kg/day for 7 days. The level of lipid peroxidation (LP), total antioxidant capacity (TAC), total thiol molecules (TTM), antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT), and nitric oxide (NO) as a marker of nitrosative stress, and tumor necrosis factor alpha (TNF-alpha) as a mediator of inflammation and apoptosis were measured in the colon homogenate. Treatment by DSS increased bowel LP, NO, and TNF-alpha while decreasing TAC, SOD, CAT, and TTM. All measured parameters were improved by Z. clinopoides treatment and reached close to normal levels. The present study further supports the role of oxidative/nitrosative stresses and TNF-alpha in the pathogenesis of colitis and protective effects of this herb. The data are promising for further preclinical studies directed towards understanding mechanism of action and cross-species and cross-model comparisons for potential protective effects.
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http://dx.doi.org/10.1080/15376510701533996DOI Listing
February 2009

Effects of Satureja khuzestanica on Serum Glucose, Lipids and Markers of Oxidative Stress in Patients with Type 2 Diabetes Mellitus: A Double-Blind Randomized Controlled Trial.

Evid Based Complement Alternat Med 2010 Dec 27;7(4):465-70. Epub 2008 Feb 27.

Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Endocrinology and Metabolism Research Center (EMRC) and Faculty of Medicine, Medicinal Plants Research Center (MPRC), Tehran University of Medical Sciences (TUMS) and Drug Selecting Committee, Food and Drug Organization, and Food and Drug Laboratory Research Center, Tehran, Iran.

Satureja khuzestanica is an endemic plant of Iran that is widely distributed in the Southern part of the country. It has antioxidant properties and thus it seems to be useful in diseases related to oxidative stress such as diabetes and hyperlipidemia. The present study investigates the effect of S. khuzestanica supplement in metabolic parameters of hyperlipidemic patients with type 2 diabetes mellitus. Twenty-one hyperlipidemic patients with type 2 diabetes mellitus were randomized in a double blind, placebo controlled clinical trial to receive either S. khuzestanica (tablets contain 250 mg dried leaves) or placebo once a day for 60 days. Blood samples were obtained at baseline and at the end of the study. Samples were analyzed for levels of glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, creatinine, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxidation and ferric reducing ability (total antioxidant power, TAP). Treatment of patients by S. khuzestanica for 60 days induced significant decrease in total cholesterol (P = 0.008) and LDL-cholesterol (P = 0.03) while increased HDL-cholesterol (P = 0.02) and TAP (P = 0.007) in comparison with the baseline values. S. khuzestanica did not alter blood glucose, triglyceride, creatinin and TBARS levels. In comparison with baseline values, no significant change was observed in blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride, creatinine, TBARS and TAP in placebo-treated group. Usage of S. khuzestanica as a supplement to drug regimen of diabetic type 2 patients with hyperlipidemia is recommended.
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http://dx.doi.org/10.1093/ecam/nen018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892343PMC
December 2010

Some new carbacylamidophosphates as inhibitors of acetylcholinesterase and butyrylcholinesterase.

Z Naturforsch C J Biosci 2008 Mar-Apr;63(3-4):241-50

Department of Chemistry, Faculty of Sciences, Tarbiat Modarres University, P. O. Box 14115-175, Tehran, Iran.

The differences in the inhibition activity of organophosphorus agents are a manifestation of different molecular properties of the inhibitors involved in the interaction with the active site of enzyme. We were interested in comparing the inhibition potency of four known synthesized carbacylamidophosphates with the general formula RC(O)NHP(O)Cl2, constituting organophosphorus compounds, where R = CCl3 (1), CHCl2 (2), CH2Cl (3) and CF3 (4), and four new ones with the general formula RC(O)NHP(O)(R')2, where R' = morpholine and R = CCl3 (5), CHCl2 (6), CH2Cl (7), CF3 (8), on AChE and BuChE activities. In addition, in vitro activities of all eight compounds on BuChE were determined. Besides, in vivo inhibition potency of compounds 2 and 6, which had the highest inhibition potency among the tested compounds, was studied. The data demonstrated that compound 2 from the compound series 1 to 4 and compound 6 from the compound series 5 to 8 are the most sensitive as AChE and BuChE inhibitors, respectively. Comparing the IC50 values of these compounds, it was clear that the inhibition potency of these compounds for AChE are 2- to 100-fold greater than for BuChE inhibition. Comparison of the kinetics (IC50, Ki, kp, KA and KD) of AChE and BuChE inactivation by these compounds resulted in no significant difference for the measured variables except for compounds 2 and 6, which appeared to be more sensitive to AChE and BuChE by significantly higher kp and Ki values and a lower IC50 value in comparison with the other compounds. The LD50 value of compounds 2 and 6, after oral administration, and the changes of erythrocyte AChE and plasma BuChE activities in albino mice were studied. The in vivo experiments, similar to the in vitro results, showed that compound 2 is a stronger AChE and BuChE inhibitor than the other synthesized carbacylamidophosphates. Furthermore, in this study, the importance of electropositivity of the phosphorus atom, steric hindrance and leaving group specificity were reinforced as important determinants of inhibition activity.
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http://dx.doi.org/10.1515/znc-2008-3-414DOI Listing
August 2008

Rat Plasma Oxidation Status After Nigella Sativa L. Botanical Treatment in CCL(4)-Treated Rats.

Toxicol Mech Methods 2008 Jan;18(9):725-31

Laboratory of Toxicology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

ABSTRACT Nigella sativa Linn. (family Ranunculaceae), commonly known as black cumin, is native to the Mediterranean area and has been used for thousands of years as a health and beauty aid. The present study investigated the protective effects of Nigella sativa (NS) extract (NSE) and oil (NSO) on CCl(4)-induced nitrosative stress and protein oxidation in rat. CCl(4) (0.8 mg/kg) was used as an aid for induction of nitrosative stress. In vitro antioxidant potential was tested in the presence of 2,4-dinitrophenylhyrdazine (DPPH) as an organic nitrogen radical. Doses of 0.2, 0.3, and 1 mg/kg of the NS extract and oil were administered to CCL(4)-treated rats for 10 days. At the end of treatment, blood was taken from rats under anesthesia and plasma was separated. The concentration of nitric oxide (NO), total antioxidant power (TAP), carbonyl molecules (CM) as measure of protein oxidation (PO), tumor necrosis factor-alpha (TNF-alpha), and total thiol molecules (TTM) were measured in plasma. In vitro evaluation of antioxidant effects of NSE and NSO showed that the highest antioxidant activity (80%) was observed with the concentration of 10 and 20 mg/ml, respectively, that were equal to vitamin E (200 mg/ml). Administration of CCL(4) increased plasma PO, NO, TNF-alpha and decreased TAP and TTM. Both NSE and NSO showed significant protection against CCl(4)-induced changes in biochemical parameters, but not dose-dependently. Doses of 0.3 and 1 mg/kg were more effective than doses of 0.2 mg/kg for both NSE and NSO, but dose of 1 mg/kg was the most effective one. The results indicate the potential of NS in preventing CCL(4)-induced toxic nitrosative stress. It is concluded that NS has marked antioxidant potentials that may be beneficial in alleviating complications of many illnesses related to oxidative/nitrosative stress in humans, but preclinical safety measures should be completed before clinical trials.
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http://dx.doi.org/10.1080/15376510802232233DOI Listing
January 2008

Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms.

Hum Exp Toxicol 2007 Sep;26(9):697-703

Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

In acute respiratory distress syndrome (ARDS), there is extensive overproduction of free radicals to the extent that endogenous anti-oxidants are overwhelmed, permitting oxidative cell damage. The present study examined the benefit of the anti-oxidant compound N-acetylcysteine (NAC) in the management of ARDS by measuring patient's intracellular glutathione (inside red blood cells) and extracellular (plasma) anti-oxidant defense biomarkers and outcome. Twenty-seven ARDS patients were recruited from the intensive care unit of a teaching Hospital and randomly divided into two groups. Both groups were managed similarly by regular treatments but 17 patients received NAC 150 mg/kg at the first day that followed by 50 mg/kg/day for three days and 10 patients did not receive NAC. Treatment by NAC increased extracellular total anti-oxidant power and total thiol molecules and also improved intracellular glutathione and the outcome of the patients. In conclusion, patients with ARDS are in a deficient oxidant-anti-oxidant balance that can get a significant benefit if supplemented with NAC.
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http://dx.doi.org/10.1177/0960327107083452DOI Listing
September 2007

Study on the correlations among disease activity index and salivary transforming growth factor-beta 1 and nitric oxide in ulcerative colitis patients.

Ann N Y Acad Sci 2007 Jan;1095:305-14

Department of Toxicology & Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14155-6451, Iran.

Growth factors and nitric oxide (NO) play a major role in dysregulated immune response in ulcerative colitis (UC). Recent evidence has shown increased levels of transforming growth factor-beta(1) (TGF-beta(1)) in UC and suggested an anti-inflammatory effect for this factor. Based on our recent study, dysfunctional immunoregulation is present in saliva of UC patients, we hypothesized that salivary level of NO and TGF-beta(1) may differ by severity of UC and be useful to determine the activity of the disease. Thirty-seven UC patients and 15 healthy controls were enrolled and saliva samples were obtained. Truelove-Witts severity index and modified Truelove-Witts severity index were used to determine the severity of the disease. NO and TGF-beta(1) levels were detected in saliva of all patients and control subjects using enzyme-linked immunosorbent assay. A total of 21 patients had mild disease while 8 had moderate and 8 had severe colitis. Adjusted for baseline characteristics, the levels of NO and TGF-beta(1) in different groups were compared. Salivary NO and TGF-beta(1) levels were higher in UC patients comparing to controls (P < 0.00005 and P = 0.005, respectively). The levels of NO and TGF-beta(1) showed no significant differences among the severity groups (P = 0.46 and P = 0.23, respectively). NO levels linearly increased by age (Coeff = 1.5, r = 0.38, P = 0.02). Gender, extension of disease, and medical treatment did not affect NO and TGF-beta(1) levels. Although UC patients have abnormal amounts of NO and TGF-beta(1) in their saliva, their disease activity cannot be predicted by these factors, which may indicate a pathophysiologic role rather than being nonspecific inflammatory markers for TGF-beta(1) and NO.
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http://dx.doi.org/10.1196/annals.1397.034DOI Listing
January 2007

Benefits of Zataria multiflora Boiss in Experimental Model of Mouse Inflammatory Bowel Disease.

Evid Based Complement Alternat Med 2007 Mar 14;4(1):43-50. Epub 2006 Sep 14.

Laboratory of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Laboratory of Pharmacognosy, Faculty of Pharmacy and Medicinal Plants Research Center and Laboratory of Histopathology, School of Medicine, Tehran University of Medical Sciences Tehran, Iran.

Inflammatory bowel disease (IBD) is a chronic condition of the intestine with unknown etiology involving multiple immune, genetic and environmental factors. We were interested to examine the effect of total extract from Zataria multiflora Boiss, a folk medicinal plant on prevention and treatment of experimental IBD. Z. multiflora was administered (400, 600, 900 p.p.m.) through drinking water to IBD mice induced by intrarectal administration of acetic acid. Prednisolone was used as the standard drug for comparison. Biochemical, macroscopic and microscopic examinations of colon were performed. Biochemical evaluation of inflamed colon was done using assay of myeloperoxidase (MPO) activity and thiobarbituric acid reactive substances (TBARS) concentration as indicators of free radical activity and cell lipid peroxidation. The activity of MPO and lipid peroxidation products (TBARS) increased in acetic acid-treated groups while recovered by pretreatment of animals with Z. multiflora (400-900 p.p.m.) and prednisolone. Z. multiflora (600 and 900 p.p.m.) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared with the acetic acid-treated group. The beneficial effect of Z. multiflora (900 p.p.m.) was comparable with that of prednisolone. The antioxidant, antimicrobial and anti-inflammatory potentials of Z. multiflora might be the mechanisms by which this herbal extract protects animals against experimentally induced IBD. Proper clinical investigation should be carried out to confirm the activity in human.
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http://dx.doi.org/10.1093/ecam/nel051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810372PMC
March 2007

Determination of oxidative stress status and concentration of TGF-beta 1 in the blood and saliva of osteoporotic subjects.

Ann N Y Acad Sci 2006 Dec;1091:142-50

Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14155-6451, Iran.

Preliminary reports indicate the influence of oxidative stress and interleukins, particularly TGF-beta1, in maintenance of bone mass. This study was designed to determine any possible variations of cellular lipid peroxidation, the total antioxidant power, and concentration of TGF-beta1 in blood and saliva of osteoporotic subjects in comparison to healthy people. Blood and saliva samples of 22 osteoporotic women and 22 age-matched healthy women were collected. Samples were analyzed for thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), and concentration of TGF-beta1. The blood and saliva TAP (mean +/- SD) of osteoporotic subjects was significantly lower than that of healthy controls (606.65 +/- 119.13 vs. 665.64 +/- 63.73 mmol/L and 560.43 +/- 84.70 vs. 612.05 +/- 81.5, respectively). Blood and saliva TBARS (mean +/- SD) of osteoporotic subjects were significantly higher than those of healthy controls (0.30 +/- 0.04 vs. 0.26 +/- 0.04 and 0.23 +/- 0.03 vs. 0.16 +/- 0.04 micromol/L, respectively). Concentrations of TGF-beta1 (mean +/- SD) in plasma and saliva of osteoporotic subjects were not different in comparison to healthy subjects. Results indicate that persons with osteoporosis have an increased oxidative stress that is not accompanied by changes in TGF-beta1 levels. Use of supplementary antioxidants in osteoporotic patients may be helpful.
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http://dx.doi.org/10.1196/annals.1378.062DOI Listing
December 2006

Alterations in salivary antioxidants, nitric oxide, and transforming growth factor-beta 1 in relation to disease activity in Crohn's disease patients.

Ann N Y Acad Sci 2006 Dec;1091:110-22

Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14155-6451, Iran.

It has been postulated that oxidative stress, nitric oxide (NO), and transforming growth factor beta(1) (TGF- beta(1)) have major roles in the pathophysiology of Crohn's disease (CD). The aim of this study was to determine the salivary levels of total antioxidant capacity (TAC), specific antioxidants (i.e., uric acid, albumin, transferrin, and thiol molecules), lipid peroxidation (LPO), NO, and TGF- beta(1) in CD patients and control subjects and to also investigate their correlation with activity of the disease. Twenty-eight patients with confirmed diagnosis of CD were enrolled and whole saliva samples were obtained. Smokers, diabetics, those who suffered from periodontitis, and those who were consuming antioxidant supplements were excluded from the study. The Crohn's Disease Activity Index (CDAI) was used to determine the severity of the disease. Twenty healthy subjects were also recruited. In CD patients significant reductions in salivary levels of TAC (0.248 +/- 0.145 vs. 0.342 +/- 0.110 mmol/L), albumin (1.79 +/- 0.42 vs. 2.3 +/- 0.2 microg/mL), and uric acid (3.1 +/- 1.4 vs. 4.1 +/- 2.0 mg/dL) were found. TGF-beta(1) was significantly increased in CD patients compared to healthy subjects (3.02 +/- 1.54 vs. 2.36 +/- 0.52 ng/mL). A fourfold increase in NO levels (198.8 +/- 39.9 vs. 50.2 +/- 21.3 micromol/L) along with a fivefold increase in LPO concentration (0.146 +/- 0.064 vs. 0.027 +/- 0.019 micromol/L) was documented in CD patients in comparison to the control group. CDAI significantly correlated with the TAC, LPO, and the interaction between TAC and LPO (r(2) = 0.625, r(2) = 0.8, F-test's P < 0.00005). Saliva of CD patients exhibits an abnormal feature with respect to oxidative stress, NO, and TGF-beta(1). TAC and LPO modify the effect of each other in determination of CD severity, which underlines the importance of oxidative stress in the pathogenesis of CD.
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http://dx.doi.org/10.1196/annals.1378.060DOI Listing
December 2006

In vivo antioxidant potential of Teucrium polium, as compared to alpha-tocopherol.

Acta Pharm 2007 Mar;57(1):123-9

Laboratory of Toxicology, Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

The present study was undertaken to explore antioxidant potential of Teucrium polium (Lamiaceae) in vivo. Antioxidant activity was measured by three tests including inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, total antioxidant power (TAP), and thiobarbituric acid reactive substances (TBARS) in serum. Rats received dry extract of T. polium in 80% ethanol by intragastric intubation at doses of 50, 100 and 200 mg kg(-1) daily for 14 days. Treatment of rats with T. polium extract showed significant antioxidant activity in the DPPH test as compared to the control. T. polium extract at doses of 50 and 100 mg kg(-1) significantly increased rats TAP and decreased TBARS compared to the control. Administration of T. polium at a dose of 200 mg kg(-1) per day did not significantly alter serum TAP and TBARS. Antioxidant activities of T. polium at a doses of 50 and 100 mg kg(-1) were in all experiments comparable to that of alpha-tocopherol (10 mg kg(-1)).
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http://dx.doi.org/10.2478/v10007-007-0010-zDOI Listing
March 2007

Alteration of hepatic cells glucose metabolism as a non-cholinergic detoxication mechanism in counteracting diazinon-induced oxidative stress.

Hum Exp Toxicol 2006 Dec;25(12):697-703

Laboratory of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

The aim of this study was to evaluate effects of acute exposure to various doses of diazinon, a widely used synthetic organophosphorus (OP) insecticide on plasma glucose, hepatic cells key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress in rats. Diazinon was administered by gavage at doses of 15, 30 and 60 mg/ kg. The liver was perfused and removed under anaesthesia. The activities of glycogen phosphorylase (GP), phosphoenolpyruvate carboxykinase (PEPCK), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were analysed in liver homogenate. Administration of diazinon (15, 30 and 60 mg/kg) increased plasma glucose concentrations by 101.43% (P = 0.001), 103.68% (P = 0.000) and 160.65% (P = 0.000) of control, respectively. Diazinon (15, 30 and 60 mg/kg) increased hepatic GP activity by 43.5% (P = 0.05), 70.3% (P = 0.00) and 117.2% (P = 0.02) of control, respectively. In addition, diazinon (30 and 60 mg/kg) increased hepatic PEPCK by 77.3% (P = 0.000) and 93.5% (P = 0.000) of control, respectively. Diazinon (30 and 60 mg/kg) decreased liver TAC by 38% (P = 0.046) and 48% (P = 0.000) of control, respectively. Also diazinon (30 and 60 mg/kg) increased hepatic cell liver lipid peroxidation by 77% (P = 0.05) and 280% (P = 0.000) of control. The correlations between plasma glucose and hepatic cells TBARS (r2 = 0.537, P = 0.02), between plasma glucose and ChE activity (r2 = 0.81, P = 0.049) and between plasma glucose and hepatic cells GP activity (r2 = 0.833, P = 0.04) were significant. It is concluded that the liver cells are a site of toxic action of diazinon. Diazinon increases glucose release from liver into blood through activation of glycogenolysis and gluconeogenesis as a detoxication non-cholinergic mechanism to overwhelm diazinon-induced toxic stress. The results are in accordance with the hypothesis that OPs are a predisposing factor of diabetes.
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http://dx.doi.org/10.1177/0960327106075064DOI Listing
December 2006

Protective Effects of alpha-Tocopherol and N-Acetyl-Cysteine on Diazinon-Induced Oxidative Stress and Acetylcholinesterase Inhibition in Rats.

Toxicol Mech Methods 2007 ;17(2):109-15

Loghman-Hakim Hospital Poison Center, Faculty of Medicine, and Toxicological Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.

ABSTRACT Diazinon, an organophosphate (OP) insecticide, is widely used in agriculture and domestically. Reactive oxygen species (ROS) caused by OPs are involved in the toxicity of various pesticides. The aim of the present study was to analyze the role of diazinon in inducing oxidative stress in adult male Wistar rats and to evaluate the possible protective effects of alpha-tocopherol (TPH) and the glutathione prodrug N-acetyl-cysteine (NAC) after 4 weeks of exposure to a sublethal dose of diazinon. TPH (10 mg/kg/day), NAC (160 mg/kg/day), diazinon (25 mg/kg/day), a combination of NAC (160 mg/kg/day) and diazinon (25 mg/kg/day), and a combination of TPH (10 mg/kg/day) and diazinon (25 mg/kg/day) were given to rats orally via gavage for 4 weeks. The thiobarbituric acid reactive substances (TBARS) marker of lipid peroxides levels, total thiol molecules, and total antioxidant capacity of plasma were all analyzed as biomarkers of oxidative stress. In addition, the acetylcholinesterase (AChE) activity was measured as a biomarker of toxicity. The results from this study well indicate diazinon-induced oxidative stress demonstrated by enhanced TBARS, decreased total thiol molecules, and total antioxidant capacity. In addition, AChE activity was inhibited as a marker of OP toxicity. Data show the protective roles of TPH and NAC in reducing the diazinon-induced oxidative stress. Interestingly, both TPH and NAC recovered diazinon-induced AChE inhibition. It is concluded that supplementation with TPH and NAC can reduce toxicity of OP in human exposure.
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http://dx.doi.org/10.1080/15376510600860318DOI Listing
October 2012

Protection by pentoxifylline of diazinon-induced toxic stress in rat liver and muscle.

Toxicol Mech Methods 2007 ;17(4):215-21

Laboratory of Toxicology, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Medical Sciences/University of Tehran, Tehran, Iran.

ABSTRACT The effects of diazinon, pentoxifylline, and their combination therapy on plasma glucose, the key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress were studied in rat liver and muscle. Oxidative stress was determined by measuring the concentration of lipid peroxides and assessing total antioxidant capacity. Diazinon (60 mg/kg) and pentoxifylline (100 mg/kg) were administrated by gavage. Administration of diazinon increased blood glucose, hepatic glycogen phosphorylase (GP), and phosphoenol pyruvate carboxykinase (PEPCK) by 160.65%, 117.2%, and 93.5%, respectively, while it decreased plasma cholinesterase (ChE) by 53.82%. Diazinon-induced oxidative stress was demonstrated by decreased total antioxidant capacity and enhanced lipid peroxidation by 52.61% and 280% in liver and by 40.02% and 46.6% in muscle, respectively. Pentoxifylline increased plasma glucose, hepatic GP, and PEPCK by 98.65%, 60%, and 79.86%, respectively, while it did not change plasma ChE, liver and muscle lipid peroxides, and total antioxidant capacity. In combination therapy, pentoxifylline did not alter diazinon-induced change in muscle GP activity but restored a diazinon-induced increase in hepatic and muscle lipid peroxides by 39.18% and 42.35%, respectively. Pentoxifylline also recovered a diazinon-induced decrease in liver and muscle total antioxidant capacity and plasma ChE by 122.33%, 56.44%, and 115.62%, respectively. Pentoxifylline did not affect diazinon-induced hyperglycemia and increased hepatic GP and PEPCK or muscle GP activities. It is concluded that pentoxifylline is a good choice for the alleviation of acute toxic stress of diazinon in muscle and liver and ChE in plasma, while it is unable to recover diazinon-induced hyperglycemia.
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http://dx.doi.org/10.1080/15376510600943783DOI Listing
October 2012

Beneficial effect of phosphodiesterase-5 inhibitor in experimental inflammatory bowel disease; molecular evidence for involvement of oxidative stress.

Toxicol Mech Methods 2007 ;17(5):281-8

Laboratory of Toxicology, Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran, Iran.

ABSTRACT Inflammatory bowel disease (IBD) is a common and chronic gastrointestinal disorder characterized by intestinal inflammation and mucosal tissue damage. Reactive oxygen metabolites (ROMs) play a pathogenic role in IBD. We aimed to examine the protective effect of sildenafil, a cGMP phosphodiesterase inhibitor, in the experimental mouse model of IBD. Intrarectal instillation of acetic acid was used to induce IBD. Prednisolone was used as the standard drug for comparison. Sildenafil was used at doses of 0.75, 1.5, and 3 mg/kg. Biochemicals and macroscopic and microscopic examinations of colonic tissue were performed. Results indicated that activity of myeloperoxidase (MPO) and lipid peroxidation product (TBARS) markers of oxidative stress are increased in acetic acid-treated groups and are recovered by sildenafil pretreatment and prednisolone. Sildenafil- (1.5 and 3 mg/kg) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared to the acetic acid-treated group. The beneficial effect of sildenafil (3 mg/kg) was comparable to that of prednisolone. It is concluded that sildenafil is helpful in the management of IBD, which is presumably related to its strong antioxidative stress potential mediated through enhanced cGMP. Results of proper clinical trials will determine the possible efficacy of phosphodiesterase-5 inhibitors in human IBD.
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http://dx.doi.org/10.1080/15376510601003769DOI Listing
October 2012

Restoration of morphine-induced alterations in rat submandibular gland function by N-methyl-D-aspartate agonist.

Acta Biol Hung 2006 Sep;57(3):283-94

Department of Pharmacology and Toxicology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

The effects of morphine, 1-aminocyclobutane-cis-1,3-dicarboxylic (ACBD; NMDA agonist) and 3-((R)2-carboxypiperazin-4-yl)-propyl-l-phosphoric acid (CPP; NMDA antagonist) and their concurrent therapy on rat submandibular secretory function were studied. Pure submandibular saliva was collected intraorally by micro polyethylene cannula from anaesthetized rats using pilocarpine as secretagogue. Intraperitoneal injection of morphine (6 mg/kg) induced significant inhibition of salivary flow rate, total protein, calcium, and TGF-beta1 concentrations. Administration of ACBD (10 mg/kg) and CPP (10 mg/kg) alone did not influence secretion of submandibular glands. In combination therapy, coadministration of CPP with morphine did not influence morphine-induced changes in salivary function while ABCD could restore all morphine-induced changes. In combination treatment, ACBD prevented morphine-induced reduction of flow rate, total protein, calcium, and TGF-beta1 and reached control levels. It is concluded that morphine-induced alterations in submandibular gland function are mediated through NMDA receptors.
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http://dx.doi.org/10.1556/ABiol.57.2006.3.2DOI Listing
September 2006