Publications by authors named "Ali Mandegary"

49 Publications

The association between CYBA gene C242T variant and risk of metabolic syndrome.

Eur J Clin Invest 2020 Sep 29;50(9):e13275. Epub 2020 Jul 29.

Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Background: Both inflammation and oxidative stress may contribute to pathogenesis of metabolic syndrome (MetS). The C242T polymorphism (rs4673) in the CYBA gene, as the main components of NAD (P) H oxidase, causes inter-individual variability in the enzyme activity. We aimed to investigate the association between this polymorphism with MetS and its components.

Methods: Two hundred nine patients with MetS and 232 controls were included in this study. MetS was defined based on NCEP ATP-III A criteria with some modifications. The C242T polymorphism within CYBA gene was determined by using PCR-based restriction fragment length polymorphism (PCR-RFLP) method.

Results: After applying a multiple logistic regression model with adjusting for potential confounders of MetS including, age, sex, body mass index, hypertension, used medications, and diabetes mellitus, C242T polymorphism was found to be associated with the presence of MetS in men but not in the total population or in women. T allele as compared to C allele was associated with decreased odds of MetS in men (adjusted OR = 0.42, 95% CI = 0.24-0.74; P = .003), but not in women (adjusted OR = 1.03, 95% CI = 0.07-1.61; P = .890), or in the total population (adjusted OR = 0.72, 95% CI = 0.51-1.02; P = .063).

Conclusion: This study shows that T allele of C242T polymorphism in CYBA gene is protective against MetS in Iranian men but not in women. Further cohort studies with larger sample size in subgroups of men and women are required to confirm such association in other racial or ethnic group.
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http://dx.doi.org/10.1111/eci.13275DOI Listing
September 2020

Cytotoxicity evaluation of curcumin-loaded affibody-decorated liposomes against breast cancerous cell lines.

J Liposome Res 2020 Jul 3:1-6. Epub 2020 Jul 3.

Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.

Curcumin is known as an effective anticancer herbal medicine but unfortunately, its bioavailability is poor which necessitate efforts for developing more efficient and specific delivery systems. Human epidermal growth factor receptor 2 (HER 2) due to its overexpression in various types of cancers, is demonstrated to be a good candidate as a target for anticancer therapy. In this study, cytotoxicity of curcumin encapsulated in ZHER2:342 Affibody-decorated liposome was investigated against SKBR3 and MCF-7 cancerous cell lines. Curcumin-containing liposomes were prepared from soybeans lecetin and cholesterol by thin-film hydration method. Affibody ZHER2:342 molecules C-terminal cysteine residue were conjugated covalently to the prepared liposomes. Particle size analysis was performed using atomic force microscopy (AFM) and dynamic light scattering (DLS). Curcumin loading was measured using UV-Vis spectrophotometry and cytotoxic activity of curcumin formulations against cancerous cell lines was investigated by MTT assay. Induction of apoptosis was investigated using flow cytometry through Annexin V staining. Particle analysis showed the formation of spherical liposomes with a mean diameter of about 150 nm. Cytotoxic activity of curcumin was improved by its encapsulation in both liposomes and affibody-decorated liposomes. The Annexin V staining indicated the induction of apoptosis by affibody-decorated liposomes in both MCF-7 and SKBR3 cells. Decoration of curcumin-loaded liposomes with affibody ZHER2:342 may improve curcumin apoptotic function independently of HER2 expression level.
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http://dx.doi.org/10.1080/08982104.2020.1755981DOI Listing
July 2020

Cytotoxicity evaluation of curcumin-loaded affibody-decorated liposomes against breast cancerous cell lines.

J Liposome Res 2020 Jul 3:1-6. Epub 2020 Jul 3.

Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.

Curcumin is known as an effective anticancer herbal medicine but unfortunately, its bioavailability is poor which necessitate efforts for developing more efficient and specific delivery systems. Human epidermal growth factor receptor 2 (HER 2) due to its overexpression in various types of cancers, is demonstrated to be a good candidate as a target for anticancer therapy. In this study, cytotoxicity of curcumin encapsulated in ZHER2:342 Affibody-decorated liposome was investigated against SKBR3 and MCF-7 cancerous cell lines. Curcumin-containing liposomes were prepared from soybeans lecetin and cholesterol by thin-film hydration method. Affibody ZHER2:342 molecules C-terminal cysteine residue were conjugated covalently to the prepared liposomes. Particle size analysis was performed using atomic force microscopy (AFM) and dynamic light scattering (DLS). Curcumin loading was measured using UV-Vis spectrophotometry and cytotoxic activity of curcumin formulations against cancerous cell lines was investigated by MTT assay. Induction of apoptosis was investigated using flow cytometry through Annexin V staining. Particle analysis showed the formation of spherical liposomes with a mean diameter of about 150 nm. Cytotoxic activity of curcumin was improved by its encapsulation in both liposomes and affibody-decorated liposomes. The Annexin V staining indicated the induction of apoptosis by affibody-decorated liposomes in both MCF-7 and SKBR3 cells. Decoration of curcumin-loaded liposomes with affibody ZHER2:342 may improve curcumin apoptotic function independently of HER2 expression level.
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http://dx.doi.org/10.1080/08982104.2020.1755981DOI Listing
July 2020

EMT signaling: potential contribution of CRISPR/Cas gene editing.

Cell Mol Life Sci 2020 Jul 1;77(14):2701-2722. Epub 2020 Feb 1.

Division of Pharmacy, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.

Epithelial to mesenchymal transition (EMT) is a complex plastic and reversible cellular process that has critical roles in diverse physiological and pathological phenomena. EMT is involved in embryonic development, organogenesis and tissue repair, as well as in fibrosis, cancer metastasis and drug resistance. In recent years, the ability to edit the genome using the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system has greatly contributed to identify or validate critical genes in pathway signaling. This review delineates the complex EMT networks and discusses recent studies that have used CRISPR/Cas technology to further advance our understanding of the EMT process.
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http://dx.doi.org/10.1007/s00018-020-03449-3DOI Listing
July 2020

Boiss. extract improves spatial memory and learning capacity in scopolamine-induced amnesic rats.

Avicenna J Phytomed 2019 Nov-Dec;9(6):587-596

Herbal and Traditional Research Center, Department of Pharmacognosy, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Objective: () has been proposed for memory enhancing in Persian traditional medicine; but to now, no study has been carried out in this field yet. The aim of this research was to study the plant effect on spatial memory in scopolamine-induced amnesia and investigate anticholinesterase effect of .

Material And Methods: Aerial parts of the plant were extracted with methanol and standardized on the basis of rutin content. Male rats received three doses of extract (100, 200 and 400 mg/kg, intraperitoneal (ip) for 7 days) and 30 min after the latest dose, scopolamine (1 mg/kg) was administered to animals. Learning capacity and spatial memory were studied using morris water maze (MWM) and passive avoidance test (PAT) methods. Anticholinesterase activity was studied using Ellman's method. Physostigmine (0.3 mg/kg) and piracetam (200 mg/kg) were used as positive controls.

Results: All doses of extract significantly decreased the distance and time spent to find the platform in MWM and increased the time latency in PAT test. In both MWM and PAT tests, the highest effect of was observed at 200 mg/kg which was in accordance with AChE inhibitory effect of the plant.

Conclusion: Our findings indicate that has anti-amnesic effect and might improve memory deficit through anticholinesterase activity.
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http://dx.doi.org/10.22038/AJP.2019.13540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823527PMC
November 2019

Topoisomerase inhibitors: Pharmacology and emerging nanoscale delivery systems.

Pharmacol Res 2020 01 17;151:104551. Epub 2019 Nov 17.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore. Electronic address:

Topoisomerase enzymes have shown unique roles in replication and transcription. These enzymes which were initially found in Escherichia coli have attracted considerable attention as target molecules for cancer therapy. Nowadays, there are several topoisomerase inhibitors in the market to treat or at least control the progression of cancer. However, significant toxicity, low solubility and poor pharmacokinetic properties have limited their wide application and these characteristics need to be improved. Nano-delivery systems have provided an opportunity to modify the intrinsic properties of molecules and also to transfer the toxic agent to the target tissues. These delivery systems leads to the re-introduction of existing molecules present in the market as novel therapeutic agents with different physicochemical and pharmacokinetic properties. This review focusses on a variety of nano-delivery vehicles used for the improvement of pharmacological properties of topoisomerase inhibitors and thus enabling their potential application as novel drugs in the market.
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http://dx.doi.org/10.1016/j.phrs.2019.104551DOI Listing
January 2020

Nanoparticles Targeting STATs in Cancer Therapy.

Cells 2019 09 27;8(10). Epub 2019 Sep 27.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.

Over the past decades, an increase in the incidence rate of cancer has been witnessed. Although many efforts have been made to manage and treat this life threatening condition, it is still one of the leading causes of death worldwide. Therefore, scientists have attempted to target molecular signaling pathways involved in cancer initiation and metastasis. It has been shown that signal transducers and activator of transcription (STAT) contributes to the progression of cancer cells. This important signaling pathway is associated with a number of biological processes including cell cycle, differentiation, proliferation and apoptosis. It appears that dysregulation of the STAT signaling pathway promotes the migration, viability and malignancy of various tumor cells. Hence, there have been many attempts to target the STAT signaling pathway. However, it seems that currently applied therapeutics may not be able to effectively modulate the STAT signaling pathway and suffer from a variety of drawbacks such as low bioavailability and lack of specific tumor targeting. In the present review, we demonstrate how nanocarriers can be successfully applied for encapsulation of STAT modulators in cancer therapy.
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http://dx.doi.org/10.3390/cells8101158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829305PMC
September 2019

Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems.

Biomolecules 2019 09 25;9(10). Epub 2019 Sep 25.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discussed.
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http://dx.doi.org/10.3390/biom9100530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843293PMC
September 2019

L., Supplementary Plant with Anticholinesterase Effect for Cognition Problems: A Kinetic Study.

Curr Aging Sci 2020 ;13(2):129-135

Herbal and Traditional Medicines Research Center, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Background: The average lifespan and the aging population are rising worldwide. So Neurodegenerative Disease (ND) will be one of the most common challenges associated with this population and would be more prevalent in future. The use of Acetylcholinesterase (AChE) inhibitors is one of the most important strategies for memory impairment. Medicinal plants are the most known natural source for accessing the new therapeutic agents.

Objective: In this work, we aimed to study in vitro anticholinesterase effect of different concentrations (10, 100, 250, 500, 750 and 1000 μg/ml) of total extract of N. sativa (NTE) and its separated fractions and to study the kinetic of AChE enzyme in the presence of two concentrations of NTE (10 and 100 μg/ml).

Methods: Maceration method was used for NTE preparation and different fractions of Petroleum Ether (PTE), Chloroform (CHF) and Methanol (MF). NTE, fractions and the main component of the plant, Thymoquinone (TQ), were assayed for AChE inhibition, using Ellman's method. Kinetic study of the AChE enzyme was studied in the presence of NTE at 10 and 100 μg/ml using Linweaver- Burk plot too.

Results: NTE and all the separated fractions inhibited AChE enzyme in a concentration-dependent manner. The greatest inhibition was shown by CHF and PEF fractions (86.97% and 79.99% at 1000 μg/ml, respectively). With less intensity, NTE, TQ and MF exhibited 76.32%, 68.98 % and 48.39% enzyme inhibition at 1000μg/ml, respectively. The least IC50 value was due to CHF fraction in AChE inhibition (98.28 ± 6.74 μg/ml). Kinetic profile exhibited the mixed mode of AChE inhibition by NTE. This indicates that a particular substance could not be responsible for AChE inhibition, and probably a collection of phytochemicals are involved in this process.

Conclusions: N. sativa is a good candidate for seeking the new anticholinesterase agent and could be considered as a good supplement for the health of the elderly.
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http://dx.doi.org/10.2174/1874609812666190808153246DOI Listing
January 2020

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications.

EXCLI J 2019 28;18:287-299. Epub 2019 May 28.

Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

Bleeding is the most serious complication of warfarin anticoagulation therapy and is known to occur even at patients with therapeutic international normalized ratio (INR) range. Recently, it has been shown that microRNAs play a significant role in pharmacogenetics by regulating genes that are critical for drug function. Interaction between microRNAs and these target genes could be affected by single-nucleotide polymorphisms (SNPs) located in microRNA-binding sites. This study focused on 3'-untranslated region (3'-UTR) SNPs of the genes involved in the warfarin action and the occurrence of bleeding complications in an Iranian population receiving warfarin. A total of 526 patients under warfarin anticoagulation therapy with responding to the therapeutic dose and maintenance of the INR in the range of 2.0-3.5 in three consecutive blood tests were included in the study. Four selected 3'-UTR SNPs (rs12458, rs7294, rs1868774 and rs34669593 located in , , and genes, respectively) with the potential to disrupt/eliminate or enhance/create microRNA-binding site were genotyped using a simple PCR-based restriction fragment length polymorphism (PCR-RFLP) method. Patients with the rs12458 AT or TT genotypes of the gene had a lower risk of bleeding compared to patients with the AA genotype (adjusted OR: 0.478, 95% CI: 0.285-0.802, = 0.005, OR: 0.416, 95% CI: 0.192-0.902, = 0.026, respectively). 3'-UTR polymorphisms in other genes were not significantly associated with the risk of bleeding complications. In conclusion, the SNP rs12458A>T in the 3'UTR region of is associated with the incidence of warfarin-related bleeding at target range of INR, likely by altering microRNA binding and warfarin metabolism. Further genetics association studies are needed to validate these findings before they can be implemented in clinical settings.
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http://dx.doi.org/10.17179/excli2019-1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635724PMC
May 2019

The effects of methanolic extract of Glycyrrhiza glabra on the prevention and treatment of bleomycin-induced pulmonary fibrosis in rat: experimental study.

Drug Chem Toxicol 2019 May 9:1-7. Epub 2019 May 9.

f Department of Pharmacognosy, Herbal and Traditional Medicines Research Center , Kerman University of Medical Science , Kerman , Iran.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by dyspnea and progressive loss of lung function. In this study, the preventive and therapeutic effects of methanolic extract of Glycyrrhiza glabra on pulmonary fibrosis were investigated. Pulmonary fibrosis was induced by administration of bleomycin (BLM) into the left lung of rats. Methyl-prednisolone (M-pred, 4 mg/kg) and methanolic extract of G. glabra (500 mg/kg) were injected intraperitoneally from the 1st to 14th days in the preventive group and from the 14th to 28th days in the therapeutic group once every day. Pulmonary inflammatory and fibrotic indices were evaluated by hematoxylin and eosin (H&E) and Masson's trichrome, respectively. The level of hydroxyproline as an index of pulmonary fibrosis and malondialdehyde (MDA) as an oxidative stress biomarker and catalase were measured by the related ELISA Kits. Pulmonary inflammatory and fibrotic indices in the G. glabra and M-pred groups significantly reduced compared with BLM group. G. glabra decreased the level of hydroxyproline in pulmonary tissue similar to M-pred. MDA reduced in G. glabra and M-pred groups compared with BLM group. The activity of catalase increased in the G. glabra preventive group. According to the results, G. glabra prevented and treated pulmonary fibrosis and inflammation in rats. Therefore, G. glabra may be suggested for the prevention and treatment of pulmonary fibrosis and inflammation.
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http://dx.doi.org/10.1080/01480545.2019.1606232DOI Listing
May 2019

Shedding light on gene therapy: Carbon dots for the minimally invasive image-guided delivery of plasmids and noncoding RNAs - A review.

J Adv Res 2019 Jul 18;18:81-93. Epub 2019 Jan 18.

Neuroscience Research Center, Institute of Neuropharmacology, and Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Recently, carbon dots (CDs) have attracted great attention due to their superior properties, such as biocompatibility, fluorescence, high quantum yield, and uniform distribution. These characteristics make CDs interesting for bioimaging, therapeutic delivery, optogenetics, and theranostics. Photoluminescence (PL) properties enable CDs to act as imaging-trackable gene nanocarriers, while cationic CDs with high transfection efficiency have been applied for plasmid DNA and siRNA delivery. In this review, we have highlighted the precursors, structure and properties of positively charged CDs to demonstrate the various applications of these materials for nucleic acid delivery. Additionally, the potential of CDs as trackable gene delivery systems has been discussed. Although there are several reports on cellular and animal approaches to investigating the potential clinical applications of these nanomaterials, further systematic multidisciplinary approaches are required to examine the pharmacokinetic and biodistribution patterns of CDs for potential clinical applications.
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http://dx.doi.org/10.1016/j.jare.2019.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383136PMC
July 2019

Necrotic, apoptotic and autophagic cell fates triggered by nanoparticles.

Autophagy 2019 01 13;15(1):4-33. Epub 2018 Sep 13.

j Life Sciences Institute, University of Michigan , Ann Arbor , MI , USA.

Nanomaterials have gained a rapid increase in use in a variety of applications that pertain to many aspects of human life. The majority of these innovations are centered on medical applications and a range of industrial and environmental uses ranging from electronics to environmental remediation. Despite the advantages of NPs, the knowledge of their toxicological behavior and their interactions with the cellular machinery that determines cell fate is extremely limited. This review is an attempt to summarize and increase our understanding of the mechanistic basis of nanomaterial interactions with the cellular machinery that governs cell fate and activity. We review the mechanisms of NP-induced necrosis, apoptosis and autophagy and potential implications of these pathways in nanomaterial-induced outcomes. Abbreviations: Ag, silver; CdTe, cadmium telluride; CNTs, carbon nanotubes; EC, endothelial cell; GFP, green fluorescent protein; GO, graphene oxide; GSH, glutathione; HUVECs, human umbilical vein endothelial cells; NP, nanoparticle; PEI, polyethylenimine; PVP, polyvinylpyrrolidone; QD, quantum dot; ROS, reactive oxygen species; SiO, silicon dioxide; SPIONs, superparamagnetic iron oxide nanoparticles; SWCNT, single-walled carbon nanotubes; TiO, titanium dioxide; USPION, ultra-small super paramagnetic iron oxide; ZnO, zinc oxide.
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http://dx.doi.org/10.1080/15548627.2018.1509171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287681PMC
January 2019

Health Concerns of Various Nanoparticles: A Review of Their in Vitro and in Vivo Toxicity.

Nanomaterials (Basel) 2018 Aug 21;8(9). Epub 2018 Aug 21.

Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University in Olomouc, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.

Nanoparticles (NPs) are currently used in diagnosis and treatment of many human diseases, including autoimmune diseases and cancer. However, cytotoxic effects of NPs on normal cells and living organs is a severe limiting factor that hinders their use in clinic. In addition, diversity of NPs and their physico-chemical properties, including particle size, shape, surface area, dispersity and protein corona effects are considered as key factors that have a crucial impact on their safe or toxicological behaviors. Current studies on toxic effects of NPs are aimed to identify the targets and mechanisms of their side effects, with a focus on elucidating the patterns of NP transport, accumulation, degradation, and elimination, in both in vitro and in vitro models. NPs can enter the body through inhalation, skin and digestive routes. Consequently, there is a need for reliable information about effects of NPs on various organs in order to reveal their efficacy and impact on health. This review covers the existing knowledge base on the subject that hopefully prepares us better to address these challenges.
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http://dx.doi.org/10.3390/nano8090634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164883PMC
August 2018

Oxidative stress in opium users after using lead-adulterated opium: The role of genetic polymorphism.

Food Chem Toxicol 2018 Oct 3;120:571-577. Epub 2018 Aug 3.

Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran. Electronic address:

Use of lead-adulterated opium has become one of the major sources of lead poisoning in Iran. This study was designed to assess clinical effects and oxidative stress and its association with GSTM1, GSTT1, NQO1, and ALAD genes polymorphisms and blood lead level (BLL) in lead-adulterated opium users. The oxidative stress status in 192 opium users with lead poisoning symptoms measured and compared with 102 healthy individuals. Gluthatione S-transferase (GST)-M1 and -T1 genes deletion, NQO1 rs1800566, and δ-aminolevulinic acid dehydratase (ALAD) rs1800435 polymorphisms were determined using PCR and PCR-RFLP. The relation between the polymorphisms, BLL, and oxidative stress parameters were analysed using multivariate linear regressions. The common symptoms of lead toxicity were gastrointestinal and neurologic complications. Oxidative stress was significantly higher in opium addicts and lipid peroxidation significantly correlated with BLL. There was significant association between ALAD rs1800435 and BLL, and the BLL was significantly lower in the patients with ALAD 1-2 genotype. Use of lead-adulterated opium causes high frequency of lead toxicity symptoms, hematological and biochemical abnormalities, and oxidative stress which are associated with BLL. Route of opioid use and the polymorphism of rs1800435 in ALAD gene are the major determinants of BLL in lead-adulterated opium users.
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http://dx.doi.org/10.1016/j.fct.2018.07.061DOI Listing
October 2018

Mancozeb induces testicular dysfunction through oxidative stress and apoptosis: Protective role of N-acetylcysteine antioxidant.

Toxicol Ind Health 2018 Nov 23;34(11):798-811. Epub 2018 Jul 23.

6 Department of Biotechnology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Mancozeb (MZB) is one of the fungicides used in pest control programs that might affect human health including reproductive system. The aim of this study was to demonstrate the mechanisms through which MZB induces testicular tissue damage and the probable protective effect of N-acetylcysteine (NAC), a modified amino acid, with antioxidant property, against MZB toxicity in an animal model. Male albino mice ( n = 8) were exposed to different doses of MZB (250 and 500 mg/kg/day) by oral gavage without or with NAC (200 mg/kg, twice/week) for 40 days. Sub-chronic MZB dose-dependently decreased sperm motility and count. Exposure to MZB increased lipid peroxidation and protein carbonyl, while it reduced antioxidant enzymes activities, total antioxidant capacity, and glutathione content. The histopathological examination clearly showed deleterious changes in the testicular structure. At the molecular levels, the results of quantitative real time-poly chain reaction (qRT-PCR) showed that MZB upregulated oxidative stress markers inducible nitric oxide synthase (iNOS) and NADPH oxidase 4 (NOX4) and downregulated expression of the glutathione peroxidase 1 (Gpx1) gene as one of the most important antioxidant enzymes. MZB also induced apoptosis dose-dependently in the testes as determined by the terminal dUTP nick-end labeling assay and immunoblotting. NAC administration decreased the mRNA levels of both iNOS and NOX4 with a concomitant increase in Gpx1 expression. It also significantly decreased MZB-induced oxidative stress and apoptosis. Collectively, the present study showed MZB-induced oxidative damage in testes leading to apoptosis. It revealed that antioxidants such as NAC can mitigate oxidant injury induced by the dithiocarbamate pesticides in the reproductive system.
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http://dx.doi.org/10.1177/0748233718778397DOI Listing
November 2018

Cyclooxygenase inhibitors combined with deuterium-enriched water augment cytotoxicity in A549 lung cancer cell line via activation of apoptosis and MAPK pathways.

Iran J Basic Med Sci 2018 May;21(5):508-516

Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.

Objectives: Combination chemotherapy is a rational strategy to increase patient response and tolerability and to decrease adverse effects and drug resistance. Recently, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to be associated with reduction in occurrence of a variety of cancers including lung cancer. On the other hand, growing evidences suggest that deuterium-enriched water (DEW, D2O) and deuterium-depleted water (DDW) play a role both in treatment and prevention of cancers. In the present study, we examined the effects of DEW and DDW in combination with two NSAIDs, celecoxib and indomethacin, on A549 human non-small lung cancer cell to identify novel treatment options.

Materials And Methods: The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW and DEW was determined. The COX-2, MAPK pathway proteins, the anti-apoptotic Bcl2 and pro-apoptotic Bax proteins and caspase-3 activity were studied for cytotoxic combinations.

Results: Co-administration of selective and non-selective COX-2 inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of A549 cells. These events were associated with activation of p38 and JNK MAPKs and decreasing pro-survival proteins Bcl-2, COX-2 and ERK1/2. Furthermore, the combination therapy activated caspase-3, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it.

Conclusion: The combination of DEW with NSAIDs might be effective against lung cancer cells by influence on principal cell signalling pathways, and this has a potential to become a candidate for chemotherapy.
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http://dx.doi.org/10.22038/IJBMS.2018.25366.6269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000214PMC
May 2018

Protective effect of standardized extract of Myrtus communis L. (myrtle) on experimentally bleomycin-induced pulmonary fibrosis: biochemical and histopathological study.

Drug Chem Toxicol 2018 Oct 11;41(4):408-414. Epub 2018 May 11.

e Department of Agriculture , Azad University of Kerman , Kerman , Iran.

Context: Myrtle (Myrtus communis L) has been used widely in traditional medicine for different respiratory disorders. Idiopathic pulmonary fibrosis (IPF) is an inflammatory disease characterized by progressive loss of lung function with poor prognosis. The pathogenesis of disease has not been completely elucidated, but probably persistent epithelial damages are involved.

Objective: Evaluation of biochemical and histopathological effect of preventive and therapeutic doses of myrtle against bleomycin (BLM)-induced pulmonary fibrosis (PF) in animal model.

Materials And Methods: Methanolic extract of M. communis was prepared by maceration method. Total flavonoid content was determined and experimentally PF was induced in rat with intratracheal instillation of a single dose of BLM (5 mg/kg) only on day 0. Myrtle antifibrotic effect was evaluated as preventive (50 mg/kg/day, intraperitoneal (i.p.) injection, from day 0-13) and therapeutic agent (50 mg/kg, i.p., from day 14-27) in comparison with methyl prednisolone (M-pred) (4 mg/kg, i.p. for 14 days).

Results: Parenchymal inflammation and fibrotic changes significantly were reduced by myrtle and M-pred. Significant decrease in hydroxyproline content and lipid peroxidation were observed in animals receiving myrtle extract while catalase activity was increased by myrtle. Improvement in inflammation and fibrosis was observed in myrtle group especially in the early phase of fibrosis (preventive regime).

Discussion And Conclusion: Myrtle extract effectively inhibited the inflammation and fibrosis of lung parenchyma in both preventive and therapeutic methods. This effect might be due to the reduction of tissue inflammation and inhibition of oxidative stress. More studies are being carried out to find main mechanisms and separation of active compounds.
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http://dx.doi.org/10.1080/01480545.2018.1459670DOI Listing
October 2018

Hematological Abnormality, Oxidative Stress, and Genotoxicity Induction in the Greenhouse Pesticide Sprayers; Investigating the Role of NQO1 Gene Polymorphism.

Toxics 2018 Feb 7;6(1). Epub 2018 Feb 7.

Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Haft-Bagh Blvd., Kerman 7616911319, Iran.

The widespread use of pesticides in agriculture represents a threat to the human populations exposed to them. In this cross-sectional study, the hematological and biochemical parameters, plasma cholinesterase (PChE) activity, oxidative stress, genotoxicity, and NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism were measured in 100 greenhouse workers occupationally exposed to pesticide mixture and 104 normal healthy controls. There was a decrease in erythrocytes (5.45%, = 0.026) and hemoglobin (3.26%, = 0.025), and an increase in mean corpuscular hemoglobin (3.54%, = 0.013) in the exposed workers. Sprayers showed a reduction in PChE (23%) and GSH (50%) levels, and an increase in lipid peroxidation (LPO) (55%), protein carbonyl (145%), Superoxide dismutase activity (61%), and total antioxidant capacity (35%) ( < 0.001 for all parameters but LPO: = 0.009). Genotoxicity parameters were significantly high in the exposed cases (for all parameters: < 0.001 but tail length: = 0.002). There was a significant correlation between oxidative stress and genotoxicity parameters, and also between these biomarkers and PChE activity. The NQO1 C609T polymorphism was not significantly associated with studied biomarkers. The findings indicate that occupational exposure to a mixture of pesticides can induce hematotoxicity, oxidative stress, and genotoxicity in greenhouse workers.
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http://dx.doi.org/10.3390/toxics6010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874786PMC
February 2018

Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression.

Food Chem Toxicol 2018 Feb 19;112:39-46. Epub 2017 Dec 19.

Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran. Electronic address:

In this study we investigated the protective effects and possible mechanisms of pirfenidone (PF) in paraquat (PQ)-induced lung injury and fibrosis in mice. Lung injury was induced by injection of PQ (20 mg/kg). Thereafter, mice orally received water and PF (100 and 200 mg/kg) for four weeks. After 28 days, the inflammation and fibrosis were determined in the lungs by analysis of histopathology, bronchoalveolar lavage fluid (BALF) cell count, lung wet/dry weight ratio, hydroxyproline content, and oxidative stress biomarkers. Expression of several genes involved in fibrogenesis and modulation of reactive oxygen species (ROS) production, such as TGF-β1, α-SMA, collagen Iα and IV, NOX1, NOX4, iNOS, and GPX1 were determined using RT-qPCR. PF significantly decreased the lung fibrosis and edema, inflammatory cells infiltration, TGF-β1 concentration, and amount of hydroxyproline in the lung tissue. PF dose-dependently improved the expression level of the studied genes to the near normal. Decreasing of lung lipid peroxidation and catalase activity, and increasing of SOD activity in the treated mice were significant compared to the control group. Pirfenidone ameliorate paraquat induced lung injury and fibrosis partly through inhibition of inflammation and oxidative stress, and downregulation of genes encoding for profibrotic cytokines and enzymatic systems for ROS production.
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http://dx.doi.org/10.1016/j.fct.2017.12.034DOI Listing
February 2018

Correction to: Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis.

Inflammation 2018 02;41(1):364

Neuroscience Research Center, Institute of Neuropharmacology, and Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Unfortunately, the original publication of this article contained mistakes, and the authors would like to correct them. The corrected details are given below.
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http://dx.doi.org/10.1007/s10753-017-0695-1DOI Listing
February 2018

Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis.

Inflammation 2018 Feb;41(1):134-142

Neuroscience Research Center, Institute of Neuropharmacology, and Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Pirfenidone is known to slow the decline in vital capacity and increase survival in idiopathic pulmonary fibrosis (IPF). Besides, administration of glucocorticoids, e.g., prednisolone has been the conventional strategy to the treatment of patients with this disease, although their efficacy is under debate. Since multiple coactivated pathways are involved in the pathogenesis of IPF, combination therapy is a foundation strategy to cover many more synergetic mechanisms and increase response. The aim of the present study was to compare the therapeutic efficacy of prednisolone plus pirfenidone with pirfenidone alone in PQ-induced lung fibrosis. After development of PQ-induced lung fibrosis, pirfenidone, prednisolone, and their combination were administered for 14 consecutive days. Lung pathological lesions, along with increased hydroxyproline were determined in the paraquat group. Paraquat also caused oxidative stress and increasing the proinflammatory and profibrotic gene expression. Pirfenidone attenuated the PQ-induced pulmonary fibrosis from the analysis of antioxidant enzymes but prednisolone had no such effect. Co-treatment with pirfenidone and prednisolone suppressed lung hydroxyproline content, TGF-β1, and TNF-α; however, prednisolone alone could not suppress pulmonary fibrosis which was significantly suppressed only by pirfenidone. Pirfenidone also suppressed the increase in MMP-2 and TIMP-1 induced by PQ. All of these effects were exaggerated when pirfenidone coadministered with prednisolone. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of hydroxyproline content, oxidative stress and proinflammatory and profibrotic gene expression during the development of PQ-induced pulmonary fibrosis in rats and combination therapy with prednisolone can represent more potent therapeutic effects.
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http://dx.doi.org/10.1007/s10753-017-0671-9DOI Listing
February 2018

Preference of Aerosolized Pirfenidone to Oral Intake: An Experimental Model of Pulmonary Fibrosis by Paraquat.

J Aerosol Med Pulm Drug Deliv 2018 02 11;31(1):25-32. Epub 2017 Jul 11.

2 Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences , Kerman, Iran .

Background: Inhalation drug delivery is a fast, effective, and safe route of delivering medication directly to the lungs. Thanks to the large surface area and highly vascularized epithelium in lung, pulmonary drug delivery has been considered as an effective route to deliver drugs to the systemic circulation. Pirfenidone (PF), an oral antifibrotic agent, has been shown to slow down the progression of the lung fibrosis. Inhalation or intrapulmonary delivery of PF appears to be a good alternative to optimize drug delivery and minimize the dosage, adverse and nonspecific effects.

Methods: Pulmonary fibrosis was induced by paraquat in rats. After induction of fibrosis, PF was administered via oral and inhalation routes for 14 consecutive days. The efficacy of oral and inhalation routes were compared by evaluating morphological changes, hydroxyproline content, tissue oxidative stress parameters, and proinflammatory and profibrotic genes expression including transforming growth factor beta 1 (TGF-β1), tumor necrosis factor alpha (TNF-α), tissue inhibitor of metalloproteinase 1 (TIMP-1), and matrix metalloproteinase 2 (MMP-2) genes.

Results: The results showed similar therapeutic effects and efficacy for both inhalation and oral routes; however, the dose of inhalation route was much less than that for oral administration.

Conclusion: In conclusion, PF offers great potential as an inhalation delivery formulation for treatment of pulmonary fibrosis.
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http://dx.doi.org/10.1089/jamp.2016.1342DOI Listing
February 2018

Glucocorticoid Receptor Genetic Variants and Response to Fluoxetine in Major Depressive Disorder.

J Neuropsychiatry Clin Neurosci 2018 23;30(1):45-50. Epub 2017 Jun 23.

From the Department of Toxicology & Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran (HN, AM); the Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran (NF, MRHS); Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran (NF); the Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran (NF, EB); the Pharmaceutics Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran (AM); the Basic Sciences in Infectious Diseases Research Center, Shiraz, Iran (KZ); and the Department of Medical Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran (KZ, SA).

Hyperactivity of the hypothalamic pituitary adrenocortical (HPA) axis is one of the main clinical findings in depression. The HPA axis is interrelated with glucocorticoid signaling via glucocorticoid receptors (GCRs). Thus, functional genetic variants on GCRs might influence therapeutic outcomes in depression. The aim of the present study was to investigate the association between three functional polymorphisms (rs41423247, rs6195, and rs6189/rs6190) on GCR and response to fluoxetine in a group of depressed patients. One hundred newly diagnosed patients completed 6 weeks of fluoxetine treatment. Response to treatment was defined as a 50% decrease in the Hamilton Depression Rating Scale score. Variants of rs41423247, rs6195, and rs6189/rs6190 polymorphisms were determined in extracted DNAs using PCR-RFLP method. Regarding rs41423247 polymorphism, carriers of the CG and GG genotype responded significantly better to fluoxetine compared with CC carriers (p=0.008, OR=3.3, 95% CI=1.35-8.07). Moreover, the G allele of rs41423247 polymorphism was strongly associated with response to fluoxetine (p=0.032, OR=2.2, 95% CI=1.09-4.44). There was no significant association between different genotypes and alleles of rs6195, rs6189/rs6190 variants, and response to fluoxetine (p=0.213 and 0.99, respectively). In conclusion, rs41423247 polymorphism might be a predictor for better response to fluoxetine. These findings support the idea that some variants of the GCR might contribute to interindividual variability of response to antidepressants.
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http://dx.doi.org/10.1176/appi.neuropsych.16120322DOI Listing
August 2018

Role of Donors and Recipients' Glutathione S-Transferase Gene Polymorphisms in Association of Oxidative Stress With Delayed Graft Function in Kidney Allograft Recipients.

Iran J Kidney Dis 2017 May;11(3):241-248

Gastroenterology and Hepatology Research Centre, Institute of Basic and Clinical Physiology Sciences; Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.

Introduction: Oxidative stress contributes to delayed graft function (DGF). Glutathione S-transferases (GSTs) are polymorphic genes which produce enzymes with protective effect against oxidative stress. This study aimed to investigate the association between donors' and recipients' GSTM1 and GSTT1 polymorphisms and DGF, creatinine clearance, and oxidative stress parameters in kidney allograft recipients.

Materials And Methods: One hundred and eighty-two donor-recipient pairs were studied. Lipid peroxidation and total antioxidant capacity were measured in the recipients' plasma as the parameters of oxidative stress. Delayed graft function was determined based on at least 10% increase, no change, or less than 10% decrease in the serum creatinine level in 3 consecutive days during the 1st week after transplantation.

Results: Lipid peroxidation was significantly greater in the recipients with DGF (P < .001). The frequency of GSTM1 null was significantly higher in the patients with DGF (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17 to 0.86; P = .02). There was also a significant association between the donors' GSTM1 polymorphism and DGF (OR, 0.31; 95% CI, 0.14 to 0.68; P = .003). A significant association was detected between combination of recipients and donors' GSTM1 polymorphism and DGF (OR, 0.20; 95% CI, 0.07 to 0.64, P = .006). The recipients' GSTM1 polymorphism, alone and in combination with donors' GSTM1 and GSTT1, significantly affected the creatinine clearance on discharge day.

Conclusions: These results suggest that the donors and recipients' GSTM1 polymorphism may be a major risk factor for oxidative stress and poor kidney allograft transplantation outcomes.
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May 2017

Anti-Inflammatory Subfractions Separated from Acidified Chloroform Fraction of Fenugreek Seeds (Trigonella foenum-graecum L.).

J Diet Suppl 2018 Jan 30;15(1):98-107. Epub 2017 May 30.

b Neuroscience Research Center, Faculty of Pharmacy , Kerman University of Medical Sciences , Kerman , Iran.

Considering the side effects of current anti-inflammatory drugs, novel therapeutic agents are desired. We have succeeded in separating flavonoid-rich fractions with anti-inflammatory effect from fenugreek seeds (Trigonella foenum-graecum L.). In this work, we aimed to carry out further fractionation to find active anti-inflammatory subfractions. Trigonelline content of the plant was determined by spectrophotometric method. Fenugreek seeds were extracted consecutively with petroleum ether, acidified chloroform (ACC), alkaline chloroform (AKC), methanol, and water. ACC fraction, which had exhibited the highest anti-inflammatory effect, was further fractionated using column chromatography. Obtained subfractions were evaluated using carrageenan-induced paw edema (CIPE) method. Animals were pretreated by test compounds, and after 30 minutes edema was induced by subcutaneous injection of 100 µl of 1% w/v carrageenan into the right paw of animals. Volume difference of both paws was measured at different times after carrageenan injection. The concentration of trigonelline was determined as 16.2%. ACC fraction inhibited paw edema significantly in comparison to control (p < .05). Four subfractions (dry weight percentage basis) were selected for pharmacological study. F3 subfraction exhibited the greatest inhibition at 15 mg/kg (p < .001). ACC fraction and F4 significantly inhibited paw edema at doses of 5, 10, and 15 mg/kg (p < .001). Phytochemical studies indicated the presence of flavonoids in ACC and active subfractions. Further separation can lead to finding active components from active subfractions, which probably belong to flavonoid phytochemicals. Considering the gastroprotective effect of fenugreek, we hope the separated fractions also would be free of gastrointestinal side effects.
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http://dx.doi.org/10.1080/19390211.2017.1326431DOI Listing
January 2018

Accelerated Burn Wound Closure in Mice with a New Formula Based on Traditional Medicine.

Iran Red Crescent Med J 2016 Nov 17;18(11):e26613. Epub 2016 Aug 17.

Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, IR Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, IR Iran.

Background: A combination of the oils of sesame, hemp, wild pistachio, and walnut has been used for treatment of skin disorders, including wound burns, in some parts of Kerman, Iran. Evaluation of this remedy in the form of a pharmaceutical formulation in animal models can pave the way for its future application in wound burn healing in humans.

Objectives: This experimental study investigated the healing potential of a new formula (NF) based on folk medicine from Iran for the treatment of third degree burns in mice. The formula was a combination of the oils of four plants: sesame ( L.), wild pistachio ( Desf.), hemp ( L.), and walnut ( L.).

Methods: Twenty-four mice were selected based on simple random sampling. Twenty-five percent of the total body surface area was burned by exposure to boiling water, according to the Walker-Mason method. NF and silver sulfadiazine (the positive control) were applied topically twice a day for 21 days. The burned area in the negative control group was left untreated. Epithelialization time and the percent of wound contraction were measured during the treatment period. The process of wound repairing was evaluated using histological (H and E and trichrome staining) and immunohistological (anti-pancytokeratin) methods.

Results: When compared to the controls, NF significantly improved wound contraction after day 10. Epithelialization time in the NF group was significantly faster than in the other groups (20 vs. 25.5 days) (P < 0.001). Histopathological and immunohistochemical findings confirmed the efficacy of the NF.

Conclusions: A new therapeutic remedy was introduced for the treatment of burn wounds. Further clinical and molecular studies are suggested to determine the exact mechanism(s) involved in the burn wound healing effect of NF.
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http://dx.doi.org/10.5812/ircmj.26613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292211PMC
November 2016

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR).

Toxicol Appl Pharmacol 2016 10 28;309:37-43. Epub 2016 Aug 28.

Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, P.O. Box 1411713138, Tehran, Iran. Electronic address:

Background: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients.

Methods: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0-3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP).

Results: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P=0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P=0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events.

Conclusion: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations.
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http://dx.doi.org/10.1016/j.taap.2016.08.026DOI Listing
October 2016

Chemical Composition, Anticonvulsant Activity, and Toxicity of Essential Oil and Methanolic Extract of Elettaria cardamomum.

Planta Med 2016 Nov 19;82(17):1482-1486. Epub 2016 Jul 19.

Neuroscience Research Center, Institute of Neuropharmacology, Kerman Univerity of Medical Sciences, Kerman, Iran.

is an aromatic spice (cardamom) native to the humid Asian areas, which contains some compounds with a potential anticonvulsant activity. Various pharmacological properties such as anti-inflammatory, analgesic, antioxidant, and antimicrobial effects have been related to this plant. This research was conducted to examine the probable protective impact of the essential oil and methanolic extract of against chemically (pentylentetrazole)- and electrically (maximal electroshock)-induced seizures in mice. In addition, neurotoxicity, acute lethality, and phytochemistry of the essential oil and methanolic extract were estimated. The TLC method showed the presence of kaempferol, rutin, and quercetin in the extract, and the concentration of quercetin in the extract was 0.5 µg/mL. The major compounds in the essential oil were 1,8-cineole (45.6 %), -terpinyl acetate (33.7 %), sabinene (3.8 %), 4-terpinen-4-ol (2.4 %), and myrcene (2.2 %), respectively. The extract and essential oil showed significant neurotoxicity in the rotarod test at the doses of 1.5 g/kg and 0.75 mL/kg, respectively. No mortalities were observed up to the doses of 2 g/kg and 0.75 mL/kg for the extract and essential oil. The essential oil was effective in both the pentylentetrazole and maximal electroshock models; however, the extract was only effective in the pentylentetrazole model. The study suggested that methanolic extract had no significant lethality in mice. Both the essential oil and methanolic extract showed movement toxicity. Anticonvulsant effects of were negligible against the seizures induced by pentylentetrazole and maximal electroshock.
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http://dx.doi.org/10.1055/s-0042-106971DOI Listing
November 2016

Pharmacological safety evaluation of a traditional herbal medicine "Zereshk-e-Saghir" and assessment of its hepatoprotective effects on carbon tetrachloride induced hepatic damage in rats.

J Ethnopharmacol 2016 Aug 15;190:387-95. Epub 2016 Jul 15.

Department of Pharmacology & Toxicology, School of Pharmacy, Kerman University of Medical Sciences, P.O. Box 7616911319, Kerman, Iran; Gastroenterology and Hepatology Research Center, Afzalipour"s Hospital, Imam Highway, P.O. Box 7616913911, Kerman, Iran. Electronic address:

Ethnopharmacological Relevance: "Zereshk-e-Saghir" (ZES), one of the traditional herbal medicines in old manuscripts of Persian hakims, has been used for the treatment of liver disorders. This current study is aimed to evaluate ZES effects on animal model to investigate its safety and hepatoprotective activity.

Materials And Methods: ZES was prepared according to a traditional method by blending aqueous extracts of Berberis vulgaris L., with fine particles of other plants including Rosa damascene Mill, Cichorium intybus L., Cucumis sativus L., Portulaca oleracea L., Rheum palmatum L., and Nardostachys jatamansi DC.. The lethality of ZES was determined in male NMRI mice. Acute organ toxicity of ZES (750 and 1500mg/kg for 15 days, orally) was evaluated by measuring the cell blood count, liver marker enzymes, creatinine, antioxidant status and histopathological examinations in rats. CCl4-induced liver toxicity was used to examine the hepatoprotective effects of the preparation. The rats were pretreated with 250, 500, 750 and 1500mg/kg ZES by gavage for 15 days. At day 16, the rats were intraperitoneally injected 1ml/kg CCl4 in olive oil. Forty-eight hours after CCl4 injection, the animals were sacrificed and their liver samples and blood were collected for determination of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase (ALT, AST, and ALP), histopathological examinations and antioxidant status.

Results: Treatment of the mice with a single dose of ZES up to 2g/kg did not cause mortality. Treatment of the rats with doses of 750 and 1500mg/kg for 15 days showed no significant hematotoxicity and hepatotoxicity. Treatment of the rats with ZES reduced the increased serum levels of ALT, AST, and ALP induced by CCl4 at the doses of 250, 500, and 750mg/kg. This was almost confirmed by histopathological examinations. Pretreatment with ZES also decreased lipid peroxidation and maintained the levels of glutathione and total antioxidant capacity.

Conclusions: The present in vivo study revealed that the long term usage of ZES was safe for organs in laboratory animals. Meanwhile, prescribing the traditionally-recommended dose of ZES can be probably used against the liver injuries induced by xenobiotics. Further studies in other models of liver injuries are recommended for finding the exact hepatoprotective mechanism of ZES.
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http://dx.doi.org/10.1016/j.jep.2016.07.043DOI Listing
August 2016