Publications by authors named "Gholamreza Karimi"

140 Publications

Preparation, evaluation, and application of dummy molecularly imprinted polymer for analysis of hesperidin in lime juice.

J Sep Sci 2021 Jan 12. Epub 2021 Jan 12.

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

Lime juice as the most commonly used natural source production can be characterized using determination of flavonoids contents such as hesperidin. So, development of analyzing methods for checking the quality and healthiness of lime juices is necessary. In this study, we aimed to set up a selective solid phase extraction method using dummy molecularly imprinting approach for extraction and separation of hesperidin in lime juice to check the quality of commercial lime juice products of Mashhad city market. The imprinted polymers were synthesized by hesperitin as dummy template due to the hesperitin solubility in the wide range of porogenic solvents. The specificity extent of synthesized polymers toward hesperidin was tested and optimum one was used as adsorbent in solid-phase extraction cartridge. The dummy molecularly imprinted polymer with high adsorption capacity for hesperidin (dissociation constant 0.12 μM) was successfully used for extraction and clean-up of hesperidin in the lime juice matrix prior to analysis by high-performance liquid chromatography. The analysis of hesperidin was done in the range of 0.312-50 μg/mL with detection limit of 0.05 μg/mL. This technique was successfully set up to remove the interfering compounds for analysis of hesperidin in commercial lime juice products.
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http://dx.doi.org/10.1002/jssc.202001094DOI Listing
January 2021

MicroRNAs and SARS-CoV-2 life cycle, pathogenesis, and mutations: biomarkers or therapeutic agents?

Cell Cycle 2021 01 31;20(2):143-153. Epub 2020 Dec 31.

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

To date, proposed therapies and antiviral drugs have been failed to cure coronavirus disease 2019 (COVID-19) patients. However, at least two drug companies have applied for emergency use authorization with the United States Food and Drug Administration for their coronavirus vaccine candidates and several other vaccines are in various stages of development to determine safety and efficacy. Recently, some studies have shown the role of different human and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microRNAs (miRNAs) in the pathophysiology of COVID-19. miRNAs are non-coding single-stranded RNAs, which are involved in several physiological and pathological conditions, such as cell proliferation, differentiation, and metabolism. They act as negative regulators of protein synthesis through binding to the 3' untranslated region (3' UTR) of the complementary target mRNA, leading to mRNA degradation or inhibition. The databases of Google Scholar, Scopus, PubMed, and Web of Science were searched for literature regarding the importance of miRNAs in the SARS-CoV-2 life cycle, pathogenesis, and genomic mutations. Furthermore, promising miRNAs as a biomarker or antiviral agent in COVID-19 therapy are reviewed.
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http://dx.doi.org/10.1080/15384101.2020.1867792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889196PMC
January 2021

Endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity may be therapeutically targeted by natural and chemical compounds: A review.

Pharmacol Res 2021 Feb 21;164:105383. Epub 2020 Dec 21.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Doxorubicin (DOX) is a chemotherapeutic agent with marked, dose-dependent cardiotoxicity that leads to tachycardia, atrial and ventricular arrhythmia, and irreversible heart failure. Induction of the endoplasmic reticulum (ER) which plays a major role in protein folding and calcium homeostasis was reported as a key contributor to cardiac complications of DOX. This article reviews several chemical compounds that have been shown to regulate DOX-induced inflammation, apoptosis, and autophagy via inhibition of ER stress signaling pathways, such as the IRE1α/ASK1/JNK, IRE1α/JNK/Beclin-1, and CHOP pathways.
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http://dx.doi.org/10.1016/j.phrs.2020.105383DOI Listing
February 2021

Natural compounds against cytotoxic drug-induced cardiotoxicity: A review on the involvement of PI3K/Akt signaling pathway.

J Biochem Mol Toxicol 2020 Dec 15:e22683. Epub 2020 Dec 15.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Cardiotoxicity is a critical concern in the use of several cytotoxic drugs. Induction of apoptosis, inflammation, and autophagy following dysregulation of the PI3K/Akt signaling pathway contributes to the cardiac damage induced by these drugs. Several natural compounds (NCs), including ferulic acid, gingerol, salvianolic acid B, paeonol, apigenin, calycosin, rutin, neferine, higenamine, vincristine, micheliolide, astragaloside IV, and astragalus polysaccharide, have been reported to suppress cytotoxic drug-induced cardiac injury. This article reviews these NCs that have been reported to have a protective effect against cytotoxic drug-induced cardiotoxicity through regulation of the PI3K/Akt signaling pathway.
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http://dx.doi.org/10.1002/jbt.22683DOI Listing
December 2020

Corrigendum to "Arsenic cardiotoxicity: An overview" [Environ. Toxicol. Pharmacol. 40 (2015) 1005-1014].

Environ Toxicol Pharmacol 2021 Feb 14;82:103539. Epub 2020 Nov 14.

Pharmaceutical Research Center and Pharmacy School, Mashhad University of Medical Sciences, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.etap.2020.103539DOI Listing
February 2021

The possible role of Sirtuins and microRNAs in hepatocellular carcinoma therapy.

Cell Cycle 2020 Dec 9;19(23):3209-3221. Epub 2020 Nov 9.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Sirtuins are NAD+-dependent histone deacetylases that regulate many cellular processes such as proliferation, apoptosis, and metabolism. SIRT (silent information regulator)-1, 5, 6 and 7, members of the mammalian Sirtuin family of proteins (SIRT1-SIRT7), are involved in carcinogenesis, prognosis, metastasis, and chemical resistant of HCC. These proteins act through the deacetylation of tumor suppressor or oncogenic factors. MicroRNAs (miRNAs) are a group of small non-coding RNAs that down regulate gene expression by targeting the 3'-untranslated region of miRNAs. MiRNAs can function as tumor suppressors or as oncogenes and are involved in progression, differentiation, apoptosis and drug resistance of tumor cells. The focus of this review is to delineate the relationship between some microRNAs and their target, Sirtuins, and to present an overview of their function in HCC as currently understood.
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http://dx.doi.org/10.1080/15384101.2020.1843813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751631PMC
December 2020

Corrigendum to "Arsenic Cardiotoxicity: An Overview" [Environmental Toxicology and Pharmacology 40 (3 (November)) (2015) 1005-1014].

Environ Toxicol Pharmacol 2021 Jan 1;81:103524. Epub 2020 Nov 1.

Pharmaceutical Research Center and Pharmacy School, Mashhad University of Medical Sciences, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.etap.2020.103524DOI Listing
January 2021

Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway.

Phytother Res 2020 Sep 28. Epub 2020 Sep 28.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Cardiotoxicity is the main concern for long-term use of the doxorubicin (DOX). Reactive oxygen species (ROS) generation leads to oxidative stress that significantly contributes to the cardiac damage induced by DOX. The nuclear factor erythroid 2-related factor (Nrf2) acts as a protective player against DOX-induced myocardial oxidative stress. Several natural compounds (NCs) with anti-oxidative effects, were examined to suppress DOX cardiotoxicity such as asiatic acid, α-linolenic acid, apigenin, baicalein, β-lapachone, curdione, dioscin, ferulic acid, Ganoderma lucidum polysaccharides, genistein, ginsenoside Rg3, indole-3-carbinol, naringenin-7-O-glucoside, neferine, p-coumaric acid, pristimerin, punicalagin, quercetin, sulforaphane, and tanshinone IIA. The present article, reviews NCs that showed protective effects against DOX-induced cardiac injury through induction of Nrf2 signaling pathway.
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http://dx.doi.org/10.1002/ptr.6882DOI Listing
September 2020

Mangiferin offers protection against deleterious effects of pharmaceuticals, heavy metals, and environmental chemicals.

Phytother Res 2021 Feb 22;35(2):810-822. Epub 2020 Sep 22.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Mangiferin (MGF) is a polyphenolic C-glucosyl-xanthone extracted from the mango tree (Mangifera indica). MGF has shown diverse effects such as antioxidant, antiapoptotic, radical scavenging, and chelating properties. MGF also has been shown to modulate inflammatory pathways. In this review, we examined and evaluated the literature dealing with the protective effects of MGF against various chemical toxicities. Our literature review indicated that the MGF-induced protective effects against the toxic effects of pharmaceuticals, heavy metals and environmental chemicals were mainly mediated via suppression of lipid peroxidation, oxidative stress (along with enhancement of the antioxidant enzyme), inflammatory factors (TNF-α, IL-6, IL-10, and IL-12), and activation of PI3K/Akt and the MAPK survival signaling pathway.
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http://dx.doi.org/10.1002/ptr.6864DOI Listing
February 2021

Probabilistic carcinogenic and non-carcinogenic risk assessment of heavy metal ingestion through consumption of different walnut cultivars: An Iranian study.

Environ Monit Assess 2020 Aug 27;192(9):599. Epub 2020 Aug 27.

Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, 1365-91775. I, Mashhad, .R, Iran.

The heavy metal levels in six walnut cultivars from five geographical zones of Iran were measured. An assessment of risks was conducted by calculating the Target Hazard Quotient (THQ) and Incremental Lifetime Cancer Risk (ILCR) by use of the Monte Carlo simulation method. The highest amounts of As and Pb were reported in Farouj samples. Also, the highest levels of Cr, Zn, Cu and Mn were determined in samples collected from Tuyserkan. Accordingly, 50th and 95th ILCRs for general population due to consumption of walnut were 1.03 × 10 and 3.11 × 10 (for As), 4.10 × 10 and 1.1 × 10 (for Cr) and 4.71 × 10 and 1.05 × 10 (for Pb), respectively. In addition, the 50th and 95th centiles of the HIs for walnut ingestion by Iranians were 1.02 and 2.05, respectively, indicating a minor chance of non-cancer effects. Based on the calculated 95% ILCR, dietary exposure to As through the consumption of walnut poses a risk to Iranian consumer health. However, ILCR values of other heavy metals (HMs) were in acceptable ranges (ILCR < 1 × 10), representing no toxicological concern for consumers. The most significantly influential parameters were determined by sensitivity analysis during the MCS. According to THQ and ILCR methods, concentration was the most sensitive parameters. For THQ method the concentration effects were ranged from 72.4 to 85.1%. Moreover, for ILCR method the effects of concentration in As, Cr, and Pb were 87.1, 79.1 and 83.54%, respectively.
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http://dx.doi.org/10.1007/s10661-020-08551-4DOI Listing
August 2020

The protective effect of natural compounds against rotenone-induced neurotoxicity.

J Biochem Mol Toxicol 2020 Dec 23;34(12):e22605. Epub 2020 Aug 23.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Rotenone is a widely used organic pesticide; its serious side effect for off-target species is neurotoxicity. The primary mechanism of rotenone toxicity is inhibition of the mitochondrial complex I. Oxidative stress, apoptosis, and reduction of autophagy are key outcomes of the inhibition of complex I. Numerous in vitro and in vivo studies have shown antioxidant, anti-apoptotic, and autophagy enhancement of a variety of natural compounds (NCs). In this manuscript, we reviewed several NCs, which have protective effects against rotenone-induced neurotoxicity.
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http://dx.doi.org/10.1002/jbt.22605DOI Listing
December 2020

Crocin Increases Gastric Cancer Cells' Sensitivity to Doxorubicin.

Asian Pac J Cancer Prev 2020 07 1;21(7):1959-1967. Epub 2020 Jul 1.

4Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: Crocin is one of the substantial constituents of saffron extract. It has multiple clinical effects including anti-cancer effects. The development of the multidrug resistance (MDR) phenotype is one of the principal causes of cancer chemotherapy failure. The multidrug resistance protein 1 (MDR1) is one of the MDR-related protein and is often overexpressed in different cancers. In the present study, we aimed to evaluate the influence of crocin on the expression and function of MDR1 protein in EPG85-257 and EPG85-257RDB gastric cancer cell lines.

Methods: The cytotoxicity effect of crocin was evaluated by the MTT assay. The impacts of crocin on the expression and function of MDR1 were assessed by Real-time RT-PCR and MTT assay, respectively.

Results: The results demonstrated that crocin decreased cell viability in a dose-dependent manner with higher intensity on the EPG85-257 than the EPG85-257RDB cells. Crocin did not make any significant changes in the MDR1 gene expression level in EPG85-257 and EPG85-257RDB cell lines. In contrast, crocin increased doxorubicin cytotoxicity in drug-resistant cells, which might be induced by reduced MDR1 activity.

Conclusion: In summary, although crocin did not affect mRNA expression of MDR1, results of MTT assay suggest that it might inhibit the MDR1 function.
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http://dx.doi.org/10.31557/APJCP.2020.21.7.1959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573416PMC
July 2020

The protective effect of melatonin on benzo(a)pyrene-induced brain injury: role of apoptosis and autophagy pathways.

Naunyn Schmiedebergs Arch Pharmacol 2020 12 7;393(12):2241-2251. Epub 2020 Jul 7.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, P.O. Box 1365-91775, Mashhad, Iran.

Benzo(a)pyrene (BaP), a toxic polycyclic aromatic hydrocarbon, is spread in different ways as an environmental pollutant. It has been proposed that BaP can induce toxicity through oxidative stress and apoptosis in vital organs. The present study evaluated the protective effect of melatonin, a circadian hormone of the pineal gland, on BaP-induced neurotoxicity focused on oxidative stress, autophagy, and apoptosis pathways. Thirty male mice in 5 groups were treated daily for 28 consecutive days: (I) control group (BaP and melatonin solvent), (II) BaP (75 mg/kg, orally), (III) and (IV) BaP + melatonin (10 and 20 mg/kg, i.p.), (V) melatonin (20 mg/kg). The oxidative stress markers were determined in the brain. Western blot was conducted for the level of LC3 II/I and Beclin1, as autophagy markers, caspase3 and Bcl2, as apoptosis proteins, and Sirt1 in the brain. The exposure of mice to BaP caused a marked increase in the malondialdehyde (MDA) level and decrease of glutathione (GSH) content in the brain. Furthermore, the Sirt1 level upregulated as well as LC3 II/I, Beclin1, and cleaved caspase3 proteins, while the level of Bcl2 did not change. Melatonin at 20 mg/kg concurrently with BaP restored the BaP alteration in the brain compared with the BaP group. In conclusion, BaP induced brain toxicity via the induction of oxidative stress, apoptosis, and autophagy, whereas melatonin afforded neuroprotection against BaP due to inhibition of these mechanisms.
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http://dx.doi.org/10.1007/s00210-020-01936-9DOI Listing
December 2020

Tropisetron ameliorates cyclophosphamide-induced hemorrhagic cystitis in rats.

Eur J Pharmacol 2020 Sep 1;883:173310. Epub 2020 Jul 1.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Hemorrhagic cystitis is one of the most important complications of cyclophosphamide, a drug widely used in cancer chemotherapy and bone marrow transplantation. 5-HT antagonists are anti-emetic agents and have been shown to have notable anti-inflammatory and antioxidant properties. This study was designed to investigate the possible protective effects of tropisetron against cyclophosphamide-induced hemorrhagic cystitis in rats. Hemorrhagic cystitis was induced in female rats by cyclophosphamide (270 mg/kg). Tropisetron (2.5, 5 and 7.5 mg/kg), granisetron (2.5 and 5 mg/kg), and ondansetron (5 mg/kg) were injected 15 min before, 4 and 8 h after cyclophosphamide. To evaluate the role of alpha7 nicotinic acetylcholine receptor (α7nAChR), its antagonist, methyllycaconitine (5 mg/kg) was administered 30 min before tropisetron. After 24 h, animals were killed under anesthesia. Macroscopic and histological changes were evaluated. Malondialdehyde (MDA), glutathione (GSH) and Evans blue were measured spectrophotometrically. Furthermore, the protein levels of p38 mitogen-activated protein kinases (P38 MAPK), p-P38, signal transducer and activator of transcription 3 (STAT3), p-STAT3 and Poly (ADP-ribose) polymerase (PARP) were determined using Western blot. Cyclophosphamide administration significantly induced histopathological damages and increased MDA, p-p38/p38, p-STAT3/STAT3, and PARP levels compared with the saline group. Tropisetron treatment diminished histopathological injuries as well as MDA level, and STAT3 activity compared to cyclophosphamide treated rats. Co-administration of methyllycaconitine with tropisetron, partially or completely reversed the protective effects of tropisetron. Our results showed that prophylactic administration of tropisetron markedly ameliorated the cyclophosphamide-induced bladder hemorrhage and inflammation in rats. These effects of tropisetron were α7nAChR dependent.
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http://dx.doi.org/10.1016/j.ejphar.2020.173310DOI Listing
September 2020

The protective effect of modafinil on vincristine-induced peripheral neuropathy in rats: A possible role for TRPA1 receptors.

Basic Clin Pharmacol Toxicol 2020 Nov 3;127(5):405-418. Epub 2020 Jul 3.

Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Vincristine (VCR) induces peripheral neuropathy. We aimed to assess the efficacy of modafinil on VCR-induced neuropathy in rats. Neuropathy was induced by intraperitoneal (i.p.) injections of VCR (0.1 mg/kg). Neuropathic groups received modafinil (5, 25 and 50 mg/kg); gabapentin (20 mg/kg); and a combination of modafinil (5 and 50 mg/kg) and gabapentin (20 mg/kg,). Then, electrophysiological, behavioural, biochemical and pathological evaluations were performed. Latencies of tail-flick and von Frey filament tests, motor nerve conduction velocity (MNCV) and excitation of nerve conduction were decreased. Moreover, the transient receptor potential cation channel ankyrin 1 (TRPA1) level was increased, while TRPV1 and N-Methyl-D-aspartate (NMDA) levels remained unchanged. Tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) levels were markedly elevated. Pre-treatment with modafinil prevented sensorimotor neuropathy by raising latencies, MNCV and excitation, reducing TRPA1, TNF-α and IL-1β levels. Modafinil improved behavioural, electrophysiological and pathological disturbances. The results showed that TRPA1 has a more important role than NMDA and TRPV1, in VCR-induced neuropathic pain. In addition, inflammatory mediators, TNF-α and IL-1β, were involved. Further, the combination of modafinil and gabapentin improved the neuroprotective effect of gabapentin. So, modafinil might be a neuroprotective agent in the prevention of VCR-induced neuropathy.
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http://dx.doi.org/10.1111/bcpt.13454DOI Listing
November 2020

Plausibility of therapeutic effects of Rho kinase inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19).

Pharmacol Res 2020 06 10;156:104808. Epub 2020 Apr 10.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2020.104808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195000PMC
June 2020

A review of the hepatoprotective effects of hesperidin, a flavanon glycoside in citrus fruits, against natural and chemical toxicities.

Daru 2020 Jun 10;28(1):305-317. Epub 2020 Apr 10.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Objectives: Liver is the most important and functional organ in the body to metabolize and detoxify endogenous compounds and xenobiotics. The major goal of the present narrative review is to assess the hepatoprotective properties of hesperidin against a variety of natural and chemical hepatotoxins via different mechanisms.

Evidence Acquisition: Scientific databases such as Scopus, Medline, Web of Science and Google scholar were thoroughly searched, based on different keywords.

Results: A variety of natural hepatotoxins such as lipopolysaccharide, concanavalin A and microcystins, and chemical hepatotoxins such as ethanol, acrylamide and carbon tetrachloride have been shown to damage hepatocytes as well as other liver cells. In addition to hepatocytes, ethanol can also damage liver hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. In this regard, the flavanone hesperidin, occur in the rind of citrus fruits, had been demonstrated to possess widespread pharmacological properties. Hesperidin exerts its hepatoprotective properties via different mechanisms including elevation in the activities of nuclear factor-like 2/antioxidant response element and heme oxygenase 1 as well as the levels of enzymatic and non-enzymatic antioxidants. Furthermore, reduction in the levels of high-mobility group box 1 protein, inhibitor of kappa B protein-alpha, matrix metalloproteinase-9 and C-reactive protein are some other important hesperidin-derived hepatoprotective mechanisms.

Conclusion: Based on several research papers, it could be concluded that hesperidin is able to protect against liver damage from inflammation and/or oxidative stress-mediated natural and chemical toxins.
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http://dx.doi.org/10.1007/s40199-020-00344-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214587PMC
June 2020

Melatonin inhibits Benzo(a)pyrene-Induced apoptosis through activation of the Mir-34a/Sirt1/autophagy pathway in mouse liver.

Ecotoxicol Environ Saf 2020 Jun 2;196:110556. Epub 2020 Apr 2.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Benzo(a)pyrene (BaP), an important environmental pollutant, is produced as the result of incomplete combustion of organic materials in many industries and food cooking process. It has been purposed that BaP induces hepatotoxicity through oxidative stress and apoptosis. Several studies have shown that melatonin can protect against chemical-induced apoptosis through autophagy pathway. In this study, we assessed the modulating effect of melatonin, a well-known antioxidant, on BaP-induced hepatotoxicity through induction of autophagy. Thirty male mice were treated daily for 28 consecutive days. BaP (75 mg/kg; oral gavage) and melatonin (10 and 20 mg/kg, i.p.) were administered to mice. The liver histopathology and the levels of apoptosis and autophagy proteins as well as the expression of miR-34a were determined. The BaP exposure induced severe liver histological injury and markedly enhanced AST, ALT and MDA level. Also, apoptosis proteins and hepatic miR-34a expression increased. However, the level of Sirt1 and autophagy markers such as LC3 II/I ratio and Beclin-1 reduced. The co-administration of melatonin reversed all changes caused by BaP. In summary, melatonin appears to be effective in BaP-induced hepatotoxicity maybe through the miR-34a/Sirt1/autophagy molecular pathway.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110556DOI Listing
June 2020

The role of noncoding RNAs and sirtuins in cancer drug resistance.

Eur J Pharmacol 2020 Jun 31;877:173094. Epub 2020 Mar 31.

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

Cancer is a rising and major health issue around the world. The acquisition of resistance to chemotherapeutic drugs is a great obstacle for the effective treatment of nearly all cancers. Drug resistance is regulated by multiple factors and mechanisms including genetic mutations, abnormal expression of some cellular transporters such as multidrug resistance (MDR) transporters, changes in apoptotic pathways, cancer stem cells, tumor microenvironment, and noncoding RNAs (ncRNAs). Evidence clearly indicates a key role for sirtuins in several characteristics of cancer drug resistance. Recent studies demonstrated the crucial impact of some ncRNAs on sirtuins expression leading to modulation of chemotherapy resistance in cancers. In this review, we will focus on the current findings about the impacts of ncRNAs on the sirtuins pathway and their role in drug resistance of cancer.
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http://dx.doi.org/10.1016/j.ejphar.2020.173094DOI Listing
June 2020

Acute lung injury: The therapeutic role of Rho kinase inhibitors.

Pharmacol Res 2020 05 2;155:104736. Epub 2020 Mar 2.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Acute lung injury (ALI) is a pulmonary illness with high rates of mortality and morbidity. Rho GTPase and its downstream effector, Rho kinase (ROCK), have been demonstrated to be involved in cell adhesion, motility, and contraction which can play a role in ALI. The electronic databases of Google Scholar, Scopus, PubMed, and Web of Science were searched to obtain relevant studies regarding the role of the Rho/ROCK signaling pathway in the pathophysiology of ALI and the effects of specific Rho kinase inhibitors in prevention and treatment of ALI. Upregulation of the RhoA/ROCK signaling pathway causes an increase of inflammation, immune cell migration, apoptosis, coagulation, contraction, and cell adhesion in pulmonary endothelial cells. These effects are involved in endothelium barrier dysfunction and edema, hallmarks of ALI. These effects were significantly reversed by Rho kinase inhibitors. Rho kinase inhibition offers a promising approach in ALI [ARDS] treatment.
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http://dx.doi.org/10.1016/j.phrs.2020.104736DOI Listing
May 2020

Protective effects of naringin against drugs and chemical toxins induced hepatotoxicity: A review.

Phytother Res 2020 Aug 17;34(8):1734-1744. Epub 2020 Feb 17.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

The liver is a vital metabolic organ for drug and xenobiotic metabolism which is influenced by chemical and natural toxins. Liver injury is associated with systemic oxidative stress, which leads to cellular necrosis, fibrosis, tissue lipid peroxidation, and depletion in glutathione levels. Considering the lack of reliable hepato-protective drugs in modern medicine, plant-derived phytoconstituents seem to be a noteworthy option. Naringin is an abundant flavonoid found in citrus fruits with various pharmacological benefits such as antioxidant, anti-inflammatory, and antiapoptotic, activities. In this review, we summarize available data from recent studies about the hepatoprotective effects of naringin against chemical toxicants and discuss the possible mechanisms of actions.
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http://dx.doi.org/10.1002/ptr.6641DOI Listing
August 2020

Occurrence of mycotoxins in rice consumed by Iranians: a probabilistic assessment of risk to health.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 Feb 6;37(2):342-354. Epub 2019 Dec 6.

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

Risks based on cancer and non-cancer endpoints, to Iranians from exposure to several mycotoxins (aflatoxin B1, ochratoxin, deoxynivalenol and T-2 toxin) following consumption of rice were evaluated. Point estimates of hazard were made for each mycotoxin and a hazard index (HI) and probabilistic estimates were based on results of Monte Carlo Simulations (MCS). All known 17 peer-reviewed studies, published in databases included in Science Direct, PubMed, Scopus and Web of Science, as well as grey literature published in Google Scholar from 2008 to 2017 were considered. The 95 and 50 centiles of Hazard Index (HI) in Iranians due to ingestion of rice were estimated to be 2.5 and 0.5, respectively. The 95 and 50 centiles of people with positive surface antigens for hepatitis B (HBsAg+) risk characterisation for AFB in Iranian consumers of rice were 81 and 79.1, respectively. The 95 and 50 centiles for risks of Iranians negative for the surface antigen of hepatitis B HBsAg (HBsAg-) were 4.4 and 2.6, respectively. Based on results of the MCS for risks to cancer effects, the 95 and 50 centiles of margins of exposure (MOE) were 233 and 231, respectively. Therefore, it is recommended to update agricultural approaches and storage methods and implement monitoring and regulations based on risks to health posed by consumption of rice by the Iranian population.
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http://dx.doi.org/10.1080/19440049.2019.1684572DOI Listing
February 2020

Determination of 17β-estradiol in commercial pasteurized and sterilized milk samples in Mashhad, Iran.

J Food Sci Technol 2019 Nov 2;56(11):4795-4798. Epub 2019 Aug 2.

2Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Due to nutritional facts of milk in human life, the quality assessment of dairy products is of the utmost importance. The aim of the current study was to determine the 17β-estradiol level in commercial pasteurized and sterilized milk brands in Mashhad, Iran. In this regard, 160 samples including 80 pasteurized (40 high-fat and 40 low-fat) and 80 sterilized milk (40 high-fat and 40 low-fat) of widely used brands from different supermarkets were collected. The mean level of 17β-estradiol was 8.2 ± 0.59 pg/ml. The mean amount of estradiol was found to be 7.6 ± 0.47, 7.9 ± 0.45, 8.6 ± 0.63, and 8.9 ± 0.54 pg/ml for the low-fat pasteurized, low-fat sterilized, high-fat pasteurized and high-fat sterilized milk, respectively. There was no significant difference between the amount of estradiol in pasteurized and sterilized milk. As expected, the level of estradiol was statistically higher in high fat milks than that of low-fat milks. Considering the levels of 17β-estradiol measured here and the maximum permissible daily level of external estradiol entered to body through edible products recommended by EU and CAC (3.5 µg), at least in the short term, there will be no remarkable impact on the endocrine system. However, judging the long-term effects of using these products is not easy and simple at all, as cancers develop during a long period of time and has a multifactorial etiology.
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http://dx.doi.org/10.1007/s13197-019-03927-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828912PMC
November 2019

The role of MicroRNAs on endoplasmic reticulum stress in myocardial ischemia and cardiac hypertrophy.

Pharmacol Res 2019 12 4;150:104516. Epub 2019 Nov 4.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

The endoplasmic reticulum (ER) is the site of production and folding of secreted, membrane bound and some organelle targeted proteins. Accumulation of misfolded or unfolded proteins in the ER makes cells undergo a stress response known as the unfolded protein response (UPR). UPR is initially protective. However, prolonged and severe ER stress can lead to the induction of apoptosis in stressed cells. Cardiac hypertrophy and myocardial ischemia accounts for substantial morbidity and mortality worldwide. Accumulating evidence suggests that aberrant cardiac cell death caused by ER stress is often associated with structural or functional cardiac abnormalities. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate posttranscriptional gene silencing. The miRNAs play important roles in regulating cardiac physiological and pathological events such as hypertrophy, apoptosis, and heart failure. In this review, we discussed the role of microRNAs on Endoplasmic Reticulum Stress in myocardial ischemia and cardiac hypertrophy to demonstrate the relation between microRNAs and the ER in cardiac cells providing potential new treatment strategies and improvement of survival.
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http://dx.doi.org/10.1016/j.phrs.2019.104516DOI Listing
December 2019

Transient receptor potential ankyrin 1 (TRPA1)-mediated toxicity: friend or foe?

Toxicol Mech Methods 2020 Jan 28;30(1):1-18. Epub 2019 Oct 28.

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

Transient receptor potential (TRP) channels have been widely studied during the last decade. New studies uncover new features and potential applications for these channels. TRPA1 has a huge distribution all over the human body and has been reported to be involved in different physiological and pathological conditions including cold, pain, and damage sensation. Considering its role, many studies have been devoted to evaluating the role of this channel in the initiation and progression of different toxicities. Accordingly, we reviewed the most recent studies and divided the role of TRPA1 in toxicology into the following sections: neurotoxicity, cardiotoxicity, dermatotoxicity, and pulmonary toxicity. Acetaminophen, heavy metals, tear gases, various chemotherapeutic agents, acrolein, wood smoke particulate materials, particulate air pollution materials, diesel exhaust particles, cigarette smoke extracts, air born irritants, sulfur mustard, and plasticizers are selected compounds and materials with toxic effects that are, at least in part, mediated by TRPA1. Considering the high safety of TRPA1 antagonists and their efficacy to resolve selected toxic or adverse drug reactions, the future of these drugs looks promising.
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http://dx.doi.org/10.1080/15376516.2019.1652872DOI Listing
January 2020

The neuroprotective activities of natural products through the Nrf2 upregulation.

Phytother Res 2019 Sep 19;33(9):2256-2273. Epub 2019 Jul 19.

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

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a basic-region leucine zipper transcription factor that regulates the expression of many Phase II detoxifying/antioxidant enzymes. Many natural products act on the Nrf2 pathway and exhibit their preventive and/or therapeutic effects by activating Nrf2 and subsequently antioxidant enzymes. In this article, we reviewed the research literature that described Nrf2 activation as a mechanism for the neuroprotective effect of natural products. Our results showed that the inhibition of Kelch-like ECH-associated protein 1 and the activation of different intracellular kinases that lead to Nrf2 phosphorylation were the main mechanisms of Nrf2 upregulation suggested for these the natural products. Although some natural compounds such as terpenoids and alkaloids were reported to protect the nervous system by Nrf2 activating, flavonoids and phenolic compounds represent the majority of the reported neuroprotective natural substances that activate Nrf2. We also evaluated the physiochemical properties of some of the same substances to predict their oral bioavailability and central nervous system penetration. The results showed that sulforaphane and berberine have good oral bioavailability and would be predicted to cross through blood-brain barrier (BBB) easily, whereas the flavonoids in general would be predicted to be less effective in BBB transition because of their relatively high polar surface area.
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http://dx.doi.org/10.1002/ptr.6427DOI Listing
September 2019

Potential angiotensin converting enzyme (ACE) inhibitors from Iranian traditional plants described by Avicenna's Canon of Medicine.

Avicenna J Phytomed 2019 Jul-Aug;9(4):291-309

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Objective: Hypertension is an important cause of cardiovascular disorders. The angiotensin converting enzyme (ACE) plays an important role in hypertension; therefore, inhibition of ACE in treatment of chronically elevated blood pressure is an important therapeutic approach. In the current review, we have provided information from Persian Traditional Plants described by Avicenna in the Canon of Medicine and a number of more current scientific databases, with a focus on angiotensin converting enzyme inhibitory activity of the following six plants: and .

Materials And Methods: A literature search was conducted and information on different traditional plants used for hypertension was collected from the Canon of Medicine and several other databases including PubMed, Scopus, Google Scholar and Web of Science.

Results: The present article highlights the antihypertensive potential of the above-noted six plants Administered doses, manner of consumption, types of extracts, preparations and derivatives, personal habits, and other geographic and epidemiologic variables have an important role in the potential efficacy of these plants.

Conclusion: Recent studies indicated a significant correlation between the traditional use of Persian plants to reduce blood pressure and angiotensin converting enzyme inhibitory activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612254PMC
July 2019

Curcumin and its analogues protect from endoplasmic reticulum stress: Mechanisms and pathways.

Pharmacol Res 2019 08 29;146:104335. Epub 2019 Jun 29.

Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

The endoplasmic reticulum (ER), a cellular organelle with multiple functions, plays an important role in several biological processes including protein folding, secretion, lipid biosynthesis, calcium homeostasis, and cellular stress. Accumulation of misfolded or unfolded proteins in the ER makes cells undergo a stress response known as the unfolded protein response (UPR). UPR is initially protective. However, prolonged and severe ER stress can lead to autophagy and/or the induction of apoptosis in stressed cell. Many studies have demonstrated that ER stress and the UPR are involved in different diseases such as neurodegenerative diseases, cancer, osteoporosis, diabetes, and inflammatory diseases. Curcumin, a natural polyphenol, has well documented evidence supporting its numerous biological properties including antioxidant, anti-inflammatory, immune-modulatory, anti-microbial, anti-ischemic, anti-angiogenesis, neuroprotective, hepatoprotective, nephroprotective, anti-atherogenic and anti-diabetic activities. In this review, the role of ER stress in several pathological condition and the potential protective effects of curcumin are discussed.
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http://dx.doi.org/10.1016/j.phrs.2019.104335DOI Listing
August 2019

Polycyclic aromatic hydrocarbons in infant formulae, follow-on formulae, and baby foods in Iran: An assessment of risk.

Food Chem Toxicol 2019 Sep 21;131:110640. Epub 2019 Jun 21.

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

Twenty-seven samples of infant formulae and follow-on formulae and fifteen samples of baby food from Iranian markets were analyzed for concentrations of four polycyclic aromatic hydrocarbons (PAH4) determined by use of gas chromatography coupled to mass spectrophotometry. An assessment of risks posed to infants and toddlers was conducted by calculating the margin of exposure and incremental lifetime cancer risk (ILCR) by use of the Monte Carlo Simulation Method. Benzo (a) anthracene, was not detected in any of the samples, while approximately 64.3% samples contained detectable amounts of benzo (a) pyrene, while chrysene was observed in three samples and benzo (b) fluoranthene was detected in one sample. One of the samples contained 1.43 μg PAH4/kg, which was greater than the maximum tolerable limit (MTL; 1 μg/kg) stated in Commission Regulation (EU) 2015/1125. Accordingly, the 95% ILCRs in the infants/toddlers due to ingestion of milk powder and baby foods were determined to be 1.3 × 10 and 7.3 × 10, respectively. Also, the 95th centiles of the MOEs, due to ingesting milk powder or baby foods by infants/toddlers were estimated to be 3.6 × 10 and 7.2 × 10, respectively. In Iran, infants and toddlers are not at serious health risk (MOE ≥ 1 × 10 and ILCR < 1 × 10).
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http://dx.doi.org/10.1016/j.fct.2019.110640DOI Listing
September 2019

Immunoregulatory and anti-inflammatory properties of (Saffron) and its main active constituents: A review.

Iran J Basic Med Sci 2019 Apr;22(4):334-344

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

The medicinal uses of saffron, the dried stigmas of L., have very long history in food coloring agent, and flavoring agent as well as traditional medicine for the treatment of several diseases. is rich in carotenoids that affect immunity. This review summarizes the putative immunoregulatory effects of saffron and its active its derivatives including crocin, crocetin and safranal. In modern studies, its active constituents including protective effects, anti-inflammatory activities and molecular mechanisms of saffron on thimmune system have been demonstrated. Furthermore, the beneficial effects of saffron on inhibition of serum levels nuclear transcription factor κB (NF-κB) p65 unit, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and some interleukin (IL) such as IL-1β, IL-6, IL-12, IL-17A were reported. Furthermore, saffron has been known as the antagonist of NF-κB and the agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). In addition, saffron down-regulates the key pro-inflammatory enzymes such as myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), phospholipase A2, and prostanoids. This review summarizes the protective roles of and its constituents against the pathogenesis of immune diseases and understanding a better management of these problems. Taken together, the main bioactive constituents of saffron may have health-promoting with important benefits in immune-related disorders. Finally, our study indicates that these bioactive constituents can affect both cellular and humoral immunity functions.
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http://dx.doi.org/10.22038/ijbms.2019.34365.8158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535192PMC
April 2019