Publications by authors named "Akram Jamshidzadeh"

63 Publications

Effectiveness of pentoxifylline in severe early-onset fetal growth restriction: A randomized double-blinded clinical trial.

Taiwan J Obstet Gynecol 2022 Jul;61(4):612-619

Hafez Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Objective: Management of pregnancy complicated by severe early-onset fetal growth restriction (FGR) is one of the most challenging obstetrical issues. So far, there has not been a proven option for the treatment or improvement of this condition. Improper immune response during placentation leads to inadequate trophoblast invasion and impaired utero-placental perfusion. Pentoxifylline improves the endothelial function and induces vasodilation by reducing the inflammatory-mediated cytokines. We have evaluated the effect of Pentoxifylline on fetal-placental perfusion, neonatal outcome, and the level of oxidative stress markers before and after the intervention in the setting of severe early-onset FGR.

Materials And Methods: This study is a pilot randomized clinical trial on 40 pregnant women who had developed early-onset growth restricted fetus. Pentoxifylline and placebo were given with a dose of 400 mg per os two times daily until delivery. Serial ultrasound examination regarding fetal weight, amniotic fluid and also utero-placenta-fetal Doppler's were done. For the assessment of serum Antioxidant level, blood sampling was done once at the beginning of the study and again, at least, three weeks after the investigation. After delivery, umbilical-cord blood gas analysis, APGAR score at 1 and 5 min, NICU admission, and neonatal death were recorded and compared between the two groups.

Results: Utero-placenta-fetal Doppler's in the Pentoxifylline group did not significantly change compared to the control group. Fetal weight gain was significantly higher in the Pentoxifylline group before (996.33 ± 317.41) and after (1616.89 ± 527.90) treatment (P = 0.002). Total serum antioxidant capacity significantly increased in the Pentoxifylline group (p < 0.036). Average 5 min Apgar score was significantly higher (P < 0.036) and the percentage of babies admitted to NICU was significantly lower (P < 0.030) in the treated group.

Conclusion: Using Pentoxifylline in pregnancy affected by FGR might show promising effects. In this study, Pentoxifylline improved the neonatal outcome, increased fetal weight gain, and reduced neonatal mortality by decreasing the level of oxidative stress markers and cutting down the inflammatory cascade.
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http://dx.doi.org/10.1016/j.tjog.2021.12.003DOI Listing
July 2022

The crucial role of oxidative stress in non-alcoholic fatty liver disease-induced male reproductive toxicity: the ameliorative effects of Iranian indigenous probiotics.

Naunyn Schmiedebergs Arch Pharmacol 2022 02 7;395(2):247-265. Epub 2022 Jan 7.

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

Several studies have focused on the high potential effects of probiotics on the reproductive system. However, there is a paucity of information regarding the ameliorative intracellular roles of indigenous Iranian yogurt-extracted/cultured probiotics on animals' reproductive health suffering from obesity and/or fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD). For this purpose, simultaneously with the consumption of D-fructose (200 g/1000 mL water, induction of NAFLD model), all pubertal animals were also gavaged every day for 63 consecutive days with extracted probiotics, including 1 × 10 CFU/mL of Lactobacillus acidophilus (LA), Bifidobacterium spp. (BIF), Bacillus coagulans (BC), Lactobacillus rhamnosus (LR), and a mixture form (LA + BIF + BC + LR). At the end of the ninth week, the indices of epididymal sperm, and oxidative stress, as well as histopathological changes, were assessed. The results show that NAFLD could induce robust oxidative stress, highlighted as considerable increments in ROS level, TBARS content, total oxidized protein levels, along with severe decrements in reduced glutathione reservoirs, total antioxidant capacity in the hepatic and testicular tissues, as well as testicular and hepatic histopathological alterations. Moreover, a significant decrease in the percentage of sperm progressive motility, sperm count, and membrane integrity along with an increment in the percentage of sperm abnormality was detected in NAFLD animals. The observed adverse effects were significantly reversed upon probiotics treatment, especially in the group challenged with a mixture of all probiotics. Taken together, these findings indicate that the indigenous yogurt-isolated/cultured probiotics had a high potential antioxidant activity and the ameliorative effect against reprotoxicity and blood biochemical alterations induced by the NAFLD model. Highlights: 1. Reproductive indices could be reversely affected by xenobiotics and diseases. 2. NAFLD and cholestasis considerably affect the reproductive system in both genders. 3. NAFLD induced hepatic and testicular oxidative stress (OS). 4. NAFLD induced histopathological alterations and spermatotoxicity through OS. 5. The adverse effects were significantly reversed upon exposure to probiotics.
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http://dx.doi.org/10.1007/s00210-021-02177-0DOI Listing
February 2022

Influence of cellular redox environment on aryl hydrocarbon receptor ligands induced melanogenesis.

Toxicol In Vitro 2022 Mar 29;79:105282. Epub 2021 Nov 29.

Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Fars, Iran. Electronic address:

Many environmental pollutants, natural compounds, as well as endogenous chemicals exert their biological/toxicological effects by reacting with the aryl hydrocarbon receptor (AhR). Previous evidence shed new light on the role of AhR in skin physiology by regulating melanin production. In this study, we investigated the effect of oxidative imbalance induced by AhR ligands on the melanogenesis process in B16 murine melanoma cells. Exposure to 6-formylindolo[3,2-b] carbazole (FICZ) or benzo-α-pyrene (BαP) led to enhanced expression of CTNNB1, MITF, and TYR genes following increased tyrosinase enzyme activity and melanin content in an AhR-dependent manner. Analysis of the presence of reactive oxygen species (ROS) as well as reduced glutathione (GSH) / oxidized glutathione (GSSG) ratio revealed that treatment with AhR ligands is associated with oxidative stress which can be ameliorated with NAC (N-acetyl cysteine) or diphenyleneiodonium chloride (DPI). On the other hand, NAC and DPI enhanced melanogenesis induced by AhR ligands by reducing the level of ROS. We have shown for the first time that a cellular redox status is a critical event during AhR ligand-induced melanogenesis.
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http://dx.doi.org/10.1016/j.tiv.2021.105282DOI Listing
March 2022

Antidotal effect of dihydroxyacetone against phosphine poisoning in mice.

J Biochem Mol Toxicol 2021 Nov 27;35(11):e22897. Epub 2021 Aug 27.

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

Phosphine (PH ) is widely used as an insecticide and rodenticide. On the contrary, many cases of PH poisoning have been reported worldwide. Unfortunately, there is no specific antidote against PH toxicity. Disruption of mitochondrial function and energy metabolism is a well-known mechanism of PH cytotoxicity. Dihydroxyacetone (DHA) is an adenosine triphosphate supplying agent which significantly improves mitochondrial function. The current study was designed to evaluate DHA's effect on inhalational PH poisoning in an animal model. DHA was injected into BALB/c mice before and/or after the start of the PH inhalation. The cytochrome c oxidase activity was assessed in the animals' brain, heart, and liver exposed to PH (for 15, 30, and 60 min, with and without the antidote). The LC of PH was calculated to be 18.02 (15.42-20.55) ppm over 2 h of exposure. Pretreatment of DHA (1 or 2 g/kg) increased the LC of PH by about 1.6- or 3-fold, respectively. Posttreatment with DHA (2 g/kg) increased the LC of PH by about 1.4-fold. PH inhibited the activity of cytochrome c oxidase in the assessed organs. It was found that DHA treatment restored mitochondrial cytochrome c oxidase activity. These findings suggested that DHA could be an effective antidote for PH poisoning.
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http://dx.doi.org/10.1002/jbt.22897DOI Listing
November 2021

Disturbed mitochondrial redox state and tissue energy charge in cholestasis.

J Biochem Mol Toxicol 2021 Sep 12;35(9):e22846. Epub 2021 Jul 12.

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

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.
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http://dx.doi.org/10.1002/jbt.22846DOI Listing
September 2021

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

Bioorg Chem 2021 09 11;114:104979. Epub 2021 May 11.

Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, 71345 Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348 Shiraz, Iran. Electronic address:

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC value of 0.11 μM and 0.17 μM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC value of 9.28 μM for l-tyrosine and 9.30 μM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC value of 68.43 μM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.
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http://dx.doi.org/10.1016/j.bioorg.2021.104979DOI Listing
September 2021

The Role of Mitochondrial Impairment and Oxidative Stress in the Pathogenesis of Lithium-Induced Reproductive Toxicity in Male Mice.

Front Vet Sci 2021 24;8:603262. Epub 2021 Mar 24.

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

Lithium (Li) is prescribed against a wide range of neurological disorders. Besides its excellent therapeutic properties, there are several adverse effects associated with Li. The impact of Li on renal function and diabetes insipidus is the most common adverse effect of this drug. On the other hand, infertility and decreased libido is another complication associated with Li. It has been found that sperm indices of functionality, as well as libido, is significantly reduced in Li-treated men. These adverse effects might lead to drug incompliance and the cessation of drug therapy. Hence, the main aims of the current study were to illustrate the mechanisms of adverse effects of Li on the testis tissue, spermatogenesis process, and hormonal changes in two experimental models. In the experiments, Leydig cells (LCs) were isolated from healthy mice, cultured, and exposed to increasing concentrations of Li (0, 10, 50, and 100 ppm). In the section of the current study, mice were treated with Li (0, 10, 50, and 100 ppm, in drinking water) for five consecutive weeks. Testis and sperm samples were collected and assessed. A significant sign of cytotoxicity (LDH release and MTT assay), along with disrupted testosterone biosynthesis, impaired mitochondrial indices (ATP level and mitochondrial depolarization), and increased biomarkers of oxidative stress were detected in LCs exposed to Li. On the other hand, a significant increase in serum and testis Li levels were detected in drug-treated mice. Moreover, ROS formation, LPO, protein carbonylation, and increased oxidized glutathione (GSSG) were detected in both testis tissue and sperm specimens of Li-treated mice. Several sperm anomalies were also detected in Li-treated animals. On the other hand, sperm mitochondrial indices (mitochondrial dehydrogenases activity and ATP levels) were significantly decreased in drug-treated groups where mitochondrial depolarization was increased dose-dependently. Altogether, these data mention oxidative stress and mitochondrial impairment as pivotal mechanisms involved in Li-induced reproductive toxicity. Therefore, based on our previous publications in this area, therapeutic options, including compounds with high antioxidant properties that target these points might find a clinical value in ameliorating Li-induced adverse effects on the male reproductive system.
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http://dx.doi.org/10.3389/fvets.2021.603262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025583PMC
March 2021

Apoptosis-inducing factor plays a role in the pathogenesis of hepatic and renal injury during cholestasis.

Naunyn Schmiedebergs Arch Pharmacol 2021 06 1;394(6):1191-1203. Epub 2021 Feb 1.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, P.O. Box 158371345, Roknabad, Karafarin St, Shiraz, Fars, Iran.

Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.
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http://dx.doi.org/10.1007/s00210-020-02041-7DOI Listing
June 2021

α-Melanocyte-Stimulating Hormone Triggers Melanogenesis Via Activation of the Aryl Hydrocarbon Receptor Pathway in B16F10 Mouse Melanoma Cells.

Int J Toxicol 2021 Mar-Apr;40(2):153-160. Epub 2021 Jan 13.

Department of Pharmacology and Toxicology, School of Pharmacy, 48435Shiraz University of Medical Sciences, Shiraz, Fars, Iran.

Melanin is a group of natural pigments that determines the human skin color and provides fundamental protection against the harmful impacts of physical and chemical stimuli. The aim of this study was to establish the regulatory role of aryl hydrocarbon receptor (AhR) in α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis. In the present study, following knockdown of AhR, murine B16F10 cells were treated with α-MSH (200 nM) and tyrosinase activities, cellular melanin content, mRNA levels of several important genes involved in melanogenesis including , , , and microphthalmia-associated transcription factor () were measured as endpoints. Exposure to α-MSH led to elevated expression of , , , and in accordance with increased tyrosinase enzyme activity as well as a significant rise in the total melanin content. Our results suggest that AhR plays a regulatory role in α-MSH-stimulated melanogenesis.
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http://dx.doi.org/10.1177/1091581820987548DOI Listing
January 2022

Spermatotoxic Effects of Single-Walled and Multi-Walled Carbon Nanotubes on Male Mice.

Front Vet Sci 2020 17;7:591558. Epub 2020 Dec 17.

College of Life Sciences, Shanxi Agricultural University, Taigu, China.

Carbon-based nanomaterials possess a remarkably high potential for biomedical applications due to their physical properties; however, their detrimental effects on reproduction are also concerned. Several reports indicate the toxicity of carbon nanotubes (CNT); nevertheless, their impact on intracellular organelles in the male reproductive organs has not been fully elucidated. Herein, we report on the reprotoxicity of single-walled (SWCNT) and multi-walled carbon nanotubes (MWCN) on several intracellular events and histological criteria in pubertal male BALB/c mice orally treated with 0, 10, and 50 mg/kg/day doses for 5 weeks. Biomarkers of oxidative stress and mitochondrial functionality, histopathological alterations, and epididymal sperm characteristics were determined. Oral administration of CNTs at 10 and 50 mg/kg evoked a significant decrement in weight coefficient, sperm viability and motility, hypo-osmotic swelling (HOS) test, sperm count, mitochondrial dehydrogenase activity, ATP content, total antioxidant capacity, and GSH/GSSH ratio in the testis and epididymal spermatozoa. On the other hand, percent abnormal sperm, testicular and sperm TBARS contents, protein carbonylation, ROS formation, oxidized glutathione level, and sperm mitochondrial depolarization were considerably increased. Significant histopathological and stereological alterations in the testis occurred in the groups challenged with CNTs. The current findings indicated that oxidative stress and mitochondrial impairment might substantially impact CNTs-induced reproductive system injury and sperm toxicity. The results can also be used to establish environmental standards for CNT consumption by mammals, produce new chemicals for controlling the rodent populations, and develop therapeutic approaches against CNTs-associated reproductive anomalies in the males exposed daily to these nanoparticles.
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http://dx.doi.org/10.3389/fvets.2020.591558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775657PMC
December 2020

In vitro and in vivo Evaluation of Succinic Acid-Substituted Mesoporous Silica for Ammonia Adsorption: Potential Application in the Management of Hepatic Encephalopathy.

Int J Nanomedicine 2020 14;15:10085-10098. Epub 2020 Dec 14.

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

Purpose: Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH ) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons).

Methods: First, MS particles containing amine groups (MS-NH) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH and MS-SA particles in adsorption of NH was investigated in vitro and in vivo. MS-NH and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH , and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model.

Results: It was figured out that both MS-NH and MS-SA significantly scavenged NH in the in vitro model. However, the NH scavenging capability of MS-SA was more significant. Administration of MS-NH and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH in the HE animal model.

Conclusion: Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.
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http://dx.doi.org/10.2147/IJN.S271883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754271PMC
January 2021

Protective Role of Probiotic Supplements in Hepatic Steatosis: A Rat Model Study.

Biomed Res Int 2020 6;2020:5487659. Epub 2020 Nov 6.

Biotechnology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Treating nonalcoholic fatty liver disease (NAFLD) is considered one of the public health priorities in the past decade. So far, probiotics have represented promising results in controlling the signs and symptoms of NAFLD. However, attempts to find the ideal probiotic strain are still ongoing. The present study is designed to find the best strain amongst suitable probiotic strains according to their ability to ameliorate histopathological and oxidative stress biomarkers in hepatic steatosis-induced rats.

Methods: Initially, four probiotics species, including () , , , and , were cultured and prepared as a lyophilized powder for animals. The experiment lasted for fifty days. Initially, hepatic steatosis was induced by excessive ingestion of D-fructose in rats for eight weeks, followed by eight weeks of administering probiotics and D-fructose concurrently. Forty-two six-week-old male rats were alienated to different groups and were supplemented with different probiotics (1∗10 CFU in 500 mL drinking water). After eight weeks, blood and liver samples were taken for further evaluation, and plasma and oxidative stress markers corresponding to liver injuries were examined.

Results: Administration of probiotics over eight weeks reversed hepatic and blood triglyceride concentration and blood glucose levels. Also, probiotics significantly suppressed markers of oxidative stress in the liver tissue.

Conclusions: Although some of the single probiotic formulations were able to mitigate oxidative stress markers, mixtures of probiotics significantly ameliorated more symptoms in the NAFLD animals. This enhanced effect might be due to probiotics' cumulative potential to maintain oxidative stress and deliver improved lipid profiles, liver function markers, and inflammatory markers.
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http://dx.doi.org/10.1155/2020/5487659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704153PMC
June 2021

The Potential Neuroprotective Role of Citicoline in Hepatic Encephalopathy.

J Exp Pharmacol 2020 16;12:517-527. Epub 2020 Nov 16.

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

Purpose: Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE.

Materials And Methods: Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue.

Results: The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal's locomotor activity and improved brain tissue markers of oxidative stress.

Conclusion: These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE.
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http://dx.doi.org/10.2147/JEP.S261986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678475PMC
November 2020

Effect of flaxseed oil on biochemical parameters, hormonal indexes and stereological changes in ovariectomized rats.

Vet Med Sci 2021 03 25;7(2):521-533. Epub 2020 Oct 25.

Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran.

The ovariectomized rat is a widely used preclinical model for studying postmenopausal and its complications. In this study, the therapeutic effect of flaxseed oil on the ovariectomized adult rats was investigated. Our results showed that biochemical parameters including calcium, oestrogen and progesterone levels increase 8 weeks after ovariectomy in rats. Also, the amount of alkaline phosphatase decreased significantly after 8 weeks compared with the OVX rat. The healing potential of flaxseed oil was proven by successfully recovering the affected tissue and preventing the unpleasant symptoms of ovariectomized rats. The biological effects of flaxseed oil may be due to high amounts of fatty acids, phytoestrogens and an array of antioxidants. The results suggest that flaxseed oil can mimic the action of oestrogen and can be a potential treatment for hormone replacement therapy (HRT).
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http://dx.doi.org/10.1002/vms3.372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025639PMC
March 2021

The mechanisms of arsenic-induced ovotoxicity, ultrastructural alterations, and autophagic related paths: An enduring developmental study in folliculogenesis of mice.

Ecotoxicol Environ Saf 2020 Nov 8;204:110973. Epub 2020 Aug 8.

Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi, 030801, PR China.

Arsenic (As) exerts a wide range of adverse effects on biological systems, including the reproductive organs in males and females. However, the mechanisms of As-induced reproductive toxicity are mostly obscure. Recently, we showed that autophagy is an essential route for AsO-induced reprotoxicity through the hypothalamic-pituitary-gonadal-sperm (HPG-S) axis in pubertal and matured F1-male mice. However, the role of autophagy in AsO- induced ovarian toxicity is mostly unknown. Hence, this study aimed to elucidate the role of oxidative stress, mitochondrial impairment, and autophagic processes in the ovary of As-exposed female mice. For this purpose, mature female mice were challenged with 0, low (0.2), medium (2), and high (20 ppm) AsO from 35-days before mating till weaning their pups, and the F1- females from weaning until maturity. Then, all the mice were sacrificed, and oxidative stress parameters, mitochondrial indices, electron microscopic evaluation of the ovaries, expression of autophagic-related genes and proteins, and autophagosome formation were assessed. It was shown that medium and high AsO doses were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in the ovary of F1-generation. A dose-dependent increment in the gene expression of PDK, PI3K, TSC2, AMPK, ULK1, ATG13, Beclin1, ATG12, ATG5, LC3, P62, ATG3, ATG7, and p62, as well as protein expression of Beclin1, and LC3- I, II, was evident in the ovaries of the As-treated animals. Moreover, a dose-dependent decrease in the expression of mTOR and Bcl-2 genes, and mTOR protein was detected with increasing doses of As, suggesting that As treatment-induced autophagy. Along with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles, transmission electron microscopy also confirmed more autophagosomes and injured mitochondria in medium and high AsO doses groups. AsO also negatively affected the mean body weight, litter size, organ coefficient, and stereological indices in female mice. Finally, in physiological conditions, arsenic trioxide (AsO) leads to an increased level of autophagy in the oocyte when many oocytes were being lost. These findings indicated that an imbalance in the oxidant-antioxidant system, mitochondrial impairment, and the autophagic process, through inhibition of mTOR, dependent and independent pathways, and Bcl-2, as well as activation of AMPK/PI3K/Beclin1/LC3 routes, could play a pivotal role in As-induced reproductive toxicity through ovarian dysfunction in females.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110973DOI Listing
November 2020

Oral administration of thiol-reducing agents mitigates gut barrier disintegrity and bacterial lipopolysaccharide translocation in a rat model of biliary obstruction.

Curr Res Pharmacol Drug Discov 2020 Apr 16;1:10-18. Epub 2020 Jun 16.

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

It has been well documented that cirrhosis is associated with the intestinal injury. Intestinal injury in cirrhosis could lead to bacterial lipopolysaccharide (LPS) translocation to the systemic circulation. It has been found that high plasma LPS is connected with higher morbidity and mortality in cirrhotic patients. Therefore, finding therapeutic approaches to mitigate this complication has great clinical value. Several investigations mentioned the pivotal role of oxidative stress in cirrhosis-associated intestinal injury. It has been well-known that the redox balance of enterocytes is disturbed in cirrhotic patients. In the current study, the effects of thiol-reducing agents N-acetylcysteine (NAC) (0.5 and 1% w: v) and dithiothreitol (DTT) (0.5 and 1% w: v) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation is investigated in a rat model of cirrhosis. Bile duct ligation (BDL) surgery was used to induce cirrhosis in male Sprague-Dawley rats. Animals (n ​= ​48; 8 animals/group) were supplemented with NAC and DTT for 28 consecutive days. Significant changes in ileum and colon markers of oxidative stress were evident in BDL rats as judged by increased reactive oxygen species (ROS), lipid peroxidation, oxidized glutathione (GSSG), and protein carbonylation along with decreased antioxidant capacity and glutathione (GSH) content. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. Moreover, serum LPS level was also significantly higher in BDL rats. NAC and DTT administration (0.5 and 1% w: v, gavage) significantly decreased biomarkers of oxidative stress, mitigated intestinal histopathological alterations, and restored tissue antioxidant capacity. Moreover, NAC and/or DTT significantly suppressed LPS translocation to the systemic circulation. The protective effects of thiol reducing agents in the intestine of cirrhotic rats could be attributed to the effect of these chemicals on the cellular redox environment and biomarkers of oxidative stress.
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http://dx.doi.org/10.1016/j.crphar.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663936PMC
April 2020

N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats.

Stress 2021 03 22;24(2):213-228. Epub 2020 Jun 22.

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

Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.
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http://dx.doi.org/10.1080/10253890.2020.1777970DOI Listing
March 2021

Cholestasis-associated reproductive toxicity in male and female rats: The fundamental role of mitochondrial impairment and oxidative stress.

Toxicol Lett 2019 Nov 11;316:60-72. Epub 2019 Sep 11.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Cholestasis is a significant decrease in bile flow. The liver is the primary organ affected by cholestasis. Chronic cholestasis could entail to tissue fibrotic changes and liver cirrhosis. Other organs, including heart, kidneys, nervous system, skeletal muscles, as well as the reproductive system, might also be affected during cholestasis. Although the cholestasis-associated pathological and biochemical alterations in organs such as liver have been widely investigated, there is little information about complications such as cholestasis-induced reproductive toxicity. The current study aimed to evaluate the pathologic effects of cholestasis on reproductive organs in both male and female animals. Rats underwent bile duct ligation (BDL) surgery. Markers of reproductive toxicity, including serum hormonal changes, tissue histopathological alterations, biomarkers of oxidative stress, and markers of mitochondrial impairment, were evaluated. Increased serum markers of liver injury and elevated level of cytotoxic molecules such as bile acids and bilirubin were evident in BDL animals. On the other hand, the serum level of hormones such as testosterone was suppressed in BDL rats. Significant histopathological alterations were also evident in the testis and ovary of BDL animals. A significant increase in oxidative stress markers, including ROS formation, lipid peroxidation, protein carbonylation, and depleted glutathione and antioxidant reservoirs were also detected in BDL rats. Moreover, mitochondrial depolarization decreased dehydrogenases activity, and depleted ATP content was detected in sperm isolated from the BDL group. These data indicate that cholestasis-associated reproductive toxicity in male and female rats is restrictedly coupled with severe oxidative stress and mitochondrial impairment.
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http://dx.doi.org/10.1016/j.toxlet.2019.09.009DOI Listing
November 2019

Ammonia-induced mitochondrial impairment is intensified by manganese co-exposure: relevance to the management of subclinical hepatic encephalopathy and cirrhosis-associated brain injury.

Clin Exp Hepatol 2019 May 13;5(2):109-117. Epub 2019 May 13.

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

Aim Of The Study: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome ensuing from liver failure. The liver is the major site of ammonia detoxification in the human body. Hence, acute and chronic liver dysfunction can lead to hyperammonemia. Manganese (Mn) is a trace element incorporated in several physiological processes in the human body. Mn is excreted through bile. It has been found that cirrhosis is associated with hyperammonemia as well as body Mn accumulation. The brain is the primary target organ for both ammonia and Mn toxicity. On the other hand, brain mitochondria impairment is involved in the mechanism of Mn and ammonia neurotoxicity.

Material And Methods: The current study was designed to evaluate the effect of Mn and ammonia and their combination on mitochondrial indices of functionality in isolated brain mitochondria. Isolated brain mitochondria were exposed to increasing concentrations of ammonia and Mn alone and/or in combination and several mitochondrial indices were assessed.

Results: The collapse of mitochondrial membrane potential, increased mitochondrial permeabilization, reactive oxygen species formation, and a significant decrease in mitochondrial dehydrogenase activity and ATP content were evident in Mn-exposed (0.005-1 mM) brain mitochondria. On the other hand, ammonia (0.005-0.5 mM) caused no significant changes in brain mitochondrial function. It was found that co-exposure of the brain mitochondria to Mn and ammonia causes more evident mitochondrial impairment in comparison with Mn and/or ammonia alone.

Conclusions: These data indicate additive toxicity of ammonia and Mn in isolated brain mitochondria exposed to these neurotoxins.
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http://dx.doi.org/10.5114/ceh.2019.85071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728860PMC
May 2019

Contrasting Role of Concentration in Rivaroxaban Induced Toxicity and Oxidative Stress in Isolated Kidney Mitochondria.

Drug Res (Stuttg) 2019 Oct 9;69(10):523-527. Epub 2019 Sep 9.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Rivaroxaban as a small molecule is able to directly and reversibly inhibit the factor Xa. This study was designed to figure out the evaluation effect of rivaroxaban on mitochondria obtained from rat kidneys. We isolated mitochondria from rat kidneys using gradient centrifugation. Then, the toxicity parameters including succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse and cytochrome c release were measured in kidneys mitochondria following the exposure to rivaroxaban. The results showed that rivaroxaban (1.4 and 2.8 mM) raised the reactive oxygen species (ROS) generation, swelling in the mitochondria, collapse in the mitochondrial membrane potential (MMP) and cytochrome c release in the mitochondria isolated from kidneys. While, rivaroxaban at a higher concentration of 5.6 mM showed the opposite effect compared to other lower concentrations. The results indicate that rivaroxaban may have antioxidant effects at high concentrations. The results suggest that rivaroxaban (5.6 mM) has protective effects against oxidative stress and mitochondrial toxicity.
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http://dx.doi.org/10.1055/a-1001-2154DOI Listing
October 2019

The Footprints of Oxidative Stress and Mitochondrial Impairment in Arsenic Trioxide-Induced Testosterone Release Suppression in Pubertal and Mature F1-Male Balb/c Mice via the Downregulation of 3β-HSD, 17β-HSD, and CYP11a Expression.

Biol Trace Elem Res 2020 May 16;195(1):125-134. Epub 2019 Jul 16.

Department of Embryo Technology Research Institute, Shahr-e Kord University, Shahr-e Kord, Iran.

Exposure to arsenic (AS) causes abnormalities in the reproductive system; however, the precise cellular pathway of AS toxicity on steroidogenesis in developing F1-male mice has not been clearly defined. In this study, paternal mice were treated with arsenic trioxide (AsO; 0, 0.2, 2, and 20 ppm in drinking water) from 5 weeks before mating until weaning and continued for male offspring from weaning until maturity (in vivo). Additionally, Leydig cells (LCs) were isolated from the testes of sacrificed F1-intact mature male mice and incubated with AsO (0, 1, 10, and 100 μM) for 48 h (in vitro). Biomarkers of mitochondrial impairment, oxidative stress, and several steroidogenic genes, including the steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleaving enzyme (P450scc; Cyp11a), 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β-hydroxysteroid dehydrogenase (17β-HSD), were evaluated. High doses of AsO interrupted testosterone (T) biosynthesis and T-related gene expression in these experimental models. Altogether, overconsumption of AsO can cause testicular and LC toxicity through mitochondrial-related pathways and oxidative stress indices as well as downregulation of androgenic-related genes in mice and isolated LCs. These results could lead to the development of preventive/therapeutic procedures against AsO-induced reproductive toxicity. Graphical Abstract Mohammad Mehdi Ommati and Reza Heidari contributed equally to this study.
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http://dx.doi.org/10.1007/s12011-019-01815-2DOI Listing
May 2020

Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats.

J Basic Clin Physiol Pharmacol 2018 Dec;30(1):91-101

Iran Food and Drug Administration (IFDA), Iran Ministry of Health, Fakhr-e Razi Street, Tehran Province, District 11, Tehran 1314715311, Iran, Phone: +98-216-1927429, Fax: +98-216-6427965.

Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.
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http://dx.doi.org/10.1515/jbcpp-2017-0221DOI Listing
December 2018

Taurine prevents mitochondrial membrane permeabilization and swelling upon interaction with manganese: Implication in the treatment of cirrhosis-associated central nervous system complications.

J Biochem Mol Toxicol 2018 Nov 28;32(11):e22216. Epub 2018 Aug 28.

Pharmaceutical Sciences Research Center, Department of Toxicology, Shiraz University of Medical Sciences, Shiraz, Fars, Iran.

Brain tissue manganese (Mn) accumulation is a cirrhosis-associated complication. Cellular mitochondria are among the potential targets for Mn-induced cytotoxicity. Taurine is one of the most abundant amino acids with high concentrations in human brain tissue. Several pharmacological properties including regulation of mitochondrial function are attributed to taurine. The current investigation was designed to evaluate the effect of taurine on Mn-induced mitochondrial impairment in isolated mice brain mitochondria. The brain mitochondria were exposed to increasing concentrations of Mn (0.1-10 mM). Taurine (0.1, 1, and 10 mM) was added as the protective agent. The severe collapse of mitochondrial membrane potential, decreased mitochondrial dehydrogenases activity, mitochondrial swelling, and depleted mitochondrial adenosine triphosphate (ATP) were evident in Mn-exposed mitochondria. It was found that taurine administration preserved mitochondrial ATP, prevented mitochondrial depolarization and swelling, and increased mitochondrial dehydrogenases activity. These data suggest mitochondrial protection as an underlying mechanism for the protective effects of taurine against Mn toxicity.
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http://dx.doi.org/10.1002/jbt.22216DOI Listing
November 2018

Biocompatibility of an Ionic Liquid-protected Silver Nanoparticle Solution as Root Canal Irrigant.

Iran Endod J 2018 ;13(3):293-298

Pathologist, Shiraz, Iran.

Introduction: The aim of this study was to assess the biocompatibility of positively charged imidazolium-based ionic liquid-protected nanosilver solution (AgNPs) root canal irrigant.

Methods And Materials: Eighteen male 4- to 5-month old Sprague-Dawley rats, weighing 200-300 gr were selected and randomly divided into 5 groups: Normal saline 0.9% (group 1), 5.25% NaOCl (group 2), 2.5% NaOCl (group 3), 2.0% chlorhexidine solution (group 4) and AgNPs at 5.7×10 M/L (group 5) were randomly injected in 5 sites of dorsal skin of each rat. Tissue inflammatory reaction were evaluated histopathologically after 2 h, 48 h and 14 days. Statistical analysis was done with SPSS version 21 and the Kruskal-Wallis H and Dunn tests were used to find statistically significant differences. The level of significance was set at 0.05.

Result: All solutions irritated the highest tissue response after 48 h. Group 1 showed lower inflammatory response compared to groups 2 and 4 (<0.05). Group 2 displayed higher inflammatory response in comparison with group 5 (<0.05). Tissue reaction to group 5 was not more severe than the reaction to group 3 or 4. It also would irritate less inflammatory response compared to group 2 (<0.05).

Conclusion: Comparing with NaOCl and CHX, it is possible to label AgNPs as a tissue compatible agent.
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http://dx.doi.org/10.22037/iej.v13i3.17386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064014PMC
January 2018

Taurine supplementation abates cirrhosis-associated locomotor dysfunction.

Clin Exp Hepatol 2018 Jun 25;4(2):72-82. Epub 2018 May 25.

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

Aim Of The Study: Hepatic encephalopathy and hyperammonemia is a clinical complication associated with liver cirrhosis. The brain is the target organ for ammonia toxicity. Ammonia-induced brain injury is related to oxidative stress, locomotor activity dysfunction, and cognitive deficit, which could lead to permanent brain injury, coma and death if not appropriately managed. There is no promising pharmacological intervention against cirrhosis-associated brain injury. Taurine (TAU) is one of the most abundant amino acids in the human body. Several physiological and pharmacological roles have been attributed to TAU. TAU may act as an antioxidant and is an excellent neuroprotective agent. This study aimed to evaluate the effect of TAU supplementation on cirrhosis-associated locomotor activity disturbances and oxidative stress in the brain.

Material And Methods: Rats underwent bile duct ligation (BDL) surgery, and plasma and brain ammonia level, plasma biochemical parameters, and rats' locomotor function were monitored. Furthermore, brain tissue markers of oxidative stress were assessed.

Results: It was found that plasma and brain ammonia was increased, and markers of liver injury were significantly elevated in the cirrhotic group. Impaired locomotor activity was also evident in BDL rats. Moreover, an increase in brain tissue markers of oxidative stress was detected in the brain of cirrhotic animals. It was found that TAU supplementation (50, 100, and 200 mg/kg, gavage) alleviated brain tissue markers of oxidative stress and improved animals' locomotor activity.

Conclusions: These data suggest that TAU is a potential protective agent against cirrhosis-associated brain injury.
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http://dx.doi.org/10.5114/ceh.2018.75956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000746PMC
June 2018

Carnosine and Histidine Supplementation Blunt Lead-Induced Reproductive Toxicity through Antioxidative and Mitochondria-Dependent Mechanisms.

Biol Trace Elem Res 2019 Jan 16;187(1):151-162. Epub 2018 May 16.

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Lead (Pb)-induced reproductive toxicity is a well-characterized adverse effect associated with this heavy metal. It has been found that Pb exposure is associated with altered spermatogenesis, increased testicular degeneration, and pathological sperm alterations. On the other hand, it has been reported that Pb-induced reproductive toxicity is associated with increased reactive oxygen species (ROS) formation and diminished antioxidant capacity in the reproductive system. Hence, administration of antioxidants as protective agents might be of value against Pb-induced reproductive toxicity. This study was designed to investigate whether carnosine (CAR) and histidine (HIS) supplementation would mitigate the Pb-induced reproductive toxicity in male rats. Animals received Pb (20 mg/kg/day, oral, 14 consecutive days) alone or in combination with CAR (250 and 500 mg/kg/day, oral, 14 consecutive days) or HIS (250 and 500 mg/kg/day, oral, 14 consecutive days). Pb toxicity was evident in the reproductive system by a significant increase in tissue markers of oxidative stress along with severe histopathological changes, seminal tubule damage, tubular desquamation, low spermatogenesis index, poor sperm parameters, and impaired sperm mitochondrial function. It was found that CAR and HIS supplementation blunted the Pb-induced oxidative stress and mitochondrial dysfunction in the rat reproductive system. Thereby, antioxidative and mitochondria-protective properties serve as primary mechanisms for CAR and HIS against Pb-induced reproductive toxicity.
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http://dx.doi.org/10.1007/s12011-018-1358-2DOI Listing
January 2019

Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury.

Biomed Pharmacother 2018 Jul 7;103:75-86. Epub 2018 Apr 7.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Betaine is a derivative of the amino acid glycine widely investigated for its hepatoprotective properties against alcoholism. The protective properties of betaine in different other experimental models also have been documented. On the other hand, the exact cellular mechanism of cytoprotection provided by betaine is obscure. The current study was designed to evaluate the hepatoprotective effects of betaine and its potential mechanisms of hepatoprotection in two animal models of acute and chronic liver injury. Bile duct ligation (BDL) was used as a model of chronic liver injury and thioacetamide (TAA)-induced hepatotoxicity was applied as the acute liver injury model. Severe increase in serum markers of liver tissue damage along with significant liver tissue histopathological changes were evident in both acute and chronic models of hepatic injury. It was also found that tissue markers of oxidative stress were significantly increased in BDL and TAA-treated animals. Moreover, liver mitochondrial indices of functionality were deteriorated in both investigated models. Betaine supplementation (10 and 50 mg/kg, i.p) ameliorated hepatic injury as judged by decreased liver tissue histopathological alterations, a significant decrease in tissue markers of oxidative stress, and mitigation of serum biomarkers of hepatotoxicity. On the other hand, betaine (10 and 50 mg/kg, i.p) protected hepatocytes mitochondria in both chronic and acute models of hepatotoxicity. These data indicate that the antioxidative and mitochondria regulating properties of betaine could play a primary role in its mechanisms of hepatoprotection.
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http://dx.doi.org/10.1016/j.biopha.2018.04.010DOI Listing
July 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

Dual effects of sulfasalazine on rat sperm characteristics, spermatogenesis, and steroidogenesis in two experimental models.

Toxicol Lett 2018 Mar 22;284:46-55. Epub 2017 Dec 22.

Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz Iran.

There are reports of sulfasalazine (Salazosulfapyridine; SASP)-induced reproductive toxicity, but there it is not known whether the SASP molecule or its intestinal metabolites are responsible for this effect. Rats received SASP (150, 300, and 600mg/kg) for 60 consecutive days (in vivo). Additionally, epididymal sperm was isolated and incubated with SASP (10μM-1600μM) (in vitro). Markers of oxidative stress, mitochondrial function, and sperm functionality, along with testis histopathology as well as several steroidogenic genes and proteins, including steroidogenic acute regulatory (StAR) protein, cytochrome P450 side chain cleavage enzyme (P450scc; Cyp11a), 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) were measured. SASP toxicity was evident as shown by severe testicular histopathological alterations, along with poor sperm parameters and increased markers of oxidative stress. Plasma testosterone level and steroidogenesis-related gene and protein (StAR, 3-beta-HSD, 17-beta-HSD) expressions, as well as mitochondrial membrane potential, were significantly decreased at high doses of SASP (in vivo). Interestingly, in vitro treatment of sperm with SASP not only caused no significant detrimental effect on rat sperm but also increased parameters of sperm functionality and decreased markers of oxidative stress. SASP had paradoxical actions on the rat sperm in these experimental models. The findings might be useful in understanding the mechanism(s) of SASP-induced reproductive toxicity. The present findings have opened a new molecular window into the relationship between disrupted steroidogenesis and mammalian reproduction indices and also are vital regarding clinical administration of SASP and human reproductive health.
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http://dx.doi.org/10.1016/j.toxlet.2017.11.034DOI Listing
March 2018

Sub-chronic boldine treatment exerts anticonvulsant effects in mice.

Neurol Res 2018 Feb 20;40(2):146-152. Epub 2017 Nov 20.

a Department of Pharmacology, School of Medicine , Shiraz University of Medical Sciences , Shiraz , Iran.

Objectives: Boldine is an aporphine alkaloid which is best known for its antioxidant, anti-inflammatory and cytoprotective characteristics. It seems that all these activities are related to boldine ability to scavenge reactive free radicals. As indicated by several pieces of evidence, free radicals generation are involved in initiation and propagation of epilepsy.

Methods: In this study, we investigated the sub-chronic effects of boldine on intraperitoneal and intravenous pentylenetetrazole (PTZ) models and electroshock-induced seizure in mice. Mice in treatment groups received different doses of boldine (once in a day for 8 days, ip.) and control group received solvent. We also evaluated the role of antioxidant activity of boldine as a part of its anti-seizure activity.

Results: The results demonstrated that sub-chronic administration of boldine increased time latencies to the onset of myoclonic and clonic seizure induced by intraperitoneal PTZ model and increased clonic seizure threshold in intravenous PTZ model. It also decreased tonic hind limb extension duration in the electroshock-induced seizure model. Co-administration of boldine with a non-effective dose of vitamin C induced the anticonvulsant activity of vitamin C. Superoxide dismutase (SOD) activity in the brain tissue of animals was increased following sub-chronic administration of boldine which all indicated antioxidant activity of boldine may be a part of its anticonvulsant activity.

Discussion: The anticonvulsant effects of boldine in three different animal models of epilepsy have been indicated. We have also shown that the antioxidant role of boldine might be a part of its anticonvulsant effect.
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http://dx.doi.org/10.1080/01616412.2017.1402500DOI Listing
February 2018
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