Afshin Mohammadi Bardbori | Shiraz University Of Medical Sciences (original) (raw)
Papers by Afshin Mohammadi Bardbori
Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscri... more Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscript so called " the Edwin Smith Papyrus " dating back to the Pyramid Age. However, apart from all respective documents remained from the antiquity, concepts and standpoints of Avicenna (Ibn Sina; a famous Persian physician) in regard of the cancer are interesting. A case of breast cancer and metastatic condition has been reported by Avicenna in the Canon of Medicine. This report can be considered as a very early report of metastatic or stage IV breast cancer. He underlined that cancer should be diagnosed and cured in the early stages. With views of Avicenna, cancer is an atrabilious (black bile) swelling (tumor) which sometimes may be accompanied by pain or swelling. He also mentioned that some vessels may be appeared around the cancerous part. Avicenna extrapolated the cancer with legs of cancer crab which can to grow around the other organs and tissues.
Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscri... more Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscript so called " the Edwin Smith Papyrus " dating back to the Pyramid Age. However, apart from all respective documents remained from the antiquity, concepts and standpoints of Avicenna (Ibn Sina; a famous Persian physician) in regard of the cancer are interesting. A case of breast cancer and metastatic condition has been reported by Avicenna in the Canon of Medicine. This report can be considered as a very early report of metastatic or stage IV breast cancer. He underlined that cancer should be diagnosed and cured in the early stages. With views of Avicenna, cancer is an atrabilious (black bile) swelling (tumor) which sometimes may be accompanied by pain or swelling. He also mentioned that some vessels may be appeared around the cancerous part. Avicenna extrapolated the cancer with legs of cancer crab which can to grow around the other organs and tissues.
![Research paper thumbnail of The highly bioactive molecule and signal substance 6-formylindolo[3,2-b]carbazole (FICZ) plays bi-functional roles in cell growth and apoptosis in vitro](https://attachments.academia-assets.com/53227706/thumbnails/1.jpg)
](through a mitochondrial-dependent pathway. Since AHR controls multiple cellular functions, a wide... more through a mitochondrial-dependent pathway. Since AHR controls multiple cellular functions, a wide range of toxicity can be expected by disturbing its endogenous functions. Keyword 6-Formylindolo[3,2-b]carbazole (FICZ) · Cell growth · Apoptosis · Mitochondrial-dependent pathway
Nitrofurantoin (N-(5-nitro-2-furfurylidine) 1-amino-hydantoine; NIT) is mainly used for the treat... more Nitrofurantoin (N-(5-nitro-2-furfurylidine) 1-amino-hydantoine; NIT) is mainly used for the treatment of acute urinary tract infections. However, its administration can be associated with liver failure or cirrhosis. The aim of this study was to determine whether NIT is a mitochondrial toxi-cant, if so, what mechanism(s) is involved. The rat liver mitochondria were isolated and treated with different doses of NIT alone or in combination with a reagent of choice for protecting thiol groups, dithiothreitol (DTT). Several mitochon-drial parameters, including succinate dehydrogenase activity (also called 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay), lipid peroxidation, superoxide dismutase activity, Reduced glutathione (GSH), and oxidized glutathione (GSSG), and GSSG (oxidized glutathione) levels were determined. The results from this study showed that simultaneous treatment of mito-chondria with NIT and DTT significantly reduces the toxicity. Here, we provide evidence that mitochondrial dysfunction followed by depletion of reduced glutathione can be reversed by DTT administration. K E Y W O R D S dithiothreitol, mitochondrial dysfunction, nitrofurantoin, oxidative stress
(2016): Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence f... more (2016): Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence for type 2 diabetes, Xenobiotica,
The aim of this study was to gain more information about the mechanisms that regulate expression ... more The aim of this study was to gain more information about the mechanisms that regulate expression of the aryl hydrocarbon receptor (AHR) target gene CYP1A1. Human hepatoma cells (HepG2 and Huh7) and human immortalized keratinocytes (HaCaT) were treated with different concentrations of the dietary polyphenolic compound curcumin (CUR) alone or in combination with the natural AHR agonist 6-formylindolo[3,2-b]carbazole (FICZ). In an earlier study, we described that CUR can activate the AHR indirectly by inhibiting metabolic clearance of FICZ. Here, we measured cell viability, activation of AHR signaling, oxidative stress and histone modifying activities in response to CUR at concentrations ranging from 0.1 to 50 mM. We observed apparent non-linear responses on cell viability and activation of AHR signaling. The CYP1A1 expression and the CYP1A1 enzyme activity in the presence of CUR reflected the histone acetylation efficiency observed in nuclear extracts. At the lowest concentration, CUR significantly decreased histone deacetylase activity and increased the FICZ-induced CYP1A1 activity. In contrast, at the highest concentration, CUR increased the formation of reactive oxygen species, significantly inhibited histone acetylation, and temporally decreased FICZ-induced CYP1A1 activity. The results suggest that CUR can both increase and decrease the accessibility of DNA and thereby influence transcriptional responses to the ligand-activated AHR. This suggestion was supported by the fact that chromatin remodeling treatments with trichostatin A, p300, or 5-aza-dC increased CYP1A1 transcription. We conclude that the AHR-dependent transcriptional efficiency is modified by factors that influence the cellular redox status and the chromatin structure.
1. Methyl tert-butyl methyl ether (MTBE) is commonly used as an octane booster and oxygenate addi... more 1. Methyl tert-butyl methyl ether (MTBE) is commonly used as an octane booster and
oxygenate additive to gasoline. The assumed toxic effects of MTBE on human health are a
matter of great debate. Exposure to MTBE has been shown to induce oxidative damage and
no mechanistic explanation is available so far. Our goals were to determine whether MTBE is
a mitochondrial toxicant, if so, what mechanism(s) is involved.
2. Male Sprague-Dawley rats were received MTBE in drinking water for 3 months. At the end
of treatments, animals were killed, liver and blood samples were collected for biochemical
and histopathological studies, and oxidative stress biomarkers. The rat liver mitochondria
were isolated and several mitochondrial indices were measured.
3. We found that zinc plasma levels were remarkably declined with MTBE and N, N, N0,
N0-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN; a zinc chelator) exposure. MTBE
induced oxidative damage and caused mitochondrial dysfunctions in rats. Supplementation
with zinc was able to protect against MTBE-induced cellular and sub-cellular toxicity.
4. Our results demonstrated that long-term exposure to MTBE is associated with zinc
deficiency, oxidative stress, and mitochondrial energy failure in rat.
The mechanisms explaining arsenic toxicity are not well understood but physiological consequences... more The mechanisms explaining arsenic toxicity are not well understood but physiological consequences of stimulated aryl hydrocarbon receptor (AHR) signaling both directly and through crosstalk with other pathways have been indicated. The aim of this study was to establish how arsenic interacts with AHR-mediated transcription. The human hepatoma cell line (HepG2-XRE-Luc) carrying a luciferase reporter under the control of two AHR response elements (AHREs) and immortalized human keratinocytes (HaCaT) were exposed to sodium arsenite (NaAsO2; As3+), alone or in combination with the endogenous high affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Luciferase activity, cytochrome P4501A1 (CYP1A1) activity, oxidative stress-related responses, metabolic clearance of FICZ, and NADPH oxidase (NOX) activity as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent gene expression were measured. Arsenic inhibited CYP1A1 enzyme activity and reduced the metabolic clearance of FICZ. Arsenic also led to activated CYP1A1 transcription, but only in cells grown in medium containing trace amounts of the endogenous ligand FICZ, pointing to an indirect mechanism of activation. Initially, arsenic caused dose-dependent inhibition of FICZ-activated AHR signaling, disturbed intracellular GSH status and increased expression of oxidative stress-related genes. Silencing of NOX4, addition of N-acetylcystein or pretreatment with arsenic itself attenuated the initial dose-dependent inhibition of AHR signaling. Arsenic pretreatment led to elevated GSH levels and sensitized the cells to ligand-dependent AHR signaling, while silencing of Nrf2 significantly reduced arsenic-mediated activation of the AHR. In addition, influence of NOX on AHR activation was also observed in cells treated with the SH-reactive metals cadmium, mercury and nickel. Together, the results suggest that SH-reactive agents via a new and possibly general NOX/H2O2-dependent mechanism can interfere with the endogenous regulation of the AHR.
CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of th... more CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely
available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering
drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase.
Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans.
However, their long-term administration is associated with a variety of myopatic complaints. The
aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet
(HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not?
Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The
first group considered as regular control and fed with a RD. Groups 2–7 including HFD control, CoQ10
(10 mg/kg), simvastatin (30 mg/kg), atorvastatin (30 mg/kg), simvastatinþCoQ10 or atorvastatinþCoQ10
treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood
samples were collected for biochemical examinations. The rat liver mitochondria were isolated and
several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial
membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined.
We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented
with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels.
Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment
and improved by co-administration with CoQ10.
Background: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in the bio... more Background: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in
the biological systems. Acute exposure to high levels of H2S is life threatening while longterm
exposure to ambient levels of H2S elicits human health effects.
Objective: To study the harmful effects of long-term exposure to low levels of H2S on human
blood cells.
Methods: 110 adult workers from Iran who were occupationally exposed to 0–90 ppb H2S
for 1–30 years were studied. The participants aged between 18 and 60 years and were exposed
directly or indirectly to sulfur compounds (exposed group). The origin of H2S was natural
gas processing plants. A control group consisting of 110 males who were not in contact
with H2S was also studied. For all participants, hematological profile including total hemoglobin
and red blood cell count and sulfhemoglobin, methemoglobin levels were measured.
Results: Among all parameters evaluated in this study the mean methemoglobin and sulfhemoglobin
levels were significantly higher among workers who were exposed to sulfur compounds
than the control group. Major differences throughout the study period for sulfhemoglobinemia
among exposed groups were observed.
Conclusion: Long-term exposure to even low levels of H2S in workplaces may have potential
harmful effects on human health.
Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worl... more Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worldwide health problem for several decades. The aim of this study was to learn how metal-induced oxidative stress triggers cell proliferation, a process of great significance for cancer.
Tomato products containing lycopene are believed to be associated with decreased risk of chronic ... more Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750 mg/kg, i.p.) before treatment with tomato extract (5 mg/kg, oral) for seven consecutive days, ADN (100 mg/kg, i.p.) plus tomato extract (5 mg/kg, oral) for 10 consecutive days, or CsA (250 mg/kg, i.p.) plus tomato extract (5 mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.
Introduction: IAChE (acetylcholinesterase) is one of the plasma ' s enzymes that plays a crucial ... more Introduction: IAChE (acetylcholinesterase) is one of the plasma ' s enzymes that plays a crucial role in nervous signal transduction in synapses and is responsible for the hydrolysis of Ach. Methods: We investigated three methods for the determination of AChE in human blood serum, using three different assays.
Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of t... more Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.
Background: Cylophosphamide is used alone or in combination with other drugs for treatment of neo... more Background: Cylophosphamide is used alone or in combination with other drugs for treatment of neoplastic diseases. Hemorrhagic cystitis is a major potential toxicity and dose limiting side effect of cyclophosphamide. The aim of this study was to evaluate the effects of lycopene compared with some antioxidants for the prevention of cyclophosphamide induced hemorrhagic cystitis in rats.
A new rapid, simple, and cost effective experimental approach to studying liposomes is proposed. ... more A new rapid, simple, and cost effective experimental approach to studying liposomes is proposed. Neutral red (NR) -a pH indicator and a weak base with pK a = 6.7, which is red while ionized in acidic media but yellow while non-ionized in alkaline media, and is used in vital staining -was selected as a model of lipophilic and hydrophilic drugs. NR accumulates in biological membranes and liposomes in ionized form, in sharp contrast to the surrounding media of liposomes and intracellular organelles. This renders them visible in a light microscope (LM). Staining with NR has been studied using pH differences between the internal and external media of liposomes. Liposomes with differing internal (pH 5) and external (pH 9) media offer the most suitable object for such staining. The influence of differential pH on the liposome trapping efficiency (LTE) has been evaluated by spectrophotometry at a wavelength of 533 nm. The percentage LTE increased from 24 to 87% for pH values outside (external medium) varying in the range 5 -9. Correlations between CBC (contrast between liposomal compartments visualized by LM) and EBC (exchange between liposomal compartments) and LTE were mathematically analyzed. Significant correlations within a 95% confidence interval were observed between EBC and CBC (r 2 = 0.93, p < 0.05) and between LTE and CBC (r 2 = 0.93, p < 0.05). No significant correlation was observed between EBC and LTE with a 95% confidence interval (EBC -LTE, r 2 = 0.66, p < 0.05).
Janus green B (JG-B) dye is used for vital staining of mitochondria and its reduction and oxidati... more Janus green B (JG-B) dye is used for vital staining of mitochondria and its reduction and oxidation shows the electron transfer chain alteration. The defect in electron transfer chain of mitochondria by paraquat is linked to free radical formation. In this present study we compared the abilities of different angiotensin-converting enzyme inhibitors, captopril (a thiol ACEi), enalapril, and lisinopril (two nonthiol ACEi) on mitochondria toxicity due to paraquat. The rat liver mitochondria were first isolated by centrifuge (at 4 • C at a speed of 7,000 g) in a mixture of 0.25 M saccharose solution and 0.05 M Tris buffer. Various concentrations of paraquat (1, 5, 10 mM), enalapril (0.25, 0.5, 1 mM), lisinopril (0.01, 0.05, 0.1 mM), and captopril (0.08, 0.1, 1 mM) on the mitochondria isolated from the liver with respect to time were investigated. Paraquat at a concentration of 5 mM was determined to be significantly different compared to control values (P < 0.05) and captopril at a concentration of 0.08 mM, lisinopril (0.01 mM), and enalapril (0.25 mM) were found not to be significantly different from controls as found by spectroscopy at wavelength of 607 nm. Simultaneous treatment of mitochondria with captopril (0.08 mM) and paraquat (5 mM) significantly ameliorates the mitochondria toxicity of paraquat (5 mM) alone (P < 0.05). Our results show that captopril is a more effective antioxidant than the nonthiol ACEi. Lisinopril (0.01 mM) and enalapril (0.25 mM) did not significantly change the mitochondrial toxicity by paraquat (5 mM) (P > 0.05). The antioxidative 98 GHAZI-KHANSARI et al.: PARAQUAT TOXICITY IN RAT LIVER MITOCHONDRIA 99
Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscri... more Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscript so called " the Edwin Smith Papyrus " dating back to the Pyramid Age. However, apart from all respective documents remained from the antiquity, concepts and standpoints of Avicenna (Ibn Sina; a famous Persian physician) in regard of the cancer are interesting. A case of breast cancer and metastatic condition has been reported by Avicenna in the Canon of Medicine. This report can be considered as a very early report of metastatic or stage IV breast cancer. He underlined that cancer should be diagnosed and cured in the early stages. With views of Avicenna, cancer is an atrabilious (black bile) swelling (tumor) which sometimes may be accompanied by pain or swelling. He also mentioned that some vessels may be appeared around the cancerous part. Avicenna extrapolated the cancer with legs of cancer crab which can to grow around the other organs and tissues.
Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscri... more Historically, one of the earliest breast cancer case descriptions comes from an Egyptian manuscript so called " the Edwin Smith Papyrus " dating back to the Pyramid Age. However, apart from all respective documents remained from the antiquity, concepts and standpoints of Avicenna (Ibn Sina; a famous Persian physician) in regard of the cancer are interesting. A case of breast cancer and metastatic condition has been reported by Avicenna in the Canon of Medicine. This report can be considered as a very early report of metastatic or stage IV breast cancer. He underlined that cancer should be diagnosed and cured in the early stages. With views of Avicenna, cancer is an atrabilious (black bile) swelling (tumor) which sometimes may be accompanied by pain or swelling. He also mentioned that some vessels may be appeared around the cancerous part. Avicenna extrapolated the cancer with legs of cancer crab which can to grow around the other organs and tissues.
through a mitochondrial-dependent pathway. Since AHR controls multiple cellular functions, a wide... more through a mitochondrial-dependent pathway. Since AHR controls multiple cellular functions, a wide range of toxicity can be expected by disturbing its endogenous functions. Keyword 6-Formylindolo[3,2-b]carbazole (FICZ) · Cell growth · Apoptosis · Mitochondrial-dependent pathway
Nitrofurantoin (N-(5-nitro-2-furfurylidine) 1-amino-hydantoine; NIT) is mainly used for the treat... more Nitrofurantoin (N-(5-nitro-2-furfurylidine) 1-amino-hydantoine; NIT) is mainly used for the treatment of acute urinary tract infections. However, its administration can be associated with liver failure or cirrhosis. The aim of this study was to determine whether NIT is a mitochondrial toxi-cant, if so, what mechanism(s) is involved. The rat liver mitochondria were isolated and treated with different doses of NIT alone or in combination with a reagent of choice for protecting thiol groups, dithiothreitol (DTT). Several mitochon-drial parameters, including succinate dehydrogenase activity (also called 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay), lipid peroxidation, superoxide dismutase activity, Reduced glutathione (GSH), and oxidized glutathione (GSSG), and GSSG (oxidized glutathione) levels were determined. The results from this study showed that simultaneous treatment of mito-chondria with NIT and DTT significantly reduces the toxicity. Here, we provide evidence that mitochondrial dysfunction followed by depletion of reduced glutathione can be reversed by DTT administration. K E Y W O R D S dithiothreitol, mitochondrial dysfunction, nitrofurantoin, oxidative stress
(2016): Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence f... more (2016): Disturbance of zinc and glucose homeostasis by methyl tert-butyl ether (MTBE); evidence for type 2 diabetes, Xenobiotica,
The aim of this study was to gain more information about the mechanisms that regulate expression ... more The aim of this study was to gain more information about the mechanisms that regulate expression of the aryl hydrocarbon receptor (AHR) target gene CYP1A1. Human hepatoma cells (HepG2 and Huh7) and human immortalized keratinocytes (HaCaT) were treated with different concentrations of the dietary polyphenolic compound curcumin (CUR) alone or in combination with the natural AHR agonist 6-formylindolo[3,2-b]carbazole (FICZ). In an earlier study, we described that CUR can activate the AHR indirectly by inhibiting metabolic clearance of FICZ. Here, we measured cell viability, activation of AHR signaling, oxidative stress and histone modifying activities in response to CUR at concentrations ranging from 0.1 to 50 mM. We observed apparent non-linear responses on cell viability and activation of AHR signaling. The CYP1A1 expression and the CYP1A1 enzyme activity in the presence of CUR reflected the histone acetylation efficiency observed in nuclear extracts. At the lowest concentration, CUR significantly decreased histone deacetylase activity and increased the FICZ-induced CYP1A1 activity. In contrast, at the highest concentration, CUR increased the formation of reactive oxygen species, significantly inhibited histone acetylation, and temporally decreased FICZ-induced CYP1A1 activity. The results suggest that CUR can both increase and decrease the accessibility of DNA and thereby influence transcriptional responses to the ligand-activated AHR. This suggestion was supported by the fact that chromatin remodeling treatments with trichostatin A, p300, or 5-aza-dC increased CYP1A1 transcription. We conclude that the AHR-dependent transcriptional efficiency is modified by factors that influence the cellular redox status and the chromatin structure.
1. Methyl tert-butyl methyl ether (MTBE) is commonly used as an octane booster and oxygenate addi... more 1. Methyl tert-butyl methyl ether (MTBE) is commonly used as an octane booster and
oxygenate additive to gasoline. The assumed toxic effects of MTBE on human health are a
matter of great debate. Exposure to MTBE has been shown to induce oxidative damage and
no mechanistic explanation is available so far. Our goals were to determine whether MTBE is
a mitochondrial toxicant, if so, what mechanism(s) is involved.
2. Male Sprague-Dawley rats were received MTBE in drinking water for 3 months. At the end
of treatments, animals were killed, liver and blood samples were collected for biochemical
and histopathological studies, and oxidative stress biomarkers. The rat liver mitochondria
were isolated and several mitochondrial indices were measured.
3. We found that zinc plasma levels were remarkably declined with MTBE and N, N, N0,
N0-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN; a zinc chelator) exposure. MTBE
induced oxidative damage and caused mitochondrial dysfunctions in rats. Supplementation
with zinc was able to protect against MTBE-induced cellular and sub-cellular toxicity.
4. Our results demonstrated that long-term exposure to MTBE is associated with zinc
deficiency, oxidative stress, and mitochondrial energy failure in rat.
The mechanisms explaining arsenic toxicity are not well understood but physiological consequences... more The mechanisms explaining arsenic toxicity are not well understood but physiological consequences of stimulated aryl hydrocarbon receptor (AHR) signaling both directly and through crosstalk with other pathways have been indicated. The aim of this study was to establish how arsenic interacts with AHR-mediated transcription. The human hepatoma cell line (HepG2-XRE-Luc) carrying a luciferase reporter under the control of two AHR response elements (AHREs) and immortalized human keratinocytes (HaCaT) were exposed to sodium arsenite (NaAsO2; As3+), alone or in combination with the endogenous high affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Luciferase activity, cytochrome P4501A1 (CYP1A1) activity, oxidative stress-related responses, metabolic clearance of FICZ, and NADPH oxidase (NOX) activity as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent gene expression were measured. Arsenic inhibited CYP1A1 enzyme activity and reduced the metabolic clearance of FICZ. Arsenic also led to activated CYP1A1 transcription, but only in cells grown in medium containing trace amounts of the endogenous ligand FICZ, pointing to an indirect mechanism of activation. Initially, arsenic caused dose-dependent inhibition of FICZ-activated AHR signaling, disturbed intracellular GSH status and increased expression of oxidative stress-related genes. Silencing of NOX4, addition of N-acetylcystein or pretreatment with arsenic itself attenuated the initial dose-dependent inhibition of AHR signaling. Arsenic pretreatment led to elevated GSH levels and sensitized the cells to ligand-dependent AHR signaling, while silencing of Nrf2 significantly reduced arsenic-mediated activation of the AHR. In addition, influence of NOX on AHR activation was also observed in cells treated with the SH-reactive metals cadmium, mercury and nickel. Together, the results suggest that SH-reactive agents via a new and possibly general NOX/H2O2-dependent mechanism can interfere with the endogenous regulation of the AHR.
CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of th... more CoQ10 shares a biosynthetic pathway with cholesterol therefore it can be a potential target of the widely
available lipid-lowering agents such as statins. Statins are the most widely prescribed cholesterol-lowering
drugs with the ability to inhibit HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase.
Preclinical and clinical safety data have shown that statins do not cause serious adverse effects in humans.
However, their long-term administration is associated with a variety of myopatic complaints. The
aim of this study was to investigate whether CoQ10 supplementation of animals under high fat diet
(HFD) treated with statins is able to bypass the mitochondrial metabolic defects or not?
Animals were divided into 7 groups and fed with either regular (RD) or HFD during experiments. The
first group considered as regular control and fed with a RD. Groups 2–7 including HFD control, CoQ10
(10 mg/kg), simvastatin (30 mg/kg), atorvastatin (30 mg/kg), simvastatinþCoQ10 or atorvastatinþCoQ10
treated orally for 30 days and fed with HFD. At the end of treatments, the animals were killed and blood
samples were collected for biochemical examinations. The rat liver mitochondria were isolated and
several mitochondrial indices including succinate dehydrogenase activity (SDA), ATP levels, mitochondrial
membrane potential (MMP) and mitochondrial permeability transition pore (MPP) were determined.
We found that triglyceride (Tg), cholesterol (Chol) and low-density lipoprotein (LDL) were augmented
with HFD compared to RD and treatment with statins remarkably lowered the Tg, Chol and LDL levels.
Mitochondrial parameters including, SDA, ATP levels, MMP and MPP were reduced with statin treatment
and improved by co-administration with CoQ10.
Background: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in the bio... more Background: Hydrogen sulfide (H2S) exhibits both physiological and toxicological roles in
the biological systems. Acute exposure to high levels of H2S is life threatening while longterm
exposure to ambient levels of H2S elicits human health effects.
Objective: To study the harmful effects of long-term exposure to low levels of H2S on human
blood cells.
Methods: 110 adult workers from Iran who were occupationally exposed to 0–90 ppb H2S
for 1–30 years were studied. The participants aged between 18 and 60 years and were exposed
directly or indirectly to sulfur compounds (exposed group). The origin of H2S was natural
gas processing plants. A control group consisting of 110 males who were not in contact
with H2S was also studied. For all participants, hematological profile including total hemoglobin
and red blood cell count and sulfhemoglobin, methemoglobin levels were measured.
Results: Among all parameters evaluated in this study the mean methemoglobin and sulfhemoglobin
levels were significantly higher among workers who were exposed to sulfur compounds
than the control group. Major differences throughout the study period for sulfhemoglobinemia
among exposed groups were observed.
Conclusion: Long-term exposure to even low levels of H2S in workplaces may have potential
harmful effects on human health.
Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worl... more Exposure to metals and metalloids including arsenic, cadmium, mercury, and nickel has been a worldwide health problem for several decades. The aim of this study was to learn how metal-induced oxidative stress triggers cell proliferation, a process of great significance for cancer.
Tomato products containing lycopene are believed to be associated with decreased risk of chronic ... more Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750 mg/kg, i.p.) before treatment with tomato extract (5 mg/kg, oral) for seven consecutive days, ADN (100 mg/kg, i.p.) plus tomato extract (5 mg/kg, oral) for 10 consecutive days, or CsA (250 mg/kg, i.p.) plus tomato extract (5 mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.
Introduction: IAChE (acetylcholinesterase) is one of the plasma ' s enzymes that plays a crucial ... more Introduction: IAChE (acetylcholinesterase) is one of the plasma ' s enzymes that plays a crucial role in nervous signal transduction in synapses and is responsible for the hydrolysis of Ach. Methods: We investigated three methods for the determination of AChE in human blood serum, using three different assays.
Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of t... more Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.
Background: Cylophosphamide is used alone or in combination with other drugs for treatment of neo... more Background: Cylophosphamide is used alone or in combination with other drugs for treatment of neoplastic diseases. Hemorrhagic cystitis is a major potential toxicity and dose limiting side effect of cyclophosphamide. The aim of this study was to evaluate the effects of lycopene compared with some antioxidants for the prevention of cyclophosphamide induced hemorrhagic cystitis in rats.
A new rapid, simple, and cost effective experimental approach to studying liposomes is proposed. ... more A new rapid, simple, and cost effective experimental approach to studying liposomes is proposed. Neutral red (NR) -a pH indicator and a weak base with pK a = 6.7, which is red while ionized in acidic media but yellow while non-ionized in alkaline media, and is used in vital staining -was selected as a model of lipophilic and hydrophilic drugs. NR accumulates in biological membranes and liposomes in ionized form, in sharp contrast to the surrounding media of liposomes and intracellular organelles. This renders them visible in a light microscope (LM). Staining with NR has been studied using pH differences between the internal and external media of liposomes. Liposomes with differing internal (pH 5) and external (pH 9) media offer the most suitable object for such staining. The influence of differential pH on the liposome trapping efficiency (LTE) has been evaluated by spectrophotometry at a wavelength of 533 nm. The percentage LTE increased from 24 to 87% for pH values outside (external medium) varying in the range 5 -9. Correlations between CBC (contrast between liposomal compartments visualized by LM) and EBC (exchange between liposomal compartments) and LTE were mathematically analyzed. Significant correlations within a 95% confidence interval were observed between EBC and CBC (r 2 = 0.93, p < 0.05) and between LTE and CBC (r 2 = 0.93, p < 0.05). No significant correlation was observed between EBC and LTE with a 95% confidence interval (EBC -LTE, r 2 = 0.66, p < 0.05).
Janus green B (JG-B) dye is used for vital staining of mitochondria and its reduction and oxidati... more Janus green B (JG-B) dye is used for vital staining of mitochondria and its reduction and oxidation shows the electron transfer chain alteration. The defect in electron transfer chain of mitochondria by paraquat is linked to free radical formation. In this present study we compared the abilities of different angiotensin-converting enzyme inhibitors, captopril (a thiol ACEi), enalapril, and lisinopril (two nonthiol ACEi) on mitochondria toxicity due to paraquat. The rat liver mitochondria were first isolated by centrifuge (at 4 • C at a speed of 7,000 g) in a mixture of 0.25 M saccharose solution and 0.05 M Tris buffer. Various concentrations of paraquat (1, 5, 10 mM), enalapril (0.25, 0.5, 1 mM), lisinopril (0.01, 0.05, 0.1 mM), and captopril (0.08, 0.1, 1 mM) on the mitochondria isolated from the liver with respect to time were investigated. Paraquat at a concentration of 5 mM was determined to be significantly different compared to control values (P < 0.05) and captopril at a concentration of 0.08 mM, lisinopril (0.01 mM), and enalapril (0.25 mM) were found not to be significantly different from controls as found by spectroscopy at wavelength of 607 nm. Simultaneous treatment of mitochondria with captopril (0.08 mM) and paraquat (5 mM) significantly ameliorates the mitochondria toxicity of paraquat (5 mM) alone (P < 0.05). Our results show that captopril is a more effective antioxidant than the nonthiol ACEi. Lisinopril (0.01 mM) and enalapril (0.25 mM) did not significantly change the mitochondrial toxicity by paraquat (5 mM) (P > 0.05). The antioxidative 98 GHAZI-KHANSARI et al.: PARAQUAT TOXICITY IN RAT LIVER MITOCHONDRIA 99