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1.
Toxicol Res (Camb) ; 13(1): tfad127, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38239270

RESUMO

Introduction: Considering the numerous drug resistance in cancer and the advancement of science in nanomedicines, it was decided to compare the effectiveness of zinc oxide nanoparticles in colon and prostate cell lines. Considering the importance of factors and Oxidative stress pathways in cancer prevention, the aim of the study is based on oxidative stress mechanisms. Methodes: In order to evaluate the effects of zinc oxide nanoparticles on colon and prostate cell lines, oxidative stress factors ROS, MDA, and GSH and mitochondrial function were evaluated. The data was analyzed with Prism v8 software, and the significance level was considered to be P < 0.05. Results: The results showed that nanoparticles induce ROS and reduce intracellular glutathione by destroying and disrupting mitochondrial function, and by increasing ROS production, damage to the lipid membrane and an increase in MDA were also evident. This effect was dose-dependent and the greatest at a concentration of 25 µg/mL. Also, ZnO nanoparticles performed better in the HT29 cell line than in the PC3 cell line. Conclusion: This study showed that exposure of HT29 and PC3 cancer cells to zinc oxide nanoparticles at different concentrations inhibited growth by cytotoxic effects.

2.
Hum Exp Toxicol ; 43: 9603271241227228, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38238028

RESUMO

INTRODUCTION: Pancreatic cancer and cervical cancer are among the most common cancers. Brown algae have anti-inflammatory, anti-cancer, anti-fungal, antioxidant, and immune-boosting properties. This study investigated the antioxidant properties and the effect of brown algae extract on pancreatic and uterine cancer cells. MATERIALS AND METHODS: In this study, Cervical (Hela) and pancreas (Paca-2) cancer cell lines were examined. The algae materials were extracted by sequential maceration method and amount of fucoxanthin content in the sample was determined by using High Performance Liquid Chromatography (HPLC) system. The cytotoxic effect of different concentrations of brown algae was measured by the MTT assay. All statistical calculations for comparing IC50 were analyzed using Graph Pad Prism software. RESULTS: the algal sample contained an average of 102.52 ± 0.12 µg of fucoxanthin per 100 g. IC50 for 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide free radical scavenging activity for methanolic extract was 2.02 and 11.98 ± 0.13 respectively. Brown algae in all fractions inhibited cell growth and survival. In Hela cell lines, the methanolic extract was the most effective inhibitor, while in Paca cell lines, hexane and methanolic extracts were particularly potent. The methanolic extract was more toxic than other fractions on Hela and Paca cell lines. CONCLUSION: This study highlights brown algae extracts strong anticancer effects on uterine and pancreatic cancer cells, suggesting its potential as a natural anticancer drug. Different fractions of the extract showed superior apoptotic and cytotoxic effects, with higher concentrations leading to increased apoptotic effects and reduced survival rates of cancer cells.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Phaeophyceae , Xantofilas , Feminino , Humanos , Antioxidantes/farmacologia , Células HeLa , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias Pancreáticas/tratamento farmacológico
3.
Toxicology ; 499: 153655, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37871686

RESUMO

The hematopoietic factor granulocyte macrophage-colony stimulating factor (GM-CSF) has been identified via its capacity to promote bone marrow progenitors' development and differentiation into granulocytes and macrophages. Extensive pre-clinical research has established its promise as a critical therapeutic target in an assortment of inflammatory and autoimmune disorders. Despite the broad literature on GM-CSF as hematopoietic of stem cells, the cyto/geno protective aspects remain unknown. This study aimed to assess the cyto/geno protective possessions of GM-CSF on cypermethrin-induced cellular toxicity on HFF-1 cells as an in vitro model. In pre-treatment culture, cells were exposed to various GM-CSF concentrations (5, 10, 20, and 40 ng/mL) with cypermethrin at IC50 (5.13 ng/mL). Cytotoxicity, apoptotic rates, and genotoxicity were measured using the MTT, Annexin V-FITC/PI staining via flow-cytometry, and the comet assay. Cypermethrin at 5.13 ng/mL revealed cytotoxicity, apoptosis, oxidative stress, and genotoxicity while highlighting GM-CSF's protective properties on HFF-1. GM-CSF markedly attenuated cypermethrin-induced apoptotic cell death (early and late apoptotic rates). GM-CSF considerably regulated oxidative stress and genotoxicity by reducing the ROS and LPO levels, maintaining the status of GSH and activity of SOD, and suppressing genotoxicity in the comet assay parameters. Therefore, GM-CSF could be promising as an antioxidant, anti-apoptotic, genoprotective and cytomodulating agent.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Células-Tronco Hematopoéticas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Células-Tronco Hematopoéticas/fisiologia , Granulócitos , Fibroblastos
4.
Toxicol Res (Camb) ; 12(4): 702-708, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37663811

RESUMO

Metformin exerts its anticancer effect through two mechanisms, directly affecting the tumor and indirectly reducing systemic insulin levels. The anticancer effects of aspirin occur by inhibiting Cyclooxygenase (COX)-2. COX-2 is absent in many cell types under normal conditions and increases under pathological conditions such as cancer. This study aims to investigate the effect of metformin and aspirin and their combination of them on A549 and PC3 cell lines. Metformin and aspirin were investigated separately and in combination on two cancer cell lines, A549 and PC3. The examined groups include the negative control of untreated cells and the positive control of cisplatin and drugs at concentrations of 15, 10, and 20 µg/ mL to investigate the mechanism of oxidative stress factors (reactive oxygen species, lipid peroxidation, Glutathione (GSH)) and apoptosis (lactate dehydrogenase). The results showed that aspirin, metformin, and their combination could affect cancer cell growth by damaging mitochondria, releasing reactive oxygen species, and activating the oxidative stress pathway. Also, these two drugs show the activation of the apoptotic pathway in cancer cells by increasing the lactate dehydrogenase factor and releasing it from the cells. By disrupting the balance of oxidants and antioxidants in the cell, metformin and aspirin cause an increase in the level of reactive oxygen species and a decrease in the level of glutathione reserves, followed by an increase in the level of lipid peroxidation and a decrease in cell viability. Unlike common chemotherapy drugs, these drugs have no known severe side effects; Therefore, in the not-so-distant future, these drugs can also be used as anticancer drugs. Highlights: Metformin and aspirin, commonly used drugs for diabetes and inflammation, inhibit the growth of cancer cell lines, A549 and PC3.Metformin and aspirin, either separately or in combination, can potentially impede cancer cell growth by disrupting mitochondrial function, inducing the release of reactive oxygen species (ROS), and activating oxidative stress pathways.Furthermore, these drugs can trigger apoptosis, a programmed cell death mechanism, in cancer cells by increasing lactate dehydrogenase (LDH) levels and facilitating its release from the cells.

5.
Toxicol Mech Methods ; 33(9): 755-765, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37537746

RESUMO

Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference in vitro model for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining via flow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 µg/mL) and methotrexate (2.5 µM) in pretreatment culture condition. Methotrexate at 2.5 µM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.


Assuntos
Amifostina , Antineoplásicos , Humanos , Amifostina/farmacologia , Amifostina/uso terapêutico , Metotrexato/toxicidade , Células Endoteliais da Veia Umbilical Humana , Estresse Oxidativo , DNA
6.
Int J Dent ; 2023: 4376579, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37293576

RESUMO

Background: Root canal obturation is performed by gutta-percha cones and sealer. Therefore, these materials, specially sealers, must be biocompatible. This study investigated the cytotoxicity and mineralization activity of two calcium silicate-based sealers (Endoseal MTA and Ceraseal) and an epoxy resin-based sealer (AH26). Materials and Methods: In this experiment, the cytotoxicity of Endoseal MTA, Ceraseal, and AH26 on human gingival fibroblast cells was examined using Methyl-Thiazol-Tetrazolium assay at time intervals of 24, 48, 72, and 120 hr. The mineralization activity of sealers was evaluated by Alizarin red staining assay. Prism, ver.3, software was used to perform statistical tests. One-way analysis of variance analysis, followed by Tukey's test, was used to determine the group differences. P-values < 0.05 were considered statistically significant. Results: Cytotoxicity of sealers decreased gradually (P < 0.0001). AH26 showed the highest level of cytotoxicity (P < 0.001). In terms of cytotoxicity, no considerable differences were observed between the two-calcium silicate-based sealers (P > 0.05). AH26 showed the lowest mineralization activity (P < 0.0001). Among the calcium silicate-based sealers, mineralization and formation of calcium nodules were more frequently observed in the Endoseal MTA group (P < 0.001). Conclusion: The examined calcium silicate-based sealers had less cytotoxicity and higher mineralization activity than the resin-based sealer (AH26). There was negligible difference between the cytotoxicity of the two-calcium silicate-based, but the cell mineralization caused by Endoseal MTA was higher.

7.
J Biochem Mol Toxicol ; 37(6): e23334, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36843476

RESUMO

Levofloxacin, the optical S-(-) isomer of ofloxacin, is a broad-spectrum antibacterial agent widely used to control various infections caused by Gram-positive and Gram-negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a-j and 12 containing 5-substituted-1,3,4-thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF-7, A549, and SKOV3. In particular, the 3-chloro- and 4-fluoro- benzyl derivatives (11b and 11h), with IC50 values of 1.69-4.76 µM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3-chloro or 4-fluoro substituent on the S-benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1-phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6-COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.


Assuntos
Antineoplásicos , Quinolonas , Antibacterianos/farmacologia , Antibacterianos/química , Levofloxacino/farmacologia , Quinolonas/farmacologia , Citotoxinas/farmacologia , Relação Estrutura-Atividade , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular
8.
Iran J Basic Med Sci ; 26(1): 57-68, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36594058

RESUMO

Objectives: Nanotechnology has helped a lot in diagnosing and treating multiple illnesses, specifically cancer, and increasing the development of targeted drug delivery methods. Nanocomposites are materials with at least one component smaller than 100 nm. Therefore, this study aims to assess the anticancer effects of silver-graphene nanocomposite on MCF-7. Materials and Methods: In this study, the rate of inhibition of cancer cell growth and production of reactive oxygen radicals, malondialdehyde, and glutathione stores in MCF7 cells were investigated. Cancer cells were exposed to nano particles for 48 hr. Silver nanoparticles and graphene both reduced the growth rate of MCF-7. Results: Subsequently, by treating the cells with silver-graphene nanocomposite, the rate of inhibition of cell growth at the highest concentration was 84.60%. Nanoparticles also inhibited the growth of cancer cells through the oxidative stress pathway by increasing the amount of intracellular ROS, followed by increasing malondialdehyde and decreasing glutathione stores, so that at the highest combined concentration of nanoparticles, the amounts of LPO and ROS increased up to 70% and 74 %, and glutathione reserves decreased by 16%. Conclusion: Treatment of MCF-7 cells with silver or graphene nanoparticles and combination treatment with these two substances against cisplatin have sound effects, and by affecting oxidative stress factors, such as increased ROS and subsequent increase in lipid membrane damage, inhibit cell growth and proliferation. According to the mathematical model, silver graphene nanocomposite> silver nanoparticles> graphene has the best effect in inhibiting the growth of cancer cells, respectively.

9.
Drug Chem Toxicol ; 46(4): 617-624, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35575100

RESUMO

Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 µM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel.


Assuntos
Acetilcisteína , Zingiber officinale , Acetilcisteína/farmacologia , Docetaxel/toxicidade , Espécies Reativas de Oxigênio , Estresse Oxidativo , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Fenóis/farmacologia
10.
Toxicol In Vitro ; 87: 105532, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36460226

RESUMO

INTRODUCTION: Paroxetine is functionally classified as a selective serotonin reuptake inhibitor. Paroxetine can induce mitochondria-dependent apoptosis through the ROS-MAPK pathway.Amitriptyline is a tricyclic antidepressant. This drug induces the expression of p53, thereby activating caspase-3. Amitriptyline has also been studied as a potential candidate for inducing oxidative stress and cytotoxicity in cancer cells, which may be more effective than other chemotherapy drugs. This study aims to to investigate the anticancer effects of paroxetine and amitriptyline and their combination treatment on HT29 and A549 cell lines for the first time. METHODS: In order to investigate the anticancer effect of two drugs, paroxetine and amitriptyline, on inhibiting the growth of A549 and HT29 cancer cells, oxidative stress factors and LDH enzyme and apoptosis tests were performed. RESULTS: Two drugs, amitriptyline and paroxetine alone, inhibited the growth of cancer cells in such a way that the inhibitory effect of the cells increased with the increase in the dose of the drug. In the simultaneous exposure of these two drugs, the inhibitory effect was much greater than the effect of single drug exposure. Also, these two drugs have caused LDH leakage and induction of apoptosis. CONCLUSION: According to the results of the study, it was found that these two drugs have the necessary ability to inhibit the growth of cancer cells by inducing apoptosis and LDH leakage and inducing oxidative stress.


Assuntos
Amitriptilina , Paroxetina , Humanos , Paroxetina/farmacologia , Amitriptilina/toxicidade , Células A549 , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Antidepressivos Tricíclicos/uso terapêutico
11.
Toxicol Mech Methods ; 33(2): 161-171, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35866224

RESUMO

The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 µM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.


Assuntos
Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Caspase 3 , Etoposídeo/toxicidade , Ubiquinona/farmacologia , Estresse Oxidativo , Glucocorticoides/toxicidade , Dexametasona/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
12.
Neurotox Res ; 40(6): 1838-1858, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36522510

RESUMO

Depression is a very common mental disorder and mechanism that is associated with mitochondrial dysfunction. In the present study, we examined the mechanisms of action of isolated brain mitochondria in rats with depression for the first time. This will help identify the mitochondrial protective pathways of the two drugs and shed light on new therapeutic goals for developing antidepressants. Forced swimming, tail suspension, and sucrose preference tests were used to assess depressive-like behaviors and the oxidative stress factors of brain tissue, and measure the gene expression of apoptotic and anti-apoptotic, neuroplasticity, and neuroinflammatory factors by RT-PCR and acetylcholinesterase (AChE) activity in brain tissue (hippocampus and prefrontal) and the serum levels of corticosterone and fasting blood sugar. The results showed that the separation of neonatal rats from their mothers induced depressive-like behaviors, weight loss, mitochondrial dysfunction, increased expression of genes involved in neuroinflammation, apoptosis, genes involved in the depressive process, and decreased expression of genes involved in mood in both the hippocampus and prefrontal cortex. Maternal separation increased serum corticosterone levels, caused dysfunction of the cholinergic system, and also increased AChE activity. Treatment with different concentrations of minocycline and edaravone (1, 20, and 50 mg/kg), 5MTHF, and citalopram for 14 days showed that these drugs improved depression-like behaviors and mitochondrial function. It also reduced the expression of genes involved in neuroinflammation, apoptosis, and depression and increased the expression of genes involved in mood. In conclusion, minocycline and edaravone have neuroprotective, mitochondrial protective, antioxidant, anti-inflammatory, and anti-apoptotic effects against depressive-like behaviors caused by chronic stress.


Assuntos
Depressão , Minociclina , Ratos , Animais , Edaravone , Minociclina/farmacologia , Minociclina/uso terapêutico , Depressão/metabolismo , Doenças Neuroinflamatórias , Corticosterona , Privação Materna , Acetilcolinesterase/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estresse Oxidativo , Hipocampo , Estresse Psicológico/tratamento farmacológico , Modelos Animais de Doenças , Comportamento Animal
13.
Microb Pathog ; 169: 105649, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35738467

RESUMO

INTRODUCTION: Clostridium perfringens is a type of gram-positive anaerobic bacilli. C.perfringens produces many toxins, of which epsilon (ε) is one of the major ones. The mechanism of epsilon's toxicity is located in the lipid of cell membrane tissues. Epsilon toxin is known as a bioterrorism agent. Inhalation of these aerosols can destroy pulmonary vascular endothelial cells and cause lung injury, which increases vascular permeability and pulmonary edema. METHODS: In this study, we investigated the toxicity of epsilon toxin by using the MTT assay, evaluated oxidative stress effects such as ROS and LPO using the DCFH and TBA reagents, and measured the GSH of the normal and lung cancer cells by using the DTNB reagent. RESULTS: The result showed that 1 µg/ml of epsilon toxin caused mitochondrial disorder and reduced the growth of the normal cell line. This toxin also induced ROS and damage to lipid membranes. Furthermore, the same effect occurred in the lung cancer cell, and the epsilon toxin inhibited cancer cell proliferation. CONCLUSION: This toxin causes toxicity by binding to lipid membranes. As the present study results have confirmed, epsilon toxin inhibits mitochondrial function and induces ROS and lipid membrane damage.


Assuntos
Células Endoteliais , Neoplasias Pulmonares , Sobrevivência Celular , Clostridium perfringens/metabolismo , Humanos , Lipídeos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
14.
Toxicol Res (Camb) ; 11(2): 272-285, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35510228

RESUMO

This study aimed to evaluate the possible protective effects of quercetin, a natural flavonoid, against nephrotoxicity induced by Di (2-ethylhexyl) phthalate (DEHP) in kidney tissue of rats and human embryonic kidney (HEK) 293 cell line. The HEK-293 cells were treated with different concentrations of quercetin 24 h before treatment with monoethylhexyl phthalate (MEHP). Male rats were treated with 200-mg/kg DEHP, 200-mg/kg DEHP plus quercetin (50 and 100 mg/kg), and 200-mg/kg DEHP plus vitamin E (20 mg/kg) for 45 days by gavage. Quercetin treatment reduced cytotoxicity and oxidative damage inducing by MEHP in HEK-293 cells. The in vivo findings showed that 100-mg/kg quercetin significantly suppressed DEHP-induced kidney damage. For exploring the involved mechanisms, the expressions of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) genes were determined via real-time Polymerase chain reaction (PCR) assay. High dose of quercetin significantly decreased the gene expressions of NF-κB and TNFα, whereas the alternations of Nrf2 and HO-1 gene expressions were not significant in quercetin groups in compared with DEHP group. These findings suggested that the suppression of DEHP-induced nephrotoxicity via quercetin is correlated, at least in part, with its potential to regulate NF-κB signaling pathway.

15.
Heliyon ; 8(2): e08940, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35198790

RESUMO

Acroptilon repens (L.) DC, commonly known as Rhaponticum repens, is a popular traditional phytomedicine. The current study was conducted to evaluate the acute and subchronic toxicity of the hydroalcoholic extract of this herb with regard to its terpenoid contents in a BALB/c mice model and to investigate the toxicity of this medicinal herb. Identification of extract components of the plant was done using gas chromatography (GC)-mass spectrometry. In order to establish the acute toxicity model, a single dose of 2000 mg/kg of the extract was given orally to male mice and in the subchronic toxicity study, the extract was consecutively administered at doses 250, 500, and 1000 mg/kg for 28 days. After 28 and 42 days, signs of toxicity and mortality were observed. Organ weight changes and the toxicity-associated parameters such as biochemical indicators, oxidative stress indices, mitochondrial parameters, apoptosis-associated gene expression levels, and pro-inflammatory cytokines were evaluated along with the histopathological examination. GC analysis showed that the terpenoids are the major components of the extract. The LD50 value (2 g/kg) was obtained in the acute toxicity assay; the subchronic administration caused a significant elevation in the serum biomarkers as well as in the levels of lipid peroxidation, protein carbonyl, and ROS. Besides, significant reductions in the superoxide dismutase and catalase activities were observed. This toxic effect was further confirmed by histological studies, cytokine assay, and gene expression assays. Following the treatment discontinuation, the abnormalities in the values of biochemical parameters and histopathological changes returned to normal. These findings demonstrate that the subchronic administration of the hydroalcoholic extract of A. repens can reversibly cause toxicity by inducing oxidative stress and mitochondrial dysfunction.

16.
Toxicol Res (Camb) ; 10(6): 1162-1170, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34956619

RESUMO

Tramadol (TR) is a centrally acting analgesic drug that is used to relieve pain. The therapeutic (0.1-0.8 mg/l), toxic (1-2 mg/l) and lethal (>2 mg/l) ranges were reported for TR. The present study was designed to evaluate which doses of TR can induce liver mitochondrial toxicity. Mitochondria were isolated from the five rats' liver and were incubated with therapeutic to lethal concentrations (1.7-600 µM) of TR. Biomarkers of oxidative stress including: reactive oxygen species (ROS), lipid peroxidation (LPO), protein carbonyl content, glutathione (GSH) content, mitochondrial function, mitochondrial membrane potential (MMP) and mitochondrial swelling were assessed. Our results showed that ROS and LPO at 100 µM and protein carbonylation at 600 µM concentrations of TR were significantly increased. GSH was decreased specifically at 600 µM concentration. Mitochondrial function, MMP and mitochondrial swelling decreased in isolated rat liver mitochondria after exposure to 100 and 300 µM, respectively. This study suggested that TR at therapeutic and toxic levels by single exposure could not induce mitochondrial toxicity. But, in lethal concentration (≥100 µM), TR induced oxidative damage and mitochondria dysfunction. This study suggested that ROS overproduction by increasing of TR concentration induced mitochondrial dysfunction and caused mitochondrial damage via Complex II and membrane permeability transition pores disorders, MMP collapse and mitochondria swelling.

17.
Cancer Inform ; 20: 11769351211056295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34819716

RESUMO

Bisphenol-A (BPA) is a synthetic chemical that has widely been used in the production of polycarbonate plastic and epoxy resins in the manufacture of consumer products. The most common path of human exposure to BPA is by oral intake that involves genotoxicity, oxidative stress, endocrine disruption, mutagenicity, and carcinogenicity in both in vitro and in vivo models. Melatonin is known as a free-radical scavenger and a powerful antioxidant agent. This study aimed to investigate the effects of melatonin on viability and genetic disorders of normal Human Gingival Fibroblasts (HGF), colon cancer (MKN45), and bone marrow stem cell (MSC) lines exposed to BPA. For this purpose, MTT and Comet assays were performed to evaluate the cytotoxicity and genotoxicity properties of BPA and the role of melatonin. The results showed that BPA exposure resulted in increased oxidative stress parameters including MDA and ROS, and decreased GSH content. The current study demonstrated the cytotoxicity and genotoxicity effects of BPA and the protective role of melatonin in preventing cytotoxicity and DNA damage are induced by BPA.

18.
DNA Repair (Amst) ; 108: 103243, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34710661

RESUMO

The phosphorylation of histone variant H2AX and formation of γH2AX is a primary response to the DNA double-strand breaks (DSBs). Detection of γH2AX is a robust and sensitive tool for diagnosis of DNA damage and repair in pre-clinical drug discovery investigations. In addition, the replication stress also leads to the formation of γH2AX and cell death and so γH2AX can serve as a surrogate marker of drug-induced cytotoxicity. Recent advances in genomic research offer an opportunity to detect γH2AX as a specific biomarker for quantitative analysis of DNA damages and repair using high content screening technology and quantitative imaging analysis. The proposed approaches identify a wide range of genetic disorders and are applied in combination with other assays in drug discovery and also for the evaluation of the efficacy of various developmental drugs. In the current review, we provide recent insights into the potential of γH2AX biomarker as a powerful tool in genotoxicity analyses for the monitoring and managing of cancer diseases.


Assuntos
Quebras de DNA de Cadeia Dupla , Dano ao DNA , Biomarcadores , Reparo do DNA , Fosforilação
19.
Naunyn Schmiedebergs Arch Pharmacol ; 394(8): 1803-1813, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34219194

RESUMO

The senescence phenomenon is historically considered as a tumor-suppressing mechanism that can permanently arrest the proliferation of damaged cells, and prevent tumor eradication by activating cell cycle regulatory pathways. Doxorubicin (DX) as an antineoplastic agent has been used for the treatment of solid and hematological malignancies for a long time, but its clinical use is limited due to irreversible toxicity on off-target tissues. Thereby, the encapsulation of plain drugs in a vehicle may decrease the side effects while increasing their permeability and availability in target cells. Here, we aimed to investigate and compare the effects of DX and DX-loaded nanoliposome (NLDX) on the induction of senescence via assessment of the occurrence of apoptosis/necrosis, genomic damage, oxidative stress, and liver pathologies. The study groups included DX (0.75, 0.5, 0.1 mg/kg/BW), NLDX groups (0.1, 0.05, 0.025 mg/kg/BW), and an untreated control group. The liver tissues were used to investigate the oxidative stress parameters and probable biochemical and histopathological alterations. Annexin V/PI staining was carried out to find the type of cellular death in the liver tissue of healthy rats exposed to different concentrations of DOX and LDOX. Data revealed that the highest dose of NLDX (0.1 mg/kg/BW) could significantly induce cellular senescence throughout significant increasing the level of genotoxic damage (p < 0.0001) and the oxidative stress (p < 0.001) compared with a similar dose of DX, in which the obtained results were further confirmed by flow cytometry and histopathological assessments of the liver tissue. This investigation provides sufficient evidence of improved therapeutic efficacy of NLDX compared with plain DX in male Wistar rats.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Senescência Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Lipossomos , Masculino , Nanopartículas , Ratos , Ratos Wistar
20.
Microb Pathog ; 156: 104820, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33932546

RESUMO

Epsilon toxin (Etx) is an enormously potent pore-forming toxin and a category B biological agent. Etx is the main virulence determinant of Clostridiumperfringens types B and D toxin. It has a cytotoxic effect on distal and collecting kidney tubules. Also, Etx crosses the blood-brain barrier, binds to myelin structures, and destroys oligodendrocytes. The main purpose of this study was to investigate the toxic effects of Etx on human blood lymphocytes, which we examined for the first time for the genetic toxicity of this bacterial toxin. In this study, after taking blood and dividing into nine groups and putting in contact with different dilutions of Etx (1,5,10,25,50,100 and 200 µM), methotrexate (750 µM), and normal saline by Cytokinesis blocked micronucleus (CBMN) assay, we looked at genetic toxicity and the level of oxidative stress created in the under study lymphocytes. The results of this study showed that Etx has significant oxidative stress effects on human lymphocytes at doses above 25 µM, and also this bacterial toxin significantly increases the number of micronuclei formed in lymphocytes. The results of this study indicate that Etx has toxic effects it is genetic and interferes with cell division processes. Thus, human lymphocytes can be used extensively in future studies on Etx.


Assuntos
Toxinas Bacterianas , Clostridium perfringens , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Barreira Hematoencefálica/metabolismo , Clostridium perfringens/metabolismo , Humanos , Linfócitos/metabolismo , Estresse Oxidativo
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