RESUMO
The use of arsenic in arsenic-based pesticides has been common in many countries in the past and today. There is considerable evidence linking arsenic exposure to hepatotoxicity and diabetes. Destructive phenomena such as hepatic oxidative stress and inflammation can interfere with glucose uptake and insulin function. In the present study, the antioxidant, anti-inflammatory, and molecular mechanism of citicoline against sodium arsenite-induced hepatotoxicity and glucose intolerance were investigated in mice. Citicoline improved glucose tolerance impaired by sodium arsenite. Citicoline increased the hepatic activity of catalase, superoxide dismutase, and glutathione peroxidase enzymes. Moreover, we found that citicoline prevents an increase in the levels of thiobarbituric acid reactive substances. Citicoline reduced levels of caspase 3, tumor necrosis factor-alpha, and interleukin 6 in sodium arsenite intoxicated groups. It was shown that citicoline increased the expression of arsenite methyltransferase, vesicle-associated membrane protein 2, peroxisome proliferator-activated receptor gamma, and sirtuin 3 to combat sodium arsenite toxicity. Citicoline reduced glucose intolerance, which was disrupted by sodium arsenite, by affecting the pancreatic and extra-pancreatic pathways involved in insulin production, secretion, and action. Based on our results, citicoline can be considered a modulating agent against arsenic-induced hepatotoxicity and hyperglycemia. Considering the relationship between arsenic exposure and the occurrence of side effects such as liver toxicity and diabetes, it is necessary to monitor and awareness of arsenic residues from sources such as drinking water.
Assuntos
Arsênio , Doença Hepática Induzida por Substâncias e Drogas , Diabetes Mellitus , Intolerância à Glucose , Insulinas , Sirtuína 3 , Camundongos , Animais , Arsênio/toxicidade , Arsênio/metabolismo , Sirtuína 3/efeitos adversos , Sirtuína 3/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo , Proteína 2 Associada à Membrana da Vesícula/farmacologia , PPAR gama/metabolismo , Citidina Difosfato Colina/efeitos adversos , Citidina Difosfato Colina/metabolismo , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/tratamento farmacológico , Diabetes Mellitus/induzido quimicamente , Antioxidantes/farmacologia , Estresse Oxidativo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Insulinas/efeitos adversos , Insulinas/metabolismo , MetiltransferasesRESUMO
Development of AS1411aptamer-conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study. AS1411aptamer was used as ligand to target nucleolin, which is highly expressed on the surface of melanoma cancer cells. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA) to increase the loading efficiency and stability of the liposomes. The liposomal structure was characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and field emission scanning electron microscopy (FESEM). In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in murine melanoma (B16) and mouse embryonic fibroblast (MEF) cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5% and 58.7 ± 4.2%, respectively. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice of both groups survived until the end of treatment and showed body weight gain. The tumor protrusion completely disappeared in 50% of the mice in these groups. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in healthy mice tissues. However, unlike the CHAL group, which showed an initial increase in tumor volume, a specific antitumor effect was observed in the AP-CHAL group from the beginning of treatment. The results showed that AP-CHAL can be used as an effective drug delivery system with high potential in the treatment of solid tumors.
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BACKGROUND: Sea cucumber is a natural resource rich in many important pharmacological compounds. this study aimed to investigate the effect of H. leucospilota extract on the induction of cell death and and Proapoptotic Activities. METHODS AND RESULTS: H. leucospilota was collected, the methanolic extract was prepared and in vitro cytotoxicity of H. leucospilota extract in the range of 12.5, 25, 50, 100, and 200 µg/mL concentrations for 48 hours on SK-BR-3 and MCR5 cells was determined. Analysis of apoptosis and cell cycle stages were performed using flow cytometry. the expressions of several apoptotic-related proteins in SK-BR-3 cells were evaluated using Western blot analysis. ROS formation and caspase activity were determined. GC-MS (involving a multistep temperature gradient and trimethylsilyl derivatives) and phytochemical analysis were used for identification of bioactive compounds. Methanolic extract inhibited the proliferation of the SK-BR-3 cell line in a dose- and time-dependent manner. As it was observed, exposure of the H. leucospilota extract triggered the apoptosis of the SK-BR-3 cells, induced DNA fragmentation, and arrested the cells in G2/M phase. treatment of the methanolic extract induced the downregulation of antiapoptotic Bcl-2 protein as well as the upregulation of Bax, caspase-3, caspase-7 proteins in SK-BR-3 cells. Methanolic extract-elicited apoptosis was accompanied with the elevated level of ROS. The GC-MS and phytochemical analysis revealed 30 compounds and the extract contained alkaloids, flavonoids, steroids, terpenoids, phenols, and saponins. CONCLUSIONS: The antiproliferative and proapoptotic activities of the tested extract suggested the pharmacologic potential of H. leucospilota. Correspondingly, further characterizations of the identified compounds are in progress.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Pepinos-do-Mar/metabolismo , Extratos de Tecidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Caspase 3 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Flavonoides/farmacologia , Humanos , Células MCF-7 , Proteínas Proto-Oncogênicas c-bcl-2 , Saponinas/farmacologiaRESUMO
The cytotoxic activity of four cyclometalated platinum(II) complexes [PtMe(vpy)(L)], containing 2-vinylpyridine (vpy) and the phosphine ligands (L) PMe2Ph (1a), PPh3 (1b), PMePh2 (1c), and P(c-Hex)3 (1d), were evaluated against human breast cancer (MDA-MB-231), human lung cancer (A549), human colon cancer (SW1116), and non-tumor epithelial breast (MCF-10 A) cell lines. The highest activity was found for 1c with IC50 values of 21.10 µM, 23.36 µM, and 12.96 µM, compared to cisplatin, which was 10.12 µM, 47.57 µM, and 19.50 µM against the A549, SW1116, and MDA-MB-231 cell lines, respectively. 1a-d showed a higher selectivity index (SI) than cisplatin. Docking studies confirmed interaction to the DNA minor groove for all complexes. Genotoxicity studies on 1c showed interactions with the genomic content of malignant cells. Compared with cisplatin as a positive control, a slight shift was found in the electrophoresis mobility, which was utilized further to study the direct interaction of 1c with DNA.
Assuntos
Antineoplásicos , Complexos de Coordenação , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Complexos de Coordenação/química , DNA/química , Humanos , Platina/química , PiridinasRESUMO
Although the therapeutic effect of liposomal arsenic trioxide arsenic trioxide (ATO) in the treatment of solid tumours has been confirmed, its dose-limiting loading is a challenging issue. To solve the problems in the preparation of liposomal ATO, different loading strategies were evaluated and compared. In addition, liposomes decorated with anti-nucleolin aptamers were developed as a novel formulation for targeted delivery with high loading efficiency and sustained releasing property in order to treat solid tumours. The liposomes were prepared by a thin-film method exploiting the passive loading strategy of Co(II) hydrogen arsenite (CHA). The structural characteristics of the liposomes were also investigated by Fourier transform infra-red spectroscopy (FT-IR), dynamic light scattering (DLS), zeta potentiometry, field emission scanning electron microscopy (FESEM), and Energy Dispersive X-ray Diffraction (EDX) techniques. To evaluate the potential cytotoxicity of this liposomal drug vehicle in vitro, MTT assay was performed on HT-29 cancer cell line. The results showed that the synthesised liposomes loaded with CHA exhibited high entrapment efficiency (77%). MTT assays showed a significant difference between the percentage of viable cells when HT -29 cells were treated with free ATO and liposomal formulation which can be corresponded to the sustained release of the drug from the liposomes. The results of this study may lead to a promising strategy for the effective treatment of solid tumours.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Trióxido de Arsênio/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: 5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells. METHODS: MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines. RESULTS: Treatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax. CONCLUSION: Mitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.
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Apoptose/efeitos dos fármacos , Ácido Dicloroacético/farmacologia , Glucose/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piruvatos/farmacologia , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais , Sinergismo Farmacológico , Fluoruracila , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos BiológicosRESUMO
Bisphenol A (BPA), which is an applied endocrine disrupting chemical in industry for producing epoxy resins and polycarbonate plastics and naringin, is an active flavanone glycoside of grapefruit and many citrus fruits. The present study evaluated the protective effect of naringin against cardiotoxicity induced by BPA. Male Wistar rats were divided into six groups. Control group received oral olive oil; and BPA group orally were administrated 50 mg/kg of BPA for 30 d consecutively to induce toxicity. 40, 80, and 160 mg/kg of naringin were orally administered for 30 consecutive, along with BPA. Naringin group orally received 160 mg/kg of naringin for 30 d consecutively. Animals were sacrificed and their biochemical, histological, and oxidative stress parameters were measured 24 h after the last treatment. Heart injury was induced by BPA as an evidence with a significant increase in levels of aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, triglyceride, lipid peroxidation, and a significant decrease in levels of glutathione, superoxide dismutase, catalase, and glutathione peroxidase and triggered myocardial disorganization, myofibrillar loss, congestion of red blood cells, and the inflammation. However, there were not any changes in the total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and alanine aminotransferase. Moreover, our results indicated that administering 80 and 160 mg/kg of naringin significantly altered all examined endpoints that were induced by BPA. Both concentrations of 80 and 160 mg/kg of naringin were more effective than 40 mg/kg. These findings indicated that naringin had a protective effect against cardiotoxicity induced by BPA through lipid-lowering properties, antioxidant activity, and suppressed lipid peroxidation.
Assuntos
Compostos Benzidrílicos/toxicidade , Cardiotoxicidade/prevenção & controle , Flavanonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cardiotoxicidade/etiologia , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Flavanonas/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer cytokine with minimal toxicity towards normal cells. Nevertheless, most primary cancers are often intrinsically TRAIL-resistant or can acquire resistance after TRAIL therapy. This study aimed to investigate the inhibitory effect of co-treatment of 3-bromopyruvate (3-BP) as a potent anticancer agent with TRAIL on colon cancer cells (HT-29). The results of present study indicated that combined treatment with 3-BP and TRAIL inhibited the proliferation of HT-29 cells to a greater extent (88.4%) compared with 3-BP (54%) or TRAIL (11%) treatment alone. In contrast, the combination of 3-BP and TRAIL had no significant inhibitory effect on the proliferation of normal cells (HEK-293) (8.4%). At a cellular mechanistic level, the present study showed that 3-BP sensitized human colon cancer cells to TRAIL-induced apoptosis via reactive oxygen species generation, upregulation of Bax, downregulation of Bcl-2 and survivin, release of cytochrome c into the cytosol, and activation of caspase-3. In normal cells, 3-BP, TRAIL, or combination of both had no significant effect on the reactive oxygen species levels, release of cytochrome c, and caspase-3 activity. Therefore, the combination of 3-BP and TRAIL can be a promising therapeutic strategy for treatment of colon cancer.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/metabolismo , Neoplasias do Colo/patologia , Mitocôndrias/efeitos dos fármacos , Piruvatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Antineoplásicos/farmacologia , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Survivina/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Recently, we found that lovastatin, a HMG-CoA reductase inhibitor, and gamma-tocopherol, one of the significant types of vitamin E in diet, additively induced apoptosis in a colorectal carcinoma cell line. In this study we mechanistically monitored the loss of mitochondrial membrane potential, amount of cytosolic cytochrome c and caspase 3 activity after treatment by lovastatin and gamma-tocopherol. HT29 cells were treated with different doses of lovastatin and gamma-tocopherol for 48 and 72 h. Lovastatin and gamma-tocopherol in combination induced the release of cytochrome c, caspase 3 activation, and loss of mitochondrial membrane potential more significantly compared to their controls. Our data showed that lovastatin plus gamma tocopherol potently induced mitochondrial membrane potential collapse, cytochrome c release along with caspase 3 activation that reveals the importance of targeting programmed cell death signaling at different points of its signaling pathway for cancer therapy.
Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Colorretais/patologia , Lovastatina/farmacologia , gama-Tocoferol/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Sinergismo Farmacológico , Células HEK293 , Células HT29 , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transdução de SinaisRESUMO
The goal of this research is the development of multiple monolithic fiber-solid phase microextraction (MMF-SPME) using a new integrated fiber for the determination of amphetamine derivatives and modafinil from unauthorized medicinal supplements. For this purpose, a monolithic fiber of metal organic framework MIL-Al (53)-deep eutectic solvent (DES)/molecularly imprinted polymers (MOF-DES/MIP) was synthesized. To find optimum microextraction conditions gas chromatography-mass spectrometer (GC-MS) was used and the influences of effective variables were investigated using one factor at a time method. After that, the significant variables were optimized using a Box-Behnken design (BBD) combined with a desirability function (DF). Under optimized conditions (desorption solvent=1500 µL of 1-octanol, pH=3.5, extraction time=35 min, [NaCl]=0% w/v and stirring rate=600 rpm), calibration graphs of analytes were linear in a concentration range of 0.1-400 µg L-1 with correlation coefficients > 0.9966. Limits of detection and quantification were in the ranges of 0.023-0.033 µg L-1 and 0.088-0.113 µg L-1, respectively. This procedure was successfully employed in determining target analytes in spiked and unspiked unauthorized medicinal supplement samples with recoveries ranging from 95.14 to 104.63%.
Assuntos
Estruturas Metalorgânicas , Polímeros Molecularmente Impressos , Polímeros , Modafinila , Microextração em Fase Sólida/métodos , Solventes Eutéticos Profundos , Cromatografia Gasosa-Espectrometria de Massas , Cromatografia Gasosa , AnfetaminasRESUMO
Bisphenol A (BPA), an endocrine disruptor, is commonly used to produce epoxy resins and polycarbonate plastics. Continuous exposure to BPA may contribute to the development of diseases in humans and seriously affect their health. Previous research suggests a significant relationship between the increased incidence of neurological diseases and the level of BPA in the living environment. Syringic acid (SA), a natural derivative of gallic acid, has recently considered much attention due to neuromodulator activity and its anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Therefore, in this study, we aimed to investigate the effects of SA on oxidative stress, apoptosis, memory and locomotor disorders, and mitochondrial function, and to identify the mechanisms related to Alzheimer's disease (AD) in the brain of rats receiving high doses of BPA. For this purpose, male Wistar rats received BPA (50, 100, and 200 mg/kg) and SA (50 mg/kg) for 21 days. The results showed that BPA exposure significantly altered the rats' neurobehavioral responses. Additionally, BPA, by increasing the level of ROS, and MDA level, increased the level of oxidative stress while reducing the level of antioxidant enzymes, such as SOD, CAT, GPx, and mitochondrial GSH. The administration of BPA at 200 mg/kg significantly decreased the expression of ERRα, TFAM, irisin, PGC-1α, Bcl-2, and FNDC5, while it increased the expression of TrkB, cytochrome C, caspase 3, and Bax. Moreover, the Western blotting results showed that BPA increased the levels of P-AMPK, GSK3b, p-tau, and Aß, while it decreased the levels of PKA, P-PKA, Akt, BDNF, CREB, P-CREB, and PI3K. Meanwhile, SA at 50 mg/kg reversed the behavioral, biochemical, and molecular changes induced by high doses of BPA. Overall, BPA could lead to the development of AD by affecting the mitochondria-dependent apoptosis pathway, as well as AMPK/PGC-1α/FNDC5 and CREB/BDNF/TrkB signaling pathways, and finally, by increasing the expression of tau and Aß proteins. In conclusion, SA, as an antioxidant, significantly reduced the toxicity of BPA.
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Background: The majority of insecticides target sodium channels. The increasing emergence of resistance to the current insecticides has persuaded researchers to search for alternative compounds. Scorpion venom gland as a reservoir of peptides or proteins, which selectively target insect sodium channels. These proteins would be an appropriate source for finding new suitable anti-insect components. Methods: Transcriptome of venom gland of scorpion Mesobuthus eupeus was obtained by RNA extraction and complementary DNA library synthesis. The obtained transcriptome was blasted against protein databases to find insect toxins against sodium channel based on the statistically significant similarity in sequence. Physicochemical properties of the identified protein were calculated using bioinformatics software. The three-dimensional structure of this protein was determined using homology modeling, and the final structure was assessed by molecular dynamics simulation. Results: The sodium channel blocker found in the transcriptome of M. eupeus venom gland was submitted to the GenBank under the name of meuNa10, a stable hydrophilic protein consisting of 69 amino acids, with the molecular weight of 7721.77 g/mol and pI of 8.7. The tertiary structure of meuNa10 revealed a conserved LCN-type cysteine-stabilized alpha/beta domain stabilized by eight cysteine residues. The meuNa10 is a member of the 3FP superfamily consisting of three finger-like beta strands. Conclusion: This study identified meuNa10 as a small insect sodium channel-interacting protein with some physicochemical properties, including stability and water-solubility, which make it a good candidate for further in vivo and in vitro experiments in order to develop a new bioinsecticide.
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Inseticidas , Venenos de Escorpião , Animais , Sequência de Aminoácidos , Escorpiões/química , Inseticidas/metabolismo , Venenos de Escorpião/genética , Cisteína/metabolismo , Canais de Sódio/química , Canais de Sódio/metabolismoRESUMO
Epidemiological evidence has associated chronic exposure to inorganic arsenic with an increased occurrence of glucose intolerance and diabetes mellitus. Furthermore, inorganic arsenic induces oxidative stress in organs such as the liver. Betaine, as a methyl donor, plays a pivotal role in homocysteine metabolism. Betaine has antioxidant and anti-inflammatory properties. Therefore, the aim of this study was to evaluate the effects of betaine against sodium arsenite-induced diabetes and hepatotoxicity in mice. Forty-eight male mice were divided into 6 groups of 8. Group 1, received distilled water every day for 4 weeks by gavage. Group 2 received 500 mg/kg betaine every day for 4 weeks by gavage. Group 3 was given 10 mg/kg NaAsO2 every day for 4 weeks by gavage. Groups 4, 5, and 6 were co-treated with 125, 250, and 500 mg/kg betaine half an hour before NaAsO2 (10 mg/kg), respectively, daily for up to 4 weeks by gavage. After 28 days of the study, the mice were fasted overnight and on day 29, fasting blood glucose was measured and glucose tolerance test was performed. On day 30, the mice were anesthetized and a blood sample was taken from the heart. Serum factors (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase activities), oxidative stress factors (malondialdehyde and glutathione levels, and the activity of superoxide dismutase, glutathione peroxidase, and catalase enzymes) and hepatic inflammatory factors (nitric oxide and tumor necrosis factor α) were measured. Histopathological studies were also performed on the liver and pancreas. In this study, it was shown that arsenic causes glucose intolerance, and oxidative/inflammatory hepatic damage. Co-administration of betaine prevents hepatotoxicity and glucose intolerance induced by arsenic in mice. Co-treatment of betaine with arsenic improved glucose intolerance and protected the liver against arsenic induced-oxidative damage and inflammation. Betaine at the dose of 500 mg/kg showed better results than the other doses. Accordingly, betaine can be suggested as a therapeutic agent against diabetogenic and hepatotoxic effects of arsenic.
Assuntos
Arsênio , Doença Hepática Induzida por Substâncias e Drogas , Diabetes Mellitus , Intolerância à Glucose , Camundongos , Masculino , Animais , Betaína/farmacologia , Arsênio/toxicidade , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Antioxidantes/metabolismo , Estresse Oxidativo , Fígado , Glutationa/metabolismo , Diabetes Mellitus/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
Gentamicin is an essential aminoglycoside antibiotic, but it is only used to treat severe bacterial infections due to its high nephrotoxicity in patients. We evaluated the preventive effects of diosmin (as a natural ingredient) on gentamicin-related kidney damage in rats. In this research, 28 male Wistar rats were divided into four groups: control, gentamicin (100 mg/kg (i.p.), daily for 1 week), gentamicin plus diosmin (50 mg/kg, p.o., daily for 2 weeks), and diosmin (50 mg/kg/day, p.o. for 2 weeks). After the final gavage, blood samples were collected for the determination of blood urea nitrogen (BUN) and creatinine. Kidneys are used for biochemical, inflammatory, and histological tests. The concentrations of creatinine, BUN, nitric oxide, malondialdehyde, tumor necrosis factor α (TNF-α), and interleukin 1 beta (IL-1ß) were significantly increased. But, the level of glutathione and activities of catalase, glutathione peroxidase, and superoxide dismutase decreased during treatment with gentamicin. On the other hand, the concentrations of creatinine, BUN, nitric oxide, malondialdehyde, TNF-α, and IL-1ß were significantly reduced, and the glutathione level, activities of catalase, and glutathione peroxidase were significantly increased via co-administration with diosmin. Diosmin had ameliorative impacts against gentamicin-related kidney injury due to its antioxidant and anti-inflammatory activities.
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Diosmina , Nefropatias , Ratos , Masculino , Animais , Gentamicinas/toxicidade , Catalase , Diosmina/farmacologia , Diosmina/uso terapêutico , Ratos Wistar , Creatinina , Óxido Nítrico , Fator de Necrose Tumoral alfa/farmacologia , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Rim , Glutationa , Malondialdeído , Glutationa PeroxidaseRESUMO
BACKGROUND AND OBJECTIVE: In the design of modern metal-based anticancer drugs, platinum-based complexes have gained growing interest. In this study, the anticancer activity of half-lantern cyclometalated Pt(II)âPt(II) complexes was evaluated using MTT, apoptosis, cell cycle analysis, and DNA binding studies. MATERIALS AND METHODS: The cytotoxicity of Pt(II)âPt(II) complexes were evaluated against different cancer cell lines, such as human lung (A549), breast (MCF-7, and MDA-MB-231), ovarian (SKOV-3), and colon (HT-29) as well as normal breast (MCF-10A), and human lung fibroblast (MRC-5) cells using MTT assay. BioLegend's PE Annexin, V Apoptosis Detection Kit with 7AAD, was applied to assess the apoptotic effects of 1A and 1B compound against MCF-7 and A549 cell lines. Cell cycle analysis was determined using the flow cytometry method. The interaction of compounds with four different DNA structures with PDB codes (1BNA, 1LU5, 3CO3, and 198D) has been investigated by molecular docking. To achieve binding to DNA experimentally, the electrophoresis mobility shift assay and comet assay were applied. RESULTS: In the evaluation of cytotoxic effects, 1A showed the highest cytotoxicity among the studied compounds, and it showed higher potency with more selectivity against normal cell lines than cisplatin. This compound had IC50 of 7.24, 2.21, 1.18, 2.71, 10.65, 18.32, and 49.21 µM against A549, SKOV3, HT29, MCF-7, MDA-MB-231, MRC-5, and MCF-10A, respectively, whereas cisplatin had IC50 of 9.75, 19.02, 107.23, 15.20, 18.09, 14.36, and 24.21 µm, respectively, on the same cell lines. In order to check the DNA binding activity of 1A, and 1B, electrophoretic mobility was also conducted, which indicated that the binding of these compounds led to a slight change in electrophoretic mobility to DNA. The migration of chromosomal DNA from the nucleus in the form of a tail or comet was executed in the comet assay of 1A on MCF-7. Examination of apoptosis of 1A and 1B on the MCF-7 cancer cell line showed that it could increase induction of apoptosis in this cancerous cell in a concentration-dependent manner. Investigating the effect of 1A using cell cycle analysis on MCF-7 cancer cell line showed that this complex affects stage G1 and S of the cell cycle. CONCLUSION: 1A has the potential to play a significant role in future biopharmaceutical studies.
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Antineoplásicos , Platina , Antineoplásicos/química , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Platina/químicaRESUMO
Arsenic as a heavy metal and toxic pollutant has been established that has the hepatotoxic effect in animal and human models. Previous studies showed that mitochondria as the first target of arsenic toxicity has a pathogenic role in liver diseases. This study investigated alpha lipoic acid (ALA) as an antioxidant could ameliorate against liver toxicity induced by arsenic in rat mitochondria. First, mitochondria were isolated by the liver tissue centrifugation protocol. Then, isolated mitochondria were exposed with different concentrations of ALA and arsenic in different times for receiving the optimum dose and time. Finally, mitochondria were pretreated with the optimum concentrations and times of ALA and then treated with optimum concentration and time of arsenic (160 µg/ml; 30 min). The results demonstrated a significant decrease in total mitochondrial dehydrogenase activity (mitochondrial complex II) by 3, 4 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay after arsenic exposure. Mitochondria treated with arsenic also showed a significant increase in ROS generation, MMP, and MDA levels. The activity of mitochondrial catalase and mitochondrial GSH significantly decreased after exposure of mitochondria with arsenic. Pretreatment of mitochondria with ALA improved mitochondrial complex II activity; decreased mitochondrial membrane damage, MDA, and ROS amounts; and ameliorated mitochondrial GSH levels and mitochondrial catalase activity. These findings revealed that arsenic induced oxidative stress and mitochondria dysfunction, while ALA improved mitochondrial function through increasing of antioxidant defense or preserving of complex II, but suggested that ALA could prevent from mitochondria dysfunction.
Assuntos
Arsênio , Ácido Tióctico , Animais , Arsênio/metabolismo , Arsênio/toxicidade , Mitocôndrias , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/farmacologiaRESUMO
BACKGROUND: There is limited research examining reasons causing refractory chronic constipation (RCC) in children. The effects of lead (Pb) and cadmium (Cd) exposures on this condition have been even less clear. However, some related factors may contribute to evaluation of blood lead levels (BLLs) and blood cadmium levels (BCLs). OBJECTIVE: The present study aimed to examine the relationship between Pb and Cd exposures and RCC in children living in the city of Ahvaz, Khuzestan Province, in Southwestern Iran. METHODS: This study was performed on a total number of 48 children aged 2-13 years, including 36 medically-diagnosed RCC cases and 12 controls referring to a pediatric clinic in the city of Ahvaz. Their BLLs and BCLs were then determined using a graphite furnace atomic absorption spectrophotometer. The data from the researcher-designed questionnaire were also recoded and the related risk factors were analyzed through Spearman's correlation and logistic regression analysis. RESULTS: The findings revealed that the geometric means of Pb and Cd in blood samples in the control group were 58.95 µg/dL and 0.45 µg/dL; respectively. These values in the case group were equally 45.26 µg/dL and 0.26 µg/dL; respectively. A significant difference was additionally observed between BCLs in the case and control groups (P<0.01). All children in both groups also had BLLs greater than the permissible limit endorsed by the World Health Organization (WHO) (≤10 µg/dL). On the other hand, 8.3% of the individuals in the case group and 33.3% of those in the control group had BCLs higher than the acceptable range mentioned by WHO (≤0.5 µg/dL). CONCLUSION: Pb and Cd exposures due to environmental pollution and susceptibility to heavy metals may not be associated with RCC in children living in the city of Ahvaz. Although this research was the first one providing data on BLLs and BCLs in children with RCC, the findings could be useful for designing future epidemiologic studies.
Assuntos
Cádmio , Chumbo , Cádmio/análise , Criança , Constipação Intestinal/induzido quimicamente , Humanos , Irã (Geográfico)/epidemiologia , Chumbo/análise , Fatores de RiscoRESUMO
OBJECTIVE: Bisphenol A (BPA) is an organic synthetic compound, often used in manufacturing polycarbonate plastics. Researches have shown the role of BPA as an endocrine disruptor. The present study intended to evaluate the hepatoprotective properties of naringin, an active flavanone glycoside present in many citrus fruit, against hepatotoxicity induced by BPA. MATERIALS AND METHODS: Male Wistar rats were orally treated with 50 mg/kg BPA for 30 consecutive days for induction of toxicity and 40, 80 and 160 mg/kg naringin for the same period along with BPA or alone. RESULTS: This study demonstrated that BPA significantly increased serum levels of triglyceride, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipid peroxidation, and aspartate aminotransferase (AST) and significantly reduced catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity, glutathione (GSH) and caused periportal inflammation and microvesicular steatosis in rat tissue. However, BPA did not change serum levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, alanine aminotransferase (ALT), or low-density lipoprotein-cholesterol (LDL-C). Furthermore, the results displayed that administration of 80 and 160 mg/kg naringin improved hepatotoxicity and altered lipid peroxidation level, serum values of triglyceride and liver enzymes, and oxidative stress factors that were induced by BPA. The effect of two doses of 80 and 160 mg/kg naringin was more noticeable than that of dose 40 mg/kg. CONCLUSION: The findings suggested the protective effects of naringin against BPA-induced hepatotoxicity via ameliorating liver histopathological alteration, suppressing oxidative stress and lipid-lowering properties.
RESUMO
Nonalcoholic fatty liver disease (NAFLD) occurs due to lipid metabolic disorders, which is associated with hepatic oxidative stress and inflammation. There is no definitive drug treatment for this disease. Accordingly, the present study aimed to evaluate the effects of dimethyl fumarate (DMF) as one of the superior effective drugs that induces a transcription factor of nuclear factor erythroid 2-related factor 2 (Nrf2) on development of NAFLD in mice. The metabolic disturbance in High-fat diet (HFD)-treated animals was associated with hyperlipidemia, increased activity levels of hepatic enzymes in serum, hyperglycemia, hyperinsulinemia, oxidative stress and inflammation. DMF supplementation had anti-inflammatory, antioxidant, anti-lipogenic and molecular compatibility effects induced by HFD in mice. In comparison to the HFD group, the DMF therapy could significantly suppress the sterol regulatory element binding protein-1 c (SREBP-1c) gene and protein levels, as well as upregulate the Nrf2 gene and protein levels. Additionally, the anti-inflammatory activity was observed for the DMF by inhibiting the nuclear factor kappa B (NF-κB) level. DMF reduces the development of NAFLD induced by HFD in mice through the modulation of transcription factors Nrf2, SREBP-1c and NF-κB. Thus, DMF can be considered as an effective candidate in the treatment of human NAFLD.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Fumarato de Dimetilo/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
OBJECTIVES: The purpose of this study was to investigate cytotoxicity and membrane toxicity effects induced by Mesobuthus eupeus venom (MEV) on the HT-29 cell line. MATERIALS AND METHODS: To determine the in vitro cytotoxicity via MTT assays, HT-29 (as cancer cell line) and Hek-293T (as normal cell) were treated through different concentrations of MEV, and cytotoxicity effects were then measured through assessment of mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) generation, and apoptosis induction. The colony formation assay was performed to measure the antiproliferative effect of MEV on HT-29 cells. Nuclei alterations were also observed during apoptosis following DAPI staining. Besides, atomic force microscopy (AFM) was used to detect alterations in morphology and ultrastructure of the cells at a nanoscale level. RESULTS: According to MTT and clonogenic assays, MEV caused a significant decrease in cell viability and proliferation of HT-29 cells while it did not have any impact on normal cells and the IC50 value was found to be 10 µg/ml. Induction of apoptosis was also confirmed by flowcytometric analysis in HT-29 cells. Moreover, the results indicated that MEV had led to a suppression of proliferation and induction of apoptosis through increased ROS and depolarization of mitochondria. Furthermore, AFM imaging demonstrated apoptosis cell death after being treated with MEV in HT-29 cells. CONCLUSION: This study showed that MEV had an antiproliferative effect on HT-29 cells by inducing apoptosis through the mitochondria signaling pathway. These findings suggested that MEV could be used as a promising natural remedy for cancer treatment.