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1.
Int J Nanomedicine ; 15: 3471-3482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547008

RESUMO

Introduction: Nanoparticles are at the forefront of rapidly developing nanotechnology and have gained much attention for their application as an effective drug delivery system and as a mediated therapeutic agent for cancer. However, the cytotoxicity of nanoparticles is still relatively unknown and, therefore, additional study is required in order to elucidate the potential toxicity of these nanoparticles on cells. Materials and Methods: Thus, the following work aimed to investigate the capability of Beta vulgaris (beetroot) water extract (BWE; 200 mg/kg) to protect hepatic tissue following silver nanoparticles (AgNPs; 80 mg/kg; >100 nm) intoxication in male rats. Results: AgNPs-intoxication elevated the liver function markers - including serum transaminases and alkaline phosphatase activities - and decreased serum levels of albumin and total proteins, in addition to disturbing the oxidation homeostasis. This is evidenced by the increased lipid peroxidation, the depleted glutathione, and the suppressed activity of superoxide dismutase and catalase. In addition, an apoptotic reaction was observed following AgNPs treatment, as indicated by the up-regulation of p53 and down-regulating Bcl-2 expressions, examined by the immunohistochemistry method. Furthermore, AgNPs exhibited a marked elevation in liver DNA damage that was indicated by an increase in tail length, tail DNA% and tail movement. However, BWE eliminated the biochemical and histological alterations, reflecting its hepatoprotection effect in response to AgNPs. Discussion: Collectively, the present data suggest that BWE could be used following AgNPs as a potential therapeutic intervention to minimize AgNPs-induced liver toxicity.


Assuntos
Beta vulgaris/química , Sucos de Frutas e Vegetais , Fígado/patologia , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Dano ao DNA , Fragmentação do DNA/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Nanopartículas Metálicas/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
2.
Toxicon ; 181: 57-68, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32353570

RESUMO

This study aimed to identify the bioactive compounds of the ethyl acetate extract of Aspergillus niger SH2-EGY using GC-MS and to evaluate their protective role against aflatoxin B1 (AFB1)-induced oxidative stress, genotoxicity and cytotoxicity in rats. Six groups of male Sprague-Dawley rats were treated orally for 4 weeks included the control group, AFB1-treated group (80 µg/kg b.w); fungal extract (FE)-treated groups at low (140) or high dose (280) mg/kg b.w and the groups treated with AFB1 plus FE at the two tested doses. The GC-MS analysis identified 26 compounds. The major compounds found were 1,2,3,4,6-Penta-trimethylsilyl Glucopyranose, Fmoc-L-3-(2-Naphthyl)-alanine, D-(-)-Fructopyranose, pentakis (trimethylsilyl) ether, bis (2-ethylhexyl) phthalate, trimethylsilyl ether-glucitol, and octadecanamide, N-(2- methylpropyl)-N-nitroso. The in vivo results showed that AFB1 significantly increased serum ALT, AST, creatinine, uric acid, urea, cholesterol, triglycerides, LDL, carcinoembryonic antigen, alpha-fetoprotein, interleukin-6, Malondialdehyde, nitric oxide, Bax, caspase-3 and P53 mRNA expression, chromosomal aberrations and DNA fragmentation. It decreased serum TP, albumin, HDL, Bcl-2 mRNA expression, hepatic and renal TAC, SOD and GPx content and induced histological changes in the liver and kidney. FE prevented these disturbances in a dosage-dependent manner. It could be concluded that A. niger SH2-EGY extract is safe a promising agent for pharmaceutical and food industries.


Assuntos
Aflatoxina B1/toxicidade , Antioxidantes/uso terapêutico , Aspergillus niger , Animais , Fragmentação do DNA/efeitos dos fármacos , Inativação Metabólica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
3.
Clin Sci (Lond) ; 134(11): 1191-1218, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32432676

RESUMO

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.


Assuntos
Eosinófilos/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Interleucina-33/farmacologia , Infarto do Miocárdio/fisiopatologia , Sístole/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fragmentação do DNA/efeitos dos fármacos , Diástole/efeitos dos fármacos , Eosinofilia/patologia , Eosinófilos/efeitos dos fármacos , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Mediadores da Inflamação/sangue , Interleucina-33/administração & dosagem , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esplenomegalia/patologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
4.
Anticancer Res ; 40(5): 2525-2536, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366397

RESUMO

BACKGROUND/AIM: Mast cell transformation, as manifested in mastocytosis, can be a serious condition for which there are limited therapeutic options. Mastocytosis cells can be sensitive to histone deacetylase (HDAC) inhibitors, but their sensitivity to other histone-modifying enzymes has not been assessed. Here we addressed this issue. MATERIALS AND METHODS: Inhibitors of histone methyl transferases, histone demethylases, histone acetyl transferases and HDACs were tested for their effects on growth, viability, caspase-3 activation and annexin V/DRAQ7 staining in transformed mast cells. RESULTS: Transformed mast cells underwent cell death in response to histone methyl transferase and HDAC inhibition, but were not sensitive to histone demethylase or histone acetyl transferase inhibition. Histone methyl transferase inhibition led to cell death with characteristics of apoptosis, as judged by caspase-3 activation. However, DNA fragmentation was not apparent and Annexin V+/DRAQ7- cells were not predominant, suggesting a type of cell death differing from classical apoptosis. CONCLUSION: Histone methyl transferase inhibition could be developed as a novel regimen for targeting mastocytosis.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Metiltransferases/antagonistas & inibidores , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastocitose/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Histonas/metabolismo , Humanos , Mastocitose/tratamento farmacológico , Mastocitose/etiologia , Mastocitose/patologia
5.
Environ Toxicol ; 35(9): 930-941, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32309901

RESUMO

Platinum nanoparticles (PtNPs) attract much attention due to their excellent biocompatibility and catalytic properties, but their toxic effects on normal (CHANG) and cancerous (HuH-7) human liver cells are meagre. The cytotoxic and apoptotic effects of PtNPs (average size, 3 nm) were determined in CHANG and HuH-7 cells. After treating these cells were with PtNPs (10, 50, 100, 200, and 300 µg/mL) for 24 and 48 hours, we observed dose- and time-dependent cytotoxicity, as evaluated by using (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide, a tetrazole) (MTT) and neutral red uptake (NRU) assays. The production of reactive oxygen species (ROS) was increased in both cells after treatment with the above dose of PtNPs for 24 and 48 hours. Determination of morphological changes of cells, chromosome condensation, mitochondrial membrane potential, and caspase-3 assays showed that PtNPs induce cytotoxicity and apoptosis in CHANG and HuH-7 cells by altering the cell morphology and density, increasing cell population in apoptosis, and causing chromosome condensation. Furthermore, we have studied fragmentation of DNA using alkaline single cell gel electrophoresis and expression of apoptotic genes by real-time PCR (RT-PCR). The percentage of DNA fragmentation was more at 300 µg/mL for 48 hours in both cells, but slightly more fragmentation was found in HuH-7 relative to CHANG cells. Considering all of the above parameters, PtNPs elicited cytotoxicity on CHANG and HuH-7 cells by blocking cell proliferation and inducing apoptosis. Thus this study may be useful in in vitro laboratory studies using cell lines for screening the genotoxic and apoptotic potential of nanoparticles.


Assuntos
Apoptose/efeitos dos fármacos , Dano ao DNA , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas Metálicas/química , Estresse Oxidativo/efeitos dos fármacos , Platina/farmacologia , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Morte Celular , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Fígado/metabolismo , Fígado/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/genética , Platina/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
PLoS One ; 15(3): e0224052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32168344

RESUMO

BACKGROUND: Codeine, a 3-methylmorphine, and other related opioids have been implicated in androgen suppression, although the associated mechanisms remain unclear. AIM: Therefore, the objective of the current study was to elucidate the in vivo molecular mechanisms underlying codeine-induced androgen suppression. METHODS: This study made use of twenty-one healthy male rabbits, distributed into three groups randomly, control and codeine-treated groups. The control had 1ml of normal saline daily p.o. The codeine-treated groups received either 4mg/kg b.w of codeine or 10mg/kg b.w of codeine p.o. for six weeks. Reproductive hormonal profile, testicular weight, testicular enzymes, oxidative and inflammatory parameters, testicular DNA fragmentation, histological examination and apoptosis marker were evaluated to examine the effects of codeine use. KEY FINDINGS: Oral administration of codeine resulted in testicular atrophy and alterations in testicular histomorphology, elevated testicular enzymes, and suppression of circulatory and intra-testicular testosterone. These changes were associated with a marked rise in oxidative markers and decline in the activities of testicular enzymatic antioxidants, as well as oxidative DNA damage, inflammatory response, testicular DNA fragmentation, and caspase-dependent apoptosis (p<0.05). SIGNIFICANCE: In conclusion, chronic codeine use resulted in testicular degeneration and testosterone suppression, which is attributable to TNF-α/nitric oxide-/oxidative stress-mediated caspase-dependent apoptotic testicular cell death and loss of testicular function.


Assuntos
Caspase 3/metabolismo , Codeína/toxicidade , Fragmentação do DNA/efeitos dos fármacos , Óxido Nítrico/metabolismo , Testículo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Administração Oral , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Codeína/administração & dosagem , Masculino , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Testículo/metabolismo , Testosterona/metabolismo
7.
Food Chem Toxicol ; 137: 111134, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006631

RESUMO

Tebuconazole is an effective systemic fungicide that belongs to the triazoles family. It has been widely used in both agricultural and medical sectors for the control of fungal diseases. Although TEB poses serious threats to mammals health, studies regarding its cardiotoxicity are very limited. Thus, we aimed to evaluate the effects of TEB on some biochemical parameters, the induction of apoptosis and DNA damage in the heart tissue. Male Wistar rats were treated with TEB at varied oral doses for 28 consecutive days. This study demonstrates that TEB decreased cardiac acetylcholinesterase, increased serum marker enzymes such as creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH), and altered the lipid profile by increasing serum levels of total cholesterol (T-CHOL), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, TEB increased levels of p53 and Bax/Bcl2 ratio, released the cytochrome c into the cytosol and activated caspase-9 and caspase-3. Besides, our results showed that TEB induced genotoxic effects. TEB induced DNA fragmentation and increased the frequency of micronucleated bone marrow cells. Moreover, TEB treatment developed fibrosis in the myocardium. Our results suggest that TEB exposure may affect myocardial cells normal functioning and triggers apoptosis.


Assuntos
Cardiotoxicidade/etiologia , Fungicidas Industriais/toxicidade , Triazóis/toxicidade , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Cardiotoxicidade/fisiopatologia , LDL-Colesterol/metabolismo , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
8.
Mol Med Rep ; 21(3): 1258-1266, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016451

RESUMO

Hesperetin is a natural flavonoid with robust antioxidant properties. Our previous study reported that hesperetin can prevent cataract formation. However, an important consideration regarding hesperetin consumption is the limited bioavailability due to its poor solubility. The present study investigated the anti­cataract effects of α­glucosyl hesperidin in vivo and in vitro using a selenite­induced cataract model. SD rats (age, 13 days) were orally administered PBS (0.2 ml) or α­glucosyl hesperidin (200 mg/kg) on days 0, 1 and 2. Sodium selenite was subcutaneously administered to the rats 4 h after the first oral administration on day 0. Antioxidant levels in the lens and blood were measured on day 6. In vitro, human lens epithelial cells were treated with sodium selenite (10 µM) and/or hesperetin (50 or 100 mM) for 24 h and analyzed for apoptosis markers using sub­G1 population and Annexin V­FITC/propidium iodide staining and DNA ladder formation. α­glucosyl hesperidin treatment significantly reduced the severity of selenite­induced cataract. The level of antioxidants was significantly reduced in the selenite­treated rats compared with in the controls; however, they were normalized with α­glucosyl hesperidin treatment. In vitro, hesperetin could significantly reduce the number of cells undergoing apoptosis induced by sodium selenite in human lens epithelial cell lines. Overall, oral consumption of α­glucosyl hesperidin could delay the onset of selenite­induced cataract, at least in part by modulating the selenite­induced cell death in lens epithelial cells.


Assuntos
Antioxidantes/administração & dosagem , Catarata/tratamento farmacológico , Glucosídeos/administração & dosagem , Hesperidina/análogos & derivados , Selenito de Sódio/efeitos adversos , Administração Oral , Animais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Catarata/induzido quimicamente , Catarata/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Glucosídeos/química , Hesperidina/administração & dosagem , Hesperidina/química , Humanos , Cristalino/efeitos dos fármacos , Cristalino/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
9.
JAMA ; 323(1): 35-48, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910279

RESUMO

Importance: Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective: To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants: The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions: Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures: The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results: Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance: Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration: ClinicalTrials.gov Identifier: NCT01857310.


Assuntos
Suplementos Nutricionais , Ácido Fólico/farmacologia , Infertilidade Masculina/tratamento farmacológico , Sêmen/efeitos dos fármacos , Zinco/farmacologia , Adolescente , Adulto , Fragmentação do DNA/efeitos dos fármacos , Suplementos Nutricionais/efeitos adversos , Feminino , Fertilização In Vitro , Ácido Fólico/efeitos adversos , Ácido Fólico/uso terapêutico , Humanos , Nascimento Vivo , Masculino , Pessoa de Meia-Idade , Análise do Sêmen , Contagem de Espermatozoides , Falha de Tratamento , Adulto Jovem , Zinco/efeitos adversos , Zinco/uso terapêutico
10.
Exp Hematol ; 81: 32-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954171

RESUMO

Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC20 levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mieloma Múltiplo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bussulfano/farmacologia , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melfalan/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Panobinostat/farmacologia , Sulfonamidas/farmacologia
11.
Dalton Trans ; 49(4): 1232-1240, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31903474

RESUMO

Three asymmetric tridentate acyl hydrazone Schiff base ligands namely L1, L2 and L3 were prepared via condensation of 4-methoxybenzohydrazide with picolinaldehyde, 1-(pyridin-2-yl)ethanone and phenyl(pyridin-2-yl)methanone respectively. Three bio-relevant mononuclear zinc(ii) complexes [Zn(L1)Cl2]·2H2O (1), [Zn(L2)Cl2] (2) and [Zn(L3)Cl2] (3) were synthesized by treatment of zinc(ii) chloride with the corresponding Schiff base ligands and characterised by the usual physicochemical techniques. The solid state structures of complexes 1 and 3 were evaluated by single crystal X-ray analysis. All complexes were able to hydrolyse the P-O bond of the phosphate monoester in 90% (v/v) DMSO-water medium using 4-nitrophenylphosphate (4-NPP) as the model substrate and the trend in their activity is 1≈2 > 3. On considering the highly efficient hydrolysis properties, complexes 1-3 were tested as potential therapeutic agents for cancer using HCT116 (human colorectal carcinoma), HepG2 (human hepatocellular carcinoma) and A549 (human non-small lung carcinoma) cells. Complex 2 showed the highest IC50 values for anti-cancer activity towards all three cell lines among the three complexes and complex 3 showed the least activity as observed in the phosphatase activity study. The internucleosomal degradation of DNA during apoptosis can be detected by cell death detection ELISA. DNA fragmentation that leads to cell death was examined and when induced by complex 2 in HepG2 cells a significant level of DNA fragmentation was observed at regular intervals of time.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Hidrazonas/química , Monoéster Fosfórico Hidrolases/metabolismo , Zinco/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Cinética , Bases de Schiff/química
12.
Food Chem Toxicol ; 136: 110971, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751644

RESUMO

Outbred male rats were repeatedly injected intraperitoneally two-level sub-lethal doses of lead acetate and/or cadmium chloride solutions 3 times a week during 6 weeks. The animals developed explicit, even if moderate, subchronic intoxication characterized by a large number of indices, both common to both metals (including increased DNA fragmentation coefficient) and lead-specific. Special attention was paid to hemodynamic and electrocardiographic effects. The combined action of lead and cadmium was modeled with the help of the Response Surface Methodology to obtain additional support for the previously substantiated postulates of combined toxicity's typological ambiguity. This is dependent on which particular effect comes under consideration, on its level, and on the acting dose ratio. For one and the same toxic combination, the type of combined toxic action can vary from synergistic to contra-directional. In particular, the actions of lead and cadmium on blood pressure were found to be opposite in direction. Furthermore, it is shown once again that the systemic toxic effects of a metal combination, its in vivo genotoxicity included, can be more or less attenuated by background administration of a theoretically justified composition of biologically active agents.


Assuntos
Cádmio/toxicidade , Chumbo/toxicidade , Animais , Animais não Endogâmicos , Cádmio/sangue , Cloreto de Cádmio/administração & dosagem , Cloreto de Cádmio/toxicidade , Fragmentação do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Ecocardiografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Chumbo/sangue , Masculino , Mutagênicos/toxicidade , Miocárdio/patologia , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/toxicidade , Ratos , Testes de Toxicidade Subcrônica
13.
Exp Parasitol ; 209: 107810, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31801691

RESUMO

Fasciolosis is a neglected tropical disease caused by the liver fluke Fasciola gigantica. The absence of successful vaccine and emerging resistance in flukes against the drug of choice, triclabendazole, has necessitated the search for alternatives including phyto-therapeutic approaches. Curcumin and thymoquinone, the active ingredients of Curcuma longa and Nigella sativa plants respectively, were first screened for their binding affinity with Glutathione-S-transferase (GST) molecule through in silico molecular docking followed by in vitro treatment of worms with varying concentrations of the test compounds. The in silico molecular docking of curcumin and thymoquinone with sigma GST revealed strong hydrogen bonding as well as hydrophobic interactions with high fitness scores but showing inter-specific differences. The in vitro treatment of F. gigantica worms with both curcumin and thymoquinone resulted in a significant increase in the generation of reactive oxygen species (ROS) whereas the level of reduced glutathione, a primary redox regulator, was found to be significantly decreased (p < 0.05). The two compounds not only inhibited the GST activity, which is an important detoxification enzyme and also a key drug/vaccine target for the control of fasciolosis but also significantly inhibited the activity of antioxidant enzymes glutathione peroxidase and glutathione reductase that are vital in maintenance of redox homeostasis. The immunohistochemistry performed using anti sigma GST polyclonal antibodies revealed that both the compounds used in the present study significantly reduced immunofluorescence in the vitellaria, developing eggs present in the ovary and the intestinal caecae indicating inhibition of GST enzyme in these regions of the worms. Further, following treatment with curcumin and thymoquinone, chromatin condensation and DNA fragmentation was also observed in F. gigantica worms. In conclusion, both curcumin and thymoquinone generated oxidative stress in the worms by production of ROS and significantly inhibiting their antioxidant and detoxification ability. The oxidative stress along with induction of apoptotic like events would compromise the survival ability of worms within the host. However, further studies are required to establish their anthelmintic potential alone and in combination with the commonly used anthelmintic drugs under in vivo conditions.


Assuntos
Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Curcumina/farmacologia , Fasciola/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzoquinonas/química , Búfalos , Cromatina/efeitos dos fármacos , Curcumina/química , Dano ao DNA/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Eletroforese em Gel de Ágar , Inibidores Enzimáticos/farmacologia , Fasciola/citologia , Fasciola/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/antagonistas & inibidores , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Imuno-Histoquímica , Microscopia Confocal , Modelos Moleculares , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo
14.
Theriogenology ; 142: 177-183, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31600638

RESUMO

Testicular cancer is one of the most common malignancy in young men, chemotherapy induced damage in cancerous cells as well as healthy tissue, and we decided to investigate recovery effect of zinc (Zn) on chemotherapy-induced complications in rat chromatin integrity and testicular histomorphometry. The male rats (n = 40) were treated with BEP at appropriate dose levels of BEP (0.75, 7.5, and 1.5 mg/kg) for 9 weeks, with or without Zn; testicular histology, sperm DNA methylation, ubiquitination, DNA fragmentation and protamination were further assessed through immunofluorescence. BEP treatment significantly increased ubiquitination, and DNA fragmentation, considerably reducing global DNA methylation and protamination (P < 0.001), resulting in degenerative changes in testicular structure. Zn restored normal DNA methylation, protamination and structure of male gonads, maintained spermatogonial stem cells, and significantly reduced the mean percentage of ubiquitination and sperm DNA fragmentation as compared with BEP group (P < 0.001). We found that supplementation of Zn following chemotherapy can improve chromatin integrity, testicular organization and spermatogenesis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromatina/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Zinco/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Cromatina/metabolismo , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citoproteção/genética , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Preservação da Fertilidade/métodos , Instabilidade Genômica/efeitos dos fármacos , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/prevenção & controle , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/patologia , Protaminas/metabolismo , Ratos , Ratos Wistar , Espermatozoides/metabolismo , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Ubiquitinação/efeitos dos fármacos , Zinco/uso terapêutico
15.
Biomed Pharmacother ; 121: 109665, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810137

RESUMO

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of cancer-related death worldwide. The treatment of metastatic CRC considered palliative for many years aiming for an improved life, with little hope of a cure, highlighting the need for developing novel targeted therapy for CRC. Human protein kinases constitute a complicated system with complex internal and external interactions, which stimulates various cellular processes such as cell growth, metabolism, survival, and apoptosis. This study investigated the effect of a combination of atypical Protein Kinase C (PKC) inhibitor (either ICA-I or ζ-Stat) and 5-FU (a thymidylate synthase inhibitor) on CRC cells viability concerning cellular DNA damage. In this study, we took multiple approaches such as colony formation assay, flow cytometry, DNA ladder assay, TUNEL assay, etc. to examine the CRC cell viability and apoptosis as a function of combination treatment. Our findings showed that the combination of atypical PKC inhibitor and 5-FU synergistically reduced the viability of CRC cells and induced apoptosis. Additionally, the DNA ladder and TUNEL assays indicated that there was a notable DNA damage and fragmentation because of lack of thymidylate synthase and due to the deactivation of atypical PKC dependent CDK7. These data suggest that the simultaneous knockdown of upstream atypical PKC protein and downstream DNA damage repairing mechanism would be a useful approach to combat CRC and to improve overall patients' survival rate.


Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Dano ao DNA , Fluoruracila/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Fluoruracila/química , Humanos , Imidazóis/farmacologia , Modelos Biológicos , Organofosfatos/farmacologia , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/química , Fator de Transcrição TFIIH/metabolismo , Ensaio Tumoral de Célula-Tronco
16.
Food Chem ; 309: 125702, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31685370

RESUMO

Our previous study indicated that nanocomposite packaging material (Nano-PM) containing nano-Ag, nano-TiO2, nano-SiO2 and nanoattapulgite alleviated postharvest senescence of Flammulina velutipes by regulating respiration and energy metabolism. In this study, extracellular ATP (eATP) and programmed cell death (PCD) were employed as critical factors to further investigate the senescence mechanism of postharvest F. velutipes. Results demonstrated that Nano-PM delayed apyrase activity decrease and stimulated critical oxidative phosphorylation-related gene expression to inhibit eATP content increase, which is a crucial signaling molecule related to delaying senescence. The regulation of eATP resulted in alleviating PCD including chromosomal concentration, DNA fragmentation, Ca2+ influx, high caspase-1 activity and cytochrome c content and leading to high cell viability. Overall, Nano-PM alleviated PCD and postharvest senescence of F. velutipes by regulating extracellular ATP.


Assuntos
Trifosfato de Adenosina/metabolismo , Apoptose , Flammulina/metabolismo , Embalagem de Alimentos/métodos , Nanocompostos/química , Apoptose/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Flammulina/efeitos dos fármacos , Nanocompostos/toxicidade , Óxido Nítrico/análise , Dióxido de Silício/química , Prata/química , Titânio/química
17.
Molecules ; 24(23)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783504

RESUMO

Male subfertility is a global issue in human reproduction as well as in animal reproduction. Bacterial infection and semen contamination are still widely overlooked. As the collection of ejaculates is not a sterile process, it is necessary to add antimicrobial agents to avoid a possible depreciation of semen samples. As traditionally used antibiotics have been questioned because of an ever-increasing bacterial resistance, natural bioactive molecules could offer an alternative because of their antibacterial and antioxidant properties. As such, we decided to compare the effects of selected natural biomolecules (resveratrol-RES, quercetin-QUE and curcumin-CUR) with routinely used antibiotics in animal biotechnologies (penicillin-PEN, gentamicin-GEN and kanamycin-KAN) on the rabbit sperm vitality in the presence of Enterococcus faecalis. Changes in the sperm structural integrity and functional activity were monitored at 0, 2, 4 and 6 h. Computer-assisted sperm analysis (CASA) was used for the assessment of spermatozoa motility. Production of reactive oxygen species (ROS) was evaluated using chemiluminiscence, while the mitochondrial membrane potential (ΔΨm) was examined using the JC-1 dye. Finally, the sperm chromatin dispersion (SCD) test was used to assess DNA fragmentation, and changes to the membrane integrity were evaluated with the help of annexin V/propidium iodide. The motility assessment revealed a significant sperm motility preservation following treatment with GEN (p < 0.001), followed by PEN and CUR (p < 0.01). QUE was the most capable substance to scavenge excessive ROS (p < 0.001) and to maintain ΔΨm (p < 0.01). The SCD assay revealed that the presence of bacteria and antibiotics significantly (p < 0.05) increased the DNA fragmentation. On the other hand, all bioactive compounds readily preserved the DNA integrity (p < 0.05). In contrast to the antibiotics, the natural biomolecules significantly maintained the sperm membrane integrity (p < 0.05). The microbiological analysis showed that GEN (p < 0.001), KAN (p < 0.001), PEN (p < 0.01) and CUR (p < 0.01) exhibited the strongest antibacterial activity against E. faecalis. In conclusion, all selected biomolecules provided protection to rabbit spermatozoa against deleterious changes to their structure and function as a result of Enterococcus faecalis contamination. Therefore, administration of RES, QUE and/or CUR to rabbit semen extenders in combination with a carefully selected antibacterial substance may be desirable.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sêmen/microbiologia , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/microbiologia , Curcumina/química , Curcumina/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/metabolismo , Infertilidade Masculina/microbiologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Quercetina/química , Quercetina/farmacologia , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/química , Resveratrol/farmacologia , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/microbiologia
18.
PLoS One ; 14(12): e0225475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31790434

RESUMO

Rapid sample preparation is one of the leading bottlenecks to low-cost and efficient sample component detection. To overcome this setback, a technology known as Lyse-It has been developed to rapidly (less than 60 seconds) lyse Gram-positive and-negative bacteria alike, while simultaneously fragmenting DNA/RNA and proteins into tunable sizes. This technology has been used with a variety of organisms, but the underlying mechanism behind how the technology actually works to fragment DNA/RNA and proteins has hitherto been studied. It is generally understood how temperature affects cellular lysing, but for DNA/RNA and protein degradation, the temperature and amount of energy introduced by microwave irradiation of the sample, cannot explain the degradation of the biomolecules to the extent that was being observed. Thus, an investigation into the microwave generation of reactive oxygen species, in particular singlet oxygen, hydroxyl radicals, and superoxide anion radicals, was undertaken. Herein, we probe one aspect, the generation of reactive oxygen species (ROS), which is thought to contribute to a non-thermal mechanism behind biomolecule fragmentation with the Lyse-It technology. By utilizing off/on (Photoinduced electron transfer) PET fluorescent-based probes highly specific for reactive oxygen species, it was found that as oxygen concentration in the sample and/or microwave irradiation power increases, more reactive oxygen species are generated and ultimately, more oxidation and biomolecule fragmentation occurs within the microwave cavity.


Assuntos
Métodos Analíticos de Preparação de Amostras/métodos , Técnicas Bacteriológicas/métodos , Fragmentação do DNA/efeitos dos fármacos , Detergentes/farmacologia , Estabilidade de RNA/efeitos dos fármacos , Fragmentação do DNA/efeitos da radiação , DNA Bacteriano/química , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/efeitos da radiação , Hidrólise/efeitos da radiação , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/genética , Listeria monocytogenes/efeitos da radiação , Micro-Ondas , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Oxigênio/análise , Oxigênio/metabolismo , Proteólise/efeitos dos fármacos , Proteólise/efeitos da radiação , Estabilidade de RNA/efeitos da radiação , RNA Bacteriano/química , RNA Bacteriano/efeitos dos fármacos , RNA Bacteriano/efeitos da radiação , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Staphylococcus aureus/efeitos da radiação , Temperatura , Fatores de Tempo , Vibrio cholerae/efeitos dos fármacos , Vibrio cholerae/genética , Vibrio cholerae/efeitos da radiação
19.
Cryobiology ; 91: 18-22, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31734127

RESUMO

As the largest proportion of male infertility population, asthenozoospermia patients often resort to sperm cryopreservation to preserve fertility as well as to enrich motile sperm for assisted reproductive techniques (ART), although it may cause some cryodamage during the freezing-thawing process. The objective of this study was to investigate whether mitochondrial antioxidant Mito-Tempo was effective in preventing cryodamage of asthenozoospermic spermatozoa. Asthenozoospermic semen samples were collected and cryopreserved in media supplemented with different concentrations (0.0, 1.0, 10 and 100 µM) of Mito-Tempo. We measured sperm motility, viability, membrane integrity, DNA fragmentation, mitochondrial membrane potential, oxidation product, and antioxidant enzymes activities. Supplementation of the cryopreservation media with Mito-Tempo (10 and 100 µM) induced a significant improvement in sperm viability, motility, membrane integrity, mitochondrial membrane potential and chromatin integrity (P < 0.05). Significant enhancement of antioxidant enzymes activities accompanied by the decreased formation of oxidation products (ROS and MDA) was also observed in groups supplemented with Mito-Tempo (10 and 100 µM). It is concluded that mitochondria targeted antioxidant Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients after cryopreservation.


Assuntos
Antioxidantes/farmacologia , Astenozoospermia/metabolismo , Criopreservação/métodos , Crioprotetores/farmacologia , Preservação do Sêmen/métodos , Cromatina , Fragmentação do DNA/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Congelamento , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Análise do Sêmen/métodos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
20.
Pak J Pharm Sci ; 32(4(Supplementary)): 1797-1803, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31680075

RESUMO

Leukemia is a type of blood cancer where abnormal and immature leucocytes are produced in the bone marrow. Methadone hydrochloride is a man-made drug that is commonly used in the maintenance treatment for drug addiction. The objective of this research was to determine the cytotoxic activity and apoptotic effects of methadone hydrochloride treatment towards two leukemia cell lines which are CCRF-CEM and HL-60. CCRF-CEM and HL-60 cells were treated with methadone hydrochloride for 24 and 48 hours to determine the cytotoxic activity. IC50 at 24 hours obtained for CCRF-CEM was 121.6µmol/L while IC50 for HL-60 cells was 97.18µmol/L. Result obtained from DNA fragmentation assay showed no characteristic DNA ladder pattern in CCRF-CEM leukemia cells treated with methadone hydrochloride. Characteristics DNA ladder pattern was observed in methadone hydrochloride treated HL-60 cells. Formation of comets was seen in methadone hydrochloride treated CCRF-CEM and HL-60 cells with varying degree of DNA damage. The comets formed by methadone hydrochloride treated HL-60 cells were more prominent as compared to methadone-treated CCRF-CEM cells. The expression of apoptotic-related proteins in methadone-treated CCRF-CEM and HL-60 cells were checked by incubating the cell lysate with Raybio® Human Apoptosis Antibody Array. Significant alterations in expression level of apoptosis-related proteins in methadone hydrochloride treated CCRF-CEM cells were found involving upregulation of caspase-8 expression and downregulation of survivin expression. Methadone hydrochloride induced apoptosis in HL-60 cells involved upregulation of Bid and caspase-8 expression and downregulation of Bcl-2, p21 and survivin expression.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Leucemia/tratamento farmacológico , Metadona/farmacologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima/efeitos dos fármacos
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