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1.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067102

RESUMO

Significant antibacterial properties of non-thermal plasma (NTP) have converted this technology into a promising alternative to the widespread use of antibiotics in assisted reproduction. As substantial data available on the specific in vitro effects of NTP on male reproductive cells are currently missing, this study was designed to investigate selected quality parameters of human spermatozoa (n = 51) exposed to diffuse coplanar surface barrier discharge NTP for 0 s, 15 s, 30 s, 60 s and 90 s. Sperm motility characteristics, membrane integrity, mitochondrial activity, production of reactive oxygen species (ROS), DNA fragmentation and lipid peroxidation (LPO) were investigated immediately following exposure to NTP and 2 h post-NTP treatment. Exposure to NTP with a power input of 40 W for 15 s or 30 s was found to have no negative effects on the sperm structure or function. However, a prolonged NTP treatment impaired all the sperm quality markers in a time- and dose-dependent manner. The most likely mechanism of action of high NTP doses may be connected to ROS overproduction, leading to plasma membrane destabilization, LPO, mitochondrial failure and a subsequent loss of motility as well as DNA integrity. As such, our findings indicate that appropriate plasma exposure conditions need to be carefully selected in order to preserve the sperm vitality, should NTP be used in the practical management of bacteriospermia in the future.


Assuntos
Gases em Plasma/farmacologia , Espermatozoides/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Superóxidos/metabolismo , Fatores de Tempo
2.
Int J Biol Macromol ; 182: 1590-1601, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34015407

RESUMO

Pancreatic cancer is the fourth most lethal cancer type worldwide. Due to multiple levan applications including anticancer activities, studies related to levansucrase production are of interest. To our knowledge, levan effect on pancreatic cancer cells has not been tested previously. In this work, among eighteen bacterial honey isolates, Bacillus subtilis MT453867 showed the highest levan yield (33 g/L) and levansucrase production (8.31 U/mL). One-factor-at-a-time technique increased levansucrase activity by 60% when MgSO4 was eliminated. The addition of 60 g/L banana peels enhanced the enzyme activity (192 U/mL). Placket Burman design determined the media composition for maximum levan yield (54.8 g/L) and levansucrase production (505 U/mL). The identification of levan was confirmed by thin-layer chromatography, Fourier-Transform Infrared spectrometric analysis, 13C-nuclear-magnetic resonance, and 1H-nuclear-magnetic resonance. Both crude and dialyzed levan completely inhibited the pancreatic cancer cell line at 100 ppm with no cytotoxicity on the normal retinal cell line. The LD50 of crude levan was 4833 mg/kg body weight. Levan had strong antioxidant activity and significantly reduced the expression of CXCR4 and MCM7 genes in pancreatic cancer cells with significant DNA fragmentation. In conclusion, Bacillus subtilis MT453867 levan is a promising adjunct to pancreatic-anticancer agents with both anti-cancer and chemoprotective effects.


Assuntos
Antineoplásicos/metabolismo , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Frutanos/metabolismo , Hexosiltransferases/metabolismo , Antineoplásicos/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Frutanos/farmacologia , Humanos , Componente 7 do Complexo de Manutenção de Minicromossomo/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores CXCR4/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Int J Biol Macromol ; 181: 1196-1206, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33991555

RESUMO

Loading propolis by a simple process using genipin as a crosslinking agent and fabrication of a novel PVA/Chitosan-Propolis membrane scaffolds were reported for wound dressing applications. The research is focused on the effects of propolis on characterization properties of membrane such as chemical structure, surface morphology, degradation ratio, crystallinity, hydrophilicity, water uptake capacity, water vapour transmission rate and mechanical aspect. It was noticed that water uptake capacity and hydrophilicity properties of membrane considerably affected by the propolis. By addition of (0.50, % v/v) propolis, the contact angle of the PVA/Chitosan membrane was remarkably decreased from 86.29° ± 3 to 45 ± 2°. 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenylte-trazolium (MTT) bromide test and SEM were used to analyse the cytocompatibility of the membranes and morphology of cells on membrane. The propolis incorporated membrane showed cell proliferation rate 176 ± 13%, 775 ± 1%, and 853 ± 23%, at 24 h, 27 h and 120 h, respectively. SEM images also supported the cell behaviour on membrane. DNA fragmentation was also investigated with genotoxicity test. The studies on the interactions between membranes and MEF cells revealed that the incorporation of propolis into membrane promoted cell proliferation. These overall results presented that propolis incorporated membranes could have potentially appealing application as scaffolds for wound healing applications.


Assuntos
Materiais Biocompatíveis/química , Quitosana/química , Própole/química , Cicatrização/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Quitosana/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Humanos , Iridoides/química , Membranas Artificiais , Testes de Mutagenicidade , Própole/farmacologia
4.
Chem Biol Interact ; 343: 109444, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33939975

RESUMO

Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study, we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [b]naphtho [2,1-d]furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC50 values of 3.06 and 0.98 µM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using melanoma cells in a murine model in vivo, CNFD induced a potent anti-tumor activity. Herein, we describe, for the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/tratamento farmacológico , Naftoquinonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , DNA/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MAP Quinase Quinase 4/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Naftoquinonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920365

RESUMO

Taurine is one of the main ingredients used in energy drinks which are highly consumed in adolescents for their sugary taste and stimulating effect. With energy drinks becoming a worldwide phenomenon, the biological effects of these beverages must be evaluated in order to fully comprehend the potential impact of these products on the health due to the fact nutrition is closely related to science since the population consumes food to prevent certain diseases. Therefore, the aim of this study was to evaluate the biological effects of taurine, glucose, classic Red Bull® and sugar-free Red Bull® in order to check the food safety and the nutraceutical potential of these compounds, characterising different endpoints: (i) Toxicology, antitoxicology, genotoxicology and life expectancy assays were performed in the Drosophila melanogaster model organism; (ii) The in vitro chemopreventive activity of testing compounds was determined by assessing their cytotoxicity, the proapoptotic DNA-damage capability to induce internucleosomal fragmentation, the strand breaks activity and the modulator role on the methylation status of genomic repetitive sequences of HL-60 promyelocytic cells. Whereas none tested compounds showed toxic or genotoxic effect, all tested compounds exerted antitoxic and antigenotoxic activity in Drosophila. Glucose, classic Red Bull® and sugar-free Red Bull® were cytotoxic in HL-60 cell line. Classic Red Bull® induced DNA internucleosomal fragmentation although none of them exhibited DNA damage on human leukaemia cells. In conclusion, the tested compounds are safe on Drosophila melanogaster and classic Red Bull® could overall possess nutraceutical potential in the in vivo and in vitro model used in this study. Besides, taurine could holistically be one of the bioactive compounds responsible for the biological activity of classic Red Bull®.


Assuntos
Citotoxinas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Bebidas Energéticas/análise , Glucose/farmacologia , Taurina/farmacologia , Animais , Bebidas Adoçadas Artificialmente/análise , Cafeína/análise , Bebidas Gaseificadas/análise , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Metilação de DNA/efeitos dos fármacos , Suplementos Nutricionais/análise , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Feminino , Células HL-60 , Humanos , Longevidade/efeitos dos fármacos , Masculino
6.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33923922

RESUMO

Doxorubicin increases endothelial permeability, hence increasing cardiomyocytes' exposure to doxorubicin (DOX) and exposing myocytes to more immediate damage. Reactive oxygen species are major effector molecules of doxorubicin's activity. Mangiferin (MGN) is a xanthone derivative that consists of C-glucosylxanthone with additional antioxidant properties. This particular study assessed the effects of MGN on DOX-induced cytotoxicity in human umbilical vein endothelial cells' (HUVECs') signaling networks. Mechanistically, MGN dramatically elevated Nrf2 expression at both the messenger RNA and protein levels through the upregulation of the PI3K/AKT pathway, leading to an increase in Nrf2-downstream genes. Cell apoptosis was assessed with a caspase-3 activity assay, transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining was performed to assess DNA fragmentation, and protein expression was determined by Western blot analysis. DOX markedly increased the generation of reactive oxygen species, PARP, caspase-3, and TUNEL-positive cell numbers, but reduced the expression of Bcl-2 and antioxidants' intracellular concentrations. These were effectively antagonized with MGN (20 µM), which led to HUVECs being protected against DOX-induced apoptosis, partly through the PI3K/AKT-mediated NRF2/HO-1 signaling pathway, which could theoretically protect the vessels from severe DOX toxicity.


Assuntos
Doxorrubicina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Xantonas/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Fragmentação do DNA/efeitos dos fármacos , Imunofluorescência , Humanos , Marcação In Situ das Extremidades Cortadas , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
7.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672866

RESUMO

Parkinsons Disease (PD) is the second most common neurodegenerative disease worldwide, and is characterized by a progressive degeneration of dopaminergic neurons. Without an effective treatment, it is crucial to find new therapeutic options to fight the neurodegenerative process, which may arise from marine resources. Accordingly, the goal of the present work was to evaluate the ability of the monoterpenoid lactone Loliolide, isolated from the green seaweed Codium tomentosum, to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells and their anti-inflammatory effects in RAW 264.7 macrophages. Loliolide was obtained from the diethyl ether extract, purified through column chromatography and identified by NMR spectroscopy. The neuroprotective effects were evaluated by the MTT method. Cells' exposure to 6-OHDA in the presence of Loliolide led to an increase of cells' viability in 40%, and this effect was mediated by mitochondrial protection, reduction of oxidative stress condition and apoptosis, and inhibition of the NF-kB pathway. Additionally, Loliolide also suppressed nitric oxide production and inhibited the production of TNF-α and IL-6 pro-inflammatory cytokines. The results suggest that Loliolide can inspire the development of new neuroprotective therapeutic agents and thus, more detailed studies should be considered to validate its pharmacological potential.


Assuntos
Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Clorófitas/química , Lactonas/farmacologia , Monoterpenos/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Benzofuranos/química , Linhagem Celular Tumoral , Citocinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Humanos , Lactonas/química , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estrutura Molecular , Monoterpenos/química , NF-kappa B/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
8.
Medicine (Baltimore) ; 100(9): e24918, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655953

RESUMO

BACKGROUND: Sperm DNA fragmentation (SDF) may hinder embryonic development and growth, increasing the risk of spontaneous miscarriage, and is considered an important factor affecting male infertility (MI). Traditional Chinese herbal medicine is considered effective in the treatment of MI due to SDF by nourishing kidney essence or promoting blood circulation for removing blood stasis. The objective of this systematic review protocol is to evaluate the effectiveness and safety of traditional Chinese herbal medicine on the treatment of MI associated with SDF. METHODS: We searched the PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP Chinese Science, Technology Journal Database, and Wanfang Database until the end of 2020 for English and Chinese published literature. Randomized controlled trials (RCTs) to evaluate the effectiveness and safety of traditional Chinese herbal medicine for the treatment of MI associated with SDF will be included. Study selection and data extraction were performed independently by 2 reviewers, and the quality evaluation and risk assessment were assessed by the Cochrane collaboration's tool, and use the RevMan 5.3 software for meta-analysis. CONCLUSION: This study will evaluate the efficacy and safety of traditional Chinese herbal medicine for the treatment of MI due to SDF, which may provide some help for the clinician's decision. PROSPERO REGISTRATION NUMBER: CRD42020221053.


Assuntos
Fragmentação do DNA/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Infertilidade Masculina/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Espermatozoides/metabolismo , Humanos , Infertilidade Masculina/genética , Masculino
9.
Anticancer Res ; 41(3): 1429-1438, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788734

RESUMO

BACKGROUND/AIM: Clinical significance of antitumour drugs is limited by multidrug resistance (MDR). We examined the effect of bioreductive activation of the anthracyclines, doxorubicin (DOX) and pirarubicin (PIRA), by cytochrome P450 reductase (CPR) on triggering apoptosis of leukaemia HL60 cells and their MDR counterparts. MATERIALS AND METHODS: Cell cycle and FAS expression were investigated by flow cytometry. DNA fragmentation was examined by electrophoretic analysis and caspase-3/8 activities were determined colorimetrically. RESULTS: Non-activated and CPR-activated forms of DOX and PIRA (IC90) had similar efficacy in provoking G2/M arrest of sensitive HL60 as well as resistant HL60/VINC and HL60/DOX cells and in causing DNA degradation. Interestingly, HL60/VINC cells were more prone to apoptosis induced by all studied forms of these drugs. However, no change in Fas expression was observed. CONCLUSION: Bioreductive activation of DOX and PIRA does not affect their ability to induce apoptosis of sensitive and resistant HL60 leukaemia cells.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/patologia , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo
10.
Int J Mol Sci ; 22(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33562019

RESUMO

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/biossíntese , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Fragmentação do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Sinergismo Farmacológico , Fatores de Transcrição Forkhead/biossíntese , Humanos , Membranas Mitocondriais/fisiologia
11.
J Biochem Mol Toxicol ; 35(5): e22744, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33604948

RESUMO

Saturated fatty acids, whose circulating levels are markedly increased in the body, significantly affect the growth and functions of skeletal muscle. These fatty acids may exert a detrimental effect on the undifferentiated skeletal myoblasts that may adversely affect their differentiation. In the present study, the exposure of myoblasts to excess palmitic acid caused an elevation of tumor necrosis factor-α expression and an increase in reactive oxygen species levels consistent with the enhanced inflammation and oxidative stress. Various concentrations of palmitic acid significantly decreased the mitochondrial membrane potential, induced the programmed cell death by an increase in the caspase-3 expression, and DNA fragmentation in the myoblasts. These findings suggest that the increased concentrations of saturated fatty acid in the myoblasts increase lipotoxicity by increasing inflammation and oxidative stress, decreasing the mitochondrial function, and inducing apoptosis.


Assuntos
Caspase 3/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mioblastos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/toxicidade , Fator de Necrose Tumoral alfa/biossíntese , Linhagem Celular , Fragmentação do DNA/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Mioblastos/patologia
12.
Sci Rep ; 11(1): 252, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420282

RESUMO

Lead (Pb) toxicity is one of the most prevalent causes of human neurotoxicity. The available chelator drugs used now have many adverse effects. So, in this study, the protective role of Beta vulgaris juice (BVJ) on rat neurotoxicity induced by Pb was evaluated and the results were compared with the results of dimercaptosuccinic acid (DMSA, as used drug). Additionally, the synergistic effect of BVJ and DMSA against Pb-induced neurotoxicity was assessed. The study focused on the determination of the antioxidant, anti-inflammatory, and neurological potential of BVJ (alone, and with DMSA) towards lead-induced neurotoxicity. Also, the characterization of BVJ was studied. The results showed that BVJ contains considerable quantities of polyphenols, triterpenoids, and betalains which play an important role as antioxidants and anti-inflammatory. BVJ exhibited a protective effect against neurotoxicity via the reduction of Pb levels in blood and brain. Moreover, BVJ decreased the oxidative stress, inflammation, and cell death induced by Pb. Also, BVJ regulated the activities of acetylcholine esterase and monoamine oxidase-A which changed by Pb toxicity. BVJ and DMSA combination displayed a synergistic antineurotoxic effect (combination index ˂ 1). These results were in harmony with brain histopathology. Conclusion: BVJ has a powerful efficacy in the protection from brain toxicity via diminishing Pb in the brain and blood circulation, resulting in the prevention of the oxidative and inflammatory stress. Treatment with BVJ in combination with DMSA revealed a synergistic effect in the reduction of neurotoxicity induced by Pb. Also, the antioxidant and anti-inflammatory effects of the BVJ lead to the improvement of DMSA therapy.


Assuntos
Antioxidantes/uso terapêutico , Beta vulgaris/química , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Succímero/uso terapêutico , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fragmentação do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Inflamação/tratamento farmacológico , Chumbo/sangue , Chumbo/toxicidade , Masculino , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Succímero/farmacologia
13.
Mol Biol Rep ; 48(1): 1017-1023, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33387196

RESUMO

Glioblastoma (GBM) is a lethal astrocyte-derived tumor that is currently treated with a multi-modal approach of surgical resection, radiotherapy, and temozolomide-based chemotherapy. Alternatives to current therapies are urgently needed as its prognosis remains poor. Anthracyclines are a class of compounds that show great potential as GBM chemotherapeutic agents and are widely used to treat solid tumors outside the central nervous system. Here we investigate the cytotoxic effects of doxorubicin and other anthracyclines on GL261 glioma tumor cells in anticipation of novel anthracycline-based CNS therapies. Three methods were used to quantify dose-dependent effects of anthracyclines on adherent GL261 tumor cells, a murine cell-based model of GBM. MTT assays quantified anthracycline effects on cell viability, comet assays examined doxorubicin genotoxicity, and flow cytometry with Annexin V/PI staining characterized doxorubicin-induced apoptosis and necrosis. Dose-dependent reductions in GL261 cell viability were found in cells treated with doxorubicin (EC50 = 4.9 µM), epirubicin (EC50 = 5.9 µM), and idarubicin (EC50 = 4.4 µM). Comet assays showed DNA damage following doxorubicin treatments, peaking at concentrations of 1.0 µM and declining after 25 µM. Lastly, flow cytometric analysis of doxorubicin-treated cells showed dose-dependent induction of apoptosis (EC50 = 5.2 µM). Together, these results characterized the cytotoxic effects of anthracyclines on GL261 glioma cells. We found dose-dependent apoptotic induction; however at high concentrations we find that cell death is likely necrotic. Our results support the continued exploration of anthracyclines as compounds with significant potential for improved GBM treatments.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Doxorrubicina/farmacologia , Epirubicina/farmacologia , Idarubicina/farmacologia , Neuroglia/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioma/tratamento farmacológico , Humanos , Camundongos , Modelos Biológicos , Neuroglia/metabolismo , Neuroglia/patologia
14.
Mol Biol Rep ; 48(1): 709-720, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33389482

RESUMO

I. BACKGROUND: A combination of etoposide (VP-16) and cisplatin (CDDP) is the standard treatment for certain colon cancers. These drugs promote the death of cancer cells via direct and indirect induction of the most lethal DNA lesions - DNA double-stand breaks. However, cancer cells can reverse the DNA damaging effect of anticancer drugs by triggering DNA repair processes. In eukaryotic cells, the main DNA repair pathway responsible for DNA double-stand breaks repair is non-homologous end-joining (NHEJ). Inhibitors of DNA repair are of special interest in cancer research as they could break the cellular resistance to DNA-damaging agents and increase the efficiency of standard cancer treatments. In this study, we investigated the effect of two NHEJ inhibitors, SCR7 and NU7441, on the cytotoxic mechanism of VP-16/CDDP in a LoVo human colorectal adenocarcinoma cell line. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding, whereas NU7441 is a highly potent and selective DNA-PK inhibitor.II. METHODS AND RESULTS: Both inhibitors synergistically increased the cytotoxicity of CDDP and VP-16 when combined, but the effect of SCR7 was more pronounced. SCR7 and NU7441 also significantly increased VP-16; CDDP induced DNA double-stand breaks level and delayed drug-induced DSB repair, as seen on the comet assay and measured using H2AX foci. We also observed changes in cell cycle distribution and enhanced apoptosis ratio in colorectal adenocarcinoma cells treated with DNA repair inhibitors and VP-16/CDDP.III. CONCLUSIONS: Our data support the hypothesis that NHEJ inhibitors could be used in conjunction with standard therapy to provide effective clinical improvement and allow reduction in drug doses.


Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Cisplatino/farmacologia , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , DNA de Neoplasias/genética , Etoposídeo/farmacologia , Morfolinas/farmacologia , Pirimidinas/farmacologia , Bases de Schiff/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Ensaio Cometa , Quebras de DNA de Cadeia Dupla , Fragmentação do DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Sinergismo Farmacológico , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Histonas/genética , Histonas/metabolismo , Humanos
15.
Sci Rep ; 11(1): 552, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436696

RESUMO

Zingiberaceae plants are well known for their use in ethnomedicine. Curcuma mutabilis Skornick., M. Sabu & Prasanthk., is an endemic Zingiberaceae species from Western Ghats of Kerala, India. Here, we report for the first time, the anticancer potential of petroleum ether extract from C. mutabilis rhizome (CMRP) and a novel labdane diterpenoid, (E)-14, 15-epoxylabda-8(17), 12-dien-16-al (Cm epoxide) isolated from it. CMRP was found to be a mixture of potent bioactive compounds including Cm epoxide. Both the extract and the compound displayed superior antiproliferative activity against several human cancer cell lines, without any display of cytotoxicity towards normal human cells such as peripheral blood derived lymphocytes and erythrocytes. CMRP treatment resulted in phosphatidylserine externalization, increase in the levels of intracellular ROS, Ca2+, loss of mitochondrial membrane potential as well as fragmentation of genomic DNA. Analyses of transcript profiling and immunostained western blots of extract-treated cancer cells confirmed induction of apoptosis by both intrinsic and extrinsic pathways. The purified compound, Cm epoxide, was also found to induce apoptosis in many human cancer cell types tested. Both CMRP and the Cm epoxide were found to be pharmacologically safe in terms of acute toxicity assessment using Swiss albino mice model. Further, molecular docking interactions of Cm epoxide with selected proteins involved in cell survival and death were also indicative of its druggability. Overall, our findings reveal that the endemic C. mutabilis rhizome extract and the compound Cm epoxide isolated from it are potential candidates for development of future cancer chemotherapeutics.


Assuntos
Antineoplásicos Fitogênicos , Curcuma/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Neoplasias/patologia , Extratos Vegetais/química , Raízes de Plantas/química , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos de Epóxi/isolamento & purificação , Humanos , Índia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Fosfatidilserinas/metabolismo , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo
16.
Exp Eye Res ; 202: 108342, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33144094

RESUMO

B-N-methylamino-L-alanine (BMAA), a cyanotoxin produced by most cyanobacteria, has been proposed to cause long term damages leading to neurodegenerative diseases, including Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) and retinal pathologies. Previous work has shown diverse mechanisms leading to BMAA-induced degeneration; however, the underlying mechanisms of toxicity affecting retina cells are not fully elucidated. We here show that BMAA treatment of rat retina neurons in vitro induced nuclear fragmentation and cell death in both photoreceptors (PHRs) and amacrine neurons, provoking mitochondrial membrane depolarization. Pretreatment with the N-Methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevented BMAA-induced death of amacrine neurons, but not that of PHRs, implying activation of NMDA receptors participated only in amacrine cell death. Noteworthy, BMAA stimulated a selective axonal outgrowth in amacrine neurons, simultaneously promoting growth cone destabilization. BMAA partially decreased the viability of Müller glial cells (MGC), the main glial cell type in the retina, induced marked alterations in their actin cytoskeleton and impaired their capacity to protect retinal neurons. BMAA also induced cell death and promoted axonal outgrowth in differentiated rat pheochromocytoma (PC12) cells, implying these effects were not limited to amacrine neurons. These results suggest that BMAA is toxic for retina neurons and MGC and point to the involvement of NMDA receptors in amacrine cell death, providing new insight into the mechanisms involved in BMAA neurotoxic effects in the retina.


Assuntos
Diamino Aminoácidos/toxicidade , Células Ependimogliais/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Doenças Retinianas/induzido quimicamente , Neurônios Retinianos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Sobrevivência Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Células Ependimogliais/patologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Doenças Retinianas/metabolismo , Doenças Retinianas/prevenção & controle , Neurônios Retinianos/patologia
17.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33313945

RESUMO

Shikonin is the major active component in Lithospermum erythrorhizon and has pharmacological effects including reducing inflammation, aiding resistance to bacteria and promoting wound healing. However, the effect of shikonin on lipoteichoic acid (LTA)­induced acute lung injury (ALI) remains to be elucidated. ALI is a serious illness resulting from significant pulmonary inflammation caused by various diseases, such as sepsis, acid aspiration and trauma. The present study found that shikonin significantly attenuated LTA­induced ALI. Following shikonin treatment, the accumulation of pulmonary neutrophils and expression of TNFα, IL­1ß and IL­6 were decreased in mice with LTA­induced ALI. Furthermore, Shikonin promoted neutrophil apoptosis by increasing the activation of caspase­3 and reducing the expression of the antiapoptotic myeloid cell leukemia­1 (Mcl­1) protein. However, shikonin treatment did not influence the expression of B­cell lymphoma­2. The findings of the present study demonstrated that shikonin protected against LTA­induced ALI by promoting caspase-3 and Mcl­1­related neutrophil apoptosis, suggesting that shikonin is a potential agent that can be used in the treatment of sepsis­mediated lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/farmacologia , Naftoquinonas/farmacologia , Neutrófilos/citologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Caspase 3/metabolismo , Citocinas/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Naftoquinonas/uso terapêutico , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ácidos Teicoicos/toxicidade , Proteína Supressora de Tumor p53/metabolismo
18.
J Ethnopharmacol ; 269: 113702, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33340598

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Oxidative stress is one of the underlying causes of male infertility. Medicinal plants have many benefits for infertility treatment in men. AIM OF THE STUDY: In the present study, we evaluated in vitro effects of Capparis spinosa leaf extract on human sperm function, DNA fragmentation, and oxidative stress. MATERIALS AND METHODS: We conducted this study on the hydroalcoholic extract of C. spinosa. Polyphenol compounds and antioxidant effects of the leaf and fruit extract were determined by HPLC and DPPH method, respectively. Flavones and flavonols, total flavonoid, total phenolic content, tannin, and the total carbohydrate content were determined calorimetrically. Semen samples from 50 healthy men (20-45 years) were divided into control and experimental (15, 30, and 45 ppm of C. spinosa leaf extract) groups. Motility, viability, lipid peroxidation, and DNA fragmentation were evaluated 24 h after incubation. RESULTS: The antioxidant effect of leaf extract was six times greater than fruit. Progressive and total motility of caper-treated groups (30 and 45 ppm) were crucially higher than the control group. Viability in all treatments was significantly higher than the control group. There was no significant difference in lipid peroxidation. DNA fragmentation in the caper-treated group (45 ppm) was significantly lower than the control group. CONCLUSIONS: Our results suggest the potential positive in vitro effect of C. spinosa leaf extract on human sperm function. The use of C. spinosa leaf extract or its active metabolites in the sperm culture medium may be beneficial for maintaining motility, vitality, and sperm DNA. Since these effects were observed at very low concentrations of caper, other non-antioxidant mechanisms must be considered.


Assuntos
Antioxidantes/farmacologia , Capparis/química , Fragmentação do DNA/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Espermatozoides/efeitos dos fármacos , Adulto , Antioxidantes/química , Antioxidantes/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Etnofarmacologia , Frutas/química , Humanos , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Plantas Medicinais/química , Polifenóis/química , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Sêmen/química , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/citologia , Adulto Jovem
19.
J Sci Food Agric ; 101(2): 486-496, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32643802

RESUMO

BACKGROUND: Aspergillus flavus, a saprophytic fungus, is regularly detected in oil-enriched seeds. During colonization, this organism releases aflatoxins that pose a serious risk to food safety and human health. Therefore, an eco-friendly biological approach to inhibit the pathogen is desirable. RESULTS: Experimental results indicated that A. flavus spores could not germinate in potato dextrose broth culture medium, when the concentration of Sub3 exceeded 0.15 g L-1 . Morphological evaluation performed by flow cytometry and scanning electron microscopy indicated that spores were shrunken and pitted following Sub3 exposure. Physiological assessment using propidium iodide, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide, 2,7-dichlorodihydrofluorescein diacetate and 4',6-diamidino-2-phenylindole staining revealed damaged cell membranes, decreased mitochondrial membrane potential, increased intracellular reactive oxygen species levels, and elevated large nuclear condensation and DNA fragmentation. Moreover, mitochondrial dehydrogenase activity was reduced by 29.42% and 45.48% after treatment with 0.1 and 0.15 g L-1 Sub3, respectively. Additionally, colonization capacity in peanut was significantly decreased, and the number of spores on seeds treated with Sub3 was decreased by 26.86% (0.1 g L-1 ) and 77.74% (0.15 g L-1 ) compared with the control group. CONCLUSION: Sub3 likely inhibits A. flavus by crossing the cell wall and targeting the cell membrane, disrupting mitochondrial energy metabolism, and inducing DNA damage, leading to spore death. Thus, Sub3 may provide a useful biocontrol strategy to control A. flavus growth in peanuts. © 2020 Society of Chemical Industry.


Assuntos
Antifúngicos/farmacologia , Arachis/microbiologia , Aspergillus flavus/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/metabolismo , Aspergillus flavus/genética , Aspergillus flavus/crescimento & desenvolvimento , Fragmentação do DNA/efeitos dos fármacos , Metabolismo Energético/imunologia , Armazenamento de Alimentos , Mitocôndrias/efeitos dos fármacos , Sementes/microbiologia , Esporos Fúngicos/efeitos dos fármacos , Esporos Fúngicos/genética , Esporos Fúngicos/crescimento & desenvolvimento
20.
Anticancer Res ; 40(12): 6869-6877, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33288579

RESUMO

BACKGROUND/AIM: Maslinic acid, a natural plant-derived triterpenoid compound, exhibits pharmacological activities, including anti-cancer. In the present study, we investigated the cytotoxic effects of maslinic acid on human cervical cancer HeLa cells in vitro and further investigated the molecular mechanism of maslinic acid-induced DNA damage and repair. MATERIALS AND METHODS: Cell viability was measured by flow cytometry. DNA condensation (apoptotic cell death), DNA damage, and DNA fragmentation (DNA ladder) were assayed by DAPI staining, comet assay, and agarose gel electrophoresis, respectively. The expression of DNA damage and repair proteins was assayed by western blotting. RESULTS: Maslinic acid decreased total cell viability and induced DNA condensation, damage, and fragmentation in HeLa cells. Furthermore, maslinic acid elevated the levels of p-ATMSer1981, p-ATRSer428, p53, p-p53Ser151, p-H2A.XSer139, BRCA1 and PARP at 30-40 µM. However, it decreased the levels of DNA-PK and MGMT. CONCLUSION: Maslinic acid reduced the number of viable HeLa cells by inducing DNA damage and altering the expression of proteins involved in DNA damage and repair.


Assuntos
Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Triterpenos/farmacologia , Neoplasias do Colo do Útero/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Fragmentação do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA , Feminino , Células HeLa , Humanos , Neoplasias do Colo do Útero/metabolismo
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