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1.
J Agric Food Chem ; 67(38): 10637-10645, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31513389

RESUMO

Previous studies have shown that selenite, a representative of inorganic form selenium, exerts its anticancer effect by inducing apoptosis in androgen-dependent LNCaP prostate cancer cells, but few studies have determined the nature of cell death induced by selenite in metastatic androgen-refractory PC-3 cells. Our study showed that necrosis-like cell death rather than apoptosis, pyroptosis, or autophagic cell death was caused by selenite in PC-3 cells. Mechanistically, this type of cell death was caused by ATP depletion (26.28 ± 3.39 nmol/mg of control versus 9.12 ± 2.44 nmol/mg of 10 µM selenite treatment) that resulted from phosphofructokinase activity reduction (100.17 ± 0.17% of control versus 21.74 ± 6.65% of 10 µM selenite treatment). Our study also showed that ROS production is necessary for the decrease in cellular ATP levels and in phosphofructokinase activity. To our knowledge, this is the first study showing that selenite can induce necrosis-like cell death in PC-3 cells. Our findings support selenite as an effective compound for the therapy of apoptosis-resistant prostate cancer.


Assuntos
Morte Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Neoplasias da Próstata/fisiopatologia , Ácido Selenioso/farmacologia , Trifosfato de Adenosina/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Fosfofrutoquinases/metabolismo , Neoplasias da Próstata/metabolismo
2.
Chem Biol Interact ; 313: 108821, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525342

RESUMO

Decrease in the bioavailability of vasoactive nitric oxide (NO), derived from the endothelial nitric oxide synthase (NOS3), underlines vascular endothelial damage. Our expanding knowledge on mature red blood cells (RBCs) makes it supposable that RBCs might contribute to vascular function and integrity via their active NO synthetizing system (RBC-NOS3). This "rescue" mechanism of RBCs could be especially important during pregnancy with smoking habit, when smoking acts as an additional stressor and causes active change in the redox status. In this study RBC populations of 82 non-smoking (RBC-NS) and 75 smoking (RBC-S) pregnant women were examined. Morphological variants were followed by confocal microscopy and quantified by a microscopy based intelligent analysis software. Fluorescence activated cell sorting was used to examine the translational and posttranslational regulation of RBC-NOS, Arginase-1 and the formation of the major product of lipid peroxidation, 4-hydroxy-2-nonenal. To survey the rheological parameters of RBCs like elasticity and plasticity atomic force microscopy-based measurement was applied. Significant morphological and functional differences of RBCs were found between the non-smoking and smoking groups. The phenotypic variations in RBC-S population, even the characteristic biconcave disc-shaped cells, could be connected to impaired NOS3 activation and are compromised in their physiological properties. Membrane lipid studies reveal an elevated lipid oxidation state well paralleled with the changed elastic and plastic activities. These features can form a basic tool in the prenatal health screening conditions; hence the compensatory mechanism of RBC-S population completely fails to sense and rescue the acute oxidative stress conditions.


Assuntos
Arginase/metabolismo , Eritrócitos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Fumar/efeitos adversos , Adulto , Aldeídos/metabolismo , Estudos de Casos e Controles , Morte Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Microscopia de Força Atômica , Gravidez
3.
Int J Nanomedicine ; 14: 6217-6229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496682

RESUMO

Background: Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic drugs. Purpose: The objective of this study was to use the aqueous and hexane extracts of Lampranthus coccineus and Malephora lutea F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential. Methods: The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio. Results: The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for Lampranthus coccineus and Malephora lutea aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of L. coccineus and M. lutea showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of L. coccineus and M. lutea resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of L. coccineus and M. lutea with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of L. coccineus and M. lutea. Conclusion: These results highlight that SNPs of L. coccineus and M. lutea could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.


Assuntos
Aizoaceae/química , Antivirais/farmacologia , Química Verde , Nanopartículas Metálicas/química , Prata/farmacologia , Animais , Antivirais/química , Morte Celular/efeitos dos fármacos , Cercopithecus aethiops , Ligantes , Metabolômica , Nanopartículas Metálicas/ultraestrutura , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Prata/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Células Vero
4.
Int J Nanomedicine ; 14: 6539-6553, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496699

RESUMO

Aim: This paper reports on the incorporation of oleic acid (OA) within nanostructured lipid carriers (OA-NLC) to improve the anti-inflammatory effects in the presence of albumin. Materials and methods: NLCs produced via hot high-shear homogenization/ultrasonication were characterized in terms of particle size, zeta potential, and toxicity. We examined the effects of OA-NLC on neutrophil activities. Dermatologic therapeutic potential was also elucidated by using a murine model of leukotriene B4-induced skin inflammation. Results: In the presence of albumin, OA-NLC but not free OA inhibited superoxide generation and elastase release. Topical administration of OA-NLC alleviated neutrophil infiltration and severity of skin inflammation. Conclusion: OA incorporated within NLC can overcome the interference of albumin, which would undermine the anti-inflammatory effects of OA. OA-NLC has potential therapeutic effects in topical ointments.


Assuntos
Portadores de Fármacos/química , Inflamação/patologia , Lipídeos/química , Nanoestruturas/química , Neutrófilos/fisiologia , Ácido Oleico/química , Soroalbumina Bovina/farmacologia , Pele/patologia , Administração Tópica , Adulto , Animais , Cálcio/metabolismo , Bovinos , Morte Celular/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Humanos , Leucotrieno B4 , Lipídeos/toxicidade , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/toxicidade , Nanoestruturas/ultraestrutura , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Ácido Oleico/toxicidade , Elastase Pancreática/metabolismo , Superóxidos/metabolismo , Adulto Jovem
5.
Br J Anaesth ; 123(5): 610-617, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542162

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is associated with reduced cerebral blood flow and impaired autoregulation after TBI, which may lead to poor outcome. Clinical evidence has implicated neurological injuries and associated neuroinflammation as causes of cardiac dysfunction. Studies on newborn pigs show an association of elevated catecholamines with a sex-dependent impairment of cerebral autoregulation after TBI. One strategy to decrease sympathetic hyperactivity is pharmacological intervention with beta blockade. We tested the hypothesis that propranolol would prevent the impairment of cerebral autoregulation and tissue changes after TBI via inhibition of interleukin-6 (IL-6) upregulation. METHODS: Using newborn pigs of both sexes equipped with a closed cranial window, TBI was induced via lateral fluid percussion injury. Propranolol was administered at 1 h post-TBI. Analyses included cerebral autoregulation (pial artery reactivity) before and 4 h post-TBI, CSF IL-6 analysed (enzyme-linked immunosorbent assay), and histopathology at 4 h post-TBI. RESULTS: Propranolol administration prevented impairment of hypotensive dilation in both male and female newborn pigs after fluid percussion injury, which was paralleled by reduced upregulation of IL-6 in the CSF. Moreover, propranolol prevented neuronal cell death in cornu amonis (CA)1 and CA3 hippocampus equivalently in male and female pigs after TBI. Papaverine-induced dilation was unchanged by TBI and propranolol. CONCLUSIONS: These data indicate that sympathetic hyperactivity noted after TBI can be limited by propranolol administration to result in improved brain outcome post-injury via block of IL-6 upregulation, and this effect is irrespective of sex.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Propranolol/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipocampo/fisiologia , Homeostase/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Suínos , Regulação para Cima/efeitos dos fármacos
6.
Nat Neurosci ; 22(10): 1635-1648, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551592

RESUMO

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.


Assuntos
Astrócitos/patologia , Inflamação/patologia , Microglia/patologia , Mitocôndrias/patologia , Degeneração Neural/patologia , Animais , Morte Celular , Dinaminas/genética , Espaço Extracelular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/genética , Neurônios/patologia , Ratos , Ratos Sprague-Dawley
7.
Int J Nanomedicine ; 14: 5017-5032, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371944

RESUMO

Background: Epigallocatechin gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast (OC) differentiation. However, the low aqueous solubility of EGCG always leads to poor bioavailability, adverse effects, and several drawbacks for clinical applications. Purpose: In this study, we synthesized EGCG-capped gold nanoparticles (EGCG-GNPs) to solve the drawbacks for clinical uses of EGCG in bone destruction disorders by direct reduction of HAuCl4 in EGCG aqueous solution. Methods and Results: The obtained EGCG-GNPs were negatively charged and spherical. Theoretical calculation results suggested that EGCG was released from GNPs in an acidic environment. Cellular uptake study showed an obviously large amount of intracellular EGCG-GNPs without cytotoxicity. EGCG-GNPs exhibited better effects in reducing intracellular reactive oxygen species levels than free EGCG. A more dramatic anti-osteoclastogenic effect induced by EGCG-GNPs than free EGCG was observed in lipopolysaccharide (LPS)-stimulated bone marrow macrophages, including decreased formation of TRAP-positive multinuclear cells and actin rings. Meanwhile, EGCG-GNPs not only suppressed the mRNA expression of genetic markers of OC differentiation but also inhibited MAPK signaling pathways. Furthermore, we confirmed that EGCG-GNPs greatly reversed bone resorption in the LPS-induced calvarial bone erosion model in vivo, which was more effective than applying free EGCG, specifically in inhibiting the number of OCs, improving bone density, and preventing bone loss. Conclusion: EGCG-GNPs showed better anti-osteoclastogenic effect than free EGCG in vitro and in vivo, indicating their potential in anti-bone resorption treatment strategy.


Assuntos
Catequina/análogos & derivados , Ouro/farmacologia , Nanopartículas Metálicas/química , Osteogênese/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Reabsorção Óssea/patologia , Catequina/farmacologia , Morte Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ligantes , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Modelos Biológicos , Ligante RANK/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Crânio/patologia , Transcrição Genética/efeitos dos fármacos
8.
Int J Nanomedicine ; 14: 5147-5157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371953

RESUMO

Background: Kaempferol (K) is a recognized anticancer drug that can conjugate with small-size gold nanoclusters (AuNCs). Materials and methods: K-AuNCs were synthesized and their use as an anticancer drug was explored using A549 lung cancer cells. Colony formation and cell migration assays were carried out. The morphology of the K-AuNCs treated A549 cells was explored using bio-atomic force microscopy. Results: The K-AuNCs were 1-3 nm in diameter and emitted strong fluorescent at 650 nm following excitation at 550 nm. The stretching and bending nature of the K-AuNCs were analyzed by the Fourier transform infrared spectroscopy. The presence of kaempferol in the AuNCs were confirmed by the PL spectroscopy. Conclusion: The synthesized K-AuNCs mainly targeted and damaged the nuclei of the cancer cells. This composite nanocluster was less toxicity to the normal human cell and higher toxicity to the A549 lunch cancer cell and these material is potential for anticancer drug delivery and bio imaging applications.


Assuntos
Antineoplásicos/uso terapêutico , Ouro/química , Quempferóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Metálicas/química , Células A549 , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Humanos , Quempferóis/farmacologia , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/ultraestrutura , Fenômenos Ópticos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
9.
Inorg Chem ; 58(17): 11294-11299, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31411862

RESUMO

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.


Assuntos
Antineoplásicos/farmacologia , Metais Pesados/química , Compostos Organometálicos/farmacologia , Polímeros/química , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Íons/química , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química
10.
Int J Nanomedicine ; 14: 5061-5071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371947

RESUMO

Background: Photodynamic therapy (PDT) is widely recognized as a promising way to cure cancer. However, the limited tumor homing property of currently available drug delivery systems (DDSs) is the bottleneck for the delivery of photodynamic agents. Purpose: In our study, we decorated silica nanoparticles (SLN) with cell membrane (CM) derived from SGC7901 cells to construct carrier (CM/SLN) which was able to to specifically target the homogenous SGC7901 cells. Materials and methods: Furthermore, the decent drug loading capability of CM/SLN was adopted to load photodynamic agent chlorins e6 (Ce6) to finally construct aDDS suitable for tumor-targeted PDT of gastric cancer. Results: The experimental results suggested that CM/SLN/Ce6 was nano-sized particles with good dispersion and stability in physiological conditions. Moreover, due to the modification of CM,CM/SLN/Ce6 could specifically target the homogenous SGC7901 cells both in vitro and in vivo. Most importantly, further in vivo results demonstrated that the CM/SLN/Ce6 showed a better anticancer outcome compared to SLN/Ce6. Conclusion: CM/SLN/Ce6 might be a promising platform for effective tumor targeted PDT of gastric cancer.


Assuntos
Membrana Celular/patologia , Nanopartículas/química , Fotoquimioterapia , Porfirinas/uso terapêutico , Dióxido de Silício/química , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Coloides , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
11.
Cancer Sci ; 110(10): 3173-3182, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464035

RESUMO

Ferroptosis is an iron-dependent, lipid peroxide-driven cell death caused by inhibition of the cystine/glutamate transporter, which is of importance for the survival of triple-negative breast cancer (TNBC) cells. Erastin is a low molecular weight chemotherapy drug that induces ferroptosis; however, poor water solubility and renal toxicity have limited its application. Exosomes, as drug delivery vehicles with low immunogenicity, high biocompatibility and high efficiency, have attracted increasing attention in recent years. Herein, we developed a formulation of erastin-loaded exosomes labeled with folate (FA) to form FA-vectorized exosomes loaded with erastin (erastin@FA-exo) to target TNBC cells with overexpression of FA receptors. The characterization, drug release, internalization and anti-tumor effect in vitro of erastin@FA-exo were determined. Erastin@FA-exo could increase the uptake efficiency of erastin into MDA-MB-231 cells; compared with erastin@exo and free erastin, erastin@FA-exo has a better inhibitory effect on the proliferation and migration of MDA-MB-231 cells. Furthermore, erastin@FA-exo promoted ferroptosis with intracellular depletion of glutathione and reactive oxygen species overgeneration. Western blot analyses revealed that erastin@FA-exo suppressed expression of glutathione peroxidase 4 (GPX4) and upregulated expression of cysteine dioxygenase (CDO1). We conclude that targeting and biocompatibility of exosome-based erastin preparations provide an innovative and powerful delivery platform for anti-cancer therapy.


Assuntos
Exossomos/química , Ácido Fólico/química , Piperazinas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Morte Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína Dioxigenase/metabolismo , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Piperazinas/química , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
Int J Nanomedicine ; 14: 5257-5270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409988

RESUMO

Background: In recent years, green synthesized silver nanoparticles have been increasingly investigated for their anti-cancer potential. In the present study, we aimed at the biosynthesis of silver nanoparticles (AgNPs) using a curcumin derivative, ST06. Although, the individual efficacies of silver nanoparticles or curcumin derivatives have been studied previously, the synergistic cytotoxic effects of curcumin derivative and silver nanoparticles in a single nanoparticulate formulation have not been studied earlier specifically on animal models. This makes this study novel compared to the earlier synthesized curcumin derivative or silver nanoparticles studies. The aim of the study was to synthesize ST06 coated silver nanoparticles (ST06-AgNPs) using ST06 as both reducing and coating agent. Methods: The synthesized nanoparticles AgNPs and ST06-AgNPs were characterised for the particle size distribution, morphology, optical properties and surface charge by using UV-visible spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). Elemental composition and structural properties were studied by energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction spectroscopy (XRD). The presence of ST06 as capping agent was demonstrated by Fourier transform infrared spectroscopy (FTIR). Results: The synthesized nanoparticles (ST06-AgNPs) were spherical and had a size distribution in the range of 50-100 nm. UV-Vis spectroscopy displayed a specific silver plasmon peak at 410 nm. The in vitro cytotoxicity effects of ST06 and ST06-AgNPs, as assessed by MTT assay, showed significant growth inhibition of human cervical cancer cell line (HeLa). In addition, studies carried out in EAC tumor-induced mouse model (Ehrlich Ascites carcinoma) using ST06-AgNPs, revealed that treatment of the animals with these nanoparticles resulted in a significant reduction in the tumor growth, compared to the control group animals. Conclusion: In conclusion, green synthesized ST06-AgNPs exhibited superior anti-tumor efficacy than the free ST06 or AgNPs with no acute toxicity under both in vitro and in vivo conditions. The tumor suppression is associated with the intrinsic apoptotic pathway. Together, the results of this study suggest that ST06-AgNPs could be considered as a potential option for the treatment of solid tumors.


Assuntos
Carcinoma de Ehrlich/patologia , Curcumina/farmacologia , Química Verde/métodos , Nanopartículas Metálicas/química , Prata/farmacologia , Neoplasias do Colo do Útero/patologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células HeLa , Humanos , Camundongos , Tamanho da Partícula , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos , Difração de Raios X
13.
Aquat Toxicol ; 214: 105265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31416018

RESUMO

The increasing use of nanoparticles (NPs) unavoidably enhances their unintended introduction into the aquatic systems, raising concerns about their nanosafety. This work aims to assess the toxicity of five oxide NPs (Al2O3, Mn3O4, In2O3, SiO2 and SnO2) using the freshwater alga Pseudokirchneriella subcapitata as a primary producer of ecological relevance. These NPs, in OECD medium, were poorly soluble and unstable (displayed low zeta potential values and presented the tendency to agglomerate). Using the algal growth inhibition assay and taking into account the respective 72 h-EC50 values, it was possible to categorize the NPs as: toxic (Al2O3 and SnO2); harmful (Mn3O4 and SiO2) and non-toxic/non-classified (In2O3). The toxic effects were mainly due to the NPs, except for SnO2 which toxicity can mainly be attributed to the Sn ions leached from the NPs. A mechanistic study was undertaken using different physiological endpoints (cell membrane integrity, metabolic activity, photosynthetic efficiency and intracellular ROS accumulation). It was observed that Al2O3, Mn3O4 and SiO2 induced an algistatic effect (growth inhibition without loss of membrane integrity) most likely as a consequence of the cumulative effect of adverse outcomes: i) reduction of the photosynthetic efficiency of the photosystem II (ФPSII); ii) intracellular ROS accumulation and iii) loss of metabolic activity. SnO2 NPs also provoked an algistatic effect probably as a consequence of the reduction of ФPSII since no modification of intracellular ROS levels and metabolic activity were observed. Altogether, the results here presented allowed to categorize the toxicity of the five NPs and shed light on the mechanisms behind NPs toxicity in the green alga P. subcapitata.


Assuntos
Clorofíceas/citologia , Exposição Ambiental , Água Doce , Nanopartículas/toxicidade , Óxidos/toxicidade , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Clorofíceas/efeitos dos fármacos , Clorofíceas/crescimento & desenvolvimento , Clorofíceas/metabolismo , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade , Poluentes Químicos da Água/toxicidade
14.
DNA Cell Biol ; 38(10): 1125-1133, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408364

RESUMO

Mammary gland involution is a regressive process for the gland to return to its prepregnancy state after lactation and comprises an initial reversible and second remodeling stage. Although many genes and the multiple expression profiles of their mRNAs have been found in this process, the mechanisms controlling the profiles are largely unknown. In this study, we identified and analyzed transcription factor Sox4 in mammary gland involution. Elevated expression of Sox4 gene in the first stage (48 h after weaning) was observed at the mRNA and protein levels in the mouse mammary gland. Immunohistochemistry of the involuting gland indicated that Sox4 was located in the nuclei of epithelial cells. Nuclear Sox4 was also detected in the second stage, but unlikely to be involved in cell death, one of the characteristic events of involution. To clarify the functional roles of Sox4 in involution, we introduced a model, including a normal mammary epithelial cell line, for finding candidate target genes of this transcription factor and examined its effect on tenascin C mRNA expression.


Assuntos
Núcleo Celular/genética , Glândulas Mamárias Animais/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição SOXC/genética , Tenascina/genética , Animais , Animais Recém-Nascidos , Morte Celular , Linhagem Celular , Núcleo Celular/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Lactação/fisiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Gravidez , Ligação Proteica , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXC/metabolismo , Tenascina/metabolismo , Transcrição Genética , Desmame
15.
Int J Nanomedicine ; 14: 5323-5338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409990

RESUMO

Background: Candida albicans as an opportunistic fungus is one of the most important causes of late-onset morbidity and mortality in patients with major burns and severely impaired immune system. In recent years, the emergence of resistance to opportunistic fungi and toxicity of antimicrobial drugs make it necessary to develop new drugs. Methods: In the present study, we investigated anticandidal effects of indolicidin, as a representative of host defense peptide, conjugated with gold nanoparticles in fluconazole-resistant clinical isolates of C. albicans. After characterizing the conjugation of indolicidin using biophysical methodologies, the cytotoxicity and hemolytic activity of the nanocomplex were examined. In addition, the expression level of ERG11, responsible for antifungal resistance, and the immunomodulatory effect of peptide-nanomaterial conjugates were assessed. Results: Our data indicated that the nanocomplex was nontoxic for the fibroblast cells and erythrocytes. Treatment with the nanocomplex significantly reduced the expression levels of the ERG11 gene in fluconazole-resistant C. albicans isolates and the iNOS gene in macrophages. Conclusion: The study data provides a chance to develop innovative therapies for the treatment of C. albicans burn infections. However, further investigation is required to examine the efficiency of the nanocomplex.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Queimaduras/microbiologia , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Fluconazol/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Animais , Peptídeos Catiônicos Antimicrobianos/química , Queimaduras/tratamento farmacológico , Candida albicans/genética , Morte Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fluconazol/química , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Fúngicos , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
16.
Int J Nanomedicine ; 14: 4741-4754, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456635

RESUMO

Background: Ipomoea batatas (L.) Lam.(Ib) has high content of various beneficial nutrients which helps in improving and maintaining human health. It is well known as a functional food and also a valuable source of unique natural products. It contains various phenolic and flavonoid bioactive compounds. Methods: In this study, using the outer peel of two varieties of Ib : Korean red skin sweet potato and Korean pumpkin sweet potato, silver nanoparticles (AgNPs) were synthesized (termed Ib1-AgNps and Ib2-AgNps), respectively. Characterization of Ib1-AgNPs and Ib2-AgNPs was carried out through scanning electron microscopy, Fourier-transform infrared (FT-IR) spectroscopy, energy-dispersive X-ray analysis, X-ray powder diffraction and UV-Vis spectroscopy. Further, the bio-potential of the synthesized AgNPs was investigated by antidiabetic (α-glucosidase assay), antioxidant (free radical scavenging assays), antibacterial (disc diffusion method) and cytotoxicity assays (cell viability against HepG2 cells). Results: FT-IR spectroscopy revealed the contribution of bioactive compounds existing in Ib1 and Ib2 extracts, in the biosynthesis and equilibrium of the AgNPs. Although the Ib2-AgNPs had a higher atomic percentage of Ag in comparison with Ib1-AgNPs, in the antidiabetic assay, the inhibition percentage of α-glucosidase was higher for AgNPs of Ib1 than Ib2, at all three concentrations examined. From the cytotoxicity results, HepG2 cancer cells were more sensitive to the Ib1-AgNPs in comparison to the Ib2-AgNPs-treated HepG2 cells. The antioxidant prospective was higher in Ib2-AgNPs than Ib1-AgNPs. Moreover, the Ib2-AgNPs showed inhibitory action against all five tested pathogenic bacteria, producing an inhibition zone of 8.74-11.52 mm while Ib1-AgNPs had an inhibitory effect on four of them, with an 8.67-11.23 (mm) inhibition zone. Conclusions: Overall, the results concluded that the Ib2-AgNPs exhibited relatively higher functional activity than Ib1-AgNPs, which might be credited to the greater abundance of bioactive compounds existing in Ib2 extract that acted as reducing as well as capping agents in the synthesis of Ib2-AgNPs. Overall, the current study highlights a novel cost-effective and eco-friendly AgNPs synthesis using food waste peels with biocompatibility and could be potentially utilized in biomedical and pharmaceutical industries.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Ipomoea batatas/química , Nanopartículas Metálicas/química , Prata/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , alfa-Glucosidases/metabolismo
17.
Int J Nanomedicine ; 14: 4541-4558, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417257

RESUMO

Background: Tumor metastasis is responsible for most cancer death worldwide, which lacks curative treatment. Purpose: The objective of this study was to eliminate tumor and control the development of tumor metastasis. Methods: Herein, we demonstrated a smart nano-enabled platform, in which 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2h-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) and tirapazamine (TPZ) were co-loaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) to form versatile nanoparticles (PEG-PCL-IR780-TPZ NPs). Results: The intelligence of the system was reflected in the triggered and controlled engineering. Specially, PEG-PCL not only prolonged the circulation time of IR780 and TPZ but also promoted tumor accumulation of nanodrugs through enhanced permeability and retention (EPR) effect. Moreover, reactive oxygen species (ROS) generated by IR780 armed by an 808 nm laser irradiation evoked a cargo release. Meanwhile, IR780, as a mitochondria-targeting phototherapy agent exacerbated tumor hypoxic microenvironment and activated TPZ for accomplishing hypoxia-activated chemotherapy. Most significantly, IR780 was capable of triggering immunogenic cell death (ICD) during the synergic treatment. ICD biomarkers as a "danger signal" accelerated dendritic cells (DCs) maturation, and subsequently activated toxic T lymphocytes. Conclusion: Eventually, antitumor immune responses stimulated by combinational phototherapy and hypoxia-activated chemotherapy revolutionized the current landscape of cancer treatment, strikingly inhibiting tumor metastasis and providing a promising prospect in the clinical application.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Fototerapia , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunoterapia , Indóis/uso terapêutico , Lipossomos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Fototerapia/métodos , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Temperatura Ambiente , Tirapazamina/farmacologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
18.
Int J Nanomedicine ; 14: 4637-4648, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417259

RESUMO

Aim: It has been indicated that NPs may change the amyloidogenic steps of proteins and relevant cytotoxicity. Therefore, this report assigned to explore the impact of ZVFe NPs on the amyloidogenicity and cytotoxicity of α-synuclein as one of the many known amyloid proteins. Methods: The characterization of α-synuclein at amyloidogenic condition either alone or with ZVFe NPs was carried out by fluorescence, CD, UV-visible spectroscopic methods, TEM study, docking, and molecular modeling. The cytotoxicity assay of α-synuclein amyloid in the absence and presence of ZVFe NPs was also done by MTT, LDH, and flow cytometry analysis. Results: ThT fluorescence spectroscopy revealed that ZVFe NPs shorten the lag phase and accelerate the fibrillation rate of α-synuclein. Nile red and intrinsic fluorescence spectroscopy, CD, Congo red adsorption, and TEM studies indicated that ZVFe NP increased the propensity of α-synuclein into the amyloid fibrillation. Molecular docking study revealed that hydrophilic residues, such as Ser-9 and Lys-12 provide proper sites for hydrogen bonding and electrostatic interactions with adsorbed water molecules on ZVFe NPs, respectively. Molecular dynamics study determined that the interacted protein shifted from a natively discorded conformation toward a more packed structure. Cellular assay displayed that the cytotoxicity of α-synuclein amyloid against SH-SY5Y cells in the presence of ZVFe NPs is greater than the results obtained without ZVFe NPs. Conclusion: In conclusion, the existence of ZVFe NPs promotes α-synuclein fibrillation at amyloidogenic conditions by forming a potential template for nucleation, the growth of α-synuclein fibrillation and induced cytotoxicity.


Assuntos
Amiloide/metabolismo , Ferro/química , Nanopartículas Metálicas/química , alfa-Sinucleína/metabolismo , Amiloide/química , Benzotiazóis/química , Morte Celular , Linhagem Celular Tumoral , Vermelho Congo/química , Humanos , Cinética , L-Lactato Desidrogenase/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxazinas/química , Agregados Proteicos , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Tirosina/química , alfa-Sinucleína/química , alfa-Sinucleína/ultraestrutura
19.
Physiol Rev ; 99(4): 1765-1817, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31364924

RESUMO

Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.


Assuntos
Morte Celular , Citotoxicidade Imunológica , Cardiopatias/patologia , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Humanos , Mitocôndrias Cardíacas/imunologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/imunologia , Miocárdio/metabolismo , Necrose , Piroptose , Transdução de Sinais
20.
Int J Nanomedicine ; 14: 5849-5863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440050

RESUMO

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).


Assuntos
Dermatite Atópica/tratamento farmacológico , Emulsões/química , Óleos/química , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Administração Cutânea , Animais , Cânfora/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dermatite Atópica/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Orelha/patologia , Humanos , Imunoglobulina E/sangue , Imunossupressores/administração & dosagem , Masculino , Mentol/química , Camundongos , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Baço/efeitos dos fármacos , Substância P/metabolismo , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Resultado do Tratamento , Perda Insensível de Água/efeitos dos fármacos
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