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1.
Nat Commun ; 12(1): 5214, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471131

RESUMO

Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Substâncias Protetoras/farmacologia , RNA Nucleolar Pequeno/metabolismo , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/genética , Homeostase , Inflamação , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante , RNA Nucleolar Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
2.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361745

RESUMO

The edible parts of the plants Camellia sinensis, Vitis vinifera and Withania somnifera were extensively used in ancient practices such as Ayurveda, owing to their potent biomedical significance. They are very rich in secondary metabolites such as polyphenols, which are very good antioxidants and exhibit anti-carcinogenic properties. This study aims to evaluate the anti-cancerous properties of these plant crude extracts on human liver cancer HepG2 cells. The leaves of Camellia sinensis, Withania somnifera and the seeds of Vitis vinifera were collected and methanolic extracts were prepared. Then, these extracts were subjected to DPPH, α- amylase assays to determine the antioxidant properties. A MTT assay was performed to investigate the viability of the extracts of HepG2 cells, and the mode of cell death was detected by Ao/EtBr staining and flow cytometry with PI Annexin- V FITC dual staining. Then, the protein expression of BAX and BCl2 was studied using fluorescent dye to determine the regulation of the BAX and BCl2 genes. We observed that all the three extracts showed the presence of bioactive compounds such as polyphenols or phytochemicals. The W. somnifera bioactive compounds were found to have the highest anti-proliferative activity on human liver cancer cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Camellia sinensis/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vitis/química , Withania/química , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Flavonoides/química , Flavonoides/isolamento & purificação , Células Hep G2 , Humanos , Picratos/antagonistas & inibidores , Picratos/química , Extratos Vegetais/química , Folhas de Planta/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sementes/química , Transdução de Sinais , Taninos/química , Taninos/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificação , alfa-Amilases/genética , alfa-Amilases/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
3.
Chem Pharm Bull (Tokyo) ; 69(8): 760-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334519

RESUMO

Daldinins are a novel type of naturally occurring tricyclic heterocycles isolated from Daldinia concentrica. In this study, four daldinin A derivatives with different alkyl side chains were synthesized using the same synthetic protocol. Bioactivity tests first indicated that the daldinin A derivatives showed significant protection for endothelial cells against damage caused by high glucose. The derivative compound with three carbon atoms on the alkyl side exhibited the best effect.


Assuntos
Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hiperglicemia/tratamento farmacológico , Ascomicetos/química , Morte Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Hiperglicemia/metabolismo , Estrutura Molecular
4.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443670

RESUMO

Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds 11, 28, and 29 are potent against S. aureus biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL.


Assuntos
Bactérias/crescimento & desenvolvimento , Farmacorresistência Bacteriana/efeitos dos fármacos , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Bactérias/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/fisiologia , Inibidores do Crescimento/química , Células HEK293 , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Pirazóis/química
5.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443427

RESUMO

Pterostilbene, a natural metabolite of resveratrol, has been indicated as a potent anticancer molecule. Recently, several pterostilbene derivatives have been reported to exhibit better anticancer activities than that of the parent pterostilbene molecule. In the present study, a series of pterostilbene derivatives were designed and synthesized by the hybridization of pterostilbene, chalcone, and cinnamic acid. The cytotoxic effect of these hybrid molecules was determined using two oral cancer cell lines, HSC-3 and OECM-1. (E)-3-(2-((E)-4-Hydroxystyryl)-4,6-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (4d), with IC50 of 16.38 and 18.06 µM against OECM-1 and HSC-3, respectively, was selected for further anticancer mechanism studies. Results indicated that compound 4d effectively inhibited cell proliferation and induced G2/M cell cycle arrest via modulating p21, cyclin B1, and cyclin A2. Compound 4d ultimately induced cell apoptosis by reducing the expression of Bcl-2 and surviving. In addition, cleavage of PARP and caspase-3 were enhanced following the treatment of compound 4d with increased dose. To conclude, a number of pterostilbene derivatives were discovered to possess potent anticancer potentials. Among them, compound 4d was the most active, more active than the parent pterostilbene.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Estilbenos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Poli(ADP-Ribose) Polimerases/metabolismo , Estilbenos/química , Relação Estrutura-Atividade
6.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443429

RESUMO

A series of 16 new derivatives of harmine N9-Cinnamic acid were synthesized and fully characterized using NMR and MS. The in vitro antibacterial evaluation revealed that most of the synthesized harmine derivatives displayed better antibacterial activities against Gram-positive strains (S. aureus, S. albus and MRSA) than Gram-negative strains (E. coli and PA). In particular, compound 3c showed the strongest bactericidal activity with a minimum inhibitory concentration of 13.67 µg/mL. MTT assay showed that compound 3c displayed weaker cytotoxicity than harmine with IC50 of 340.30, 94.86 and 161.67 µmol/L against WI-38, MCF-7 and HepG2 cell lines, respectively. The pharmacokinetic study revealed that the distribution and elimination of 3c in vivo were rapid in rats with an oral bioavailability of 6.9%.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacocinética , Cinamatos/síntese química , Cinamatos/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/administração & dosagem , Cinamatos/química , Feminino , Humanos , Injeções Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Conformação Molecular , Ratos Sprague-Dawley , Fatores de Tempo
7.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443439

RESUMO

Ten polyketide derivatives (1-10), including a new natural product named (E)-2,4-dihydroxy-3-methyl-6-(2-oxopent-3-en-1-yl) benzaldehyde (1), and five known diketopiperazines (11-15), were isolated from the mangrove-sediment-derived fungus Aspergillus sp. SCSIO41407. The structures of 1-15 were determined via NMR and MS spectroscopic analysis. In a variety of bioactivity screening, 3 showed weak cytotoxicity against the A549 cell line, and 2 exhibited weak antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 3, 5, and 6 showed inhibition against acetylcholinesterase (AChE) with IC50 values of 23.9, 39.9, and 18.6 µM. Compounds 11, 12, and 14 exhibited obvious inhibitory activities of lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) with IC50 values of 19.2, 20.9, and 8.7 µM, and they also suppressed RANKL-induced osteoclast differentiation in bone marrow macrophages cells (BMMCs), with the concentration of 5 µM. In silico molecular docking with AChE and NF-κB p65 protein were also performed to understand the inhibitory activities, and 1, 11-14 showed obvious protein/ligand-binding effects to the NF-κB p65 protein.


Assuntos
Aspergillus/efeitos dos fármacos , Dicetopiperazinas/farmacologia , Sedimentos Geológicos/microbiologia , Policetídeos/farmacologia , Rhizophoraceae/química , Células A549 , Acetilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Dicetopiperazinas/química , Humanos , Lipopolissacarídeos/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Policetídeos/química , Espectroscopia de Prótons por Ressonância Magnética , Ligante RANK/farmacologia
8.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443442

RESUMO

The general aim of this study was to evaluate physicochemical properties, prebiotic activity and anticancer potential of jackfruit (Artocarpus heterophyllus) seed flour. The drying processes of jackfruit seeds were performed at 50, 60 and 70 °C in order to choose the optimal temperature for obtaining the flour based on drying time, polyphenol content and antioxidant capacity. The experimental values of the moisture ratio during jackfruit seed drying at different temperatures were obtained using Page's equation to establish the drying time for the required moisture between 5 and 7% in the flour. The temperature of 60 °C was considered adequate for obtaining good flour and for performing its characterization. The chemical composition, total dietary fiber, functional properties and antioxidant capacity were then examined in the flour. The seed flour contains carbohydrates (73.87 g/100 g), dietary fiber (31 g/100 g), protein (14 g/100 g) and lipids (1 g/100 g). The lipid profile showed that the flour contained monounsaturated (4 g/100 g) and polyunsaturated (46 g/100 g) fatty acids. Sucrose, glucose, and fructose were found to be the predominant soluble sugars, and non-digestible oligosaccharides like 1-kestose were also found. The total polyphenol content was 2.42 mg of gallic acid/g of the sample; furthermore, the antioxidant capacity obtained by ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) was 901.45 µmol Trolox/100 g and 1607.87 µmol Trolox/100 g, respectively. The obtained flour exhibited good functional properties, such as water and oil absorption capacity, swelling power and emulsifier capacity. Additionally, this flour had a protective and preventive effect which is associated with the potential prebiotic activity in Lactobacillus casei and Bifidobacterium longum. These results demonstrate that jackfruit seed flour has good nutritional value and antioxidant and prebiotic activity, as well as potential protective effects and functional properties, making it an attractive food or ingredient in developing innovative functional products.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Artocarpus/química , Fenômenos Químicos , Farinha/análise , Prebióticos , Sementes/química , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Dessecação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Umidade , Cinética , Lipídeos/análise , Extratos Vegetais/farmacologia , Polifenóis/análise , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Superóxido Dismutase/metabolismo , Viscosidade , Água/química
9.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443454

RESUMO

Two new abietane diterpenoids (1,2), along with five known diterpenoids (3-7), were first isolated and purified from the stems of Clerodendrum bracteatum. The structures of the new compounds were established by extensive analysis of mass spectrometric and 1-D, 2-D NMR spectroscopic data. Their antioxidant activities were determined on DPPH radical scavenging and ABTS. The in vitro cytotoxic activities of the compounds were evaluated against the HL-60 and A549 cell lines by the MTT method.


Assuntos
Abietanos/isolamento & purificação , Abietanos/farmacologia , Antioxidantes/farmacologia , Clerodendrum/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Células A549 , Abietanos/química , Morte Celular/efeitos dos fármacos , Diterpenos/química , Células HL-60 , Humanos , Espectroscopia de Ressonância Magnética
10.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443457

RESUMO

Curcumin extracted from the rhizome of Curcuma Longa has been used in therapeutic preparations for centuries in different parts of the world. However, its bioactivity is limited by chemical instability, water insolubility, low bioavailability, and extensive metabolism. In this study, the coaxial electrospinning technique was used to produce both poly (ε-caprolactone) (PCL)-curcumin and core-shell nanofibers composed of PCL and curcumin in the core and poly (lactic acid) (PLA) in the shell. Morphology and physical properties, as well as the release of curcumin were studied and compared with neat PCL, showing the formation of randomly oriented, defect-free cylindrical fibers with a narrow distribution of the dimensions. The antibacterial and antibiofilm potential, including the capacity to interfere with the quorum-sensing mechanism, was evaluated on Pseudomonas aeruginosa PAO1, and Streptococcus mutans, two opportunistic pathogenic bacteria frequently associated with infections. The reported results demonstrated the ability of the Curcumin-loading membranes to inhibit both PAO1 and S. mutans biofilm growth and activity, thus representing a promising solution for the prevention of biofilm-associated infections. Moreover, the high biocompatibility and the ability to control the oxidative stress of damaged tissue, make the synthesized membranes useful as scaffolds in tissue engineering regeneration, helping to accelerate the healing process.


Assuntos
Anti-Infecciosos/farmacologia , Biofilmes , Curcumina/farmacologia , Infecções/microbiologia , Nanofibras/química , Engenharia Tecidual , Biofilmes/efeitos dos fármacos , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Liberação Controlada de Fármacos , Sequestradores de Radicais Livres/farmacologia , Humanos , Cinética , Testes de Sensibilidade Microbiana , Picratos/química , Poliésteres/química , Percepção de Quorum/efeitos dos fármacos , Termogravimetria
11.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445291

RESUMO

Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.


Assuntos
Neoplasias Ósseas/patologia , Ácido Clorogênico/farmacologia , Doxorrubicina/farmacologia , Osteossarcoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Cardiotônicos/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácido Clorogênico/administração & dosagem , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Osteossarcoma/tratamento farmacológico , Ratos
12.
Theranostics ; 11(16): 7735-7754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335961

RESUMO

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Compostos Organometálicos/farmacologia , Osteoclastos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Medula Óssea/metabolismo , Neoplasias Ósseas , Osso e Ossos/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/farmacologia , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Cadeias alfa de Integrinas/metabolismo , Camundongos , Mieloma Múltiplo/metabolismo , Compostos Organometálicos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteólise/patologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/uso terapêutico , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nat Commun ; 12(1): 5103, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429409

RESUMO

Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.


Assuntos
Colesterol/metabolismo , Ferroptose/fisiologia , Homeostase , Metabolismo dos Lipídeos , Neoplasias/metabolismo , Animais , Neoplasias da Mama , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glutationa Peroxidase/metabolismo , Humanos , Hidroxicolesteróis , Neoplasias Pulmonares , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Biomed Res Int ; 2021: 6613439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337035

RESUMO

Methods: Immunohistochemical staining, sequencing, and genetic analysis of liver cancer tissues were performed. The antitumor efficacy of single-agent or combination treatment was measured by cell counting kit-8 assay and colony formation assays. Their antiproliferative and apoptosis activity is evaluated by cell cycle analyses and wound healing assays. The DNA-related proteins were also measured by Western blotting and immunohistochemical staining. The HepG2 xenograft model was used to detect the effects of lenvatinib-alisertib on the antitumor activity. Results: AURKA was found to be upregulated in HCC tissues (77.3%, 17/22). Combined alisertib and lenvatinib treatment significantly enhanced the inhibition of proliferation and migration in HepG2 and Hep3B cell lines compared to single-agent treatments (all Ps < 0.01). Alisertib alone or in combination with lenvatinib demonstrated a significant increase in the percentage of super-G2 cells (lenvatinib 1 µM vs. lenvatinib 1 µM + alisertib 0.1 µM 8.84 ± 0.84 vs. 34.0 ± 1.54, P < 0.001). Discontinuous spindles and missegregated chromosomes in HCC cells treated with alisertib in combination with lenvatinib were observed. We further revealed that combined treatment inhibited the expression of DNA damage pathway proteins compared to those of single-agent treatments. In nude mice, combined administration of alisertib combined with lenvatinib significantly enhanced the suppression of tumor growth and induced apoptosis (all Ps < 0.01). Conclusions: Our findings provide evidence for the possible use of alisertib in combination with lenvatinib in the treatment of HCC for better therapeutic outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Azepinas/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Dano ao DNA , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Quinolinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Aurora Quinase A/metabolismo , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
15.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443300

RESUMO

Frutalin is a plant lectin with beneficial immunobiological action, although the access to its active form is still restricted. Moreover, there is a knowledge gap on isoform activity and glycosylation impact on its bioactivity, and recombinant production protocols were seen as ineffective. Here, a simpler and faster production and purification protocol was developed, attaining a yield of purified frutalin 3.3-fold higher than that obtained previously. Hemagglutination assays confirmed that this frutalin isoform could not agglutinate rabbit erythrocytes, while maintaining the native tetrameric structure, as indicated by DLS analysis, and strong interaction with methyl-alpha-galactose, in fluorescence spectroscopy studies. The cytotoxicity of the recombinant frutalin isoform was shown in a broad panel of human cancer cells: colon (HCT116), melanoma (A375), triple-negative breast cancer (MDA-MB-231), and ovarian (IGROV-1). Treatment with 8.5-11.8 µM TrxFTL reduced proliferation of all cancer cells to half in 48 h. This anti-proliferative effect encompasses the p53 pathway since it was significantly reduced in p53-null colon cancer cells (HCT116 p53-/-; GI50 of 25.0 ± 3.0 µM), when compared to the isogenic p53-positive cells (HCT116 p53+/+; GI50 of 8.7 ± 1.8 µM; p < 0.002). This recombinantly produced frutalin isoform has relevant cytotoxic effect and its biological activity is not dependent on glycosylation. The developed E. coli production and purification protocol generates high yield of non-glycosylated frutalin isoform with potent cytotoxic activity, enabling the development of novel anticancer p53-targeting therapies.


Assuntos
Galectinas/farmacologia , Neoplasias/patologia , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Difusão Dinâmica da Luz , Escherichia coli/metabolismo , Galactose/metabolismo , Galectinas/química , Galectinas/isolamento & purificação , Glicosilação/efeitos dos fármacos , Hemaglutinação/efeitos dos fármacos , Modelos Moleculares , Peso Molecular , Coelhos , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Espectrometria de Fluorescência
16.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443308

RESUMO

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by 1H-NMR, 13C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC50 = 1.89 µM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cinamatos/síntese química , Cinamatos/farmacologia , Desenho de Fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/química , DNA Topoisomerases Tipo II/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Quinolonas/química , Inibidores da Topoisomerase/farmacologia
17.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443489

RESUMO

Hydrogel formulations (masks or patches, without tissue support) represent the new frontier for customizable skin beauty and health. The employment of these materials is becoming popular in wound dressing, to speed up the healing process while protecting the affected area, as well as to provide a moisturizing reservoir, control the inflammatory process and the onset of bacterial development. Most of these hydrogels are acrylic-based at present, not biodegradable and potentially toxic, due to acrylic monomers residues. In this work, we selected a new class of cellulose-derived and biodegradable hydrogel films to incorporate and convey an active compound for dermatological issues. Films were obtained from a combination of different polysaccharides and clays, and berberine hydrochloride, a polyphenolic molecule showing anti-inflammatory, immunomodulatory, antibacterial and antioxidant properties, was chosen and then embedded in the hydrogel films. These innovative hydrogel-based systems were characterized in terms of water uptake profile, in vitro cytocompatibility and skin permeation kinetics by Franz diffusion cell. Berberine permeation fitted well to Korsmeyer-Peppas kinetic model and achieved a release higher than 100 µg/cm2 within 24 h. The latter study, exploiting a reliable skin model membrane, together with the biological assessment, gained insights into the most promising formulation for future investigations.


Assuntos
Berberina/administração & dosagem , Sistemas de Liberação de Medicamentos , Metilgalactosídeos/química , Pele/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Células HaCaT , Humanos , Cinética , Permeabilidade , Fibras de Estresse/efeitos dos fármacos , Fibras de Estresse/metabolismo , Difração de Raios X
18.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443502

RESUMO

Two triterpene saponins, including a novel serjanic acid derivative, were isolated from Chenopodium hybridum L. (Amaranthaceae) aerial parts. Their structures were elucidated by a combination of spectroscopic methods (MS, 1D and 2D NMR). Both compounds were evaluated for cytotoxicity and selectivity on skin, prostate, gastrointestinal, thyroid and lung cancer cells. Their effect was dose and time-dependent with varied potency, the highest against prostate PC3 and melanoma WM793, where IC50 was lower than the reference drug doxorubicin. Structure-activity relationship is briefly discussed.


Assuntos
Chenopodiaceae/química , Glicosídeos/farmacologia , Triterpenos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glicosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Triterpenos/química , Triterpenos/isolamento & purificação
19.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443546

RESUMO

Recent studies found that short-chain fatty acids (SCFAs), which are produced through bacterial fermentation in the gastrointestinal tract, have oncoprotective effects against cervical cancer. The most common SCFAs that are well known include acetic acid, butyric acid, and propionic acid, among which propionic acid (PA) has been reported to induce apoptosis in HeLa cells. However, the mechanism in which SCFAs suppress HeLa cell viability remain poorly understood. Our study aims to provide a more detailed look into the mechanism of PA in HeLa cells. Flow cytometry analysis revealed that PA induces reactive oxygen species (ROS), leading to the dysfunction of the mitochondrial membrane. Moreover, PA inhibits NF-κB and AKT/mTOR signaling pathways and induces LC3B protein levels, resulting in autophagy. PA also increased the sub-G1 cell population that is characteristic of cell death. Therefore, the results of this study propose that PA inhibits HeLa cell viability through a mechanism mediated by the induction of autophagy. The study also suggests a new approach for cervical cancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Propionatos/farmacologia , Neoplasias do Colo do Útero/patologia , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , NF-kappa B/metabolismo , Propionatos/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
20.
FASEB J ; 35(9): e21795, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403508

RESUMO

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated ß-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.


Assuntos
Senescência Celular/efeitos dos fármacos , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Núcleo Pulposo/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo
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