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1.
J Agric Food Chem ; 68(6): 1609-1620, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31957426

RESUMO

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted, yielding very low phenolic bioavailability what makes it difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4'-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of reactive oxygen species (ROS) levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.


Assuntos
Anti-Inflamatórios/farmacologia , Neuroblastoma/metabolismo , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Peróxido de Hidrogênio/toxicidade , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Neuroblastoma/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/metabolismo
2.
Cell Mol Life Sci ; 77(2): 351-363, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31222373

RESUMO

Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.


Assuntos
Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Estilbenos/farmacologia , Regiões 3' não Traduzidas/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco , Transcrição Genética/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismo , Neoplasias da Bexiga Urinária
3.
Braz J Med Biol Res ; 52(12): e8834, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826181

RESUMO

Polydatin (PD), a monocrystalline polyphenolic drug mainly found in the roots of Polygonum cuspidatum, has various pharmacological activities. Long non-coding RNAs (lncRNA) DiGeorge syndrome critical region gene 5 (DGCR5) was found to participate in the suppression of multiple cancers. Here, we proposed to study the effect of PD on myocardial infarction (MI) by inducing DGCR5. CCK-8 assay was performed to detect the viability of H9c2 cells. Flow cytometry was utilized to test apoptosis of H9c2 cells. These results determined the optimal concentration and effect time of hypoxia as well as PD. Si-DGCR5 was transfected into cells and the expression level was determined by qRT-PCR. Western blot was utilized to evaluate the expression of apoptosis-related proteins, Bcl-2, Bax, and cleaved-caspase-3, as well as autophagy-associated proteins including Beclin-1, p62, and LC3-II/LC3-I. As a result, PD efficiently attenuated hypoxia-induced apoptosis and autophagy in H9c2 cells. The expression of DGCR5 was down-regulated by hypoxia and up-regulated by PD. Besides, knocking-down the expression of DGCR5 inhibited the protection of PD in H9c2 cells. In addition, PD up-regulated the accumulation of DGCR5, DGCR5 decreased the expression of Bcl-2 and p62, raised the expression of Bax and cleaved-caspase-3, and the proportion of LC3-II/LC3-I. PD stimulated the PI3K/AKT/mTOR and MEK/ERK signaling pathways via up-regulating the expression of DGCR5. Our data demonstrated that PD reduced cell apoptosis and autophagy induced by hypoxia in cardiomyocytes. Moreover, PD activated PI3K/AKT/mTOR and MEK/ERK signaling pathways by up-regulating the expression of DGCR5.


Assuntos
Apoptose/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glucosídeos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , RNA Longo não Codificante/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Linhagem Celular , Citoproteção , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
4.
Fitoterapia ; 139: 104367, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629045

RESUMO

Ca2+-activated Cl- channels (CaCCs) wildly exist in many tissues which play an important role in ion transport and excitation conduction, especially fluid secretion and smooth muscle contraction in epithelial tissues. TMEM16A as a classic CaCC expresses in the intestine, and has become a potential target of intestinal physiological and pathological researches and therapeutic drug screening. In this study, we identified trans-δ-viniferin (TVN), a resveratrol dimmer, could inhibit TMEM16A activity in TMEM16A expressed FRT cells with IC50 of 19.7 µM, it also prevented Ca2+-activated Cl- current in HT-29 cells with IC50 of 4.65 µM and in colonic mucosa. In the mechanism studies, TVN showed no significant inhibition on CFTR and basal Na+/K+-ATPase in both intestinal epithelial cells and colonic tissues, except for inhibition of calcium concentration and Ca2+-activated K+ channel to some degree. In anti-diarrheal studies, TVN could effectively prevent diarrhea caused by rotavirus infection and reduce the pellet number in IBS-D mice. These physiological effects are at least partially attributed to the inhibitory effect of TVN on CaCC-mediated intestinal fluid secretion and the reduction of smooth muscle contraction force by inhibiting TMEM16A. Collectively, the present study identified a new pharmacological target of TVN which provided the theoretical basis for the application of TVN in the treatment of rotavirus-infected diarrhea and IBS-D.


Assuntos
Benzofuranos/farmacologia , Canais de Cloreto/antagonistas & inibidores , Diarreia/tratamento farmacológico , Células Epiteliais/efeitos dos fármacos , Resorcinóis/farmacologia , Estilbenos/farmacologia , Animais , Cálcio/análise , Diarreia/virologia , Motilidade Gastrointestinal/efeitos dos fármacos , Células HT29 , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Rotavirus
5.
Planta Med ; 85(16): 1263-1274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31604352

RESUMO

In an effort to identify agents from natural products that inhibit protein tyrosine phosphatase 1B (PTP1B), 5 new prenylated stilbenes, (±)-styrastilbene A (1: ), styrastilbene B (2: ), and (±)-styrastilbenes C - E (3, 4: , and 7: ), along with 4 known structurally related compounds (5, 6, 8: , and 9: ), were isolated from the roots of Artocarpus styracifolius. Their structures were elucidated by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), ultraviolet (UV), and infrared (IR). Based on these isolates, a new plausible biosynthetic pathway for the unusual stilbene derivatives 3: -8: with a tetracyclic ring system is proposed. Among these compounds, 1: -3, 8: , and 9: displayed significant PTP1B inhibitory effects with IC50 values ranging from 2.40 (95% confidence interval [CI]: 2.21 - 2.59) to 8.80 (95% CI: 8.28 - 9.32) µM. Moreover, kinetic analysis and molecular docking simulations were performed to provide insight into the inhibition type as well as the interaction and binding mode of these active isolates with PTP1B. Our results revealed mixed-type PTP1B inhibition for all compounds tested. Docking simulations of these stilbene derivatives showed negative binding energies and close proximity to residues at the allosteric and catalytic sites of PTP1B. These findings suggest that these compounds may have a potential to be further developed as agents for the management of type 2 diabetes mellitus.


Assuntos
Artocarpus/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Estilbenos/farmacologia , Raízes de Plantas/química , Prenilação , Estilbenos/química
6.
Biofouling ; 35(7): 758-767, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31505984

RESUMO

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections, which are one of the most common infectious disease types in humans. UPEC infections involve bacterial cell adhesion to bladder epithelial cells, and UPEC can also form biofilms on indwelling catheters that are often tolerant to common antibiotics. In this study, the anti-biofilm activities of t-stilbene, stilbestrol, t-resveratrol, oxyresveratrol, ε-viniferin, suffruticosol A, and vitisin A were investigated against UPEC. t-Resveratrol, oxyresveratrol, and ε-viniferin, suffruticosol A, and vitisin A significantly inhibited UPEC biofilm formation at subinhibitory concentrations (10-50 µg ml-1). These findings were supported by observations that t-resveratrol and oxyresveratrol reduced fimbriae production and the swarming motility in UPEC. Furthermore, t-resveratrol and oxyresveratrol markedly diminished the hemagglutinating ability of UPEC, and enhanced UPEC killing by human whole blood. The findings show that t-resveratrol, oxyresveratrol, and resveratrol oligomers warrant further attention as antivirulence strategies against persistent UPEC infections.


Assuntos
Biofilmes , Extratos Vegetais/farmacologia , Resveratrol/farmacologia , Estilbenos/farmacologia , Escherichia coli Uropatogênica/efeitos dos fármacos , Aderência Bacteriana/efeitos dos fármacos , Proteínas de Escherichia coli/metabolismo , Fímbrias Bacterianas/metabolismo , Escherichia coli Uropatogênica/fisiologia , Virulência/efeitos dos fármacos
7.
Eur J Med Chem ; 183: 111697, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536891

RESUMO

A series of cis restricted 1,2,4-triazole analogs of combretastatin A-4 (CA-4) were designed and synthesized. The antiproliferative activity of these compounds was measured on hepatocellular carcinoma HepG2, leukemia HL-60, and breast cancer MCF-7 cell lines. The obtained results showed a substantial ability of the synthesized anilides to inhibit tumor growth. On HepG2 cells, 5o and 5r showed potent IC50 values of 0.10 and 0.04 µM, respectively. While on HL-60 cells, the IC50 values were 0.004 and 0.01 µM for 5b and 5i, respectively. The inhibitory activity of tubulin polymerization was evaluated on HepG2 cells. The anilide 5r showed a remarkable tubulin inhibition compared to CA-4. Moreover, flow cytometry studies showed that HepG2 cells treated with the most potent compounds 5b and 5r were arrested in the G2/M phase of the cell cycle. This effect was accompanied by cellular apoptosis and activation of caspase-3. Molecular modeling showed several hydrogen bonding and van der Waals interactions with several important amino acids inside the colchicine binding site of tubulin.


Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Estilbenos/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
8.
Fitoterapia ; 138: 104350, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473333

RESUMO

Three new bibenzyl derivatives (bletstrins A-C, 1-3), including two bibenzyls that have hydroxyl-substituted chiral centers on the aliphatic bibenzyl bridge, along with eighteen known stilbenoids (4-21) were isolated from the tubers of Bletilla striata. The structures of new compounds were elucidated by the use of 1D/2D NMR spectroscopic data. The absolute configurations of bletitrins A and B were determined by optical rotation value. Compounds 13-16 were isolated from the Orchidaceae for the first time. Most of the isolated compounds were evaluated for their antibacterial activities against three gram-positive bacterial strains and one gram-negative bacterial strain. Compounds 4, 10, 12, 14, 15, 16 and 18 showed potent inhibitory activities, with MICs of (6-52 µg/mL) against S. aureus ATCC 6538.


Assuntos
Antibacterianos/farmacologia , Orchidaceae/química , Tubérculos/química , Estilbenos/farmacologia , Antibacterianos/isolamento & purificação , Bibenzilas/isolamento & purificação , Bibenzilas/farmacologia , China , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Estilbenos/isolamento & purificação
9.
Food Chem Toxicol ; 132: 110730, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369850

RESUMO

Mulberry leaf is a newly accepted vegetable for daily diet. It tastes good and has multiple health benefits, including antioxidant and anti-inflammatory activities. However, the chemicals responsible for these health benefits remain unveiled. Prenylated phenolics are characteristic bioactive compounds in mulberry leaf, which are recognized as good antioxidants. In this work, moracin N was purified from mulberry leaf. It showed better antioxidant activities than resveratrol. The EC50 value of cellular antioxidant activity was 24.92 µM, and the IC50 value against DPPH radical was 40.00 µM. The prenyl group rendered the molecule more membrane affinity which improved the bioavailability. The furan ring was critical for the antioxidant behaviour. The cell viability test revealed that moracin N had a good safety. These results pointed out that moracin N contributed to the antioxidant activity of mulberry leaf.


Assuntos
Antioxidantes/farmacologia , Benzofuranos/análise , Benzofuranos/farmacologia , Morus/química , Folhas de Planta/química , Estilbenos/análise , Estilbenos/farmacologia , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Estrutura Molecular , Análise Espectral/métodos , Estilbenos/química , Estilbenos/farmacocinética
10.
J Agric Food Chem ; 67(37): 10321-10329, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31419115

RESUMO

Pterostilbene (PTS) is a phenolic compound with diverse pharmacologic activities. However, its potential for inhibiting obesity-related colorectal cancer (CRC) remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT-29 colorectal adenocarcinoma cells. The results demonstrated that PTS could downregulate the expression of aCM-induced fatty acid-binding protein 5 (FABP5) and prometastatic factors such as vascular endothelial growth factor, matrix metalloproteinase-2 (MMP2), MMP9, and extracellular tumor necrosis factor α via inhibiting aCM-induced nuclear factor-kappa B (NF-κB), ß-catenin, and peroxisome proliferator-activated receptor γ (PPAR-γ). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation that are upstream of NF-κB, ß-catenin, and PPAR-γ. Therefore, we suggest that PTS could alleviate adiposity-induced metastasis in CRC via inhibiting cell migration through downregulating FABP5 gene expression.


Assuntos
Adipócitos/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/fisiopatologia , Meios de Cultivo Condicionados/química , Proteínas de Ligação a Ácido Graxo/metabolismo , Estilbenos/farmacologia , Células 3T3 , Animais , Linhagem Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Meios de Cultivo Condicionados/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Eur J Med Chem ; 182: 111597, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31422225

RESUMO

Fatty acid synthase (FASN) is a lipogenic enzyme that is selectively upregulated in malignant cells. There is growing consensus on the oncogenicity of FASN-driven lipogenesis and the potential of FASN as a druggable target in cancer. Here, we report the synthesis and FASN inhibitory activities of two novel galloyl esters of trans-stilbene EC1 and EC5. Inhibition of FASN was accompanied by a loss in AKT activation and profound apoptosis in several non-small cell lung cancer (NSCLC) cells at the growth inhibitory concentrations of EC1 and EC5. Both FASN and phospho-AKT levels were concurrently downregulated. However, addition of a lipid concentrate to the treated cells reinstated cell viability and reversed the loss of FASN and AKT protein levels, thus recapitulating the causal relationship between FASN inhibition and the loss in cell viability.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ésteres/farmacologia , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Gálico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Estilbenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
12.
Biomed Pharmacother ; 117: 109160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387166

RESUMO

BACKGROUND: Pinosylvin possesses several biological properties, including anti-inflammatory, antitumor, and antioxidant characteristics. However, the effects of pinosylvin on the migration and invasion of human oral cancer cells and the underlying mechanisms remain unclear. HYPOTHESIS/PURPOSE: In this research, we investigated the outcome of different concentrations of pinosylvin (0-80 µM) on the metastatic and invasive abilities of SAS, SCC-9, and HSC-3 cells. METHODS AND RESULTS: Western blotting assay and Gelatin zymography assay indicated that pinosylvin inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and reduced its protein level but increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). Additionally, the wound healing assay and Transwell method showed that pinosylvin reduced the migration of SAS, SCC-9 and HSC-3 oral cancer cells. Besides, pinosylvin decreased the phosphorylation of ERK1/2 protein experssion in both SAS and SCC-9 cells. CONCLUSION: These results indicate that pinosylvin is a potential anticancer agent for preventing oral cancer metastasis.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Neoplasias Bucais/tratamento farmacológico , Invasividade Neoplásica/patologia , Estilbenos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , Neoplasias Bucais/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-2/metabolismo
13.
Eur J Med Chem ; 180: 637-647, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351395

RESUMO

Stilbenes with well-known antioxidant and antiradical properties are beneficial in different pathologies including cardiovascular diseases. The present research was performed to investigate the potential protective effect of resveratrol (1) and piceatannol (2), against hypoxia-induced oxidative stress in the H9c2 cardiomyoblast cell line, and the underlying mechanisms. Compounds 1 and 2 significantly inhibited the release of peroxynitrite and thiobarbituric acid levels at na no- or submicromolar concentrations, and this effect was more evident in piceatannol-treated cells, that significantly increased MnSOD protein level in a concentration dependent manner. Furthermore, since piceatannol, which is far less abundant in natural sources, displayed a higher bioactivity than the parent compound, we hereby report on a very fast synthesis and detailed structure-based design of a focused stilbene library. Finally, taking into account that hypoxia-induced ROS accumulation also increases expression and activity of 5-lipoxygenase (5-LOX) with production of leukotrienes, we have disclosed structural key factors crucial for 5-LOX activity. Among the synthesized analogues ( 3-7), compound 7 was the most effective in improving cardiomyocytes viability and in 5-LOX inhibition. In conclusion, modeling and experimental studies provided the basis for further optimization of stilbene analogues as multi-target inhibitors of the inflammatory and oxidative pathway.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Hipóxia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Miócitos Cardíacos/metabolismo , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Ratos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
14.
Chem Biol Interact ; 310: 108754, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323227

RESUMO

Diabetic cardiomyopathy (DCM) is one of the leading causes of morbidity and mortality in diabetic patients. Piceatannol (PIC) has protective effects against cardiovascular disease; however, it remains unknown whether it also protects against DCM. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate the effects of PIC on the viability of high glucose (HG)-induced H9C2 cells. Protein expression and mRNA levels were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. In vivo, physical and biochemical analyses, together with transthoracic echocardiography and hemodynamic measurements, were used to detect the effects of PIC treatment on cardiac function in DCM rats. Reactive oxygen species production was determined using an ELISA kit, and inflammatory cytokines were detected by RT-PCR. Pathological changes were assessed by hematoxylin-eosin staining, immunohistochemical staining, and TUNEL staining. According to the results, PIC treatment improved cell viability and inhibited cell apoptosis in HG-induced H9C2 cardiac myoblasts. In addition, PIC not only attenuated the over-production of interleukin-6 (IL-6) (P < 0.05) and tumor necrosis factor alpha (TNF-α) (P < 0.05), but also improved the expression of nuclear factor E2-related factor 2 (Nrf2) (P < 0.05) and heme oxygenase-1 (HO-1) (P < 0.01). Importantly, knockdown of Nrf2 suppressed PIC-mediated activation of the Nrf2/HO-1 pathway and abolished its anti-inflammatory effects. In vivo, oral administration of PIC suppressed STZ-induced inflammation, oxidative stress hypertrophy, fibrosis(myocardial collagen volume fraction in 5 mg/kg and 10 mg/kg PIC group was decreased 25.83% and 55.61% compared with the DM group), and apoptosis(Caspase-3 level in 5 mg/kg and 10 mg/kg PIC group was decreased 13.21% and 33.91% compared with the DM group), thereby relieving cardiac dysfunction and improving both fibrosis and pathological changes in cardiac tissues of diabetic rats. These findings define for the first time that the effects of PIC against DCM can be attributed to its role in inflammation and oxidative stress inhibition.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Estilbenos/farmacologia , Animais , Linhagem Celular , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos , Estilbenos/uso terapêutico
15.
Biomater Sci ; 7(9): 3855-3865, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31305807

RESUMO

Fluorogens with aggregation-induced emission (AIE) characteristics (AIEgens) possess unique optical properties, design flexibility, and multi-functional capabilities and have established their niche as smart materials since their discovery in 2001. In recent years, AIEgens have found varied applications in sensing, imaging, and therapy in biomedical research. In this work, we systematically and comprehensively investigate the in vitro anticancer activity of AIEgens. We report the high cytotoxicity of AIEgens against cancer cells, especially against cancer stem cells (CSCs) which show high resistance to existing therapeutic drug regimens. Furthermore, we explore the role of AIEgens as novel image-guided chemotherapy agents that offer a new avenue for efficient cancer treatment.


Assuntos
Antineoplásicos/química , Corantes Fluorescentes/química , Fármacos Fotossensibilizantes/química , Estilbenos/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/farmacologia , Hemólise , Humanos , Invasividade Neoplásica , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Imagem Óptica/métodos , Fotoquimioterapia , Estilbenos/farmacologia , Nanomedicina Teranóstica
16.
Mol Carcinog ; 58(10): 1876-1885, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292999

RESUMO

Sirtuin-1 and -3 (SIRT1 and SIRT3) are important nicotinamide adenine dinucleotide (NAD+ )-dependent deacetylases known to regulate a variety of cellular functions. Studies have shown that SIRT1 and SIRT3 were overexpressed in human melanoma cells and tissues and their inhibition resulted in a significant antiproliferative response in human melanoma cells and antitumor response in a mouse xenograft model of melanoma. In this study, we determined the antiproliferative efficacy of a newly identified dual small molecule inhibitor of SIRT1 and SIRT3, 4'-bromo-resveratrol (4'-BR), in human melanoma cell lines (G361, SK-MEL-28, and SK-MEL-2). Our data demonstrate that 4'-BR treatment of melanoma cells resulted in (a) decrease in proliferation and clonogenic survival; (b) induction of apoptosis accompanied by a decrease in procaspase-3, procaspase-8, and increase in the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP); (c) marked downregulation of proliferating cell nuclear antigen (PCNA); and (d) inhibition of melanoma cell migration. Further, 4'-BR caused a G0/G1 phase arrest of melanoma cells that was accompanied by an increase in WAF-1/P21 and decrease in Cyclin D1/Cyclin-dependent kinase 6 protein levels. Furthermore, we found that 4'-BR causes a decrease in lactate production, glucose uptake, and NAD+ /NADH ratio. These responses were accompanied by downregulation in lactate dehydrogenase A and glucose transporter 1 in melanoma cells. Collectively, our data suggest that dual inhibition of SIRT1 and SIRT3 using 4'-BR imparted antiproliferative effects in melanoma cells through a metabolic reprogramming and affecting the cell cycle and apoptosis signaling. Therefore, concomitant pharmacological inhibition of SIRT1 and SIRT3 needs further investigation for melanoma management.


Assuntos
Melanoma/tratamento farmacológico , Resorcinóis/farmacologia , Sirtuína 1/genética , Sirtuína 3/genética , Estilbenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácido Láctico/metabolismo , Melanoma/genética , Melanoma/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Sirtuína 1/antagonistas & inibidores , Sirtuína 3/antagonistas & inibidores
17.
Nutrients ; 11(7)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277394

RESUMO

This study investigated the protective effect and the molecular mechanism of piceatannol on hydrogen peroxide (H2O2)-induced retinal pigment epithelium cell (ARPE-19) damage. Piceatannol treatment significantly inhibited H2O2-induced RPE cell death and reactive oxygen species (ROS) generation by 64.4% and 75.0%, respectively. Results of flow cytometry showed that H2O2-induced ARPE-19 cells apoptosis was ameliorated by piceatannol supplementation, along with decreased relative protein expressions of Bax/Bcl-2, Cleave-Caspase-3, and Cleave-PARP. Moreover, piceatannol treatment induced NF-E2-related factor 2 (Nrf2) signaling activation, which was evidenced by increased transcription of anti-oxidant genes, glutamate-cysteine ligase catalytic subunit (GCLc), SOD, and HO-1. Knockdown of Nrf2 through targeted siRNA alleviated piceatannol-mediated HO-1 transcription, and significantly abolished piceatannol-mediated cytoprotection. LY294002 (PI3K inhibitor) dramatically blocked piceatannol-mediated increasing of Nrf2 nuclear translocation, HO-1 expression, and cytoprotective activity, indicating the involvement of PI3K/Akt pathway in the cytoprotective effect of piceatannol. The results from this suggest the potential of piceatannol in reducing the risk of age-related macular degeneration.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Estilbenos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Citoproteção , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais
18.
Eur J Pharmacol ; 859: 172526, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31283935

RESUMO

Pterostilbene (PTE) is a natural dimethylated analog of resveratrol, which exerts antioxidative, hypolipidemic and hypoglycemic effects; however, the underlying mechanism is not yet clear. In this study, we evaluated the effects of PTE on diabetic rats and clarified the underlying mechanism. Diabetes was induced in rats by streptozotocin (STZ) and a high-sugar and high-fat diet. Rats were then treated with PTE (20, 40 and 80 mg/kg/d) for 8 weeks. Oral glucose tolerance test (OGTT) was performed to measure the glycometabolism of the diabetic rats at the end of the treatment. Fasting blood glucose (FBG), fasting insulin (FINS) and lipid profile were determined using an automatic biochemistry analyzer and serum inflammatory factors were analyzed by enzyme-linked immunosorbent assay. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were also analyzed by spectrophotometry to evaluate the anti-oxidant effects. The expression of proteins of PPARγ and PI3K/Akt signaling pathway related proteins in adipose tissue of the diabetic rats was analyzed by Western blotting. PTE treatment significantly reduced weight loss, FBG, insulin resistance, serum lipid levels and inflammatory factors. PTE treatment also inhibited oxidative stress by decreasing MDA expression and increasing SOD expression. Simultaneously, PTE treatment significantly ameliorated morphological impairment of the pancreas in diabetic rats. Furthermore, PTE treatment significantly increased the protein expression of PPARγ, PI3K, p-Akt, GLUT4 and IRS-1 in adipose tissues of diabetic rats. This study suggests that PTE can exert antidiabetic effects via the PI3K/Akt signaling pathway.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Jejum/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Estilbenos/uso terapêutico
19.
Chem Pharm Bull (Tokyo) ; 67(7): 640-647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257319

RESUMO

Neuroinflammation manifested by over-activation of microglial cells plays an essential role in neurodegenerative diseases. Short-term activation of microglia can be beneficial, but chronically activated microglia can aggravate neuronal dysfunction possibly by secreting potentially cytotoxic substances such as tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO), which can result in dysfunction and death of neurons. Therefore inhibiting over-activation of microglia and the production of cytotoxic intermediates may become an effective therapeutic approach for neuroinflammation. In this paper, we review our continuous research on natural inhibitors of over-activated microglia from traditional herbals, including flavonoids, lignans, sesquiterpene coumarins, and stilbenes.


Assuntos
Produtos Biológicos/química , Microglia/metabolismo , Animais , Produtos Biológicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Lignanas/química , Lignanas/farmacologia , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/biossíntese , Estilbenos/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
20.
Chem Pharm Bull (Tokyo) ; 67(7): 648-653, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257320

RESUMO

Diabetic embryopathy is a diabetic complication, in which maternal hyperglycemia in early pregnancy causes birth defects in newborn infants. Under maternal diabetic conditions, hyperglycemia disturbs intracellular molecular activities and organelles functions. These include protein misfolding in the endoplasmic reticulum (ER), overproduction of reactive oxygen species (ROS) in mitochondria, and high levels of nitric oxide (NO). The resultant ER, oxidative, and nitrosative stresses activate apoptotic machinery to cause cell death in the embryo, ultimately resulting in developmental malformations. Based on the basic research data, efforts have been made to develop interventional strategies to alleviate the stress conditions and to reduce embryonic malformations. One of the challenges in birth defect prevention is to identify effective and safe agents to be used in pregnancy. One approach is to search and characterize naturally occurring phytochemicals, including flavonoids, curcuminoids and stilbenoids, for use in prevention of diabetic embryopathy.


Assuntos
Anormalidades Congênitas/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Gravidez em Diabéticas/prevenção & controle , Curcumina/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Gravidez , Estilbenos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico
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