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1.
Braz J Med Biol Res ; 53(10): e9183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901688

RESUMO

H1N1 virus-induced excessive inflammatory response contributes to severe disease and high mortality rates. There is currently no effective strategy against virus infection in lung. The present study evaluated the protective roles of a natural compound, lapiferin, in H1N1 virus-induced pulmonary inflammation in mice and in cultured human bronchial epithelial cells. Initially, Balb/C mice were grouped as Control, H1N1 infection (intranasally infected with 500 plaque-forming units of H1N1 virus), lapiferin (10 mg/kg), and H1N1+lapiferin (n=10/group). Lung histology, expression of inflammatory factors, and survival rates were assessed after 14 days of exposure. Administration of lapiferin significantly alleviated the virus-induced inflammatory infiltrate in lung tissues. Major pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, were decreased at both mRNA and protein levels by lapiferin administration in the lung homogenate. Lapiferin also reduced inflammatory cell numbers in bronchoalveolar fluid. Mechanistically, lapiferin suppressed the transcriptional activity and protein expression of NF-κB p65, causing inhibition on NF-κB signaling. Pre-incubation of human bronchial epithelial cells with an NF-κB signaling specific activator, ceruletide, significantly blunted lapiferin-mediated inhibition of pro-inflammatory cytokines secretion in an air-liquid-interface cell culture experiment. Activation of NF-κB signaling also blunted lapiferin-ameliorated inflammatory infiltrate in lungs. These results suggested that lapiferin was a potent natural compound that served as a therapeutic agent for virus infection in the lung.


Assuntos
Vírus da Influenza A Subtipo H1N1 , NF-kappa B/metabolismo , Pneumonia , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Animais , Citocinas , Humanos , Inflamação , Camundongos , Transdução de Sinais
2.
Anticancer Res ; 40(10): 5529-5538, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988876

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is a unique subtype that lacks expression of several conventional biomarkers and has a higher incidence of lymph node invasion and distal metastasis among all breast cancers. Anoikis resistance is the fundamental reason behind tumor cells' survival without their attachment to the extracellular matrix and metastasis to distal organs. Therefore, finding novel anti-cancer drugs that can suppress anoikis resistance in cancer cells is critical for patients with TNBC. MATERIALS AND METHODS: Curcumol, a natural compound, was used to assess whether it can inhibit the anoikis resistance and affects cell mortality and motility of IV2-1 TNBC cells. RESULTS: Curcumol suppressed anoikis resistance and inhibited TNBC cell survival in suspension. Additionally, these anti-cancer effects induced by curcumol could be related to the YAP1/Skp2 molecular pathway. CONCLUSION: Curcumol is an effective Skp2-targeted therapy that attenuates anoikis resistance and metastasis in TNBC cells.


Assuntos
MicroRNAs/genética , Proteínas Quinases Associadas a Fase S/genética , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Anoikis/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
3.
Zhongguo Zhong Yao Za Zhi ; 45(12): 2817-2826, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32627455

RESUMO

Zerumbone(ZER), one of humulane-type sesquiterpenoids, showed its unique advantage against tumor activities. The main underlying mechanisms include inhibiting the growth and proliferation of cancer cells, inducing apoptosis of cancer cells and differentiation of cancer cells, regulating immune function, inhibiting invasion and metastasis of cancer cells, and reversing multidrug resistance of cancer cells. Studies on ZER focusing its cytotoxic or anti-tumor is one of hot topic. Currently, with the increasing studies on ZER, the clarified mechanisms are getting rich. The present paper describes a summary of its anti-tumor mechanism of action and helps to provide significant reference to more in-depth research.


Assuntos
Antineoplásicos/farmacologia , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
4.
Chem Biol Interact ; 330: 109167, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603660

RESUMO

Recently, it has been shown that drimane-type sesquiterpenoids isolated from Zygogynum pancheri, a species native to New Caledonia, possessed significant α-amylase inhibitory activities. To further explore their antidiabetic potential, we investigated the effect of 1ß-O-(E-cinnamoyl)-6α-hydroxy-9epi-polygodial (D) and 1ß-E-O-p-methoxycinnamoyl-bemadienolide (L), two of the most active compounds of the series, on diabetic model rats. Compounds D and L (2 mg kg/day) were daily and orally administrated for 30 days to streptozotocin (STZ) (150 mg/kg) induced male diabetic Wistar rats. Animals were allocated into five groups of six rats. Comparatively to diabetic rats, treatments with D and L compounds were able to significantly (P < 0.05) decrease Fasting Blood Glucose (FBG) (70.15%, 71.02%), serum total cholesterol (46.27% and 39.38%), triglycerides (56.60% and 58.15%), creatinine (37.31% and 36.49%) and uric acid levels (67.76% and 69.68%), respectively. Compounds D and L also restored the altered plasma enzyme (aspartate aminotransferase, AST (47.83% and 43.20%), alanine aminotransferase, ALT (49.76% and 48.35%, alkaline phosphatase, ALP (72.78% and 73.21%)) and lactate dehydrogenase, LDH (47.95% and 53.93%) levels to near normal, respectively. Administration of Glymepiride, significantly (p < 0.05) reduced FBG (73.94%) in STZ induced diabetic rats. Additionally, the compounds D and L exhibited inhibitory effects in vivo on lipase activity of diabetic rats (54.83% and 52.25%), respectively. The outcomes of this study suggested that these two drimanes could be considered as efficient hypoglycemic, hypolipidemic and antiobesity agents for diabetes management and its complications.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Sesquiterpenos Policíclicos/isolamento & purificação , Animais , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/farmacologia , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipolipemiantes/isolamento & purificação , Hipolipemiantes/farmacologia , Masculino , Nova Caledônia , Extratos Vegetais/química , Sesquiterpenos Policíclicos/farmacologia , Ratos , Ratos Wistar , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Winteraceae/química
5.
Mol Immunol ; 124: 109-116, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32554101

RESUMO

Disordered collagen production by fibroblasts in response to tissue injury contributes to pulmonary fibrosis (PF). Therefore, elimination of collagen deposition has becoming a potential target in PF treatment which despite standard anti-fibrosis regiment still remains challenge. Curcumin and curcumol are regarded as the main active components extraction from the rhizomes of Curcuma zedoaria, which is widely used for inhibition the proliferation of multiple cells. However, the molecular basis for the function of curcumin and curcumol in limiting fibrogenesis still unknown. In this study, we have investigated the effects of curcumin and curcumol in the fibroblast overproliferation model human lung fibroblast (HLF) inducing by TGF-ß1. The growth-inhibitory effects of the components wasn't observed from 8 to 64 µg/ml. Administration of curcumin or curcumol significantly diminished the level of hydroxyproline hydroxyproline and α-smooth muscle actin (α-SMA), also the collagen Ⅰ (Col-Ⅰ) and collagen Ⅲ (Col-Ⅲ) deposition were reduced in the HLF. Furthermore, related to the collagen synthesis proteins including N-terminal pro-peptide for Type Ⅰ collagen (PⅠNP), N-terminal pro-peptide for Type Ⅲ collagen (PⅢNP) and prolyl-hydroxylase (PHD) were degraded gracefully at dose-dependent manner. Autophagy as the scavenger was crippled in TGF-ß1-fibroblast overproliferation HLF, conversely the increased autophagosomes have been spotted in cytoplasm under transmission electron microscope which is consistent with up-regulation of Beclin1 and ATG7 after treatment with curcumin or curcumol in this study. Additionally, blocking autophagy by inhibitor chloroquine (CQ) caused collagen deposition, providing further evidence regard to autophagy activation capacity of curcumin and curcumol. Our findings provide a detailed understanding that the function of curcumin and curcumol on decreasing collagen deposition mediating by autophagy mechanism, which may also inspire the further research on PF at different perspectives.


Assuntos
Autofagia/efeitos dos fármacos , Colágeno/efeitos dos fármacos , Curcumina/farmacologia , Fibroblastos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Células Cultivadas , Curcuma , Humanos , Extratos Vegetais/farmacologia , Fibrose Pulmonar/patologia
6.
Int J Nanomedicine ; 15: 3193-3206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440118

RESUMO

Background: Certain patients with triple-negative breast cancer cannot tolerate the serious adverse effects of cytotoxic chemotherapy agents, which significantly affect the disease prognosis. Purpose: Research into the combined use of photosensitizers and non-cytotoxic antineoplastic drugs for the safe treatment of triple-negative breast cancer is vital. Methods: In this study, the photosensitizer indocyanine green and the natural drug parthenolide were co-loaded into thermosensitive liposomes. Under a near-infrared irradiation, indocyanine green reached excitation levels, releasing heat, and the liposome underwent a phase transition, releasing the drug were researched. Results: Thus, indocyanine green and parthenolide exert synergistic antineoplastic effects. In the nude mice xenograft MDA-MB-231 tumor model, the tumor inhibition rate of indocyanine green-parthenolide thermosensitive liposomes was approximately 2.08-fold than that of paclitaxel and demonstrated a good initial safety evaluation. Conclusion: Photosensitizers and non-cytotoxic antineoplastic agents in combination with nanoscale carriers should be further investigated for the treatment of tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Verde de Indocianina/uso terapêutico , Sesquiterpenos/uso terapêutico , Temperatura , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Hidrodinâmica , Verde de Indocianina/administração & dosagem , Verde de Indocianina/farmacologia , Lipossomos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos
7.
Toxicology ; 440: 152475, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32344006

RESUMO

OBJECTIVES: Curcumol, a guaiane-type sesquiterpenoid hemiketal extracted from the herb Rhizoma Curcumae, exhibits multiple-pharmacological activities. We previously reported that curcumol ameliorated hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. In this study, we aimed to investigate the effect of curcumol on HSC migration and adhesion, and reveal its regulation mechanisms. MATERIALS AND METHODS: Cellular viability was determined by Cell Counting Kit-8. Cell migration was detected by boyden chamber and cell scratch experiment. Recombinant human periostin (rh POSTN) and adeno-associated viral (AAV)-GFP-periostin were used to achieve POSTN overexpression in vitro and in vivo, respectively. Nuclear factor kappa B (NF-κB)-p65 overexpression was achieved by using plasmid. ELISA was conducted to detect POSTN level. Immunohistochemistry, qRT-PCR, Western blotting, and immunofluorescence were performed to assess associated factor expression. RESULTS: Curcumol suppressed HSC migration and adhesion, and reduced the secretion and expression of POSTN. By gain of function POSTN in HSCs, using rh POSTN, we found that the inhibition of HSC migration and adhesion by curcumol depended on the decrease of POSTN. Besides, curcumol protection against chronic CCl4-caused hepatic fibrosis could be impaired by POSTN overexpression. Moreover, we showed that curcumol repressed NF-κB signaling and the production of pro-inflammatory factor. Importantly, curcumol down-regulation of POSTN was rescued by knock-in of NF-κB, as well as the inhibition of HSC migration and adhesion. CONCLUSION: These findings reveal the molecular mechanism of curcumol-reduced HSC migration and adhesion, by which points to the possibility of using curcumol based on NF-κB dependent POSTN for the treatment of fibrogenesis.


Assuntos
Moléculas de Adesão Celular/antagonistas & inibidores , Células Estreladas do Fígado/efeitos dos fármacos , Sesquiterpenos/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Intoxicação por Tetracloreto de Carbono/patologia , Intoxicação por Tetracloreto de Carbono/prevenção & controle , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Contagem de Células , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Proteínas Recombinantes
8.
Zhongguo Zhong Yao Za Zhi ; 45(1): 37-51, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237409

RESUMO

The genus Carpesium plants contain many kinds of sesquiterpenes. Up to now, more than 201 sesquiterpene compounds have been isolated and identified, including 86 germacranolides, 30 eudesmanolides, 29 guaianolides, 23 sesquiterpene dimers, 9 pseudoguaianes, 9 carabranolides, 7 xanthanolides, 6 sesquiterpenes without lactone, 1 eremophilane and 1 tricyclo dodecane sesquiterpene. The reported sesquiterpenes possess a series of pharmacological properties, such as anti-tumor, anti-inflammatory, antibacterial, antiparasitic, insecticidal, and antiviral activities. This paper summarizes the 201 chemical structures and biological activities of sesquiterpenes in genus Carpesium, and provides the scientific basis for the further development and utilization.


Assuntos
Asteraceae/química , Sesquiterpenos/farmacologia , Antibacterianos , Anti-Inflamatórios , Lactonas , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/química
9.
Oncol Rep ; 43(6): 1986-1994, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236584

RESUMO

Costunolide being a sesquiterpene lactone, is known to have anticancer properties. The present study investigated the anticancer effects of costunolide against the H1299 human non­small­cell lung cancer (NSCLC) cell line. Inhibition of cell viability by costunolide was assessed via a MTT assay. Furthermore, the apoptotic rate was detected using Annexin V/propidium iodide labeling. A colony forming cell assay was performed to investigate the antiproliferative effects of costunolide. Wound healing and Transwell assays were performed to determine the inhibitory effects of costunolide on migration and invasion, respectively. Western blot analysis was undertaken to determine protein expression, and reverse transcription­quantitative PCR was performed to assess mRNA expression levels. The results demonstrated that costunolide inhibited the viability of H1299 cells, with a half maximal inhibitory concentration value of 23.93±1.67 µM and induced cellular apoptosis in a dose­dependent manner. Furthermore, the colony formation, migrative and invasive abilities of the H1299 cells were inhibited in a dose­ or time­dependent manner. The protein expression levels of E­cadherin increased and those of N­cadherin decreased following treatment with costunolide, which suggested that costunolide inhibited epithelial­to­mesenchymal transition. The mRNA levels of B­Raf, E­cadherin, N­cadherin, integrins α2 and ß1, as well as matrix metalloproteinases 2 were also found to be regulated costunolide. These findings indicate the potential of costunolide in the treatment of NSCLC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Sesquiterpenos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Transdução de Sinais/efeitos dos fármacos
10.
Phytomedicine ; 68: 153191, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32135457

RESUMO

BACKGROUND: Atractylenolide I (ATL-1) is a natural herbal compound used in traditional Chinese medicine that has exhibited anti-cancer properties. The anti-tumorigenic activity of ATL-1 against colorectal cancer (CRC) and the underlying signaling pathways involved in its mechanisms are examined here. HYPOTHESIS: ATL-1 exerts therapeutic effect against CRC by disrupting glucose metabolism and cancer stem cell maintenance via AKT/mTOR pathway regulation. STUDY DESIGN: In vitro studies were performed in COLO205 and HCT116 CRC cell lines and in vivo studies were conducted in a mouse xenograft model of CRC tumor. METHODS: CRC cells were treated with ATL-1 at various concentrations, with or without inhibitors of AKT or mTOR. Cell proliferation, apoptosis, invasion, stemness maintenance, glucose metabolism, and AKT/mTOR signaling were evaluated. CRC tumor-xenografted mice were treated with an AKT inhibitor and/or ATL-1, and glucose metabolism and stemness maintenance were examined in tumor tissues. RESULTS: ATL-1 significantly inhibited the invasion of CRC cells by inducing their apoptosis, possibly via the excessive production of reactive oxygen species. Glucose metabolism (Warburg effect) was also altered and stem-like traits were suppressed by ATL-1. In addition, ATL-1 effectively acted as an inhibitor or AKT/mTOR by downregulating the phosphorylation of proteins related to the AKT/mTOR pathway. In vivo studies showed that tumor weight and volume were reduced by ATL-1 and that aerobic glycolysis, stemness maintenance, and AKT/mTOR activation were impaired by ATL-1 in colorectal tumors. CONCLUSIONS: ATL-1 acts as an effective agent to suppress colorectal tumor progression, mainly by inhibiting CRC cell proliferation through altering apoptosis, glucose metabolism, and stem-like behavior. These processes were mediated by the AKT/mTOR signaling pathway both in vitro and in vivo. ATL-1 may be a potential agent to be used in molecular-targeted strategies for cancer treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Células HCT116 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Phytomedicine ; 69: 153184, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32199253

RESUMO

BACKGROUND: ß-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of ß-Elemene on MDR cancer cells remain unknown. PURPOSE: In this study, we posit the hypothesis that ß-elemene possesses antimetastatic effects on MDR cancer cells. METHODS: Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of ß-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of ß-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of ß-Elemene. RESULTS: In this study, we found that ß-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that ß-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that ß-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that ß-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after ß-Elemene treatment. CONCLUSION: Our results suggested that ß-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Camundongos Nus , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética
12.
Biomed Res Int ; 2020: 6892961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149121

RESUMO

Inflammatory mediators and inflammatory cells in the inflammatory microenvironment promote the transformation of normal cells to cancer cells in the early stage of cancer, promote the growth and development of cancer cells, and induce tumor immune escape. The monomeric active ingredient ß-elemene is extracted from the traditional Chinese medicine Curcuma wenyujin and has been proven to have good anti-inflammatory and antitumor activities in clinical applications for more than 20 years in China. Recent studies have found that this traditional Chinese medicine plays a vital role in macrophage infiltration and M2 polarization, as well as in regulating immune disorders, and it even regulates the transcription factors NF-κB and STAT3 to alter inflammation, tumorigenesis, and development. In addition, ß-elemene regulates not only different inflammatory factors (such as TNF-α, IFN, TGF-ß, and IL-6/10) but also oxidative stress in vivo and in vitro. The excellent anti-inflammatory and antitumor effects of ß-elemene and its ability to alter the inflammatory microenvironment of tumors have been gradually elaborated. Although the study of monomeric active ingredients in traditional Chinese medicines is insufficient in terms of quality and quantity, the pharmacological effects of more active ingredients of traditional Chinese medicines will be revealed after ß-elemene.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Sesquiterpenos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , China , Curcuma/química , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Medicina Tradicional Chinesa , NF-kappa B , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo , Fator de Transcrição STAT3/efeitos dos fármacos , Sesquiterpenos/química , Fatores de Transcrição/efeitos dos fármacos
13.
Mol Carcinog ; 59(4): 399-411, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027051

RESUMO

Exploiting metabolic vulnerabilities of cancer cells with nontoxic, plant derived compounds constitutes a novel strategy for both chemoprevention and treatment. A high-throughput screening approach was used to evaluate a library of natural products to determine the most synergistic combination in precursor-B cell acute lymphoblast leukemia. Dimethylaminoparthenolide and shikonin effectively inhibited proliferation resulting in cell death in primary and immortalized leukemia cells, while having negligible effects on normal cells. Dimethylaminoparthenolide and shikonin have been shown separately to inhibit cell survival and proliferative signaling and activate tumor suppressors and proapoptotic pathways. Untargeted metabolomics and metabolic flux analysis with stable isotopically labeled glucose and glutamine exhibited a global shift in metabolism following treatment. Pathway analysis indicated significant differences in amino acid, antioxidant, tricarboxylic acid cycle, and nucleotide metabolism. Together, dimethylaminoparthenolide and shikonin reduced the shunting of glycolytic intermediates into the pentose phosphate pathway for biosynthetic purposes. Similarly, the incorporation of glutamine and glutamine-derived metabolites into purine and pyrimidine synthesis was inhibited by the combination of dimethylaminoparthenolide and shikonin, effectively impeding biosynthetic pathways critical for leukemia cell survival. This approach demonstrates that a synergistic pair of compounds with malignant cell specificity can effectively target metabolic pathways crucial to leukemia cell proliferation and induce apoptosis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Naftoquinonas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Glucose/metabolismo , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
14.
Acta Cir Bras ; 34(12): e201901205, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049185

RESUMO

PURPOSE: To investigate the effects of huperzine A (HupA) on hippocampal inflammatory response and neurotrophic factors in aged rats after anesthesia. METHODS: Thirty-six Sprague Dawley rats (20-22 months old) were randomly divided into control, isofluran, and isoflurane+HupA groups; 12 rats in each group. The isoflurane+HupA group was intraperitoneally injected with 0.2 mg/kg of HupA. After 30 min, isoflurane inhalation anesthesia was performed in the isoflurane and isoflurane+HupA groups. After 24 h from anesthesia, Morris water maze experiment and open-field test were performed. Hippocampal inflammatory and neurotrophic factors were determined. RESULTS: Compared with isoflurane group, in isofluran+HupA group the escape latency of rats was significantly decreased (P < 0.05), the original platform quadrant residence time and traversing times were significantly increased (P < 0.05), the central area residence time was significantly increased (P < 0.05), the hippocampal tumor necrosis factor α, interleukin 6 and interleukin 1ß levels were significantly decreased (P < 0.05), and the hippocampal nerve growth factor, brain derived neurotrophic factor and neurotrophin-3 levels were significantly increased (P < 0.05). CONCLUSION: HupA may alleviate the cognitive impairment in rats after isoflurane anesthesia by decreasing inflammatory factors and increasing hippocampal neurotrophic factors in hippocampus tissue.


Assuntos
Alcaloides/farmacologia , Anestésicos Inalatórios/efeitos adversos , Hipocampo/efeitos dos fármacos , Isoflurano/efeitos adversos , Fatores de Crescimento Neural/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Sesquiterpenos/farmacologia , Anestesia/efeitos adversos , Animais , Ensaio de Imunoadsorção Enzimática , Hipocampo/metabolismo , Humanos , Interleucina-1beta/análise , Interleucina-6/análise , Masculino , Aprendizagem em Labirinto , Fatores de Crescimento Neural/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
15.
Cell Immunol ; 349: 104046, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32057354

RESUMO

Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1ß production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1ß secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/prevenção & controle , Lactonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sesquiterpenos/farmacologia , Adulto , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/fisiologia , Proteínas Adaptadoras de Sinalização CARD/antagonistas & inibidores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/fisiologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/fisiologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Nigericina/farmacologia , Poli I-C/farmacologia , Polimerização/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Ácido Úrico/farmacologia
16.
Cancer Res ; 80(3): 406-417, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32015157

RESUMO

Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression. SIGNIFICANCE: This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/patologia , Metilação de DNA , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Proliferação de Células , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Prognóstico , Sesquiterpenos/farmacologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Org Biomol Chem ; 18(4): 642-645, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31916553

RESUMO

Photeroids A (1) and B (2), two structurally fascinating meroterpenoids, were isolated from the deep-sea-derived fungus Phomopsis tersa FS441. Their structures were sufficiently established by a comprehensive interpretation of the spectroscopic data, NMR spectra, and ECD calculation. Photeroids A and B represented the first phenolic sesquiterpene meroterpenoids featuring a highly fused 6/6/6/6 tetracyclic ring system derived through a rarely-occurring hetero-Diels-Alder reaction via an orthoquinone methide intermediate. Additionally, they were also evaluated for their cytotoxic activities against four human cancer cells, wherein compounds 1 and 2 exhibited moderate cytotoxic activities.


Assuntos
Ascomicetos/química , Fenóis/farmacologia , Sesquiterpenos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Fenóis/química , Fenóis/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
18.
Chem Commun (Camb) ; 56(10): 1517-1520, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31919484

RESUMO

The pseudoguaianelactones A (1) and B (2), two novel sesquiterpene lactones with an unprecedented [5,7,7] ring system featuring an α-methylene-γ-lactone moiety, together with a new pseudoguaianelactone C (3) were isolated from the roots of Lindera glauca. Pseudoguaianelactones A-C (1-3) inhibited nitric oxide (NO) production, with IC50 values ranging from 1.38 to 4.00 µM. Moreover, all compounds significantly suppressed the production of pro-inflammatory mediators (TNF-α, IL-6, IL-1ß and PGE2) and the protein expression of the enzymes iNOS and COX-2.


Assuntos
Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Lindera/química , Óxido Nítrico Sintase Tipo II/metabolismo , Sesquiterpenos/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Citocinas/metabolismo , Lindera/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Células RAW 264.7 , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
19.
J Agric Food Chem ; 68(10): 3006-3016, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-31986035

RESUMO

An increase in crop competitiveness relative to weed interference has the potential to reduce crop yield losses. In this study, the effects of phytoalexin resveratrol were examined in Zea mays L. (corn) and in the weed species Ipomoea grandifolia (Dammer) O'Donell (morning glory). At a concentration range from 220 to 2200 µM resveratrol exerted a stimulus on Z. mays seedling growth that was more pronounced at low concentrations; in the weed species I. grandifolia, resveratrol exerted inhibitory action on seedling growth in all of the assayed concentration range. In I. grandifolia, resveratrol also inhibited the respiratory activity of the primary roots. In mitochondria isolated from Z. mays roots, resveratrol at concentrations above 440 µM inhibited the respiration coupled to ADP phosphorylation and the activities of NADH-oxidase, succinate-oxidase, and ATPsynthase. These effects were not reproduced in Z. mays grown in the presence of resveratrol as the respiratory activities of the roots were not affected. The finding that the resveratrol exerts beneficial effects on growth of Z. mays seedlings and inhibits the growth of I. grandifolia heightens the potential of resveratrol application for crop protection.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Ipomoea/efeitos dos fármacos , Resveratrol/farmacologia , Zea mays/efeitos dos fármacos , Ipomoea/crescimento & desenvolvimento , Ipomoea/metabolismo , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Plantas Daninhas/metabolismo , Resveratrol/análise , Sesquiterpenos/análise , Sesquiterpenos/farmacologia , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo
20.
PLoS One ; 15(1): e0227484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923212

RESUMO

Nosema ceranae is a microsporidian parasite that causes nosemosis in the honey bee (Apis mellifera). As alternatives to the antibiotic fumagillin, ten nutraceuticals (oregano oil, thymol, carvacrol, trans-cinnmaldehyde, tetrahydrocurcumin, sulforaphane, naringenin, embelin, allyl sulfide, hydroxytyrosol) and two immuno-stimulatory compounds (chitosan, poly I:C) were examined for controlling N. ceranae infections. Caged bees were inoculated with N. ceranae spores, and treatments were administered in sugar syrup. Only two compounds did not significantly reduce N. ceranae spore counts compared to the infected positive control, but the most effective were sulforaphane from cruciferous vegetables, carvacrol from oregano oil, and naringenin from citrus fruit. When tested at several concentrations, the highest sulforaphane concentration reduced spore counts by 100%, but also caused 100% bee mortality. For carvacrol, the maximum reduction in spore counts was 57% with an intermediate concentration and the maximum bee mortality was 23% with the highest concentration. For naringenin, the maximum reduction in spore counts was 64% with the highest concentration, and the maximum bee mortality was only 15% with an intermediate concentration. In the longevity experiment, naringenin-fed bees lived as long as Nosema-free control bees, both of which lived significantly longer than infected positive control bees. While its antimicrobial properties may be promising, reducing sulforaphane toxicity to bees is necessary before it can be considered as a candidate for controlling N. ceranae. Although further work on formulation is needed with naringenin, its effect on extending longevity in infected bees may give it an additional value as a potential additive for bee feed in honey bee colonies.


Assuntos
Abelhas/microbiologia , Suplementos Nutricionais/análise , Nosema/fisiologia , Animais , Abelhas/efeitos dos fármacos , Abelhas/metabolismo , Cicloexanos/farmacologia , Cimenos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Flavanonas/farmacologia , Isotiocianatos/farmacologia , Longevidade/efeitos dos fármacos , Nosema/efeitos dos fármacos , Sesquiterpenos/farmacologia , Esporos Fúngicos/fisiologia
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