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1.
Artigo em Inglês | MEDLINE | ID: mdl-38864839

RESUMO

A Gram-stain-positive, strictly anaerobic, endospore-forming and rod-shaped (0.6-0.8×2.7-13.1 µm) bacterium, designated as 5 N-1T, was isolated from a yellow water sample collected from the manufacturing process of Nongxiangxing baijiu in the Yibin region of Sichuan, PR China. Growth occurred at 15-40 °C (optimum growth at 37 °C), at pH 6.0-9.0 (optimum growth at pH 7.0) and in NaCl concentrations of 0-1 % (w/v) and ethanol concentrations of 0-2 % (v/v). The major fatty acids in strain 5 N-1T were C16 : 0, C18 : 0 and C14 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, four unidentified aminophospholipids and one unidentified lipid. Phylogenetic analysis of its 16S rRNA gene sequence indicated that strain 5 N-1T was most closely related to Clostridium weizhouense YB-6T (97.70 %) and Clostridium uliginosum DSM 12992T (97.56 %). The average nucleotide identity and digital DNA‒DNA hybridization values between strain 5 N-1T and the above two type strains were 80.89 and 80.05 % and 25.80 and 25.30 %, respectively, which were all below the species thresholds. The genome size of strain 5 N-1T was 3.5 Mbp and the DNA G+C content was 27.5 mol%. Based on the results of phenotypic and genotypic analyses, strain 5 N-1T represents a novel species of the genus Clostridium, for which the name Clostridium aquiflavi sp. nov. is proposed. The type strain is Clostridium aquiflavi 5 N-1T (=CICC 24886T=JCM 35355T).


Assuntos
Técnicas de Tipagem Bacteriana , Composição de Bases , Clostridium , DNA Bacteriano , Ácidos Graxos , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , China , RNA Ribossômico 16S/genética , Ácidos Graxos/análise , DNA Bacteriano/genética , Clostridium/genética , Clostridium/isolamento & purificação , Clostridium/classificação , Microbiologia da Água , Fosfolipídeos/análise
2.
Biol Pharm Bull ; 46(10): 1412-1420, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37779042

RESUMO

Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Neoplasias Pancreáticas , Humanos , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Microambiente Tumoral , Neoplasias Pancreáticas
3.
Tohoku J Exp Med ; 260(4): 315-327, 2023 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-37258137

RESUMO

The incidence, prevalence, and economic burden of heart failure have continued to increase worldwide. It remains unclear whether LCZ696 can ameliorate calcium reuptake in the sarcoplasmic reticulum via the sarcoplasmic endoplasmic reticulum calcium ion-ATPase 2α (SERCA2α)-dependent pathway during cardiac diastole. We investigated whether LCZ696 could ameliorate tachycardia-induced myocardial injury by modulating cardiac SERCA2α levels. A tachycardia-induced myocardial injury model was established by daily intraperitoneal administration of 60 mg/kg isoprenaline (ISO) for 2 weeks. LCZ696 was orally administered for the following 4 weeks. SERCA2α and calcium ion (Ca2+)-related protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. For additional in vitro studies, HL-1 cardiomyocytes were used. A SERCA2α overexpression vector was constructed and transfected into HL-1 cells. The expression of SERCA2α and Ca2+-related proteins were also measured using qRT-PCR and western blotting. Our in vivo results demonstrated that myocardial injury was successfully induced by intraperitoneal administration of ISO. The expression of both SERCA2α- and Ca2+-related proteins was impaired. Oral administration of LCZ696 increased the expression of SERCA2α, alleviated Ca2+-related protein impairment and cardiac Ca2+ dyshomeostasis, and ameliorated myocardial injury. These results were compared with our in vitro findings. Ca2+-related proteins are affected by the overexpression of SERCA2α. LCZ696 improved tachycardia-induced myocardial injury by increasing SERCA2α expression, which reversed the development of heart failure in ISO-induced mice. These results provide new insights into how sustained LCZ696 treatment in heart failure improves cardiac function through intracellular Ca2+-regulatory mechanisms.


Assuntos
Cálcio , Insuficiência Cardíaca , Camundongos , Animais , Tetrazóis/farmacologia , Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo , Combinação de Medicamentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Taquicardia/complicações , Taquicardia/tratamento farmacológico , Isoproterenol/farmacologia
4.
Bioorg Med Chem Lett ; 66: 128723, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35395369

RESUMO

An ethanolic extract of the stem of Abies spectabilis exhibited strong cytotoxicity against MIA PaCa-2 human pancreatic cancer cells preferentially under nutrient-deprived conditions. Therefore, phytochemical investigation of this bioactive extract was carried out, and that led the isolation of ten compounds (1-10) including a new abietane-type diterpene (1). The structure of the new compound (1) was elucidated by combined spectroscopic techniques, including HRFABMS, NMR and quantum ECD calculation. All the isolated compounds were evaluated for their efficacy against MIA PaCa-2 human pancreatic cancer cell line by employing an anti-austerity strategy. Among the tested compounds, dehydroabietinol (5) displayed the most potent activity with a PC50 value of 6.6 µM. Dehydroabietinol (5) was also found to retard the MIA PaCa-2 cell migration under normal nutrient-rich conditions displaying its anti-metastatic potential. Investigation on the mechanism suggested that dehydroabietinol (5) is an inhibitor of the key cancer cell survival Akt/mTOR/autophagy signaling pathway.


Assuntos
Abies , Antineoplásicos Fitogênicos , Neoplasias Pancreáticas , Abietanos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Extratos Vegetais/uso terapêutico , Neoplasias Pancreáticas
5.
Bioorg Med Chem ; 54: 116563, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34942553

RESUMO

Pancreatic cancer is one of the deadliest types of malignancies. A new intervention aiming to combat pancreatic cancer is targeting its extra-ordinary ability to tolerate nutrition starvation, a phenomenon known as "Austerity". As a part of a research program aiming to develop a new-generation of anticancer agents, known as "anti-austerity agents", guggulsterone derivatives (GSDs) were identified as unique anti-austerity agents in terms of potency and selectivity. These agents are able to exert preferential cytotoxic activity only under nutrient-deprived conditions with little or no toxicity under normal conditions. In the present study, a library of 14 GSDs was synthesized and screened against PANC-1 human pancreatic cells. Among tested compounds, GSD-11 showed the most potent activity with PC50 a value of 0.72 µM. It also inhibited pancreatic cancer cell migration and colony formation in a concentration-dependent manner. A mechanistic study revealed that this compound can inhibit the activation of the Akt/mTOR signaling pathway. Therefore, GSD-11 could be a promising lead compound for the anticancer drug discovery against pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Pancreáticas/tratamento farmacológico , Pregnenodionas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pregnenodionas/síntese química , Pregnenodionas/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362064

RESUMO

Cardiac shock wave therapy (CSWT) is a novel therapeutic procedure for patients with angina that is refractory to conventional therapy. We investigated the potential mechanism and therapeutic efficacy of non-R-wave-triggered CSWT to attenuate myocardial dysfunction in a large animal model of hypertensive cardiomyopathy. Sustained elevated blood pressure (BP) was induced in adult pigs using a combination of angiotensin-II and deoxycorticosterone acetate (DOCA). Two sessions of non-R-wave-triggered CSWT were performed at 11 and 16 weeks. At 10 weeks, systolic and diastolic blood pressure, LV posterior wall thickness and intraventricular septum thickness significantly increased in both the hypertension and CSWT groups. At 20 weeks, +dP/dt and end-systolic pressure-volume relationship (ESPVR) decreased significantly in the hypertension group but not the CSWT group, as compared with week 10. A significant improvement in end-diastolic pressure-volume relationship (EDPVR) was observed in the CSWT group. The CSWT group exhibited significantly increased microvascular density and vascular endothelial growth factor (VEGF) expression in the myocardium. Cytokine array demonstrated that the CSWT group had significantly reduced inflammation compared with the hypertension group. Our results demonstrate that non-R-wave-triggered CSWT is safe and can attenuate LV systolic and diastolic dysfunction via enhancement of myocardial neovascularization and anti-inflammatory effect in a large animal model of hypertensive cardiomyopathy.


Assuntos
Cardiomiopatias , Tratamento por Ondas de Choque Extracorpóreas , Hipertensão , Animais , Suínos , Tratamento por Ondas de Choque Extracorpóreas/métodos , Fator A de Crescimento do Endotélio Vascular , Angina Pectoris , Cardiomiopatias/etiologia , Cardiomiopatias/terapia , Hipertensão/complicações , Hipertensão/terapia
7.
Extremophiles ; 25(1): 39-49, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33123748

RESUMO

Halomonas alkalicola CICC 11012s can grow at pH 12.5, the highest pH at which the organisms in the genus Halomonas can grow. Genomic analysis reveals that H. alkalicola adapts to alkaline stress using a variety of adaptive strategies; however, the detailed mechanism for its growth at high-alkaline conditions has not been elucidated. Therefore, in this study, the adaptations of H. alkalicola in response to extreme alkaline stress were investigated. A sharp decrease of alkaliphilic tolerance was observed in mutants E. coli ΔEctonB and H. alkalicola ΔHatonB. Expressions of the gene clusters encoding TonB-dependent transport system and iron complex transport system in H. alkalicola grown under extreme alkaline conditions were markedly up-regulated. We then compared the intracellular ionic iron content and iron-chelating ability of mutant strain with those of wild-type strain to understand the influence of TonB-dependent transport system on the alkaline responses. The results indicated that the presence of TonB-dependent transport system increased the alkaline tolerance of H. alkalicola grown at high-alkaline conditions, but had no effects when the strain was grown at neutral pH and low-alkaline conditions. Meanwhile, the presence of this system increased the transport and accumulation of ionic irons to maintain intracellular metabolic homeostasis, which in turn could increase the tolerance of the strain to extreme alkaline conditions. Based on the results, we established a model representing the interactions between TonB-dependent transport system, alkaline tolerance, and intracellular ionic iron that could help deepen the understanding of the alkaline response mechanism of alkaliphilic bacteria.


Assuntos
Proteínas de Bactérias/genética , Halomonas/metabolismo , Ferro/metabolismo , Proteínas de Membrana/genética , Estresse Fisiológico , Álcalis , Proteínas de Bactérias/metabolismo , Transporte Biológico , Escherichia coli/metabolismo , Halomonas/genética , Concentração de Íons de Hidrogênio , Proteínas de Membrana/metabolismo
8.
Bioorg Med Chem Lett ; 40: 127967, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33753259

RESUMO

An ethanolic extract of Derris scandens flowers showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived condition, with a PC50 value of 0.7 µg/mL. Phytochemical investigation of this active extract led to the isolation of four prenylated isoflavones (1-4) including a new compound named 4'-O-methylgrynullarin (1). The structure elucidation of the new compound was achieved by HRFABMS and NMR spectroscopic analysis. The isolated compounds exhibited potent anti-austerity activity against four different human pancreatic cancer cell lines under nutrient-deprived conditions. The new compound 4'-O-methylgrynullarin (1) was also found to inhibit PANC-1 cell migration and colony formation under nutrient-rich condition. Mechanistically, compound 1 inhibited key survival proteins in the Akt/mTOR signaling pathway. Therefore, 4'-O-methylgrynullarin (1) can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Morte Celular/efeitos dos fármacos , Hemiterpenos/farmacologia , Isoflavonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Derris/química , Ensaios de Seleção de Medicamentos Antitumorais , Flores/química , Hemiterpenos/síntese química , Hemiterpenos/isolamento & purificação , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
9.
Bioorg Med Chem ; 30: 115950, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33383442

RESUMO

From the leaves of Ancistrocladus abbreviatus (Ancistrocladaceae), six 5,1'-coupled naphthyldihydroisoquinoline alkaloids were isolated, ancistrobrevidines A-C (5-7), 5-epi-dioncophyllidine C2 (10), 6-O-methylhamatinine (8), and 6-O-methylancistectorine A3 (9); the two latter compounds were already known from related plants. Most strikingly, this series comprises alkaloids belonging to three different subclasses of naphthylisoquinolines. Ancistrobrevidine C (7) and the alkaloids 8 and 9, displaying the S-configuration at C-3 and an oxygen function at C-6, are three further representatives of the large subgroup of 5,1'-coupled Ancistrocladaceae-type compounds found in nature. 5-epi-Dioncophyllidine C2 (10), lacking an oxygen function at C-6 and having the R-configuration at C-3, is only the third representative of a 5,1'-linked Dioncophyllaceae-type naphthylisoquinoline. Likewise rare are 5,1'-coupled hybrid-type alkaloids, which are 6-oxygenated and 3R-configured. The ancistrobrevidines A (5) and B (6) are the only second and third examples of such 5,1'-linked naphthylisoquinolines in Ancistrocladus species showing the landmarks of both, Ancistrocladaceae- and Dioncophyllaceae-type naphthylisoquinolines. In the roots of A. abbreviatus, two further unprecedented 5,1'-coupled alkaloids were discovered, ancistrobreviquinones A (11) and B (12), consisting of a 3,4-naphthoquinone portion coupled to a tetrahydroisoquinoline subunit. They are the very first quinoid naphthylisoquinolines possessing an ortho-diketone entity. Ancistrobrevidine C (7) exerted pronounced antiproliferative activities against HeLa cervical cancer cells and preferential cytotoxicity towards PANC-1 human pancreatic cancer cells under nutrient-deprived conditions following the antiausterity approach. Moreover, 7 suppressed the migration of PANC-1 cells and significantly inhibited colony formation under nutrient-rich conditions in a concentration-dependent manner, and induced dramatic alteration in cell morphology, leading to cell death.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Magnoliopsida/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , 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 , Humanos , Conformação Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Raízes de Plantas/química , Relação Estrutura-Atividade
10.
J Nat Prod ; 84(5): 1607-1616, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34008971

RESUMO

The antiausterity strategy is a promising approach for the discovery of lead compounds with unprecedented anticancer activities by targeting the tolerance of cancer cells to nutrition starvation. These agents are selectively cytotoxic under the tumor microenvironment-mimicking condition of nutrition starvation, without apparent toxicity in the normal nutrient-rich condition. In this study, an ethanol extract of Betula alnoides showed antiausterity activity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 13.2 µg/mL. Phytochemical investigation of this active extract led to the isolation of eight benzophenones (1-8), including six new compounds, named betuphenones A-F (2-7), and three known xanthones (9-11). The structure elucidation of the new compounds was achieved by HRFABMS, NMR, and ECD spectroscopic analyses. A plausible biogenetic pathway of the new compounds was proposed. Compounds 1-7 displayed antiausterity activity with PC50 values of 4.9-8.4 µM. Moreover, compounds 2 and 7 induced alterations in PANC-1 cell morphology under nutrient-deprived conditions and also inhibited PANC-1 colony formation under nutrient-rich conditions.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/farmacologia , Betula/química , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofenonas/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Tailândia , Microambiente Tumoral/efeitos dos fármacos
11.
Chem Biodivers ; 18(9): e2100389, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34213070

RESUMO

Pancreatic tumors are hypovascular, which leads to a poor nutrient supply to support the aggressively proliferating tumor cells. However, human pancreatic cancer cells have extreme resistance to nutrition starvation, which enables them to survive under severe metabolic stress conditions within the tumor microenvironment, a phenomenon known as "austerity" in cancer biology. Discovering agents which can preferentially inhibit the cancer cells' ability to tolerate starvation conditions represents a new generation of anticancer agents. In this study, geranyl 2,4-dihydroxy-6-phenethylbenzoate (GDP), isolated from Boesenbergia pandurata rhizomes, exhibited potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition starvation conditions. GDP also possessed PANC-1 cell migration and colony formation inhibitory activities under normal nutrient-rich conditions. Mechanistically, GDP inhibited PI3K/Akt/mTOR/autophagy survival signaling pathway, leading to selective PANC-1 cancer cell death under the nutrition starvation condition. Therefore, GDP is a promising anti-austerity agent for drug development against pancreatic cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
12.
Bioorg Med Chem Lett ; 30(16): 127352, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32631550

RESUMO

Human pancreatic cancer is resistant to almost all conventional chemotherapeutic agents. It is known to proliferate aggressively within hypovascular tumor microenvironment by exhibiting remarkable tolerance to nutrition starvation,  a phenomenon termed as "austerity". Search for the new agents that eliminate the tolerance of cancer cells to nutrition starvation is a promising strategy in anticancer drug discovery. In this study, two new meroterpenoids named callistrilones O and P (1 and 2) together with eight known triterpenes (3-10) were isolated from the active dichloromethane extract of Callistemon citrinus leaves. The structure elucidation of the new compounds was achieved by HRFABMS, 1D, 2D NMR, and ECD quantum calculations. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells. Among these, callistrilone O (1) exhibited the most potent preferential cytotoxicity with a PC50 value of 0.3 nM, the strongest activity with over 2000 times potent than the positive control arctigenin. Callistrilone O (1) induced dramatic alterations in PANC-1 cell morphology leading to cell death under nutrient-deprived conditions. Compound 1 also inhibited PANC-1 cell migration and -PANC-1 colony formation under the nutrient-rich condition.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Myrtaceae/química , Neoplasias Pancreáticas/tratamento farmacológico , Terpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Egito , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/patologia , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Pancreáticas
13.
J Nat Prod ; 83(7): 2221-2232, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32573227

RESUMO

Human pancreatic cancer cells display remarkable tolerance to nutrition starvation that help them to survive in a hypovascular tumor microenvironment, a phenomenon known as "austerity". The elucidation of agents countering this tolerance is an established antiausterity strategy in anticancer drug discovery. In this study, a Callistemon citrinus leaf extract inhibited the viability of PANC-1 human pancreatic cancer cells preferentially under nutrient-deprived medium (NDM) with a PC50 value of 7.4 µg/mL. Workup of this extract resulted in the isolation of three new meroterpenoids, callistrilones L-N (1-3), together with 14 known compounds (4-17). The structure elucidation of the new compounds was achieved by HRFABMS and by NMR and ECD spectroscopic analysis. The new compounds showed highly potent preferential cytotoxicity against PANC-1 cells with PC50 values ranging from 10 to 65 nM in NDM. Of these, callistrilone L (1) inhibited PANC-1 cell migration and colony formation in a normal nutrient-rich condition. Callistrilone L (1) also strongly suppressed the migration of PANC-1 cells in real time. Mechanistically, 1 was found to inhibit the Akt/mTOR and autophagy activation pathway. Callistrilone L (1) and related meroterpenoids are promising leads for anticancer drug development based on the antiausterity strategy used in this work.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Myrtaceae/química , Neoplasias Pancreáticas/patologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Análise Espectral/métodos
14.
Chem Biodivers ; 17(10): e2000495, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32865330

RESUMO

Human pancreatic tumor cells such as PANC-1 are known for their ability to tolerate nutrient starvation and thrive under the hypovascular tumor microenvironment, a phenomenon termed as 'austerity'. A search of agents that preferentially inhibit the cancer cell viability under the starvation condition without toxicity in the nutrient-rich condition is a promising approach in anticancer drug discovery. In this study, a triterpene lactone, 3ß-hydroxy-13,28-epoxyurs-11-en-28-one (ursenolide), isolated from a Callistemon citrinus extract has shown strong preferential cytotoxicity against PANC-1 cells under nutrient starvation with PC50 value of 0.4 µm. Ursenolide-induced rounding of PANC-1 cell morphology followed by rupture of the cell membrane leading to cell death. In a real-time cell migration study, ursenolide was found to inhibit PANC-1 cell migration significantly. Mechanistically, it inhibited GRP78 and GRP94 under the starvation condition suggesting inhibition of unfolded protein response (UPR), an adaptive process of cell survival during starvation. It also inhibited the phosphorylation of the key survival protein Akt and mTOR. Overall results suggested that ursenolide is a potential anticancer agent against pancreatic cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Lactonas/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Myrtaceae/química , Neoplasias Pancreáticas/tratamento farmacológico , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Glicoproteínas de Membrana/metabolismo , Conformação Molecular , Neoplasias Pancreáticas/patologia , Desdobramento de Proteína/efeitos dos fármacos , Triterpenos/química , Triterpenos/isolamento & purificação , Células Tumorais Cultivadas
15.
Opt Lett ; 44(7): 1758-1761, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933140

RESUMO

Driven by the development of nanophotonics and integrated optics, manipulating polarization of light with metastructures has been extensively studied in recent decades. So far there is still a high demand for more efficient ways to control the polarization state of light with extraordinary performance. In this Letter, we report on constructing multifunctional wave plates with stereo-metastructure arrays (SMAs) by two-photon absorption polymerization. In one frequency range, the SMA can turn the polarization direction of incident linearly polarized (LP) light to its orthogonal direction, acting as a half-wave plate (HWP). In the other frequency range, it converts the LP incident light to circularly polarized (CP) light, acting as a quarter-wave plate (QWP). Such a multifunctional element is expected to possess an energy efficiency as high as 75%. By encoding SMAs with different rotation angles at different spatial areas, we show that SMAs can be applied in imaging and sensing, where the focal-plane-array (FPA) imaging demonstrates patterned contrast following different structural distribution.

16.
J Nat Prod ; 82(11): 3133-3139, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31682126

RESUMO

An ethanolic extract of Anneslea fragrans leaves showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition, with a PC50 value of 9.6 µg/mL. Phytochemical investigation of this active extract led to the isolation of two new secondary metabolites, fragranones A (1) and B (2), along with 15 previously reported compounds. The structure elucidation of the new compounds was achieved by HRFABMS, acid hydrolysis, NMR, and ECD spectroscopic analysis. Fragranone A (1) is the first example of a rare natural product bearing an acetonide glucose moiety. Fragranone B (2) is representative of a rare class of natural products with a threonolactone unit linked to a chalcone through an ether linkage. The isolated compounds exhibited antiausterity activity against PANC-1 cells under nutrient-deprived conditions, and betulin (14) was found to be the most potent compound tested, with a PC50 value of 8.4 µM. In addition, fragranone A (1) was found to suppress PANC-1 cancer cell migration in real time.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ericales/química , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular
17.
J Nat Prod ; 81(8): 1877-1883, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30070833

RESUMO

Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in a hypovascular tumor microenvironment. Searching for agents that preferentially inhibit cancer cell viability under nutrition starvation conditions is a novel antiausterity strategy in anticancer drug discovery. In the present study, a hexane extract of the peels of Citrus hystrix fruits showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells using a nutrient-deprived medium. Phytochemical investigation of this bioactive extract led to the isolation of 10 coumarins (1-10) including a new furanocoumarin (1). The isolated compounds were tested for their preferential cytotoxic activity against three different human pancreatic cancer cell lines [PANC-1, MIA PaCa-2, and PSN-1]. Among these, bergamottin (7) was identified as the most active constituent. In real-time live imaging, 7 was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (7) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, 7 inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (7) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Citrus/química , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Movimento Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Organelas/efeitos dos fármacos , Organelas/ultraestrutura , Tailândia , Microambiente Tumoral , Ensaio Tumoral de Célula-Tronco , Cicatrização/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 27(21): 4898-4903, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947153

RESUMO

The chloroform extract of the Japanese cypress Chamaecyparis obtusa was found to kill PANC-1 human pancreatic cancer cells preferentially in the nutrient-deprived medium without causing toxicity in the nutrient rich condition. Phytochemical investigation on this extract led to the isolation of a new sesquiterpene (1), together with the six sesquiterpenes (2-7) and a lignan (8). The isolated compounds were tested for their preferential cytotoxicity activity against five different human pancreatic cancer cell lines [PANC-1, MIA PaCa2, CAPAN-1, PSN-1, and KLM-1] by utilizing an antiausterity strategy. Among them, α-cadinol (2) was identified as the most active constituent. α-Cadinol (2) was found to inhibit the activation of Akt/mTOR pathway, and the hyperactivation of autophagy leading to preferential PANC-1 cell death during nutrient-starvation.


Assuntos
Antineoplásicos Fitogênicos/química , Chamaecyparis/química , Ciclodecanos/química , Sesquiterpenos/química , Terpenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Chamaecyparis/metabolismo , Ciclodecanos/isolamento & purificação , Ciclodecanos/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Microscopia de Fluorescência , Conformação Molecular , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/toxicidade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Terpenos/isolamento & purificação , Terpenos/toxicidade
19.
Bioorg Med Chem Lett ; 27(9): 1967-1971, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28342587

RESUMO

From the chloroform extract of the leaves of Uvaria dac, four new highly-oxygenated cyclohexene derivatives named uvaridacols I-L (1-4) were isolated together with nine previously reported compounds (5-13). Their structures were determined based on the extensive NMR spectroscopic data and circular dichroism spectroscopic analysis. Among the new compounds, uvaridacol L (4) displayed strong preferential cytotoxicity in the nutrient deprived medium against five different tested pancreatic cancer cell lines, PANC-1 (PC50, 20.1µM), PSN-1 (PC50, 9.7µM), MIA PaCa-2 (PC50, 29.1µM), Capan-1 (73.0µM) and KLM-1 (25.9µM).


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cicloexenos/química , Cicloexenos/farmacologia , Oxigênio/química , Uvaria/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Cicloexenos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Folhas de Planta/química
20.
Int J Biol Macromol ; 273(Pt 2): 132706, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38825294

RESUMO

Benzene, as a common volatile organic compound, represents serious risk to human health and environment even at low level concentration. There is an urgent concern on visualized, sensitive and real time detection of benzene gases. Herein, by doping Fe3+ and graphene quantum dots (GQDs), a cellulose nanocrystal (CNC) chiral nematic film was designed with dual response of photonic colors and fluorescence to benzene gas. The chiral nematic CNC/Fe/GQDs film could respond to benzene gas changes by reversible motion. Moreover, chiral nematic film also displays reversible responsive to humidity changes. The resulting CNC/Fe/GQDs chiral nematic film showed excellent response performance at benzene gas concentrations of 0-250 mg/m3. The maximal reflection wavelength film red shifted from 576 to 625 nm. Furthermore, structural color of CNC/Fe/GQDs chiral nematic film change at 44 %, 54 %, 76 %, 87 %, and 99 % relative humidity. Interestingly, due to the stability of GQDs to water molecules, CNC/Fe/GQDs chiral nematic film exhibit fluorescence response to benzene gas even in high humidity (RH = 99 %) environment. Besides, we further developed a smartphone-based response network system for quantitively determinization and signal transformation. This work provides a promising routine to realize a new benzene gas response regime and promotes the development of real-time benzene gas detection.


Assuntos
Benzeno , Celulose , Nanopartículas , Celulose/química , Benzeno/química , Benzeno/análise , Nanopartículas/química , Pontos Quânticos/química , Grafite/química , Fluorescência , Gases/análise , Gases/química , Cor , Fótons
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