Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
1.
Pharm Biol ; 62(1): 621-633, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39056547

RESUMO

CONTEXT: Pyrus calleryana Decne (Rosaceae), renowned for its therapeutic properties, is known to moisturize the lungs (removing dryness; relieving cough), clear heat (acting as an antipyretic; febrifuge) and aid in detoxification (relieving pyogenic inflammation; eliminating toxins). However, scientific evidence supporting its efficacy in wound healing is lacking. OBJECTIVE: This study investigated P. calleryana samples collected over a year to explore metabolite variations and their impact on skin wound-healing activities. MATERIALS AND METHODS: P. calleryana (PC) twigs and leaves were collected from the Matsu Islands, Taiwan, spanning 2018-2020. Extracts were prepared using 95% ethanol or water, and we assessed the chemical composition, total phenolic/triterpenoid contents and antioxidant properties. Metabolites were analysed via LC-MS/MS and molecular networking. Wound healing potential was evaluated on WS-1 cells through MTT and migration assays, and gene expression analyses, with tests including control (DMSO), compounds 1 (3'-hydroxylbenzyl-4-hydroxybenzoate-4'-O-ß-glucopyranoside) and 2 (vanilloylcalleryanin) (100 µM), and a positive control (ascorbic acid, 100 µM) for 24 h. RESULTS: Significant variations in extract compositions were observed based on the solvent used, with distinct metabolomic profiles in extracts collected during different months. Notably, compounds 1 and 2 showed no cytotoxic effects on human dermal fibroblast cells and significantly accelerated wound closure at 100 µM. A gene expression analysis indicated upregulation of wound healing-associated genes, including MMP-1 (matrix metalloproteinase-1) and COL1A1 (collagen, type 1, alpha 1). CONCLUSIONS: This study reports the first evidence of PC compounds aiding wound healing. Utilizing Global Natural Products Social Molecular Networking (GNPS) and principal component analysis (PCA) approaches, we unveiled metabolomic profiles, suggesting the potential to expedite wound-healing.


Assuntos
Extratos Vegetais , Pyrus , Cicatrização , Cicatrização/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia , Pyrus/química , Estações do Ano , Taiwan , Antioxidantes/farmacologia , Folhas de Planta , Espectrometria de Massas em Tandem , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Movimento Celular/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos
2.
Mar Drugs ; 21(8)2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37623737

RESUMO

Inflammation is a critical defense mechanism that is utilized by the body to protect itself against pathogens and other noxious invaders. However, if the inflammatory response becomes exaggerated or uncontrollable, its original protective role is not only demolished but it also becomes detrimental to the affected tissues or even to the entire body. Thus, regulating the inflammatory process is crucial to ensure that it is resolved promptly to prevent any subsequent damage. The role of neutrophils in inflammation has been highlighted in recent decades by a plethora of studies focusing on neutrophilic inflammatory diseases as well as the mechanisms to regulate the activity of neutrophils during the overwhelmed inflammatory process. As natural products have demonstrated promising effects in a wide range of pharmacological activities, they have been investigated for the discovery of new anti-inflammatory therapeutics to overcome the drawbacks of current synthetic agents. Octocorals have attracted scientists as a plentiful source of novel and intriguing marine scaffolds that exhibit many pharmacological activities, including anti-inflammatory effects. In this review, we aim to provide a summary of the neutrophilic anti-inflammatory properties of these marine organisms that were demonstrated in 46 studies from 1995 to the present (April 2023). We hope the present work offers a comprehensive overview of the anti-inflammatory potential of octocorals and encourages researchers to identify promising leads among numerous compounds isolated from octocorals over the past few decades to be further developed into anti-inflammatory therapeutic agents.


Assuntos
Antozoários , Produtos Biológicos , Animais , Produtos Biológicos/farmacologia , Inflamação/tratamento farmacológico , Neutrófilos , Compostos Radiofarmacêuticos
3.
Mar Drugs ; 20(10)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36286463

RESUMO

In recent decades, aquaculture techniques for soft corals have made remarkable progress in terms of conditions and productivity. Researchers have been able to obtain larger quantities of soft corals, thus larger quantities of biologically active metabolites, allowing them to study their biological activity in many pharmacological assays and even produce sufficient quantities for clinical trials. In this review, we summarize 201 secondary metabolites that have been identified from cultured soft corals in the era from 2002 to September 2022. Various types of diterpenes (eunicellins, cembranes, spatanes, norcembranes, briaranes, and aquarianes), as well as biscembranes, sterols, and quinones were discovered and subjected to bioactivity investigations in 53 different studies. We also introduce a more in-depth discussion of the potential biological effects (anti-cancer, anti-inflammatory, and anti-microbial) and the mechanisms of action of the identified secondary metabolites. We hope this review will shed light on the untapped potential applications of aquaculture to produce valuable secondary metabolites to tackle current and emerging health conditions.


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/metabolismo , Diterpenos/farmacologia , Esteróis/metabolismo , Aquicultura , Quinonas
4.
Int J Mol Sci ; 23(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36555103

RESUMO

Biscembranoids are the distinctive tetraterpenoids owing a 14/6/14 membered tricyclic scaffold that have been mainly discovered in the soft corals, especially the genera Sarcophyton, Lobophytum and Sinularia. Recent findings have demonstrated the great anti-inflammatory potential of biscembranoid analogues in human neutrophils, motivating more chemical and biological explorations targeting these marine-derived natural products. In the current study, the chemical diversity of biscembranoids derived from the cultured-type Sarcophyton trocheliophorum von Marenzeller was illustrated through MS/MS molecular networking (MN) profiling approach. Based on the MN patterns, the prioritization of unknown biscembranoid derivatives was putatively analyzed. As a result, the biscembrane targeting isolation afforded two new metabolites, sarcotrochelides A (1) and B (2), along with six known analogues (3-8). Their structures and relative configurations were determined by spectroscopic methods. In vitro neutrophil inflammatory inhibition was further investigated for all isolates based on reduced superoxide anion (O2•-) generation detections. Compounds 5-8 showed significant dose-dependently inhibitory effects, suggesting the cruciality of 6,7-dihydrooxepin-2(5H)-one moiety and saturated γ-lactone ring in their reactive oxygen species (ROS)-dependent anti-inflammatory properties.


Assuntos
Antozoários , Diterpenos , Animais , Humanos , Espectrometria de Massas em Tandem , Antozoários/química , Superóxidos/metabolismo , Análise Espectral , Anti-Inflamatórios/química , Diterpenos/farmacologia , Estrutura Molecular
5.
Molecules ; 27(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35889335

RESUMO

The fruit of Tetradium ruticarpum (TR) is commonly used in Chinese herbal medicine and it has known antiproliferative and antitumor activities, which can serve as a good source of functional ingredients. Although some antiproliferative compounds are reported to be present in TR fruit, most studies only focused on a limited range of metabolites. Therefore, in this study, the antiproliferative activity of different extracts of TR fruit was examined, and the potentially antiproliferative compounds were highlighted by applying an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based multi-informative molecular networking strategy. The results showed that among different extracts of TR fruit, the EtOAc fraction F2-3 possessed the most potent antiproliferative activity against HL-60, T24, and LX-2 human cell lines. Through computational tool-aided structure prediction and integrating various data (sample taxonomy, antiproliferative activity, and compound identity) into a molecular network, a total of 11 indole alkaloids and 47 types of quinolone alkaloids were successfully annotated and visualized into three targeted bioactive molecular families. Within these families, up to 25 types of quinolone alkaloids were found that were previously unreported in TR fruit. Four indole alkaloids and five types of quinolone alkaloids were targeted as potentially antiproliferative compounds in the EtOAc fraction F2-3, and three (evodiamine, dehydroevodiamine, and schinifoline) of these targeted alkaloids can serve as marker compounds of F2-3. Evodiamine was verified to be one of the major antiproliferative compounds, and its structural analogues discovered in the molecular network were found to be promising antitumor agents. These results exemplify the application of an LC-MS/MS-based multi-informative molecular networking strategy in the discovery and annotation of bioactive compounds from complex mixtures of potential functional food ingredients.


Assuntos
Alcaloides , Evodia , Quinolonas , Alcaloides/análise , Alcaloides/farmacologia , Cromatografia Líquida , Evodia/química , Frutas/química , Humanos , Alcaloides Indólicos/análise , Alcaloides Indólicos/farmacologia , Extratos Vegetais/química , Quinolonas/análise , Espectrometria de Massas em Tandem
6.
Bioorg Chem ; 114: 105150, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328853

RESUMO

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50-7.67 µM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.


Assuntos
Antineoplásicos/farmacologia , Sesterterpenos/farmacologia , Terpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Sesterterpenos/síntese química , Sesterterpenos/química , Estereoisomerismo , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química
7.
Mar Drugs ; 19(4)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917402

RESUMO

The marine sponge of the genus Geodia, Jaspis, Rhabdastrella, and Stelletta are characterized chemically by a variety of isomalabaricane triterpenes. This class of compounds drew spotlights in marine lead discovery due to their profound anti-proliferative properties. Further research on exploring its chemical diversity led to the identifications of two new isomalabaricane-type triterpenes rhabdastin H (1) and rhabdastin I (2). Their structures were unraveled using a series of spectroscopic approaches. These isolates were found to exhibit unique structural features with the only reported tetrahydrofuran functionality among all marine-derived isomalabaricanes. Both compounds 1 and 2 showed activities against K562 (IC50 11.7 and 9.8 µM) and Molt4 (IC50 16.5 and 11.0 µM) leukemic cells in MTT cell proliferative assay.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Poríferos/metabolismo , Triterpenos/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Células K562 , Estrutura Molecular , Neoplasias/patologia , Relação Estrutura-Atividade , Triterpenos/isolamento & purificação
8.
Mar Drugs ; 19(10)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34677460

RESUMO

Sponge-derived scalaranes are remarkable sesterterpenoids previously found to exhibit profound inhibitory effects against neutrophilic inflammation. In our current work, we constructed the metabolomic profile of marine sponge Lendenfeldia sp. for the first time using a tandem mass spectrometry (MS/MS) molecular networking approach. The results highlighted the rich chemical diversity of these scalaranes, motivating us to conduct further research to discover novel scalaranes targeting neutrophilic inflammation. MS- and NMR-assisted isolation and elucidation led to the discovery of seven new homoscalaranes, lendenfeldaranes K-Q (1-7), characterized by methylation at C-24, together with five known derivatives, lendenfeldarane B (8), 25-nor-24-methyl-12,24-dioxoscalar-16-en-22-oic acid (9), 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (10), felixin B (11), and 23-hydroxy-20-methyldeoxoscalarin (12). Scalaranes 1-4 and 6-12 were assayed against superoxide anion generation and elastase release, which represented the neutrophilic inflammatory responses of respiratory burst and degranulation, respectively. The results indicated that 1-3 and 6-12 exhibited potential anti-inflammatory activities (IC50 for superoxide anion scavenging: 0.87~6.57 µM; IC50 for elastase release: 1.12~6.97 µM).


Assuntos
Anti-Inflamatórios/farmacologia , Neutrófilos/efeitos dos fármacos , Poríferos , Sesterterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Organismos Aquáticos , Humanos , Inflamação/prevenção & controle , Sesterterpenos/química , Relação Estrutura-Atividade
9.
Mar Drugs ; 18(9)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32825198

RESUMO

Scalarane-type sesterterpenoids are known for their therapeutic potential in cancer treatments. However, the anti-inflammatory properties of this class of metabolites remain elusive. Our current work aimed to investigate the anti-inflammatory scalaranes from marine sponge Lendenfeldia sp., resulting in the isolation of six new 24-homoscalaranes, lendenfeldaranes E-J (1-6). The structures of the new metabolites were determined by extensive spectroscopic analyses, and the absolute configuration of 1 was established by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 were discovered to individually reduce the generation of superoxide anions, and compound 1 displayed an inhibitor effect on the release of elastase. These three compounds were proven to be the first anti-neutrophilic scalaranes.


Assuntos
Anti-Inflamatórios/farmacologia , Neutrófilos/efeitos dos fármacos , Poríferos/química , Sesterterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Humanos , Elastase de Leucócito/metabolismo , Estrutura Molecular , Neutrófilos/metabolismo , Via Secretória , Sesterterpenos/química , Sesterterpenos/isolamento & purificação , Relação Estrutura-Atividade , Superóxidos/metabolismo
10.
Mar Drugs ; 18(5)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455584

RESUMO

Octocoral Sinularia leptoclados has been identified as a source of bioactive 9,11-secosteroids. This study adopted a targeted isolation approach to the discovery and analysis of five 9,11-secosteroids, including two novel compounds named sinleptosterols A (1) and B (2) as well as five known analogues (8αH-3ß,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (3), 8ßH-3ß,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9-one (4), leptosterol A (5), (24S)-3ß,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9-one (6), and 3ß,11-dihydroxy-9,11-secogorgost-5-en-9-one (7)) in terms of 1H-NMR patterns and potency against neutrophilic inflammation. The structure of secosteroids 1 and 2 was deduced from general spectroscopic analysis and an examination of NMR spectra. Among the above-mentioned isolates, compound 4 had the most pronounced effect in inhibiting elastase release and superoxide anion generation, with the IC50 values of 2.96 and 1.63 µM, respectively.


Assuntos
Antozoários , Anti-Inflamatórios/farmacologia , Neutrófilos/efeitos dos fármacos , Secoesteroides/farmacologia , Animais , Anti-Inflamatórios/química , Espectroscopia de Ressonância Magnética , Secoesteroides/química , Relação Estrutura-Atividade
11.
Mar Drugs ; 18(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991544

RESUMO

In the current study, an NMR spectroscopic pattern-based procedure for probing scalarane derivatives was performed and four new 24-homoscalaranes, lendenfeldaranes A-D (1- 4), along with three known compounds, 12α-acetoxy-22-hydroxy-24-methyl-24-oxoscalar-16-en- 25-al (5), felixin F (6), and 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (7) were isolated from the sponge Lendenfeldia sp. The structures of scalaranes 1-7 were elucidated on the basis of spectroscopic analysis. Scalaranes 1-7 were further evaluated for their cytotoxicity toward a series of human cancer cell lines and the results suggested that 5 and 7 dominated in the anti- proliferative activity of the extract. The 18-aldehyde functionality was found to play a key role in their activity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Poríferos/química , Sesterterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sesterterpenos/química , Sesterterpenos/isolamento & purificação
12.
Mar Drugs ; 16(4)2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29587440

RESUMO

The 7-Acetylsinumaximol B (7-AB), a bioactive cembranoid, was originally discovered from aquaculture soft coral Sinularia sandensis. The current study investigated the anti-proliferative property of 7-AB towards the NCI-N87 human gastric cancer cell line. An MTT cell proliferative assay was applied to evaluate cell survival, and immunofluorescence staining and western blotting were employed to analyze the effects of 7-AB on autophagy and apoptosis. Our results showed that 7-AB exerted a concentration-dependent anti-proliferative effect on NCI-N87 cells, and fluorescence staining indicated that the effect was due to the apoptosis induced by 7-AB. In addition, the 7-AB-induced anti-proliferation towards NCI-N87 cells was associated with the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (such as caspase-3/-9, Bax and Bad), and inhibition of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1). The 7-AB treatment also triggered endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/ATF4/CHOP apoptotic pathway. Furthermore, 7-AB initiated autophagy in NCI-N87 cells and induced the expression of autophagy-related proteins, including Atg3, Atg5, Atg7, Atg12, LC3-I, and LC3-II. Taken together, our findings suggested that 7-AB has the potential to be further developed as a useful anti-cancer or adjuvant agent for the treatment of human gastric cancer.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Diterpenos/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
13.
Mar Drugs ; 16(1)2018 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-29316672

RESUMO

Our continuous search for marine bioactive secondary metabolites led to the screening of crude extracts from a variety of aquaculture soft corals. The ethyl acetate (EtOAc) extract of Lobophytum crassum showed a distinctive chemical profile that was different from the wild type. It demonstrated significant anti-proliferative activity against Molt 4 leukemia cell with an IC50 value of 1 µg/mL after 24 h. Chemical investigation focusing on the unique peaks in L. crassum profile led to the discovery of a new α-tocopherol crassumtocopherol C (1), and two new cembrane-based diterpenoids culobophylins D (2) and E (3), along with ten known cembranoids (4-13). The structures of these isolates were elucidated using extensive spectroscopic techniques and a comparison with previously published data of related metabolites. Compound 2 was found to possess the first identified saturated internal C4-O-C14 linkage six-membered ring among all cembrane-type diterpenoids. The anti-proliferative activity of all the isolates (except 3) was evaluated against a limited panel of leukemia cell lines (Molt 4, K562, U937, and Sup-T1). The major compounds 8 and 10 exhibited the most anti-proliferative potent effect, with IC50 values ranging from 1.2 to 7.1 µM. The Structure Activity Relationship (SAR) of the isolates suggested that the presence of lactone moieties is crucial for the anti-proliferative activity against leukemia cells. Our work indicated that the development of an efficient aquaculture protocols for soft corals led to the discovery of new secondary metabolites with unique structural features. Such protocols can lead to a sustainable supply of biologically active compounds in enough quantities for the pharmaceutical industry.


Assuntos
Antozoários/metabolismo , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Aquicultura , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Metabolismo Secundário , Análise Espectral , Relação Estrutura-Atividade
14.
Mar Drugs ; 16(6)2018 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-29914195

RESUMO

Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-κB (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia/tratamento farmacológico , Poríferos/metabolismo , Talina/metabolismo , Terpenos/farmacologia , Acetilcisteína/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Células HEK293 , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesterterpenos/química , Sesterterpenos/farmacologia , Talina/genética , Terpenos/química , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mar Drugs ; 16(3)2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29495481

RESUMO

Four new briarane diterpenoids, briaviolides K-N (1-4), have been obtained from the cultured-type octocoral Briareum violaceum. Using a spectroscopic approach, the structures of briaranes 1-4 were identified. This study employed an in vitro model of lipopolysaccharide (LPS)-induced inflammation in the murine macrophage RAW 264.7 cell line, and found that among the four briaranes, briarane 2 possessed anti-inflammatory activity against inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions in cells. In addition, principal component analysis using the chemical global positioning system (ChemGPS) for natural products (ChemGPS-NP) was employed in order to analyze the structure-activity relationship (SAR), and the results indicated that the ring conformation of the compound has a leading role in suppressing the expressions of pro-inflammatory iNOS and COX-2 proteins in macrophages.


Assuntos
Antozoários/metabolismo , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Lipopolissacarídeos/imunologia , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Conformação Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Análise de Componente Principal , Células RAW 264.7 , Relação Estrutura-Atividade
16.
Mar Drugs ; 16(6)2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-29890785

RESUMO

Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1⁻68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9⁻99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Terpenos/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Autofagia/efeitos dos fármacos , Benzoquinonas , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Próstata/citologia , Ligação Proteica , Terpenos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Mar Drugs ; 16(1)2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29315210

RESUMO

Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Naftiridinas/farmacologia , Poríferos/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Naftiridinas/administração & dosagem , Naftiridinas/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
18.
Mar Drugs ; 15(10)2017 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-29065512

RESUMO

Abstract: Cembrane-type diterpenoids are among the most frequently encountered natural products from the soft corals of the genus Lobophytum. In the course of our investigation to identify anti-inflammatory constituents from a wild-type soft coral Lobophytumcrassum, two new cembranoids, lobophyolide A (1) and B (2), along with five known compounds (3-7), were isolated. The structures of these natural products were identified using NMR and MS spectroscopic analyses. Compound 1 was found to possess the first identified α-epoxylactone group among all cembrane-type diterpenoids. The in vitro anti-inflammatory effect of compounds 1-5 was evaluated. The results showed that compounds 1-5 not only reduced IL-12 release, but also attenuated NO production in LPS-activated dendritic cells. Our data indicated that the isolated series of cembrane-type diterpenoids demonstrated interesting structural features and anti-inflammatory activity which could be further developed into therapeutic entities.


Assuntos
Antozoários/química , Anti-Inflamatórios/farmacologia , Células Dendríticas/efeitos dos fármacos , Diterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diterpenos/química , Diterpenos/isolamento & purificação , Interleucina-12/metabolismo , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Óxido Nítrico/metabolismo , Cultura Primária de Células , Relação Estrutura-Atividade
19.
J Nat Prod ; 79(10): 2674-2680, 2016 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-27759384

RESUMO

Zoanthus kuroshio is a colorful zoanthid with a fluorescent pink oral disc and brown tentacles, which dominates certain parts of the Taiwanese and Japanese coasts. This sea anemone is a rich source of biologically active alkaloids. In the current investigation, two novel halogenated zoanthamines [5α-iodozoanthenamine (1) and 11ß-chloro-11-deoxykuroshine A (2)], along with four new zoanthamines [18-epi-kuroshine A (3), 7α-hydroxykuroshine E (4), 5α-methoxykuroshine E (5), and 18-epi-kuroshine E (6)], and six known compounds were isolated from Z. kuroshio. Compounds 1 and 2 are the first examples of halogenated zoanthamine-type alkaloids isolated from nature. Compounds 3 and 6 are the first zoanthamine stereoisomers with a cis-junction of the A/B rings. All isolated compounds were evaluated for their anti-inflammatory activities by measuring their effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Anti-Inflamatórios/isolamento & purificação , Azepinas/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hidrocarbonetos Halogenados/isolamento & purificação , Quinolinas/química , Anêmonas-do-Mar/química , Alcaloides/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Humanos , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Japão , Estrutura Molecular , Neutrófilos/metabolismo , Elastase Pancreática/efeitos dos fármacos , Elastase Pancreática/metabolismo , Estereoisomerismo , Superóxidos/química , Taiwan
20.
J Nat Prod ; 79(11): 2805-2813, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27808511

RESUMO

Six new and 16 known lanostanoids were isolated from the sclerotia of Poria cocos. The structures of the new isolates were elucidated to be 16α-hydroxy-3-oxo-24-methyllanosta-5,7,9(11),24(31)-tetraen-21-oic acid (1), 3ß,16α,29-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (2), 3ß,16α,30-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (3), 3ß-acetoxy-16α,24ß-dihydroxylanosta-7,9(11),25-trien-21-oic acid (4), 3ß,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (5), and 3α,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (6), based on extensive spectroscopic analyses. The absolute configuration of 4 was determined using Mosher's method. The antiproliferative activity of the isolated compounds (except 3 and 4) was evaluated against four leukemic cell lines (Molt 4, CCRF-CEM, HL 60, and K562). Dehydropachymic acid (9), dehydroeburicoic acid (12), pachymic acid (14), and lanosta-7,9(11),24-trien-21-oic acid (20) exhibited an antiproliferative effect on the CCRF-CEM cancer cell line with IC50 values of 2.7, 6.3, 4.9, and 13.1 µM, respectively. Both dehydropachymic acid (9) and dehydroeburicoic acid (12) showed antiproliferative effects against Molt 4 (IC50 13.8 and 14.3 µM) and HL 60 (IC50 7.3 and 6.0 µM) leukemic cell lines. Primary computational analysis using a chemical global positioning system for natural products (ChemGPS-NP) on the active lanostanoids from P. cocos suggested that targets other than topoisomerases may be involved in the antiproliferative activity.


Assuntos
Antineoplásicos Fitogênicos , Produtos Biológicos , Lanosterol/análogos & derivados , Wolfiporia/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , DNA Topoisomerases/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Concentração Inibidora 50 , Lanosterol/química , Lanosterol/isolamento & purificação , Lanosterol/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Triterpenos/química , Triterpenos/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA