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1.
Phytochemistry ; 216: 113869, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37739201

RESUMO

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.


Assuntos
Limoninas , Melia azedarach , Melia azedarach/química , Limoninas/farmacologia , Limoninas/química , Lipopolissacarídeos/farmacologia , Macrófagos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química
2.
Food Chem Toxicol ; 177: 113850, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37225032

RESUMO

Two new germacrane-type sesquiterpenoids, chrysanthemolides A (1) and B (2), and four known germacrane-type sesquiterpenoids, hanphyllin (3), 3ß-hydroxy-11α,13-dihydro-costunolide (4), costunolide (5), and 6,7-dimethylmethylene-4-aldehyde-1ß-hydroxy-10(15)-ene-(4Z)-dicyclodecylene (6), were isolated and identified from the flowers of Chrysanthemum indicum. The structures of the new compounds were elucidated via high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR) spectra and electronic circular dichroism (ECD). Meanwhile, all the isolates were tested for their hepatoprotective activity in tert-butyl hydroperoxide (t-BHP) injured AML12 cells. Compounds 1, 2, and 4 showed significant protective effects at 40 µM, comparable with the positive control resveratrol at 10 µM. As the most potent one, compound 1 was chosen for further studies. Compound 1 dose-dependently increased the viability of t-BHP-injured AML12 cells. Furthermore, compound 1 decreased reactive oxygen species accumulation, while increased glutathione level, heme oxygenase-1 level and superoxide dismutase activity, through anchoring in the binding site of Kelch domain of the Kelch-like ECH-associated protein 1 (Keap1) to promote the dissociation of nuclear factor erythroid 2-related factor 2 from Keap1 and translocation to nuclei. In summary, germacrane-type sesquiterpenoids from C. indicum might be further developed to protect liver against oxidative damage.


Assuntos
Chrysanthemum , Sesquiterpenos , Chrysanthemum/química , Flores/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Sesquiterpenos/farmacologia , Sesquiterpenos/análise , Sesquiterpenos de Germacrano/farmacologia , Sesquiterpenos de Germacrano/análise
3.
Molecules ; 28(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36770712

RESUMO

The tuberous root of Ophiopogon japonicus (Thunb.) Ker-Gawl. is a well-known Chinese medicine also called Maidong (MD) in Chinese. It could be divided into "Chuanmaidong" (CMD) and "Zhemaidong" (ZMD), according to the geographic origins. Meanwhile, the root of Liriope spicata (Thunb.) Lour. var. prolifera Y. T. Ma (SMD) is occasionally used as a substitute for MD in the market. In this study, a reliable pressurized liquid extraction and HPLC-DAD-ELSD method was developed for the simultaneous determination of nine chemical components, including four steroidal saponins (ophiopojaponin C, ophiopogonin D, liriopesides B and ophiopogonin D'), four homoisoflavonoids (methylophiopogonone A, methylophiopogonone B, methylophiopogonanone A and methylophiopogonanone B) and one sapogenin (ruscogenin) in CMD, ZMD and SMD. The method was validated in terms of linearity, sensitivity, precision, repeatability and accuracy, and then applied to the real samples from different origins. The results indicated that there were significant differences in the contents of the investigated compounds in CMD, ZMD and SMD. Ruscogenin was not detected in all the samples, and liriopesides B was only found in SMD samples. CMD contained higher ophiopogonin D and ophiopogonin D', while the other compounds were more abundant in ZMD. Moreover, the anticancer effects of the herbal extracts and selected components against A2780 human ovarian cancer cells were also compared. CMD and ZMD showed similar cytotoxic effects, which were stronger than those of SMD. The effects of MD may be due to the significant anticancer potential of ophiopognin D' and homoisoflavonoids. These results suggested that there were great differences in the chemical composition and pharmacological activity among CMD, ZMD and SMD; thus, their origins should be carefully considered in clinical application.


Assuntos
Medicamentos de Ervas Chinesas , Ophiopogon , Neoplasias Ovarianas , Saponinas , Compostos de Espiro , Humanos , Feminino , Ophiopogon/química , Linhagem Celular Tumoral , Saponinas/farmacologia , Saponinas/química , Medicamentos de Ervas Chinesas/química
4.
Acta Pharmacol Sin ; 44(2): 434-445, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35945312

RESUMO

Interleukin (IL)-1ß is a culprit of adipose tissue inflammation, which in turn causes systematic inflammation and insulin resistance in obese individuals. IL-1ß is mainly produced in monocytes and macrophages and marginally in adipocytes, through cleavage of the inactive pro-IL-1ß precursor by caspase-1, which is activated via the NLRP3 inflammasome complex. The nuclear factor-κB (NF-κB) transcription factor is the master regulator of inflammatory responses. Brindle berry (Garcinia cambogia) has been widely used as health products for treating obesity and related metabolic disorders, but its active principles remain unclear. We previously found a series of polyisoprenylated benzophenones from brindle berry with anti-inflammatory activities. In this study we investigated whether 14-deoxygarcinol (DOG), a major polyisoprenylated benzophenone from brindle berry, alleviated adipose tissue inflammation and insulin sensitivity in high-fat diet fed mice. The mice were administered DOG (2.5, 5 mg · kg-1 · d-1, i.p.) for 4 weeks. We showed that DOG injection dose-dependently improved insulin resistance and hyperlipidemia, but not adiposity in high-fat diet-fed mice. We found that DOG injection significantly alleviated adipose tissue inflammation via preventing macrophage infiltration and pro-inflammatory polarization of macrophages, and adipose tissue fibrosis via reducing the abnormal deposition of extracellular matrix. In LPS plus nigericin-stimulated THP-1 macrophages, DOG (1.25, 2.5, 5 µM) dose-dependently suppressed the activation of NLRP3 inflammasome and NF-κB signaling pathway. We demonstrated that DOG bound to and activated the deacetylase Sirtuin 2, which in turn deacetylated and inactivated NLRP3 inflammasome to reduce IL-1ß secretion. Moreover, DOG (1.25, 2.5, 5 µM) dose-dependently mitigated inflammatory responses in macrophage conditioned media-treated adipocytes and suppressed macrophage migration toward adipocytes. Taken together, DOG might be a drug candidate to treat metabolic disorders through modulation of adipose tissue remodeling.


Assuntos
Resistência à Insulina , NF-kappa B , Animais , Camundongos , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Camundongos Obesos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Sirtuína 2/metabolismo
5.
Phytochemistry ; 201: 113280, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35716716

RESUMO

Eleven undescribed tetracyclic triterpenoids, meliazedarachins A-K, along with twenty-six known compounds were isolated from the fruits of Melia azedarach L.. Their structures were determined by HRESIMS, UV, IR, NMR, X-ray diffraction, electronic circular dichroism (ECD) spectra, and the modified Mosher's method. The cytotoxic activities of all the isolates were measured. Meliazedarachin K and mesendanin N showed cytotoxicity against five human cancer cell lines with IC50 values ranging from 9.02 to 31.31 µM. Meliazedarachin K showed significant cytotoxicity against HCT116 cell line with IC50 value of 9.02 ± 0.84 µM. 21α-methylmelianodiol showed significant cytotoxicity against HCT116 and RKO cell lines with IC50 values of 10.16 ± 1.22 and 8.57 ± 0.80 µM, respectively.


Assuntos
Antineoplásicos , Melia azedarach , Neoplasias , Triterpenos , Frutas/química , Humanos , Melia azedarach/química , Estrutura Molecular , Triterpenos/química
6.
Nat Prod Res ; 36(12): 3085-3094, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34694166

RESUMO

Three new biflavonoids, umcephabiovins C - E (1 - 3), along with fourteen known compounds were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures and configurations were elucidated by UV, IR, NMR, ECD, and HR-ESI-MS spectra. Compounds 1 - 3 exhibited significant α-glucosidase inhibitory activity with IC50 values of 7.05 ± 2.66, 24.45 ± 4.73, and 1.84 ± 1.14 µM, respectively. Compound 11 showed moderate cytotoxicity against the BaF3/T315I cell line.


Assuntos
Biflavonoides , Cephalotaxus , Biflavonoides/química , Biflavonoides/farmacologia , Cephalotaxus/química , Estrutura Molecular , Folhas de Planta/química , alfa-Glucosidases/metabolismo
7.
Acta Pharmacol Sin ; 43(7): 1780-1792, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34789920

RESUMO

Interleukin-1ß (IL-1ß), a key pro-inflammatory cytokine, is majorly produced by macrophages through NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, which has been identified as the culprit to deteriorate the inflammatory crosstalk between macrophages and adipocytes. Ainsliadimer C (AC) is a disesquiterpenoid isolated from Ainsliaea macrocephala. In the current study, we investigated the effects of AC on adipose tissue inflammation in co-culture of macrophages and adipocytes in vitro as well as in LPS-treated mice in vivo. We showed that AC (20-80 µM) dose-dependently inhibited the secretion of IL-1ß from LPS plus ATP-stimulated THP-1 macrophages by inhibiting the activation of NLRP3 inflammasome. Furthermore, we found that AC treatment activated NAD+-dependent deacetylase Sirtuin 1 (SIRT1), resulting in reduced acetylation level of NLRP3. Molecular modeling analysis revealed that binding of AC to sirtuin-activating compound-binding domain increased the affinity of the substrate to the catalytic domain of SIRT1. Moreover, AC (80 µM) significantly attenuated macrophage-conditioned medium-induced inflammatory responses in 3T3-L1 adipocytes. In LPS-induced acute inflammatory mice, administration of AC (20, 60 mg·kg-1·d-1, ip) for 5 days significantly suppressed the pro-inflammatory cytokine levels in serum and epididymal white adipose tissue (eWAT), attenuated macrophage infiltration into eWAT, and mitigated adipose tissue inflammation. The beneficial effects of AC were blocked by co-administration of a selective SIRT1 inhibitor EX-527 (10 mg·kg-1·d-1). Taken together, AC suppresses NLRP3-mediated IL-1ß secretion through activating SIRT1, leading to attenuated inflammation in macrophages and adipose tissue, which might be a candidate to treat obesity-associated metabolic diseases.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Tecido Adiposo/metabolismo , Animais , Citocinas/metabolismo , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sirtuína 1/metabolismo
8.
Acta Pharmacol Sin ; 43(5): 1285-1298, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34417576

RESUMO

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of the mitogen-activated protein kinases and nuclear factor-κB signalling pathways. Furthermore, BBR decreased microRNA-155-5p secretion by macrophages, which in turn ameliorated liver injury. Moreover, BBR mitigated inflammatory responses in both LPS-stimulated macrophages and TNF-α-treated adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue remodelling, and subsequently inhibited the secretion of microRNA-155-5p by macrophages, which alleviated adiposity, insulin resistance and liver injury in obese mice. The modulation of adipose tissue remodelling by activating SIRT3 could contribute to the anti-hyperlipidemic and anti-hyperglycemic effects of BBR.


Assuntos
Berberina , Resistência à Insulina , MicroRNAs , Sirtuína 3 , Tecido Adiposo , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Dieta Hiperlipídica , Inflamação , Camundongos , MicroRNAs/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo
9.
Chin J Nat Med ; 19(7): 481-490, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247771

RESUMO

Honokiol is the dominant biphenolic compound isolated from the Magnolia tree, and has long been considered as the active constituent of the traditional Chinese herb, 'Houpo', which is widely used to treat symptoms due to 'stagnation of qi'. Pharmacological studies have shown that honokiol possesses a wide range of bioactivities without obvious toxicity. Honokiol protects the liver, kidneys, nervous system, and cardiovascular system through reducing oxidative stress and relieving inflammation. Moreover, honokiol shows anti-diabetic property through enhancing insulin sensitivity, and anti-obese property through promoting browning of adipocytes. In vivo and in vitro studies indicated that honokiol functions as an anti-cancer agent through multiple mechanisms: inhibiting angiogenesis, promoting cell apoptosis, and regulating cell cycle. A variety of therapeutic effects of honokiol may be associated with its physiochemical properties, which make honokiol readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier, with high bioavailability. In the future, more clinical researches on honokiol are needed to fully authenticate its therapeutic values.


Assuntos
Compostos de Bifenilo , Medicamentos de Ervas Chinesas/farmacologia , Lignanas , Magnolia , Apoptose , Compostos de Bifenilo/farmacologia , Humanos , Lignanas/farmacologia
10.
Chin J Nat Med ; 18(7): 517-525, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32616192

RESUMO

Nagilactone E (NLE), a natural product with anticancer activities, is isolated from Podocarpus nagi. In this study, we reported that NLE increased programmed death ligand 1 (PD-L1) expressions at both protein and mRNA levels in human lung cancer cells, and enhanced its localization on the cell membrane. Mechanistically, NLE increased the phosphorylation and expression of c-Jun, and promoted the localization of c-Jun in the nucleus, while silencing of c-Jun by small interfering RNA (siRNA) reduced NLE-induced PD-L1. Further study showed that NLE activated the c-Jun N-terminal kinases (JNK), the upstream of c-Jun, and its inhibitor SP600125 reversed the NLE-increased PD-L1. Moreover, NLE-induced PD-L1 increased the binding intensity of PD-1 on the cell surface. In summary, NLE upregulates the expression of PD-L1 in lung cancer cells through the activation of JNK-c-Jun axis, which has the potential to combine with the PD-1/PD-L1 antibody therapies in lung cancer.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Diterpenos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactonas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Diterpenos/química , Humanos , Lactonas/química , Estrutura Molecular
11.
Anticancer Agents Med Chem ; 20(8): 982-988, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32286950

RESUMO

BACKGROUND: Cassane-type diterpenoids are widely distributed in the medical plants of genus Caesalpinia. To date, plenty of cassane diterpenoids have been isolated from the genus Caesalpinia, and some of them were documented to exhibit multiple biological activities. However, the effects of these compounds on autophagy have never been reported. OBJECTIVE: To investigate the effects and mechanisms of the cassane diterpenoids including Phanginin R (PR) on autophagy in Non-Small Cell Lung Cancer (NSCLC) A549 cells. METHODS: Western blot analysis and immunofluorescence assay were performed to investigate the effects of the compounds on autophagic flux in A549 cells. The pathway inhibitor and siRNA interference were used to investigate the mechanism of PR. MTT assay was performed to detect cell viability. RESULTS: PR treatment upregulated the expression of phosphatidylethanolamine-modified microtubule-associated protein Light-Chain 3 (LC3-II) in A549 cells. Immunofluorescence assay showed that PR treatment increased the production of red-fluorescent puncta in mRFP-GFP-LC3 plasmid-transfected cells, indicating PR promoted autophagic flux in A549 cells. PR treatment activated the c-Jun N-terminal Kinase (JNK) signaling pathway while it did not affect the classical Akt/mammalian Target of Rapamycin (mTOR) pathway. Pretreatment with the JNK inhibitor SP600125 or siRNA targeting JNK or c-Jun suppressed PR-induced autophagy. In addition, cotreatment with the autophagy inhibitor Chloroquine (CQ) or inhibition of the JNK/c-Jun signaling pathway increased PR-induced cytotoxicity. CONCLUSION: PR induced cytoprotective autophagy in NSCLC A549 cells via the JNK/c-Jun signaling pathway, and autophagy inhibition could further improve the anti-cancer potential of PR.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Substâncias Protetoras/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Caesalpinia/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estrutura Molecular , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Molecules ; 25(6)2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168948

RESUMO

Psidium guajava, a popular food and medicine dual purposes plant cultivated in tropical and subtropical regions, has been widely used as food crop and folk medicine, such as anti-diabetes agent, around the world. Triterpenoids have been considered as the major active ingredients of P. guajava. In the present study, a high-performance liquid chromatography coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD) method was developed for simultaneous determination of nine triterpenoids in P. guajava. Pressurized liquid extraction (PLE) was performed for sample preparation, and the analysis was achieved on a Cosmosil 5C18-MS-II (Nacalai Tesque, Kyoto, Japan) column eluted with gradient 0.1% aqueous formic acid-methanol system. The drift tube temperature of ELSD was set at 40 °C, and nitrogen flow-rate was at 1.6 L/min. All calibration curves for the analytes showed good linear regression (R2 > 0.9992) within test ranges. The established method was validated for intra-day and inter-day precisions (RSDs < 5%) and accuracy (recovery 94.23-106.87%). The validated method was successfully applied to determinate nine triterpenoids in 15 samples from the leave or fruit of P. guajava. In addition, the α-glucosidase inhibition assay showed good α-glucosidase inhibition activity in almost all the determined triterpenoids. The present study suggested that triterpenoids should be the quality control markers for P. guajava and HPLC-DAD-ELSD was an effective tool for the quality control of P. guajava.


Assuntos
Medicamentos de Ervas Chinesas/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Psidium/química , Triterpenos/química , alfa-Glucosidases/química , Calibragem , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Formiatos/química , Frutas/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Extração Líquido-Líquido/métodos , Metanol/química , Variações Dependentes do Observador , Folhas de Planta/química , Controle de Qualidade , Solventes/química , Triterpenos/isolamento & purificação
13.
Acta Pharmacol Sin ; 41(5): 698-705, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32047261

RESUMO

Norditerpenoids and dinorditerpenoids represent diterpenoids widely distributed in the genus Podocarpus with notable chemical structures and biological activities. We previously reported that nagilactone E (NLE), a dinorditerpenoid isolated from Podocarpus nagi, possessed anticancer effects against lung cancer cells in vitro. In this study we investigated the in vivo effect of NLE against lung cancer as well as the underlying mechanisms. We administered NLE (10 mg·kg-1·d-1, ip) to CB-17/SCID mice bearing human lung cancer cell line A549 xenograft for 3 weeks. We found that NLE administration significantly suppressed the tumor growth without obvious adverse effects. Thereafter, RNA sequencing (RNA-seq) analysis was performed to study the mechanisms of NLE. The effects of NLE on A549 cells have been illustrated by GO and pathway enrichment analyses. CMap dataset analysis supported NLE to be a potential protein synthesis inhibitor. The inhibitory effect of NLE on synthesis of total de novo protein was confirmed in Click-iT assay. Using the pcDNA3-RLUC-POLIRES-FLUC luciferase assay we further demonstrated that NLE inhibited both cap-dependent and cap-independent translation. Finally, molecular docking revealed the low-energy binding conformations of NLE and its potential target RIOK2. In conclusion, NLE is a protein synthesis inhibitor with anticancer activity.


Assuntos
Fator 4 Ativador da Transcrição/antagonistas & inibidores , Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Diterpenos/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Inibidores da Síntese de Proteínas/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Células A549 , Fator 4 Ativador da Transcrição/biossíntese , Fator 4 Ativador da Transcrição/genética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/genética , Diterpenos/administração & dosagem , Diterpenos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/isolamento & purificação , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas
14.
Toxicol Appl Pharmacol ; 389: 114882, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953203

RESUMO

Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural dinorditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-ß1 (TGF-ß1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-ß1-induced expression of fibrotic markers including type I and III collagen, fibronectin, α-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-ß1-induced up-regulation of TßR I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TßR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.


Assuntos
Diterpenos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Proteína Smad2/metabolismo , Terpenos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores/metabolismo , Bleomicina/farmacologia , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Chem Biodivers ; 16(5): e1900137, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957408

RESUMO

A pair of new glycosidic epimers, cablinosides A (1a) and B (1b) were isolated from the leaves of Pogostemon cablin. The structures with absolute configurations of 1a and 1b were elucidated by extensive NMR investigation, and quantum chemical CD calculations. The epimer mixture 1 showed moderate α-glucosidase inhibitory activity and no significant cytotoxic activity against HepG2 cells.


Assuntos
Glicosídeos/química , Fenilacetatos/química , Pogostemon/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Fenilacetatos/isolamento & purificação , Fenilacetatos/farmacologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Pogostemon/metabolismo , Estereoisomerismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
16.
Fitoterapia ; 134: 346-354, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30858046

RESUMO

Fourteen acetylbenzofuran derivatives, including three undescribed carbon skeletons with a newly formed hexane or benzene ring on the other side of the benzofuran ring, (±)-eupatonin A (1), (±)-eupatonin B (2), and eupatonin C (3), two new benzofurans (-)-12ß-hydroxygynunone (4) and (+)-12-hydroxyl-13-noreuparin (5), as well as 9 known ones (6-14), were isolated from 95% ethanol extract of the roots of Eupatorium chinense. Their structures were determined by spectroscopic methods and quantum chemical DFT and TDDFT calculations of the NMR chemical shifts and ECD spectra, which helped in the determination of the relative configurations of 1 and 2 and the absolute configurations of 4 and 5, respectively. 1 and 2 were further identified to be racemic mixtures by chiral HPLC analysis. All compounds were evaluated for insulin-stimulated glucose uptake in differentiated C2C12 myotubes. Compounds 1, 3, 4, 5, 11, 12, and 13 markedly enhanced insulin-mediated glucose uptake. (±)-Eupatonin A (1) activated the IRS-1/Akt/GSK-3ß signaling pathway and enhanced insulin stimulated GLUT4 membrane translocation in C2C12 myotubes. On LPS stimulated RAW264.7 macrophages, several compounds exhibited significant inhibitory effect on NO production with IC50 values ranging from 4.94 to 9.70 µΜ. (±)-Eupatonin A (1) again dose-dependently suppressed LPS-induced NO production and decreased the expression of inducible NO synthase (iNOS), through inhibiting NF-κB activity.


Assuntos
Benzofuranos/farmacologia , Eupatorium/química , Macrófagos/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Animais , China , Proteínas de Ligação a DNA/metabolismo , Glucose/metabolismo , Insulina , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
17.
Food Funct ; 10(3): 1288-1294, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30843544

RESUMO

Curcumenol was firstly revealed as a pair of hemiacetal-ketone tautomers in solutions by using temperature variation 1H-NMR experiments, 2D NMR, and chemical methods. Quantum chemical calculation allowed the explanation of its spectroscopic behavior. An antioxidative SAR study on its derivatives verified the tautomeric bio-significance. Curcumenol also remarkably enhanced myogenic differentiation and mitochondrial function.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Plantas Comestíveis/química , Sesquiterpenos/química , Animais , Linhagem Celular , Isomerismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular
18.
Phytomedicine ; 52: 32-39, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599910

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death around the world. Epithelial-mesenchymal transition (EMT) has been documented to increase motility and invasiveness of cancer cells, which promotes cancer metastasis. PURPOSE: This study aims to investigate the inhibitory effects and mechanisms of the dinorditerpenoids and norditerpenoids isolated from the seeds of Podocarpus nagi against transforming growth factor (TGF)-ß1-induced EMT. METHODS: A series of dinorditerpenoids and norditerpenoids were isolated from the seeds of P. nagi. Western blot and quantitative real-time PCR assays were performed to determine the expression levels of relative proteins and mRNA, along with immunofluorescence, Smad-binding element (SBE)-luciferase and chromatin immunoprecipitation (ChIP) assays for the mechanism study. Transwell assays were conducted to determine the effect of the compounds on cell migration and invasion. RESULTS: Nagilactone E (NLE) showed the superior inhibitory effect against TGF-ß1-induced EMT. NLE treatment dramatically inhibited TGF-ß1-induced expression of EMT markers in A549 cells. Mechanism study indicated that NLE markedly suppressed TGF-ß1-induced Smad2 and Smad3 activation and nuclear translocation. SBE-luciferase and ChIP assays showed that NLE inhibited the combining of Smad3 to SBE in the promoters of the cell signaling factors. NLE co-treatment attenuated TGF-ß1-induced up-regulation of the protein and mRNA levels of TGF-ß receptor TßRI. Furthermore, NLE inhibited TGF-ß1-stimulated cell migration and invasion, as well as up-regulation of the key signaling proteins related with migration and invasion. CONCLUSION: NLE inhibited TGF-ß/Smad signaling pathway, thereafter suppressed TGF-ß1-induced EMT, migration and invasion in NSCLC A549 cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Fator de Crescimento Transformador beta1/farmacologia , Células A549 , Movimento Celular/efeitos dos fármacos , Gleiquênias/química , Humanos , Invasividade Neoplásica , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
19.
Phytochemistry ; 160: 1-10, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30641334

RESUMO

Five undescribed cycloartane triterpenoids, including two cycloartane trinor-triterpenoids, were isolated from a 70% ethanol extract of the whole plant of Actaea vaginata (Ranunculaceae), together with thirteen known cycloartane triterpenoids. Their structures were determined by spectroscopic techniques and quantum chemical calculations for intramolecular noncovalent interactions with reduced density gradient method. All compounds were evaluated for their anti-inflammatory effects by a lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production model in RAW264.7 macrophage cells, and some showed potent inhibitory effects with IC50 values ranging from 5.0 to 24.4 µM. Further mechanism studies showed that one compound dose-dependently suppressed LPS-induced NO production and pro-inflammatory cytokines secretion, and decreased the expression of iNOS, through inhibiting NF-κB activation.


Assuntos
Actaea/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Modelos Moleculares , Conformação Molecular , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
20.
Molecules ; 24(1)2019 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-30621331

RESUMO

Four previously undescribed compounds, including three rarely occurring seco-dammarane triterpenoid glycosides and a pentacyclic triterpenic acid, were isolated from a 70% ethanol extract of the leaves of Cyclocarya paliurus (Juglandaceae), along with eleven known triterpenoids. Their structures were determined by spectroscopic techniques, including 2D NMR and HRESIMS, as well as chemical methods. Among them, several triterpenoids enhanced insulin stimulated glucose uptake in both 3T3-L1 adipocytes and C2C12 myotubes. Furthermore, compound 1 dose-dependently increased glucose uptake through activating AMP-activated protein kinase (AMPK)-p38 pathway. Collectively, triterpenoids from C. paliurus could be developed as insulin sensitizers, which might have therapeutic potential for insulin resistance and hyperglycemia.


Assuntos
Adipócitos/efeitos dos fármacos , Glucose/metabolismo , Juglandaceae/química , Terpenos/farmacologia , Células 3T3-L1 , Quinases Proteína-Quinases Ativadas por AMP , Adipócitos/citologia , Animais , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Glicosídeos/química , Insulina , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Folhas de Planta/química , Proteínas Quinases/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Terpenos/isolamento & purificação
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