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1.
Nat Prod Res ; : 1-7, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35319315

RESUMO

Two new diterpenoids, 12,15-di-O-acetylhypargenin B (1) and taiwanin F-12-O-ß-D-glucopyranoside (2), one new monoterpenoid, (S)-7-methyl-3-methyleneoct-6-ene-1,2-diyl diacetate (3), together with eight known compounds (4-11), were obtained from the twigs and leaves of Nageia fleuryi Hickel. The structures of the new compounds were elucidated by extensive spectroscopic techniques including HR-ESI-MS and 1 D and 2 D NMR experiments. Spectroscopic data of the known compound 4 were provided for the first time. Compounds 1 and 11 exhibited strong inhibitory activity on LPS-stimulated production of NO in RAW 264.7 murine macrophages, while compounds 1, 3, and 5 showed significant quinone reductase inducing activity in Hepa 1c1c7 murine hepatoma cells. Moreover, compounds 7 and 8 showed inhibitory activity against the proliferation of the human prostate carcinoma DU145 cells.

2.
Nat Prod Res ; 36(1): 26-36, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32375507

RESUMO

Five new lignans, euphorhirtins A-D (1-4), 5-methoxyvirgatusin (5), three artefacts, 7S-ethoxyisolintetralin (6), 7R-ethoxyisolintetralin (7), and 7R-ethoxy-3-methoxyisolintetralin (8), together with 13 known ones (9-21) were isolated from the medicinal plant Euphorbia hirta L. The structures of the compounds were elucidated by means of extensive spectroscopic analysis, including 1D and 2D NMR and HR-ESI-MS experiments. The absolute configurations of compound 1 was determined by ECD calculation. The isolates were evaluated for their inhibitory effects against the proliferation of the cancer cell lines (Hep G2, A549, and DU145) and compounds 14 and 18 showed inhibitory activity against the Hep G2 cells with IC50 values 7.2 ± 0.17 and 8.5 ± 0.36 µM.


Assuntos
Antineoplásicos Fitogênicos , Euphorbia , Lignanas , Células A549 , Antineoplásicos Fitogênicos/farmacologia , Euphorbia/química , Células Hep G2 , Humanos , Lignanas/farmacologia , Estrutura Molecular , Extratos Vegetais/farmacologia
3.
Nat Prod Res ; 36(3): 714-718, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32722947

RESUMO

Two new triterpenoids, 3ß-hydroxytirucall-7,25-dien-24-one (1) and 3ß-acetoxytirucall-7,23,25-triene (2), along with one new sesquiterpenoid, alloaromadendrane-12α,14ß-dioic acid (3), were isolated from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established on the basis of extensive spectroscopic data.


Assuntos
Apocynaceae , Triterpenos , Estrutura Molecular , Folhas de Planta , Terpenos
4.
J Ethnopharmacol ; 283: 114694, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34601084

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The flower buds of Tussilago farfara L. (Abbreviated as FTF) were widely used in traditional Chinese medicine (TCM) to treat respiratory diseases, including asthma, dry throat, great thirst, turbid saliva, stinky pus, and coughs caused by various causes. AIM OF STUDY: The aim of study is to explore the efficiency of FTF in vitro and in vivo for the treatment of lung inflammation, and to illustrate the possible mechanisms of FTF in treating inflammation-related respiratory diseases targeting NOD-like receptor 3 (NLRP3) inflammasome, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB). METHODS: Lung inflammation model in vivo was induced by exposure of mice to cigarette smoke (CS) for two weeks. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), inflammatory factors, and histology in lung tissues were investigated in presence or absence of ethanol extract of the flower buds of T. farfara L. (FTF-EtOH). In the cell-based models, nitric oxide (NO) assay, flow cytometry assay, enzyme-linked immunosorbent assay (Elisa), and glutathione (GSH) assay were used to explore the anti-inflammatory and anti-oxidant effects of FTF-EtOH. Possible anti-inflammatory mechanisms of FTF targeting NLRP3 inflammasome, Nrf2, and NF-κB have been determined using western blot, quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), immunofluorescence assay, nuclear and cytoplasmic extraction, and ubiqutination assay. RESULTS: FTF-EtOH suppressed CS-induced overproduction of inflammatory factors [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß)], and upregulation of the content of intracellular MDA in the lung homogenate of mice. In cell-based models, FTF-EtOH reduced the lipopolysaccharide (LPS)-induced overproduction of inflammatory factors, and attenuated the CS extract-induced overgeneration of reactive oxygen species (ROS). Furthermore, FTF-EtOH up-regulated Nrf2 and its downstream genes through enhancing the stability of Nrf2 protein, and inhibited the activation of NF-κB and NLRP3 inflammasome, which have been confirmed by detecting the protein levels in the mouse model. CONCLUSIONS: FTF-EtOH effectively attenuated lung inflammation in vitro and in vivo. The protection of FTF-EtOH against inflammation was produced by activation of Nrf2 and inhibitions of NF-κB and NLRP3 inflammasome. These datas definitely support the ethnopharmacological use of FTF as an anti-inflammatory drug for treating respiratory diseases in TCM.


Assuntos
Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Fumaça/efeitos adversos , Tussilago/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Flores/química , Humanos , Inflamação/induzido quimicamente , Pneumopatias/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Mucosa Respiratória/citologia , Tabaco
5.
Fitoterapia ; 147: 104758, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33069833

RESUMO

Three new isopimarane-type diterpenoids, botrysphins G-I (1-3), a new muurolane-type sesquiterpenoid, 11,12-dihydroxylentideusether (4), and two new triketides, 4-dechlorobotrysphone C (5) and 4,5-dihydroxy-3-methoxy-6-undecanoyloxy-2-cyclohexen-1-one (6), together with one known diterpenoid, sphaeropsidin A (7), one sesquiterpenoid, lentideusether (8), and one triketide sphaeropsidone (9), were isolated from culture of the fungus Botrysphaeria laricina associated with the moss Rhodobryum umgiganteum. The structures of the new compounds were established on the basis of extensive spectroscopic techniques including HRMS and 1D and 2D NMR data. Compounds 1 and 2 exhibited NO inhibitory activity with IC50 values of 13.9 µM and 41.9 µM, respectively. At the same time, these two compounds showed quinone reductase inducing activity with 2.7-fold of induction for 1 at 12.5 µM and 1.6-fold for 2 at 25.0 µM.


Assuntos
Ascomicetos/química , Diterpenos/farmacologia , Policetídeos/farmacologia , Sesquiterpenos/farmacologia , Animais , Briófitas/microbiologia , Linhagem Celular Tumoral , China , Diterpenos/isolamento & purificação , Ativadores de Enzimas/isolamento & purificação , Ativadores de Enzimas/farmacologia , Camundongos , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona) , Óxido Nítrico/metabolismo , Policetídeos/isolamento & purificação , Células RAW 264.7 , Sesquiterpenos/isolamento & purificação
6.
J Nat Prod ; 83(10): 2817-2830, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33001650

RESUMO

A pair of enantiomeric 15-nordolabellane diterpenoids, (-)- and (+)-caseadolabellols A (1a and 1b), three dolabellane diterpenoids, caseadolabellols B-D (2-4), two dolastane diterpenoids, caseadolastols A and B (5 and 6), 10 clerodane diterpenoids, caseakurzins A-J (7-16), and nine known diterpenoids (17-25) were isolated from the twigs and leaves of Casearia kurzii. The structures of the new compounds were established on the basis of extensive spectroscopic data, and those of compounds 1a, 1b, and 2 were verified by single-crystal X-ray crystallographic analysis. The enantiomers 1a and 1b were separated by chiral-phase HPLC. The absolute configurations were determined by experimental and calculated ECD data, the modified Mosher's method, or literature comparison. Compounds 1a and 5 showed significant quinone reductase-inducing activity in Hepa 1c1c7 cells, while 1b showed moderate activity. Molecular docking studies showed that 1a had greater binding affinity with Nrf2 protein (5FNQ) than 1b. The cytotoxic activity of compounds 1a, 1b, 2-12, 15, and 16 was evaluated, among which compounds 8 and 16 exhibited significant inhibitory activity against the A549 cell line. Compounds 8 and 16 induced the A549 cells to arrest at G2/M and S phases, respectively, and both compounds induced apoptosis in A549 cells.


Assuntos
Casearia/química , Diterpenos Clerodânicos/química , Antineoplásicos Fitogênicos/química , Diterpenos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Estrutura Molecular , Folhas de Planta/química
7.
Planta Med ; 86(16): 1191-1203, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32668478

RESUMO

Physalis Calyx seu Fructus, a traditional Chinese medicine consisting of the calyxes and fruits of Physalis alkekengi var. franchetii, has been used as therapy for inflammation-related respiratory diseases such as excessive phlegm, cough, sore throat, and pharyngitis for a long history in China. The aim of the present study was to investigate the chemical constituents of Physalis Calyx seu Fructus and identify the bioactive constituents responsible for its traditional application as therapy for inflammation-related diseases. In the present study, one new phenylpropanoid (1: ), two new steroids (17: and 18: ), together with 55 known constituents have been purified from the EtOH extract of Physalis Calyx seu Fructus. Among them, seven and twelve known constituents were isolated for the first time from Physalis Calyx seu Fructus and the genus Physalis, respectively. Fourteen constituents, including steroids [physalins (5:  - 9, 12:  - 14: , and 15: ) and ergostane (21: )], a sesquiterpenoid (35: ), alkaloids (36: and 37: ), and a flavonoid (44: ), showed inhibitory effects against oxidative stress. Ten constituents, including steroids (5, 6, 8, 13: , and 15: ), sesquiterpenoids (34: and 35: ), alkaloids (37: and 41: ), and a flavonoid (43: ), were found be potential anti-inflammatory constituents of this medicinal plant. The inhibition of oxidative stress and inflammatory response may be related to the regulation of Nrf2 and nuclear factor-κB pathways. The ethnomedical use of Physalis Calyx seu Fructus as a treatment for respiratory diseases might be attributed to the combined inhibitory effects of steroids, alkaloids, sesquiterpenoids, and flavonoids against oxidative stress and inflammatory response.


Assuntos
Physalis , China , Flores , Frutas , Estresse Oxidativo
8.
Fitoterapia ; 143: 104599, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32330576

RESUMO

One novel polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, laricinin A (1), two new meroterpenoids, tricycloalternarenes X and Y (2 and 3), one new coumarin, 3,4,7-trihydroxy-6-methylcoumarin (4), together with the known ethyl acetylorsellinate (5), diorcinol K (6), and tricycloalternarenes C and D (7 and 8) were obtained from culture of the fungus Botrysphaeria laricina isolated from the moss Rhodobryum umgiganteum. The structures of the new compounds were elucidated based on extensive spectroscopic techniques including HRMS and 1D and 2D NMR measurements. The absolute configuration of compound 1 was determined by ECD calculation and it was the first example of a novel group of PKS-NRPS hybrids possessing an unprecedented methyldihydropyran-isobutylpyrrolidinone skeleton. Compounds 2, 7, and 8 showed significant quinone reductase inducing activity in Hepa 1c1c7 cells.


Assuntos
Ascomicetos/química , Produtos Biológicos/farmacologia , Terpenos/farmacologia , Animais , Produtos Biológicos/isolamento & purificação , Briófitas/microbiologia , Linhagem Celular Tumoral , China , Camundongos , Estrutura Molecular , Peptídeo Sintases/metabolismo , Policetídeo Sintases/metabolismo , Metabolismo Secundário , Terpenos/isolamento & purificação
9.
J Nat Prod ; 83(4): 1217-1228, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32159343

RESUMO

Environmental toxicant- and oxidant-induced [e.g., cigarette smoke (CS)] respiratory oxidative stress and inflammatory response play a vital role in the onset and progression of COPD. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents an important mechanism for regulating intracellular oxidative stress and inflammatory response and is a promising target for developing agents against COPD. Herein, a bioactivity-guided purification of goldenberry (whole fruits of Physalis peruviana L.) led to the isolation of a novel and potent Nrf2 activator 4ß-hydroxywithanolide E (4ß-HWE). Our study indicated that (i) 4ß-HWE activated the Nrf2-mediated defensive response through interrupting Nrf2-Keap1 protein-protein interaction (PPI) via modification of Cys151 and Cys288 cysteine residues in Keap1 and accordingly suppressing the ubiquitination of Nrf2. (ii) 4ß-HWE enhanced intracellular antioxidant capacity and inhibited oxidative stress in normal human lung epithelial Beas-2B cells and wild-type AB zebrafish. (iii) 4ß-HWE blocked LPS-stimulated inflammatory response and inhibited LPS-stimulated NF-κB activation in RAW 264.7 murine macrophages. (iv) 4ß-HWE effectively suppressed oxidative stress and inflammatory response in a CS-induced mice model of pulmonary injury. Collectively, these results display the feasibility of using 4ß-HWE to prevent or alleviate the pathological progression of COPD and suggest that 4ß-HWE is a candidate or a leading molecule against COPD.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Physalis/química , Vitanolídeos/farmacologia , Animais , Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Frutas , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Camundongos , Estrutura Molecular , Fator 2 Relacionado a NF-E2/química , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fumaça , Tabaco , Vitanolídeos/química , Vitanolídeos/isolamento & purificação
10.
J Pharm Pharmacol ; 72(5): 649-669, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31826333

RESUMO

OBJECTIVES: Withanolides are a group of modified C28 ergostane-type steroids with a C-22, C-26 δ-lactone side chain or a C-23, C-26 γ-lactone side chain. They enjoy a limited distribution in the plant kingdom and predominantly occur in several genera of Solanaceae. Of which, the genus Physalis is an important resource for this type of natural molecules. The present review aims to comprehensively illustrate the structural characteristics and classification of withanolides, and particularly focus on the progression on phytochemical and pharmacological aspects of withanolides from Physalis ranging from January 2015 to June 2019. KEY FINDINGS: Approximately 351 natural withanolides with novel and unique structures have so far been identified from genus Physalis, mainly isolated from the species of P. angulata and P. peruviana. Withanolides demonstrated diverse biological activity, such as anticancer, anti-inflammatory, antimicrobial, immunoregulatory, trypanocidal and leishmanicidal activity. Their observed pharmacological functions supported the uses of Physalis species in traditional or folk medicines. SUMMARY: Due to their unique structure skeleton and potent bioactivities, withanolides are regarded to be promising drug candidates, particularly for developing anticancer and anti-inflammatory agents. Further investigations for discovering novel withanolides of genus Physalis, exploiting their pharmacological values and evaluating their potency as therapeutic agents are significant work.


Assuntos
Physalis/química , Vitanolídeos/química , Vitanolídeos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Hipoglicemiantes/farmacologia , Extratos Vegetais/química , Extratos Vegetais/classificação , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Plantas Medicinais/classificação , Tripanossomicidas/farmacologia , Vitanolídeos/análise , Vitanolídeos/classificação
11.
Free Radic Biol Med ; 152: 525-539, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31760092

RESUMO

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease resulted from airflow obstructions, and there is a driving requirement for novel and effective preventive and therapeutic agents of COPD. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been regarded to be a promising therapeutic target for COPD. Resveratrol is a natural Nrf2 activator with antioxidant and anti-inflammatory properties, however, its application is limited by its relative low efficiency and poor bioavailability. Herein, based on the skeleton of resveratrol, trans-4,4'-dihydroxystilbene (DHS) has been firstly identified to be an Nrf2 activator, which is more potent than the well-known sulforaphane (SF) and resveratrol. Our results indicate that DHS blocks Nrf2 ubiquitylation through specifically reacting with Cys151 cysteine in Keap1 protein to activate Nrf2-regulated defensive response, and thus enhances intracellular antioxidant capability. Furthermore, DHS relieves lipopolysaccharide (LPS)-stimulated inflammatory response via inhibition of NF-κB. Importantly, DHS significantly ameliorates pathological alterations (e.g. infiltration of leukocytes and fibrosis), downregulates the levels of oxidant biomarkers malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2'-deoxyguanosin (8-oxo-dG), and inhibits the overproductions of inflammatory mediators [e.g. tumor necrosis factor α (TNF-α), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9)] in a cigarette smoke (CS)-induced pulmonary impairment mice model. Taken together, this study demonstrates that DHS attenuates the CS-induced pulmonary impairments through inhibitions of oxidative stress and inflammatory response targeting Nrf2 and NF-κB in vitro and in vivo, and could be developed into a preventive agent against pulmonary impairments induced by CS.


Assuntos
Fator 2 Relacionado a NF-E2 , Doença Pulmonar Obstrutiva Crônica , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Pulmão/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fumar/efeitos adversos , Estilbenos
12.
Nat Prod Res ; 34(15): 2179-2185, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30835548

RESUMO

One new pentanortriterpenoid, 23,24,25,26,27-pentanorlanost-7,9(11)-dien-3ß,22-diol (1), one new triterpenoid, lanost-8-en-3ß,22S,23S-triol (2), together with the known triterpenoid, 23,24,25,26,27-pentanorlanost-8-en-3ß,22-diol (3), were obtained from culture of the fungus Diplodia cupressi associated with the moss Polytrichum commune. The structures of the new compounds were elucidated by extensive spectroscopic techniques including HR-ESIMS and 1 D and 2 D NMR experiments. The cytotoxicity of these compounds against human cancer cell lines (A549, Hep G2, Hepa 1c1c7, and Hela) was evaluated and compound 2 exhibited weak inhibitory activity with IC50 value of 35.0 ± 2.3 µM against the proliferation of the Hepa 1c1c7 cells.


Assuntos
Fungos/química , Triterpenos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Triterpenos/química , Triterpenos/toxicidade
13.
Biochem Biophys Res Commun ; 518(3): 526-532, 2019 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-31445708

RESUMO

Oxidative stress is one of the main pathogenesis for many human diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays a key role in regulating intracellular antioxidant responses, and thus activation of Nrf2/ARE signaling pathway is a potential chemopreventive or therapeutic strategy to treat diseases caused by oxidative damage. In the present study, we have found that treatment of Beas-2B cells with botrysphins D (BD) attenuated sodium arsenite [As (III)]-induced cell death and apoptosis. Meanwhile, BD was able to upregulate protein levels of Nrf2 and its downstream genes NQO1 and γ-GCS through inducing Nrf2 nuclear translocation, enhancing protein stability, and inhibiting ubiquitination. It was also found that BD-induced activation of the Nrf2/ARE pathway was regulated by PI3K, MEK1/2, PKC, and PERK kinases. Collectively, BD is a novel activator of Nrf2/ARE pathway, and is verified to be a potential preventive agent against oxidative stress-induced damage in human lung tissues.


Assuntos
Antioxidantes/farmacologia , Arsenitos/toxicidade , Diterpenos/farmacologia , Células Epiteliais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sódio/toxicidade , Elementos de Resposta Antioxidante/efeitos dos fármacos , Antioxidantes/química , Arsênio/toxicidade , Ascomicetos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Diterpenos/química , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
Chem Biol Interact ; 310: 108741, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299238

RESUMO

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in redox homeostasis. Activation of Nrf2 pathway by natural molecules effectively inhibits oxidants and toxicants-induced redox imbalance, and thus is able to intervene the onset and progression of many human diseases. In our previous study, a chalcone named as artocarmitin B (ACB), formed by artocarmitin A (ACA) and a trans-feruloyl substituent, was found to be a potential Nrf2 activator. In the present research, we found that ACB up-regulated the expressions of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase, modifier subunit (GCLM), inhibited Nrf2 degradation and promoted Nrf2 translocation to the nucleus under non-toxic doses. Moreover, ACB enhanced intracellular antioxidant capability in human lung epithelial cells through up-regulating reduced glutathione (GSH) level. Furthermore, ACB-induced activation of Nrf2 was related to the kinase pathways, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and protein kinase R-like endoplasmic reticulum kinase (PERK). In terms of activation of Nrf2 pathway, ACB was more potent than ACA and ferulic acid (FA) individually or in combination. Collectively, our results indicate that ACB is an novel Nrf2 activator and enhances intracellular antioxidant capacity in human lung epithelial cells.


Assuntos
Antioxidantes/farmacologia , Chalcona/farmacologia , Células Epiteliais/metabolismo , Pulmão/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Chalcona/uso terapêutico , Glutationa/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Transdução de Sinais
15.
Free Radic Biol Med ; 141: 21-33, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167117

RESUMO

Oxidative stress is involved in the onset and progression of many human diseases. Activators of the Keap1/Nrf2/ARE pathway effectively inhibit the progression of oxidative stress-induced diseases. Herein, a small library of diterpenoids was established by means of phytochemical isolation, and chemical modification on naturally occurring molecules. The diterpenoids were subjected to a NAD(P)H: quinone reductase (QR) assay to evaluate its potential inhibition against oxidative stress. Sixteen diterpenoids were found to be novel potential activators of Nrf2-mediated defensive response. Of which, an isopimarane-type diterpenoid, sphaeropsidin A (SA), was identified as a potent activator of the Keap1/Nrf2/ARE pathway, and displayed approximately 5-folds potency than that of sulforaphane (SF). SA activated Nrf2 and its downstream cytoprotective genes through enhancing the stabilization of Nrf2 in a process involving PI3K, PKC, and PERK, as well as potentially interrupting Nrf2-Keap1 protein-protein interaction. In addition, SA conferred protection against sodium arsenite [As(III)]- and cigarette smoke extract (CSE)-induced redox imbalance and cytotoxicity in human lung epithelial cells, as wells as inhibited metronidazole (MTZ)-induced oxidative insult in Tg (krt4: NTR-hKikGR)cy17 transgenic zebrafish and lipopolysaccharide (LPS)-induced oxidative damage in wild-type AB zebrafish. These results imply that SA is a lead compound for therapeutic agent against oxidative stress-induced diseases, and diterpenoid is a good resource for discovering drug candidates and leads of antioxidant therapy.


Assuntos
Elementos de Resposta Antioxidante , Diterpenos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Animais , Antioxidantes/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Homeostase , Neoplasias Hepáticas/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Oxirredução , Oxigênio/química , Poluição por Fumaça de Tabaco , Peixe-Zebra
16.
Free Radic Res ; 53(3): 348-358, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30773942

RESUMO

The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in regulating the intracellular oxidative stress, and thus activation of Nrf2 by nature-derived molecules effectively alleviates the pathological process of oxidative stress-induced chronic diseases. The isopentenyl-substituted flavonoid norartocarpin (NOR) induced the activity of NAD(P)H: quinone reductase (QR), implying that it might be a potential Nrf2 activator. Further studies indicated that NOR upregulated the protein levels of Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO1), and γ-glutamyl cysteine synthetase (GCLM) through facilitating the nuclear translocation of Nrf2 and enhancing Nrf2 protein stability. NOR-induced activation of Nrf2 pathway was associated with multiple upstream kinases, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase C (PKC), and protein kinase R-like endoplasmic reticulum kinase (PERK). Moreover, NOR protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Collectively, NOR was firstly identified to be an Nrf2 activator, which demonstrated the capability of preventing oxidative insults in human lung epithelial cells.


Assuntos
Células Epiteliais/metabolismo , Flavonoides/uso terapêutico , Pulmão/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Flavonoides/farmacologia , Humanos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais
17.
Phytomedicine ; 53: 143-153, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668393

RESUMO

BACKGROUND: Oxidative stress contributes to the pathogenesis of many human diseases. Cinnamon is a worldwide used spice, dietary supplement and traditional medicine, and is used for the therapy of oxidative stress related diseases. A well-established concept is that the functions of cinnamon preventing oxidative stress-induced diseases are attributed to the occurrence of cinnamaldehyde and its analogues. HYPOTHESIS: In our continuous searching of natural molecules with antioxidant capacity, we have found that cinnamaldehyde and its analogues in cinnamon are weak inhibitors of oxidative stress, and thus we speculate that there are novel and/or potent molecules inhibiting oxidative stress in cinnamon. STUDY DESIGN AND METHODS: A systemic phytochemical investigation of cinnamon using column chromatography was performed to identify the chemical constituents of cinnamon, and then their capacity of inhibiting oxidative stress and action of mechanism targeting Nrf2 pathway were investigated using diverse bioassay, including NAD(P)H: quinone reductase (QR) assay, immunoblot analysis, luciferase reporter gene assay, immunofluorescence and flow cytometry. RESULTS: Cinnamon improved the intracellular antioxidant capacity. A systemic phytochemical investigation of cinnamon gave the isolation of twenty-two chemical ingredients. The purified constituents were tested for their potential inhibitory effects against oxidative stress. Besides cinnamaldehyde analogues, a lignan pinoresinol (PRO) and a flavonol (-)-(2R,3R)-5,7-dimethoxy-3', 4'-methylenedioxy-flavan-3-ol (MFO) were firstly identified to be inhibitors of oxidative stress. Further study indicated that PRO and MFO activated Nrf2-mediated antioxidant response, and protected human lung epithelial cells against sodium arsenite [As(III)]-induced oxidative insults. CONCLUSION: The lignan PRO and the flavonoid MFO are two novel Nrf2 activators protecting tissues against oxidative insults, and these two constituents support the application of cinnamon as an agent against oxidative stress related diseases.


Assuntos
Antioxidantes/farmacologia , Cinnamomum zeylanicum/química , Flavonoides/farmacologia , Lignanas/farmacologia , Acroleína/análogos & derivados , Animais , Arsenitos/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Flavonoides/química , Furanos/farmacologia , Humanos , Lignanas/química , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Compostos de Sódio/toxicidade
18.
J Ethnopharmacol ; 227: 166-175, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30176347

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Rhizome of Ligusticum chuanxiong Hort. (Abbreviated as LC) is a frequently prescribed component in plenty of traditional Chinese medicine (TCM) formulas which are used to treat diabetic nephropathy (DN). The aims of the present study are to investigate the protective effect of the ethanol extract of LC rhizome (EEL) against DN in vivo, evaluate its potential mechanism, and find the evidence supporting its enthopharmacological use as an anti-DN agent. MATERIALS AND METHODS: Hepa 1c1c7 murine hepatoma cells, human breast carcinoma MDA-MB-231 cells, human renal glomerular endothelial cells (HRGEC), and RAW 264.7 murine macrophages were adopted to test the effects of EEL and its active constituents on inhibitions of oxidative stress and inflammation in vitro. A streptozotocin (STZ) -induced DN C57BL/6 mice model was established and used to investigate the preventive effect of EEL against DN in vivo. RESULTS: EEL demonstrated potential inhibitory effects against oxidative stress and inflammation in vitro. Using a STZ-induced DN mice model, it has been found that EEL treatment significantly prevented STZ-induced increases of urine production, urinary albumin excretion (UAE) and urine albumin-to-creatinine ratio (UACR), and markedly attenuated STZ-induced renal damages (e.g. glomerulosclerosis and fibrosis). The predominant bioactive constituents, Z-ligustilide (LGT), ferulic acid (FA), and tetramethylpyrazine (TMP), were inhibitors of oxidative stress and inflammation through acting with Nrf2 and NF-κB pathways. CONCLUSIONS: EEL attenuates structural and functional damages of kidney in STZ-induced DN model in vivo, which might be related to the functions of EEL on inhibitions of oxidative stress and inflammation. These finding definitely supports the ethnopharmacological use of LC as an anti-DN agent.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ligusticum , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Rizoma
19.
Bioorg Med Chem ; 26(18): 5140-5150, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30227999

RESUMO

Continuous overproduction of reactive oxygen species (ROS), termed as oxidative stress, plays a crucial role in the onset and progression of many human diseases. Activation of nuclear transcription factor erythroid 2-related factor (Nrf2) by small molecules could eliminate ROS, and thus block the pathogenesis of oxidative stress-induced diseases. In this study, a natural flavonoid library was established and tested for their potential Nrf2 inducing effects. Based on QR inducing effect of flavonoids, their structure-activity relationship (SAR) on Nrf2 induction was summarized, and twenty flavonoids were firstly identified to be potential activators of Nrf2-mediated defensive response. Then, 7-O-methylbiochanin A (7-MBA) was further investigated for its capability on the Nrf2 activation and prevention against oxidative insults in human lung epithelial cells. Further studies indicated that 7-MBA activated Nrf2 signaling pathway and protected human lung epithelial Beas-2B cells against sodium arsenite [As(III)]-induced cytotoxicity in an Nrf2-dependent manner. Activation of Nrf2 by 7-MBA upregulated intracellular antioxidant capacity, which was produced by enhancement of Nrf2 stabilization, blockage of Nrf2 ubiquitination, as well as Nrf2 phosphorylation by mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Taken together, 7-MBA is a novel isoflavone-type Nrf2 activator displaying potential preventive effect against oxidative damages in human lung epithelial cells.


Assuntos
Produtos Biológicos/farmacologia , Descoberta de Drogas , Células Epiteliais/efeitos dos fármacos , Flavonoides/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Arsênio/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Flavonoides/síntese química , Flavonoides/química , Humanos , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Relação Estrutura-Atividade
20.
Vascul Pharmacol ; 109: 72-82, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29902531

RESUMO

Excess intracellular reactive oxygen species (ROS) production is a significant causative factor of many diseases, exemplified by vascular diseases. Mitochondria are a major source of endogenous ROS, which simultaneously induce mitochondrial dysfunction. Nuclear factor-erythroid 2-related factor 2 (Nrf2) represents an important intracellular defense system that protects cells against oxidative insults caused by ROS. Therefore, molecules with the capacities of inducing Nrf2, and preventing mitochondrial dysfunction can inhibit cell apoptosis, and thus are potential drug candidates for the therapy of ROS-mediated vascular diseases. Homoeriodictyol (HE), previously isolated from Viscum articulatum Burm, has been found to be an Nrf2 inducer. In the present study, we investigated its protection on ROS-induced endothelial cell injury using a H2O2-induced human umbilical vein EA.hy926 cell oxidative insult model. Our results indicated that HE activated Nrf2 signaling pathway and protected cells against H2O2-induced cell damage. HE alleviated H2O2-induced loss of mitochondrial membrane potential (MMP), blocked the releases of cytochrome C and apoptosis inducing factor (AIF) from mitochondria, and thus inhibited mitochondria-mediated cell apoptosis. Furthermore, HE inhibited H2O2-induced changes of apoptosis-related proteins, such as Bcl-2, Bcl-xL, caspases -3, -9 and PARP. Further study demonstrated that the protection of HE against H2O2-induced endothelial cell damage was Nrf2-dependent. Collectively, our observations suggest that HE is capable of counteracting oxidative insults in endothelial cells, and has a potential to be a therapeutic agent against ROS-mediated vascular diseases.


Assuntos
Antioxidantes/farmacologia , Flavonas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Peróxido de Hidrogênio/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Oxidantes/toxicidade , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
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