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1.
Biomed Res Int ; 2021: 5561221, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414236

RESUMO

Brucea javanica oil (BJO) is beneficial for the treatment of ulcerative colitis (UC), and that quassinoids in particular brusatol are bioactive components. However, it is still uncertain whether or not other components in BJO, such as oleic acid and fatty acids, have an anti-UC effect. The present study is aimed at comparing the anti-UC effects between brusatol-enriched BJO (BE-BJO) and brusatol-free BJO (BF-BJO) and at exploring the effects and mechanisms of BE-BJO on colon inflammation and intestinal epithelial barrier function. Balb/C mice received 3% (wt/vol) DSS for one week to establish the UC model. Different doses of BE-BJO, BF-BJO, or BJO were treated. The result illustrated that BE-BJO alleviated DSS-induced loss of body weight, an increase of disease activity index (DAI), and a shortening of colon, whereas BF-BJO did not have these protective effects. BE-BJO treatment improved the morphology of colon tissue, inhibited the production and release of TNF-α, IFN-γ, IL-6, and IL-1ß in the colon tissue, and reversed the decreased expressions of ZO-1, occludin, claudin-1, and E-cadherin induced by DSS but augmented claudin-2 expression. Mechanistically, BE-BJO repressed phosphorylation of NF-κB subunit p65, suppressed RhoA activation, downregulated ROCK, and prevented phosphorylation of myosin light chain (MLC) in DSS-treated mice, indicating that the protective effect of BE-BJO is attributed to suppression of NF-κB and RhoA/ROCK signaling pathways. These findings confirm that brusatol is an active component from BJO in the treatment of UC.


Assuntos
Brucea/química , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Óleos Vegetais/administração & dosagem , Quassinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Óleos Vegetais/química , Óleos Vegetais/farmacologia , Quassinas/farmacologia , Resultado do Tratamento , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
2.
Chin J Nat Med ; 19(8): 608-620, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34419260

RESUMO

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3ß was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.


Assuntos
Apoptose , Brucea , Óleos Vegetais/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Brucea/química , Quinase 3 da Glicogênio Sintase , Humanos , Células Jurkat , Camundongos , Fosfatidilinositol 3-Quinases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Sementes/química , Transdução de Sinais
3.
Fitoterapia ; 153: 104980, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34186115

RESUMO

Four new quassinoids (1-4) and twenty known analogues (5-24) were isolated from the seeds of Brucea javanica. All the compounds belong to tetracyclic quassinoids. The structures of the new compounds were elucidated by comprehensive spectroscopic analysis, including HRESIMS and 1D, 2D NMR. In in vitro bioassays, (5-9, 17-19 and 23) showed inhibitory activities for nitric oxide (NO) release in LPS-activated MH-S macrophages and IC50 values of 0.11-45.56 µM. Among them, bruceoside B significantly decreased LPS-induced NO, secretion of inflammatory factor cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß). Western Blot was used to verify the expression of p-IκB-α, IκB-α, p-NF-κB, NF-κB, Bax, Bcl-2, Caspase-3, p-PI3K, PI3K, p-Akt, and Akt proteins in PI3K/Akt/NF-κB signal pathway. Bruceoside B inhibited the activity of Akt and its downstream pathways and reduced the activation of apoptotic. In vivo, it was found that bruceoside B had obvious therapeutic effect on LPS-induced acute lung injury (ALI) in mice, and the effect of tissue section was obvious. The regulatory signal pathway of bruceoside B on inflammation was consistent with the anti-inflammatory pathway in vitro. Therefore, the results implied that bruceoside B has a certain therapeutic effect on inflammation and has a certainly effect on acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Brucea/química , Quassinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , China , Citocinas/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quassinas/isolamento & purificação , Sementes/química
4.
In Vivo ; 35(3): 1437-1441, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33910820

RESUMO

BACKGROUND/AIM: Small-cell lung cancer (SCLC) is a recalcitrant disease with liver and other metastasis. The present study evaluated the efficacy of the traditional Chinese medicine Brucea javanica oil (BJO) combined with anlotinib, a multi-tyrosine kinase inhibitor with anti-angiogenic activity, on a nude-mouse model of SCLC liver metastasis. MATERIALS AND METHODS: The mouse model was established by injecting NCI-H446 cells (1×106) in Matrigel (20 µl) into the upper liver lobe. All animals were randomized and assigned to three groups: Control (n=8); anlotinib alone (n=8; 3 mg/kg, qd×14+7-day interval with two cycles, oral); anlotinib plus BJO (n=8; 3 mg/kg anlotinib qd×14+7-day interval with two cycles, orally; BJO: 1 g/kg, qd×6 weeks, orally). Body weight was determined every week. Six weeks after initial treatment, tumors were collected for analysis of angiogenesis using immunohistochemistry. RESULTS: The combination of anlotinib and BJO significantly inhibited growth of SCLC liver metastases and angiogenesis more than anlotinib monotherapy (p=0.043). In addition, BJO alleviated body-weight loss associated with anlotinib therapy, including general mouse condition. CONCLUSION: The results of the present study indicate that the combination of anlotinib with BJO is promisingly active against liver metastases of SCLC, and has clinical potential.


Assuntos
Brucea , Neoplasias Hepáticas , Neoplasias Pulmonares , Animais , Indóis , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medicina Tradicional Chinesa , Camundongos , Camundongos Nus , Óleos Vegetais , Quinolinas
5.
Phytomedicine ; 86: 153560, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33858739

RESUMO

BACKGROUND: The dried fruits of Brucea javanica (L.) Merr (BJ) is being widely investigated, both in lab and in clinic, to explore its potential anticancer activity and molecular mechanism involved. PURPOSE: We appraised the available literature and suggested the future research directions to improve the medicinal value of BJ. METHOD: In this review, we have summarized the scientific findings from experimental and clinical studies regarding the anticancer activity and mechanisms. RESULTS: Numerous studies have reported that BJ exerts anticancer effect on various types of cancer lines through inhibiting cell proliferation, inducing apoptosis, inhibiting migration/invasion, inducing autophagy and restraining angiogenesis. Brucea javanica triggers the generation of reactive oxygen species (ROS), release of cytochrome C, activation of mitochondrial apoptosis pathway and regulation of a series of signal pathways and proteins related to cancer. The molecular mechanism involved are inhibiting the PI3K/Akt/mTOR, NF-κB and Nrf2-Notch1 pathways; up or down modulating the levels of p53, p62, p21, Bax, and Bcl-2 respectively, and inhibiting the expression of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). Brucea javanica's efficacy in treating cancer patients either as a main or supportive treatment is also discussed in this review. CONCLUSION: This review will serve as a comprehensive resource of BJ's potential as anticancer agent and its molecular pathways. The analysis of the literature suggests that BJ can serve as a potential candidate for the treatment of cancer.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Brucea/química , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Frutas/química , Humanos , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
6.
Biomed Res Int ; 2021: 6631533, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816622

RESUMO

Endometrial cancer (EC) is a common gynecological malignancy worldwide whose therapy mainly depends on chemotherapy. In past years, an increasing number of studies indicate that hollow MnO2 could serve as a nanoplatform in the drug delivery system. The Brucea javanica oil emulsion (BJOE) has been illustrated to play a vital role in cancers. However, knowledge about the combined effect of H-MnO2-PEG/BJOE in endometrial cancer remains ambiguous up to now. In the present work, we prepared a drug-delivery vector H-MnO2-PEG by chemical synthesis and found that H-MnO2-PEG significantly inhibited cell proliferation in endometrial cancer cells. Moreover, the combination of H-MnO2-PEG/BJOE could repress cell proliferation more efficiently and promote cell apoptosis. Mechanistically, we found that BJOE exerted its role as a promoter of endometrial apoptosis by regulating relative protein expressions. In general, the present study demonstrates that H-MnO2-PEG functions as a critical vector in the tumor microenvironment of endometrial cancer and the significant effect of H-MnO2-PEG/BJOE on cancer cells, suggesting a new paradigm for the treatment of endometrial cancer.


Assuntos
Apoptose/efeitos dos fármacos , Brucea/química , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio , Compostos de Manganês , Óxidos , Óleos Vegetais , Linhagem Celular Tumoral , Emulsões , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Óxidos/química , Óxidos/farmacologia , Óleos Vegetais/química , Óleos Vegetais/farmacologia
7.
Toxicology ; 451: 152680, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33465425

RESUMO

Brusatol occurs as a characteristic bioactive principle of Brucea javanica (L.) Merr., a traditional medicinal herb frequently employed to tackle cancer in China. This work endeavored to unravel the potential anti-cancer activity and action mechanism of brusatol against non-small cell lung cancer (NSCLC) cell lines. The findings indicated that brusatol remarkably inhibited the growth of wild-type NSCLC cell lines (A549 and H1650) and epidermal growth factor receptor-mutant cell lines (PC9 and HCC827) in a dose- and time-related fashion, and profoundly inhibited the clonogenic capability and migratory capacity of PC9 cells. Treatment with brusatol resulted in significant apoptosis in PC9 cells, as evidenced by Hoechst 33342 staining and flow cytometric analysis. The apoptotic effect was closely related to induction of G0-G1 cell cycle arrest, stimulation of reactive oxygen species (ROS) and malondialdehyde, decrease of glutathione levels and disruption of mitochondrial membrane potential. Furthermore, pretreatment with N-acetylcysteine, a typical ROS scavenger, markedly ameliorated the brusatol-induced inhibition of PC9 cells. Western blotting assay indicated that brusatol pronouncedly suppressed the expression levels of mitochondrial apoptotic pathway-associated proteins Bcl-2 and Bcl-xl, accentuated the expression of Bax and Bak, and upregulated the protein expression of XIAP, cleaved caspase-3/pro caspase-3, cleaved caspase-8/pro caspase-8, and cleaved PARP/total PARP. In addition, brusatol significantly suppressed the expression of Nrf2 and HO-1, and abrogated tBHQ-induced Nrf2 activation. Combinational administration of brusatol with four chemotherapeutic agents exhibited marked synergetic effect on PC9 cells. Together, the inhibition of PC9 cells proliferation by brusatol might be intimately associated with the modulation of ROS-mediated mitochondrial-dependent pathway and inhibition of Nrf2-mediated antioxidant response. This novel insight might provide further evidence to buttress the antineoplastic efficacy of B. javanica, and support a role for brusatol as a promising anti-cancer candidate or adjuvant to current chemotherapeutic medication in the therapy of EGFR-mutant NSCLC.


Assuntos
Antioxidantes/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Quassinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Brucea , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores
8.
Nat Prod Res ; 35(12): 2037-2043, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31434501

RESUMO

The chemical investigation of the root barks leaves and stem barks of Brucea antidysenterica J. F. Mill. (Simaroubaceae) led to the isolation of a new pregnane glycoside, named Bruceadysentoside A or 3-O-ß-L-arabinopyranosyl-pregn-5-en-20-one (1) together with seventeen known compounds. Their structures were established from spectral data, mainly HRESIMS, 1 D and 2 D NMR and by comparison with literature data. Compounds 1, 2, 5, 6, 8, 10, 12 and 13 were tested in vitro for their effects on the viability of two different human cancer cell lines, namely prostate PC-3 adenocarcinoma cells and colorectal HT-29 adenocarcinoma cells. No substantial activities were recorded for 2, 10, 12 and 13 (up to 10 µM concentration). 1, 5 and 8 did not show strong anti-proliferative effects up to 100 µM, however, 6 exhibited a stronger anti-proliferative effect with IC50 values of ∼ 100 µM against PC-3 and ∼ 200 µM against HT-29.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Brucea/metabolismo , Brucea/química , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Células HT29 , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Células PC-3 , Extratos Vegetais/química , Folhas de Planta/química , Pregnanos/química , Metabolismo Secundário , Espectrometria de Massas por Ionização por Electrospray
9.
Biomed Pharmacother ; 134: 111122, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33341052

RESUMO

Brucea javanica oil (BJO), one of the main products of Brucea javanica, has been widely used in treating different kinds of malignant tumors. Quassinoids are the major category of anticancer phytochemicals of B. javanica. However, current researches on the anti-cancer effect of BJO mainly focused on oleic acid and linoleic acid, the common major components of dietary edible oils, essential and characteristic components of B. javanica like quassinoids potentially involved remained unexplored. In the current investigation, we developed an efficient HPLC method to detect brusatol, a characteristic quassinoid, and comparatively scrutinized the anti-hepatocellular carcinoma (anti-HCC) effect of BJO, brusatol-free BJO (BF-BJO), and brusatol-enriched BJO (BE-BJO) against hepatoma 22 (H22) in mice. High-performance liquid chromatography (HPLC) was utilized to identify the components in BJO. BE-BJO was extracted with 95 % ethanol. The anti-tumor effect of BJO, BF-BJO and BE-BJO was comparatively investigated, and the potential underlying mechanism was explored in H22 ascites tumor-bearing mice. The results indicated that BJO and BE-BJO significantly prolonged the survival time of H22 ascites tumor-bearing mice, while BF-BJO exhibited no obvious effect. BJO and BE-BJO exhibited pronounced anti-HCC activity by suppressing the growth of implanted hepatoma H22 in mice, including ascending weight, abdominal circumference, ascites volume and cancer cell viability, with a relatively wide margin of safety. BJO and BE-BJO significantly induced H22 cell apoptosis by upregulating the miRNA-29b gene level and p53 expression. Furthermore, BJO and BE-BJO treatment substantially downregulated Bcl-2 and mitochondrial Cytochrome C protein expression, and upregulated expression levels of Bax, Bad, cytosol Cytochrome C, caspase-3 (cleaved), caspase­9 (cleaved), PARP and PARP (cleaved) to induce H22 cells apoptosis. Brusatol was detected in BJO and found to be one of its major active anti-HCC components, rather than fatty acids including oleic acid and linoleic acid. The anti-HCC effect of BJO and BE-BJO was intimately associated with the activation of miRNA-29b, p53-associated apoptosis and mitochondrial-related pathways. Our study gained novel insight into the material basis of BJO in the treatment of HCC, and laid a foundation for a novel specific standard for the quality evaluation of BJO and its commercial products in terms of its anti-cancer application.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Brucea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Óleos Vegetais/farmacologia , Quassinas/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Brucea/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Óleos Vegetais/isolamento & purificação , Quassinas/isolamento & purificação , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Medicine (Baltimore) ; 99(47): e23197, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217831

RESUMO

BACKGROUND: Brucea javanica oil emulsion (BJOE), extracted from the Chinese herb Bruceae Fructus (Yadanzi), is a broad-spectrum anti-tumor drug and has been widely used for the treatment of liver cancer in China. The aim of this study is to systematically investigate the efficacy and safety of BJOE for the treatment of liver cancer. METHODS: Seven electronic databases including the Cochrane Library, PubMed, Excerpt Medica Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, China Scientific Journal Database, and Wanfang Database will be systematically retrieved for data extraction from their inceptions to September 2020. Cochrane Risk of Bias tool will be used to assess the risk of bias of included studies. The RevMan 5.4 and Stata 16.0 software will be applied for statistical analyses. Statistical heterogeneity will be computed by I tests. Sensitivity analysis will be conducted to evaluate the stability of the results. The publication bias will be evaluated by funnel plots and Egger test. The quality of evidence will be assessed by the GRADE system. RESULTS: The results of our research will be published in a peer-reviewed journal or presenting the findings at a relevant conference. CONCLUSION: The conclusion of this study will provide helpful evidence of the effect and safety of BJOE for the treatment of liver cancer in clinical practice. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/UC8XQ.


Assuntos
Antineoplásicos/uso terapêutico , Brucea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fitoterapia , Óleos Vegetais/uso terapêutico , Antineoplásicos/efeitos adversos , Emulsões/uso terapêutico , Humanos , Metanálise como Assunto , Fitoterapia/efeitos adversos , Óleos Vegetais/efeitos adversos , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
11.
Molecules ; 25(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228061

RESUMO

Brucea javanica oil (BJO) is widely used in traditional Chinese medicine to treat various types of cancer and inflammatory diseases. There is significant interest in understanding the medicinal activities of BJO and its molecular components, especially quassinoids, and in exploring how they can be incorporated into nanomedicine delivery strategies for improved application prospects. Herein, we cover the latest progress in developing different classes of drug delivery vehicles, including nanoemulsions, liposomes, nanostructured lipid carriers, and spongosomes, to encapsulate BJO and purified quassinoids. An introduction to the composition and medicinal activities of BJO and its molecular components, including quassinoids and fatty acids, is first provided. Application examples involving each type of drug delivery vehicle are then critically presented. Future opportunities for nanomedicine delivery strategies in the field are also discussed and considered within the context of translational medicine needs and drug development processes.


Assuntos
Brucea/química , Sistemas de Liberação de Medicamentos , Nanomedicina , Óleos Vegetais/uso terapêutico , Animais , Portadores de Fármacos/química , Humanos , Lipídeos/química , Óleos Vegetais/química , Óleos Vegetais/farmacologia
12.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Oxid Med Cell Longev ; 2020: 9867595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765809

RESUMO

The HER2-targeting antibody trastuzumab has shown effectiveness in treating HER2-positive breast and gastric cancers; however, its responses are limited. Currently, Nrf2 has been deemed as a key transcription factor in promoting cancer progression and resistance by crosstalk with other proliferative signaling pathways. Brusatol as a novel Nrf2 inhibitor has been deemed as an efficacious and safe drug candidate in cancer therapy. In this study, we firstly reported that brusatol exerted the growth-inhibitory effects on HER2-positive cancer cells by regressing Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways in these cells. More importantly, we found that brusatol synergistically enhanced the antitumor activity of trastuzumab against HER2-positive SK-OV-3 and BT-474 cells, which may be attributed to the inhibition of Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways. Furthermore, the synergistic effects were also observed in BT-474 and SK-OV-3 tumor xenografts. In addition, our results showed that trastuzumab markedly enhanced brusatol-induced ROS accumulation and apoptosis level, which could further explain the synergistic effects. To conclude, the study provided a new insight on exploring Nrf2 inhibition in combination with HER2-targeted trastuzumab as a potential clinical treatment regimen in treating HER2-positive cancers.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Brucea/química , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quassinas/uso terapêutico , Trastuzumab/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quassinas/farmacologia , Transfecção , Trastuzumab/farmacologia
14.
Medicine (Baltimore) ; 99(27): e21155, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629751

RESUMO

BACKGROUND: Brucea javanica oil emulsion injection (BJOEI) has been widely applied as a promising adjunctive drug for colorectal carcinoma (CRC). However, the exact effects and safety of BJOEI remains controversial. In this study, we aimed to summarize the efficacy and safety of BJOEI for the treatment of advanced CRC through the meta-analysis, in order to provide scientific reference for the design of future clinical trials. METHODS: Eligible prospective controlled clinical trials were searched from PubMed, Cochrane Library, Google Scholar, Medline, Web of Science (WOS), Excerpt Medica Database (Embase), Chinese BioMedical Database (CBM), China Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI) and Wanfang Database. Papers in English or Chinese published from January 2000 to May 2020 will be included without any restrictions. The clinical outcomes including therapeutic effects, quality of life (QoL), immune function and adverse events, were systematically evaluated.Study selection and data extraction will be performed independently by 2 reviewers. Review Manager 5.3 and Stata 14.0 were used for data analysis, and a fixed or random-effect model will be used depending upon the heterogeneity observed between trials. Subgroup and meta-regression analysis will be carried out depending on the availability of sufficient data. RESULTS: The results of this systematic review will be published in a peer-reviewed journal. CONCLUSION: Our study will draw an objective conclusion of the effects and safety of BJOEI for advanced CRC, and provide a helpful evidence for clinicians to formulate the best postoperative adjuvant treatment strategy for CRC patients.INPLASY registration number: INPLASY202060014.


Assuntos
Brucea/efeitos adversos , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/tratamento farmacológico , Emulsões/administração & dosagem , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Colorretais/psicologia , Emulsões/uso terapêutico , Feminino , Humanos , Injeções/métodos , Masculino , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Resultado do Tratamento
15.
BMC Complement Med Ther ; 20(1): 174, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503508

RESUMO

BACKGROUND: Javanica oil emulsion injection (JOEI) is an effective therapeutic option for patients with non-small cell lung cancer (NSCLC), but its mechanisms have not been fully elucidated. METHODS: In this study, we utilized network pharmacology to systematically investigate the bioactive components and targets of JOEI, identify common targets in NSCLC, and understand and evaluate the underlying mechanism of JOEI in the treatment of NSCLC through expression level, correlation, enrichment, Cox, survival and molecular docking analyses. The results indicated that five compounds of JOEI interact with five pivotal targets (LDLR, FABP4, ABCB1, PTGS2, and SDC4) that might be strongly correlated with the JOEI-mediated treatment of NSCLC. RESULTS: The expression level analysis demonstrated that NSCLC tissues exhibit low expression of FABP4, ABCB1, LDLR and PTGS2 and high SDC4 expression. According to the correlation analysis, a decrease in FABP4 expression was strongly correlated with decreases in LDLR and ABCB1, and a decrease in LDLR was strongly correlated with decreased PTGS2 and increased in SDC4 expression. Cox and survival analyses showed that the survival rate of the high-risk group was significantly lower than that of the low-risk group (p = 0.00388). In the survival analysis, the area under the curve (AUC) showed that the pivotal gene model exhibited the best predictive capacity over 4 years (AUC = 0.613). Moreover, the molecular docking analysis indicated that LDLR, FABP4, ABCB1, PTGS2 and SDC4 exhibit good binding activity with the corresponding compounds. CONCLUSION: In conclusion, this study predicted and verified that the mechanism of JOEI against NSCLC involves multiple targets and signaling pathways. Furthermore, this study provides candidate targets for the treatment of NSCLC, lays a good foundation for further experimental research and promotes the reasonable application of JOEI in clinical treatment.


Assuntos
Brucea/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Emulsões , Humanos , Injeções , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Mapeamento de Interação de Proteínas
16.
J Nat Med ; 74(3): 599-605, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279206

RESUMO

Two novel norquassinoids possessing a unique ketal skeleton, designated quassilactones A (1) and B (2), were isolated from the fruits of Brucea javanica (Simaroubaceae). Their structures were established by extensive NMR and HR-ESI-MS spectroscopic analysis. The absolute configuration of 1 was determined through single-crystal X-ray crystallography, and that of 2 was assigned by comparing the calculated electronic and experimental circular dichroism with compound 1. In addition, their cytotoxic activities against three human cancer cell lines and their antimicrobial activities were evaluated.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Brucea/química , Quassinas/química , Quassinas/farmacologia , Antibacterianos/química , Antineoplásicos/química , Linhagem Celular , Cristalografia por Raios X , Frutas/química , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia
17.
Nat Prod Res ; 34(8): 1186-1191, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30618292

RESUMO

An investigation on seeds of Brucea javanica led to the acquisition of a new quassinoid, 20-hydroxyyadanzigan (1), along with five known quassinoids (2-6). The structure of the new compound was elucidated on the basis of extensive spectral analysis. All of the compounds were assayed for their anticomplement activities through classical and alternative pathways. Compounds 1-6 exhibited potent anticomplement activity with CH50 and AP50 values of 0.032-0.075 mg/mL and 0.061-0.118 mg/mL, respectively. Moreover, the structure-activity relationships of these compounds are discussed.[Formula: see text].


Assuntos
Brucea/química , Proteínas Inativadoras do Complemento/farmacologia , Quassinas/isolamento & purificação , Sementes/química , Estrutura Molecular , Extratos Vegetais/química , Relação Estrutura-Atividade
18.
Molecules ; 24(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816856

RESUMO

A phytochemical study of the root and bark of Brucea antidysenterica J. F. Mill. (Simaroubaceae) afforded three new compounds, including a stilbene glycoside bruceanoside A (1), and two canthinone alkaloids bruceacanthinones A (3) and B (4), along with ten known secondary metabolites, rhaponticin (2), 1,11-dimethoxycanthin-6-one (5), canthin-6-one (6), 1-methoxycanthin-6-one (7), 2-methoxycanthin-6-one (8), 2-hydroxy-1,11-dimethoxycanthin-6-one (9), ß-carboline-1-propionic acid (10), cleomiscosin C (11), cleomiscosin A (12), and hydnocarpin (13). The structures of all the compounds were determined using spectrometric and spectroscopic methods including 1D and 2D NMR, and HRSEIMS. The identities of the known compounds were further confirmed by comparison of their data with those reported in the literature. The root and bark methanolic extracts, the dichloromethane and ethyl acetate soluble fractions, and the isolated compounds (3-13), were assessed for their cytotoxicity against the cancer cell lines A-549, MCF-7, and PC-3. The results suggested that compounds in the extracts might possess a synergic action in their cytotoxicity.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Brucea/química , Medicamentos de Ervas Chinesas/farmacologia , Estilbenos/farmacologia , Células A549 , Alcaloides/química , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/química , Humanos , Células MCF-7 , Estrutura Molecular , Células PC-3 , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Metabolismo Secundário , Estilbenos/química
19.
Langmuir ; 35(45): 14532-14542, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31635451

RESUMO

We report pH-responsive liquid crystalline lipid nanoparticles, which are dual-loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH = 7.4) to cubic (pH = 6.8) to emulsified microemulsion (pH = 5.3) phase transition with a therapeutic application in cancer inhibition. BJO is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an antitumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need for safe delivery carriers. Here, pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein-oleic acid-BJO-DOX) systems are determined by synchrotron small-angle X-ray scattering and the Langmuir film balance technique. The nanocarrier assemblies display good physical stability in the studied pH range and adequate particle sizes and ζ-potentials. Their interaction with model lipid membrane interfaces is enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO-DOX dual-loaded pH-switchable liquid crystalline nanoparticles are performed on the human breast cancer Michigan Cancer Foundation-7 (MCF-7) cell line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines exhibit enhanced antitumor efficacy. The performed preliminary studies suggest a potential reversal of the resistance of the MCF-7/DOX cells to DOX. These results highlight the necessity for further understanding the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, and emulsified microemulsion inner organizations for therapeutic outcomes.


Assuntos
Antibióticos Antineoplásicos/química , Brucea/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanopartículas/química , Óleos Vegetais/química , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Tamanho da Partícula , Sementes/química , Propriedades de Superfície
20.
Phytomedicine ; 65: 153089, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563042

RESUMO

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disease and a leading genetic cause of infant mortality. SMA is caused primarily by the deletion of the survival motor neuron 1 (SMN1) gene, which leaves the duplicate gene SMN2 as the sole source of SMN protein. The splicing defect (exon 7 skipping) of SMN2 leads to an insufficient amount of SMN protein. Therefore, correcting this SMN2 splicing defect is considered to be a promising approach for the treatment of SMA. PURPOSE: This study aimed to identify active compounds and extracts from plant resources to rescue SMA phenotypes through the correction of SMN2 splicing. STUDY DESIGN: Of available plant resources, candidates with SMA-related traditional medicine information were selected for screening using a robust luciferase-based SMN2 splicing reporter. Primary hits were further evaluated for their ability to correct the splicing defect and resultant increase of SMN activity in SMA patient-derived fibroblasts. Confirmed hits were finally tested to determine the beneficial effects on the severe Δ7 SMA mouse. METHODS: SMN2 splicing was analyzed using a luciferase-based SMN2 splicing reporter and subsequent RT-PCR of SMN2 mRNAs. SMA phenotypes were evaluated by the survival, body weights, and righting reflex of Δ7 SMA mice. RESULTS: In a screen of 492 selected plant extracts, we found that Brucea javanica extract and its major constituent Bruceine D have SMN2 splicing-correcting activity. Their ability to correct the splicing defect and the resulting increased SMN activity were further confirmed in SMA fibroblasts. Importantly, both B. javanica and Bruceine D noticeably improved the phenotypic defects, especially muscle function, in SMA mice. Reduced expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributed to the correction of splicing by B. javanica. CONCLUSION: Our work revealed that B. javanica and Bruceine D correct the SMN2 splicing defect and improve the symptoms of SMA in mice. These resources will provide another possibility for development of a plant-derived SMA drug candidate.


Assuntos
Brucea/química , Atrofia Muscular Espinal/tratamento farmacológico , Extratos Vegetais/farmacologia , Quassinas/farmacologia , Processamento Alternativo , Animais , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Éxons , Humanos , Camundongos Transgênicos , Atrofia Muscular Espinal/genética , Extratos Vegetais/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética
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