Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 190
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Life Sci ; 284: 119907, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453950

RESUMO

AIMS: This study aimed at investigating the role of Brusatol (BR) on human laryngeal squamous carcinoma cell (Hep-2) to study its underlying mechanism through in vitro and in vivo approaches. MATERIALS AND METHOD: In the present research, we employed various cell-based assays, such as cell proliferation, apoptosis, cell cycle assessment, migration and invasion assays were used to examine the anti-tumor effect of BR on Hep-2 cells. Immunohistochemistry (IHC), qRT-PCR and Western blotting were performed to study the underlying molecular mechanisms. To validate our in vitro findings we used a subcutaneous tumor-bearing model of Balb/c mice with Hep-2 cells of laryngeal carcinoma (LC) to study the inhibitory effect of BR on Hep-2 cells in vivo. KEY FINDINGS: The results indicated that BR markedly inhibited the viability, migration and invasion capacity of Hep-2 cells, with no significant toxic effect on normal Human bronchial epithelial cell line (BEAS-2B). Also, BR induced cellular apoptosis by blocking the cells in S phase to suppress cell proliferation. Immunohistochemistry results revealed that BR inhibited the protein expression levels of epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, western blotting results exhibited that BR could suppress the protein expression of both JAK2/STAT3 and their phosphorylation levels. Our in vivo experiments further validated the anti-tumor effect of BR on Hep-2 cells in vitro, where BR suppressed the growth of xenograft laryngeal tumor without apparent toxicity. SIGNIFICANCE: The present study highlights the anti-LC effect of BR by possibly abrogating JAK2/STAT3 signaling mediated EMT process. BR may be a promising therapeutic candidate for the treatment of LC.


Assuntos
Transição Epitelial-Mesenquimal , Janus Quinase 2/metabolismo , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Quassinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Laríngeas/genética , Masculino , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Fosforilação/efeitos dos fármacos , Quassinas/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase S/efeitos dos fármacos , Fase S/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
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
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.
J Pharm Pharmacol ; 73(2): 161-168, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33793798

RESUMO

OBJECTIVES: The quassinoids eurycomanone (EN) and 13α,21-dihydroeurycomanone (DHY) of Eurycoma longifolia Jack are reported to enhance spermatogenesis. This study aims to profile the pharmacokinetics of DHY, a minor and hitherto unstudied constituent, evaluate its spermatogenesis enhancement property and compare these attributes with that of the predominant EN. METHODS: Crude Eurycoma longifolia extract was chromatographed into a DHY-enriched extract (DHY-F) and an EN-enriched extract (EN-F). Male Sprague-Dawley rats were administered intravenously and orally with both extracts and their plasma levels of both quassinoids were determined. The extracts were then tested for their spermatogenesis augmentation ability in normal rats and an andrographolide-induced oligospermia model. KEY FINDINGS: Chromatographic enrichment resulted in a 28-fold increase of DHY in DHY-F and a 5-fold increase of EN in EN-F compared with non-chromatographed crude extracts. DHY showed better oral bioavailability (1.04 ± 0.58%) than EN (0.31 ± 0.19%). At 5 mg/kg, EN exhibited higher efficacy in spermatogenesis enhancement in normal rats and restoration of oligospermia to normal sperm profile versus DHY. CONCLUSIONS: Despite the better pharmacokinetic profile of DHY, EN remains the main chemical contributor to plant bioactivity. DHY-F and EN-F represent improvements in developing Eurycoma longifolia as a potential phytomedicine for male infertility particularly oligospermia.


Assuntos
Eurycoma/química , Oligospermia/tratamento farmacológico , Extratos Vegetais/farmacocinética , Quassinas/farmacocinética , Espermatogênese/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Diterpenos , Masculino , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Quassinas/isolamento & purificação , Quassinas/farmacologia , Ratos , Ratos Sprague-Dawley
5.
Sci Rep ; 11(1): 7833, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837230

RESUMO

Blastocystis sp. infection, although many remain asymptomatic, there is growing data in recent studies that suggests it is a frequent cause of gastrointestinal symptoms in children and adults. This proposes that treatment against this infection is necessary however metronidazole (MTZ), which is the current choice of treatment, has expressed non-uniformity in its efficacy in combating this infection which has led to the study of alternative treatment. In our previous study, it was established that Tongkat Ali fractions exhibited promising anti-protozoal properties which leads to the current aim of the study, to further narrow down the purification process in order to identify the specific active compound promoting the anti-protozoal effect through HPLC analysis. Based on the data analysis and in-vitro susceptibility assay, the collected Tongkat Ali fraction that demonstrated anti-blastocystis property was shown to contain eurycomanone. Previous studies have suggested that there is a mechanism in Blastocystis sp. that regulates the apoptotic process to produce higher number of viable cells when treated. In reference to this, our current study also aims to investigate the apoptotic response of Tongkat Ali extract and eurycomanone across different subtype groups with comparison to MTZ. Based on our investigation, both Tongkat Ali extract and eurycomanone induced the high apoptotic rate however exhibited a reduction in viable cell count (p < 0.05) when compared to MTZ. This study suggests that there is potential in developing a standardized treatment regardless of subtype variations which makes Tongkat Ali extract a promising anti-protozoal treatment against all Blastocystis sp. subtype groups.


Assuntos
Antiprotozoários/farmacologia , Apoptose/efeitos dos fármacos , Infecções por Blastocystis/parasitologia , Blastocystis/efeitos dos fármacos , Eurycoma/química , Metronidazol/farmacologia , Extratos Vegetais/farmacologia , Quassinas/farmacologia , Blastocystis/isolamento & purificação , Blastocystis/metabolismo , Descoberta de Drogas/métodos , Humanos , Testes de Sensibilidade Microbiana
6.
Phytochemistry ; 187: 112769, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33887559

RESUMO

Quassinoids, originating from the oxidative degradation of tetracyclic tirucallane triterpene, are a diverse class of secondary metabolites identifying from nature mostly in Simaroubaceae family. The crucial pharmacological activities and structural complexity of quassinoids have long fascinated scientists due to their medicinal uses, infamous toxicity, and unique biosynthesis. In the past few decades, 482 quassinoids, assigned to 6 skeletons, have been isolated and identified from plants. The names, classes, molecular formula, and plant sources of these secondary metabolites are collated here. This review will be a detailed update of the naturally occurring quassinoids reported from the plant kingdom, providing an in-depth discussion of their diversity, antitumor activities, structure-activity relationship.


Assuntos
Quassinas , Simaroubaceae , Extratos Vegetais , Plantas , Quassinas/farmacologia , Relação Estrutura-Atividade
7.
Oncol Rep ; 45(3): 899-910, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33650652

RESUMO

Colorectal cancer (CRC) is the third most frequently diagnosed type of cancer worldwide. Stage II CRC accounts for ~25% all CRC cases and their management after surgical resection remains a clinical dilemma due to the lack of reliable criteria for identifying patients who may benefit from adjuvant chemotherapy. Homeodomain­interacting protein kinase 2 (HIPK2), a multifunctional kinase involved in numerous signaling pathways, serves several key roles in cell response to different types of stresses, including chemotherapy­induced genotoxic damage. In the present study, immunohistochemistry was performed for HIPK2 on a tissue microarray of primary human tumor samples from 84 patients with stage II CRC, treated (30 patients) or not treated (54 patients) with adjuvant chemotherapy, and sequenced for the TP53 gene, a key HIPK2 target in genotoxic damage response. It was observed that, regardless of the TP53 gene status, a high percentage of HIPK2+ cells was associated with therapeutic vulnerability in stage II CRC, suggesting a contribution of HIPK2 to drug­response in vivo. For the in vitro characterization, HIPK2 was depleted in human CRC cells by CRISPR/Cas9 or RNA interference. HIPK2­proficient and HIPK2­defective cells were evaluated for their response to 5­fluorouracil (5­FU) and oxaliplatin (OXA). The results revealed that HIPK2 depletion induced resistance to 5­FU and OXA, and that this resistance was not overcome by brusatol, an inhibitor of the antioxidant response regulator nuclear factor erythroid 2­related factor 2 (NRF2), which is frequently overexpressed in CRC. By contrast, cell sensitivity to 5­FU and OXA was further induced by brusatol supplementation in HIPK2­proficient cells, further supporting the contribution of HIPK2 in chemotherapy response. Overall, the present results suggested that HIPK2 may be a potential predictive marker for adjuvant­treated stage II CRC and for prospective therapy with NRF2 modulators.


Assuntos
Proteínas de Transporte/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Adjuvante , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Humanos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Estadiamento de Neoplasias , Oxaliplatina/farmacologia , Proteínas Serina-Treonina Quinases/genética , Quassinas/farmacologia , Quassinas/uso terapêutico , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética
8.
J Pharm Pharmacol ; 73(6): 749-757, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33769483

RESUMO

BACKGROUND: Taxane based conventional chemotherapy serves as the standard treatment regimen for triple-negative breast cancer (TNBC). However, the efficacy is plateaued due to toxicities, chemoresistance and metastasis. Hence, the development of new therapies that provide long-term cover is needed. Brusatol, a natural quassinoid, has been implicated to inhibit the migration and proliferation of metastatic cells in lung and liver carcinoma, but its efficacy in TNBC has not been explored. METHODS: The growth inhibitory activity on TNBC cells was measured using MTT assay and flow cytometry. Epithelial to mesenchymal transition (EMT) and apoptotic markers were quantified using western blotting. The caspases using Calorimetric assay. RESULTS: Brusatol along with paclitaxel showed an enhanced growth inhibitory activity and a combined synergistic effect. In addition, brusatol was also observed to inhibit the invasion, migratory potential of TNBC cells. Mechanistically, brusatol and its combination were observed to decrease the matrix metalloproteinase (MMP) and a modest increase in the reactive oxygen species (ROS) production. Furthermore, brusatol treatment activated both intrinsic and extrinsic pathways with morphological changes of apoptosis in TNBC cells. CONCLUSION: This is the first in vitro report demonstrating antineoplastic, anti-EMT and synergistic activity of brusatol and in combination with paclitaxel in TNBC cell. Further in-vivo studies are needed to substantiate the above findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Paclitaxel/farmacologia , Quassinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Invasividade Neoplásica/prevenção & controle , Paclitaxel/administração & dosagem , Quassinas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
9.
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
10.
Biochimie ; 182: 140-151, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33484785

RESUMO

Breast cancer is a prominent type of malignancy among women with a high rate of mortality. A number of previous studies have demonstrated the anticancer potential of brucein D (BD), a quassinoid extracted from Brucea javanica, against the cancers of the pancreas, bone, and liver. We investigated the impact of BD on apoptotic as well on mitogen-activated protein kinase (MAPK) signaling cascades in breast cancer cells. The effect of BD on p38 MAPK and JNK signaling pathways and its downstream functions was deciphered in both MDA-MB-231 and MCF-7 cell lines. We noted that BD decreased the viability of breast cancer cells without affecting the growth of healthy mammary epithelial cells (MCF-10A). Flow cytometric analysis revealed that BD can increase sub-G1 cells and enhanced annexin-V-PI stained cells. The apoptogenic impact of BD was further substantiated by cleavage of procaspase-3/8 and downregulation of antiapoptotic proteins (Bcl-xL, XIAP, and survivin). Furthermore, BD also downmodulated the migratory ability, and chemokine triggered invasion of breast cancer cells. Interestingly, the pharmacological inhibition of p38 MAPK and JNK kinases abrogated the observed anticancer actions of BD. Overall, the data indicated that BD can induce substantial apoptosis and interfere with cellular invasion by modulating MAPK signaling pathway in breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Quassinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7
11.
Theranostics ; 11(2): 958-973, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391515

RESUMO

Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Quassinas/farmacologia , Receptores Androgênicos/química , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Ecotoxicol Environ Saf ; 208: 111647, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396167

RESUMO

Eurycomanone is a quassinoid compound that is derived from Eurycoma longifolia, and it is often used as an indicator to evaluate the active ingredients of Eurycoma longifolia. However, Eurycomanone has rarely been reported to have biological activity toward pests. In this study, we evaluated the antifeedant activity of eurycomanone against the diamondback moth(Plutella xylostella), with a non-selective AFC50(the concentration that corresponds to 50% antifeedant action) value and selective AFC50 of 17.5 mg/L and 14.2 mg/L, respectively, which were 2.1-fold (36.9 mg/L) and 2-fold (28.5 mg/L) lower than that of azadirachtin, respectively. In addition, eurycomanone was used to treat the roots of Brassica chinensis L. at a concentration of 100 µg/g for 72 h. The antifeedant index was found to reach 93% by tracking the leaves. After feeding with 20 µg/g eurycomanone, no pupae or eclosion were observed. To explore this mechanism, we used scanning electron microscopy to discover that eurycomanone could prevent the development of taste receptors on the maxillary palp of diamondback moth larvae. Additional electrophysiological measurements showed that eurycomanone exhibited excitatory action to the central taste neurons of diamondback moth and significantly inhibited the GABAA receptor current. Eurycomanone exhibited significant activity as an antifeedant, inhibited growth and excelled at systemic absorption.


Assuntos
Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Mariposas/crescimento & desenvolvimento , Extratos Vegetais/farmacologia , Quassinas/farmacologia , Animais , Brassica/parasitologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Folhas de Planta/parasitologia , Raízes de Plantas/parasitologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo
13.
J AOAC Int ; 104(3): 802-810, 2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-33064798

RESUMO

BACKGROUND: Quassinoids and canthin-6-one alkaloids are bioactive markers of Eurycoma longifolia (EL) and E. harmandiana (EH) and have been commercially utilized to treat inflammation and male infertility. OBJECTIVES: This study aims to reveal the contents of bioactive compounds and compare anti-inflammatory activities of these two species. METHODS: HPLC methods coupled with UV-Vis detection were developed and validated for the simultaneous analysis of the chemical profiles and their contents in EL and EH. The anti-inflammatory activities of both species were investigated using RAW 264.7 cell line. RESULTS: The HPLC methods provided a sensitivity (LOD) of 0.02-0.05 µg/mL for the eight bioactive compounds (canthin-6-one alkaloids, quassinoids, and scopoletin) with high precision (% relative standard deviation (RSD) ≤6.48) and recoveries between 80.0 and 120%. The chaparrinone: eurycomanone ratio was high in EH, whereas EL had a higher ratio of eurycomanone: chaparrinone than EH. The contents of total canthin-6-one alkaloids, quassinoids, and scopoletin were 0.01-0.75, 0.19-1.54, and 0.01-0.28 mg/g, respectively, in EL roots and 0.12-1.80, 7.05-9.26, and 0.02 mg/g, respectively, in EH roots. The anti-inflammatory effects of EL and EH extracts varied among the samples due to the variation in their chemical constituents. CONCLUSIONS: In summary, our study indicated that chaparrinone was the major compound in EH. EH exhibited anti-inflammatory activity to the same extent as EL. HIGHLIGHTS: EH and EL extracts were analyzed using developed HPLC-UV methods, revealing a high concentration of chaparrinone in EH, and an anti-inflammatory assay indicated that EH had a potency comparable to that of EL.


Assuntos
Alcaloides , Eurycoma , Quassinas , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Carbolinas , Cromatografia Líquida de Alta Pressão , Humanos , Alcaloides Indólicos , Masculino , Extratos Vegetais/farmacologia , Raízes de Plantas , Quassinas/farmacologia , Escopoletina
14.
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
15.
Bioorg Med Chem Lett ; 30(23): 127553, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971261

RESUMO

Brusatol, a quassinoid natural product, is effective against multiple diseases including hematologic malignancies, as we reported recently by targeting the PI3Kγ isoform, but toxicity limits its further development. Herein, we report the synthesis of a series of conjugates of brusatol with amino acids and short peptides at its enolic hydroxyl at C-3. A number of conjugates with smaller amino acids and peptides demonstrated activities comparable to brusatol. Through in vitro and in vivo evaluations, we identified UPB-26, a conjugate of brusatol with a L- ß-homoalanine, which exhibits good chemical stability at physiological pH's (SGF and SIF), moderate rate of conversion to brusatol in both human and rat plasmas, improved mouse liver microsomal stability, and most encouragingly, enhanced safety compared to brusatol in mice upon IP administration.


Assuntos
Aminobutiratos/farmacologia , Antineoplásicos/farmacologia , Quassinas/farmacologia , Aminobutiratos/síntese química , Aminobutiratos/metabolismo , Aminobutiratos/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quassinas/síntese química , Quassinas/metabolismo , Quassinas/toxicidade , Ratos , Relação Estrutura-Atividade
16.
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
17.
Int J Mol Med ; 46(2): 817-827, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32626948

RESUMO

Breakthroughs in cancer management result from the development of drugs that can be used for early diagnosis and effective treatment. Surgery, chemotherapy, radiotherapy and hormone therapy are the main anticancer therapies. However, traditional cancer chemotherapy is associated with serious systemic side effects. Nanoparticles (NPs) provide an effective solution for cancer treatment via the targeted delivery of drugs to cancer cells, while minimizing injury to normal cells. Glycosaminoglycan­placental chondroitin sulfate A (plCSA) is expressed in a number of tumor cells and trophoblasts. A plCSA­binding peptide (plCSA­BP) was isolated from malaria protein VAR2CSA, which can effectively promote the binding of lipid polymer NPs to tumor cells, thereby significantly enhancing the anticancer effect of encapsulated drugs. Brusatol is an important compound derived from Brucea javanica that exerts a multitude of biological effects, including inhibiting tumor cell growth, reducing the reproduction of malaria parasites, reducing inflammation and resisting virus invasion. In the present study, brusatol­loaded NPs (BNPs) or coumarin 6 NPs (CNPs), plCSA­BP and scrambled control peptide­bound BNPs or CNPs were prepared. Ovarian cancer cells (SKOV3), endometrial cancer cells (HEC­1­A) and lung cancer cells (A549) were treated with the NPs. The uptake of plCSA­CNPs by tumor cells was found to be markedly higher compared with that of other types of NPs. Further studies demonstrated that the plCSA­BNPs promoted the apoptosis of cancer cells more effectively and inhibited their proliferation, invasion and migration, accompanied by downregulation of matrix metalloproteinase (MMP)­2, MMP­9 and B­cell CLL/lymphoma 2 (BCL2) levels, but upregulation of BCL2­associated X protein BAX and cleaved caspase­3 levels. The results demonstrated the potential of brusatol delivered by plCSA­modified NPs as a chemotherapeutic agent for the targeted therapy of tumors by regulating the BCL2, BAX, cleaved caspase­3, MMP­2 and MMP­9 pathways, and indicated that it may be an effective and safe strategy for the treatment of various tumors.


Assuntos
Glicosaminoglicanos/metabolismo , Quassinas/farmacologia , Células A549 , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sulfatos de Condroitina/química , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
18.
Aging (Albany NY) ; 12(13): 13400-13421, 2020 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-32652517

RESUMO

The nuclear factor (NF)-κB and NOD-like receptor protein 3 (NLRP3) pathways promote inflammatory signaling that injures the kidneys, whereas the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway promotes anti-inflammatory signaling that inhibits oxidative damage. Penehyclidine hydrochloride (PHC) inhibits NF-κB and activates Nrf2 signaling. We investigated whether PHC induces communication between the Nrf2 and NF-κB/NLRP3 pathways, thereby protecting against renal ischemia/reperfusion (rI/R)-induced lung inflammation. Rat alveolar macrophages (NR8383 cells) were stimulated for 24 h with PHC with or without brusatol (a Nrf2 antagonist), after which they were treated for 4 h with tert-butyl hydroperoxide (10 mM). PHC Nrf2-dependently alleviated tert-butyl hydroperoxide-induced reactive oxygen species production in alveolar macrophages. Additionally, wild-type and Nrf2-/- rats were each divided into four groups: (1) sham, (2) PHC (1 mg/kg), (3) rI/R and (4) rI/R + PHC (1 mg/kg). PHC markedly induced the Nrf2 and adenosine monophosphate-activated protein kinase pathways and suppressed rI/R-induced NF-κB and NLRP3 activation in the lungs. Nrf2 deficiency diminished the ability of PHC to ameliorate rI/R-induced histopathological alterations and reactive oxygen species release in the lungs; however, PHC inhibited NLRP3 signaling Nrf2-dependently, while it inhibited NF-κB signaling Nrf2-independently. Our findings demonstrate the beneficial effects of PHC on rI/R-induced lung inflammation.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Nefropatias/complicações , Fator 2 Relacionado a NF-E2/metabolismo , Quinuclidinas/farmacologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Humanos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/patologia , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Quassinas/farmacologia , Quinuclidinas/uso terapêutico , Ratos , Ratos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , terc-Butil Hidroperóxido/toxicidade
19.
Nucleic Acids Res ; 48(16): 9109-9123, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32729622

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR-CHK1-CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Fator 2 Relacionado a NF-E2/genética , Reparo de DNA por Recombinação/genética , Células A549 , Animais , Proteína Quinase CDC2/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quinase 1 do Ponto de Checagem/genética , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Camundongos , Quassinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Reparo de DNA por Recombinação/efeitos dos fármacos , Reparo de DNA por Recombinação/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos
20.
Fitoterapia ; 146: 104651, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32504655

RESUMO

Bark and leaves of Ailanthus altissima (Mill.) Swingle are widely used in European folk medicine to treat intestinal worm infections. The study aimed to rationalize a potential anthelmintic effect of A. altissima extract against the model organism Caenorhabditis elegans. A methanol-water (7:3, v/v) extract of the primary stem bark was tested on L4 larvae of C. elegans for induction of mortality and influence on reproduction. Bioactivity-guided fractionation was performed by chromatography on MCI-gel, preparative HPLC on RP18 stationary phase and fast-centrifugal-partition-chromatography. Structural elucidation of isolated quassinoids was performed by NMR and HR-ESI-MS. The sterilizing effect on C. elegans was investigated by light microscopy and atomic force microscopy of ultra-sections. Different GFP-tagged reporter strains were used to identify involved signaling pathways. A. altissima extract (1 mg/mL) irreversibly inhibited the reproduction of C. elegans L4 larvae. This effect was dependent on the larval stage since L3 larvae and adults were less affected. Bioactivity-guided fractionation revealed the quassinoid ailanthone 1 as the major active compound (IC50 2.47 µM). The extract caused severe damages to germ cells and rachis, which led to none or only poorly developed oocytes. These damages led to activation of the transcription factor DAF-16, which plays a major role in the nematode's response to stress. A regulation via the respective DAF-2/insulin-like signaling pathway was not observed. The current findings support the traditional use of A. altissma in phytotherapy to treat helminth infections and provide a base for standardization of the herbal material.


Assuntos
Ailanthus/química , Anti-Helmínticos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Quassinas/farmacologia , Animais , Anti-Helmínticos/isolamento & purificação , Fracionamento Químico , Alemanha , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Quassinas/isolamento & purificação , Reprodução/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...