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The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.
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Proteínas Quinases Ativadas por AMP , Aconitina , Cardiotoxicidade , Histona Desacetilases , Animais , Camundongos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/etiologia , Histona Desacetilases/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Humanos , Aconitum/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Synergetic photothermal/photodynamic/chemotherapy receives significant attention for precise in vivo cancer treatment. Despite plenty of encouraging photosensitizers explored, integrated nanoagents with multiple functions are still highly desired. In this study, novel nanocomposites coupling black phosphorus (BP) nanosheets, gold nanorods (AuNRs), carbon nanodots (CDs), and doxorubicin (Dox) are prepared. The nanoagents exhibit high antitumor activity on account of their broad light absorption, excellent catalytic ability, and significant photothermal and photodynamic effects. CDs not only emit bright fluorescence for accurate diagnosis and guiding of tumor treatment but also catalyze the generation of ROS for photodynamic therapy (PDT). The released Dox induces apoptosis of cells and increases the levels of H2O2 to promote PDT. AuNRs are the main photothermal therapy (PTT) material that converts light into heat. Moreover, BP can be used to enhance both PTT and PDT efficiencies, and the two therapy modes can be cooperatively reinforced. It is also found that the local immune microenvironment of the tumors is activated. The strategy makes good use of the features of each component. Satisfactory antitumor phenomena are well confirmed by in vitro and in vivo results. This study provides new insights into enhanced synergetic therapy, highlighting the great utility of BP-based nanoagents in the field of nanomedicine.
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Nanotubos , Neoplasias , Fotoquimioterapia , Humanos , Carbono/uso terapêutico , Linhagem Celular Tumoral , Ouro/uso terapêutico , Peróxido de Hidrogênio , Neoplasias/tratamento farmacológico , Fósforo/uso terapêutico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente TumoralRESUMO
Objective: COVID-19 has evolved into a major global public health event. The number of people reporting insomnia is growing exponentially during the pandemic. This study aimed to explore the relationship between aggravated insomnia and COVID-19-induced psychological impact on the public, lifestyle changes, and anxiety about the future. Methods: In this cross-sectional study, we used the questionnaires from 400 subjects who were obtained from the Department of Encephalopathy of the Wuhan Hospital of Traditional Chinese Medicine between July 2020 and July 2021. The data collected for the study included demographic characteristics of the participants and psychological scales consisting of the Spiegel Sleep Questionnaire, the Fear of COVID-19 Scale (FCV-19S), the Zung Self-Rating Anxiety Scale (SAS), and the Zung Self-Rating Depression Scale (SDS). The independent sample t-test and one-way ANOVA were used to compare the results. Correlation analysis of variables affecting insomnia was performed using Pearson correlation analysis. The degree of influence of the variables on insomnia was determined using linear regression, and a regression equation was derived. Results: A total of 400 insomnia patients participated in the survey. The median age was 45.75 ± 15.04 years. The average score of the Spiegel Sleep Questionnaire was 17.29 ± 6.36, that of SAS was 52.47 ± 10.39, that of SDS was 65.89 ± 8.72, and that of FCV-19S was 16.09 ± 6.81. The scores of FCV-19S, SAS, and SDS were closely related to insomnia, and the influencing degree was in the following order: fear, depression, and anxiety (OR = 1.30, 0.709, and 0.63, respectively). Conclusion: Fear of COVID-19 can be one of the primary contributors to worsening insomnia.
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COVID-19 , Distúrbios do Início e da Manutenção do Sono , Humanos , Adulto , Pessoa de Meia-Idade , Modelos Lineares , Qualidade do Sono , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Pandemias , Estudos Transversais , COVID-19/epidemiologia , Análise de Regressão , Ansiedade/epidemiologia , Depressão/epidemiologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Mufangji decoction (MFJD), a famous traditional Chinese medicine formula in Synopsis of Golden Chamber (Jingui yaolue), has been utilized to treat cough and asthma and release chest pain over 2000 years in China. Chinese old herbalist doctor use MFJD to treat lung cancer and cancerous pleural fluid, but the preventive effect of MFJD on lung cancer and the underlying mechanism are indefinite. AIM OF THE STUDY: The goal of this study is to explore the efficacy and mechanism of Mufangji decoction preventing lung cancer referring to the traditional use. MATERIALS AND METHODS: Tumor allograft experiment and host versus tumor experiment were used to observe the direct anti-tumor effect and indirect anti-tumor immune effect, the mouse lung carcinogenic model was used to evaluate the dose-response and the preventive effect of MFJD on lung cancer. The active ingredients of MFJD were obtained by UPLC-MS/MS. The potential targets of MFJD were screened by network pharmacology and transcriptomics. The therapeutic targets and pathways of MFJD on lung cancer were obtained by protein-protein interaction, molecular docking and David database. The predicted results were verified in vitro and in vivo. RESULTS: MFJD could significantly prevent tumor growth in host versus tumor experiment but could not in tumor allograft experiment, indicating an anti-tumor immune effect against lung cancer. MFJD could reduce lung nodules with a dose-response in mouse lung carcinogenic model. Myeloperoxidase (MPO) was selected as the core target due to the highest degree value in Protein-Protein interaction network and had potently binding activity to sinomenine and dehydrocostus lactone in molecular docking. In vivo, MPO-expressed neutrophils are negatively correlated with lung cancer progression and MFJD could promote the neutrophil-related immune surveillance. In vitro, sinomenine and dehydrocostus lactone could promote neutrophil phagocytosis, MPO and ROS production in a dose dependent manner. The major compounds from MFJD were identified to regulate 36 targets for lung cancer prevention by UPLC-MS/MS, network pharmacology and transcriptomics. David database exhibited that MFJD plays an important role in immunoregulation by modulating 4 immune-related biological processes and 3 immune-related pathways. CONCLUSIONS: MFJD prevents lung cancer by mainly promoting MPO expression to maintain neutrophil immune surveillance, its key compounds are sinomenine and dehydrocostus lactone.
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Medicamentos de Ervas Chinesas , Neoplasias Pulmonares , Animais , Cromatografia Líquida , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Camundongos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Espectrometria de Massas em Tandem , TranscriptomaRESUMO
This report presents nanoparticles composed of a liquid gallium core with a reduced graphene oxide (RGO) shell (Ga@RGO) of tunable thickness. The particles are produced by a simple, one-pot nanoprobe sonication method. The high near-infrared absorption of RGO results in a photothermal energy conversion of light to heat of 42.4%. This efficient photothermal conversion, combined with the large intrinsic thermal expansion coefficient of liquid gallium, allows the particles to be used for photoacoustic imaging, that is, conversion of light into vibrations that are useful for imaging. The Ga@RGO results in fivefold and twofold enhancement in photoacoustic signals compared with bare gallium nanoparticles and gold nanorods (a commonly used photoacoustic contrast agent), respectively. A theoretical model further reveals the intrinsic factors that affect the photothermal and photoacoustic performance of Ga@RGO. These core-shell Ga@RGO nanoparticles not only can serve as photoacoustic imaging contrast agents but also pave a new way to rationally design liquid metal-based nanomaterials with specific multi-functionality for biomedical applications.
Assuntos
Gálio , Grafite , Nanopartículas , Técnicas Fotoacústicas , Meios de Contraste , Ouro , Técnicas Fotoacústicas/métodos , Fototerapia/métodosRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreak is progressing rapidly, and poses significant threats to public health. A number of clinical practice results showed that traditional Chinese medicine (TCM) plays a significant role for COVID-19 treatment. OBJECTIVE: To explore the active components and molecular mechanism of semen armeniacae amarum treating COVID-19 by network pharmacology and molecular docking technology. METHODS: The active components and potential targets of semen armeniacae amarum were retrieved from traditional Chinese medicine systems pharmacology (TCMSP) database. Coronavirus disease 2019-associated targets were collected in the GeneCards, TTD, OMIM and PubChem database. Compound target, compound-target pathway and medicine-ingredient-target disease networks were constructed by Cytoscape 3.8.0. Protein-protein interaction (PPI) networks were drawn using the STRING database and Cytoscape 3.8.0 software. David database was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The main active components were verified by AutoDock Vina 1.1.2 software. A lipopolysaccharide (LPS)-induced lung inflammation model in Institute of Cancer Research (ICR) mice was constructed and treated with amygdalin to confirm effects of amygdalin on lung inflammation and its underlying mechanisms by western blot analyses and immunofluorescence. RESULTS: The network analysis revealed that nine key, active components regulated eight targets (Proto-oncogene tyrosine-protein kinase SRC (SRC), interleukin 6 (IL6), mitogen-activated protein kinase 1 (MAPK1), mitogen-activated protein kinase 3 (MAPK3), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), HRAS proto-oncogene (HRAS), caspase-3 (CASP3)). Gene ontology and KEGG enrichment analysis suggested that semen armeniacae amarum plays a role in COVID-19 by modulating 94 biological processes, 13 molecular functions, 15 cellular components and 80 potential pathways. Molecular docking indicated that amygdalin had better binding activity to key targets such as IL6, SRC, MAPK3, SARS coronavirus-2 3C-like protease (SARS-CoV-2 3CLpro) and SARS-CoV-2 angiotensin converting enzyme II (ACE2). Experimental validation revealed that the lung pathological injury and inflammatory injury were significantly increased in the model group and were improved in the amygdalin group. CONCLUSION: Amygdalin is a candidate compound for COVID-19 treatment by regulating IL6, SRC, MAPK1 EGFR and VEGFA to involve in PI3K-Akt signalling pathway, VEGF signalling pathway and MAPK signalling pathway. Meanwhile, amygdalin has a strong affinity for SARS-CoV-2 3CLpro and SARS-CoV-2 ACE2 and therefore prevents the virus transcription and dissemination.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important risk factor for developing lung cancer. Aged citrus peel (chenpi) has been used as a dietary supplement for respiratory diseases in China. OBJECTIVE: To explore the mechanism and candidate compounds of chenpi preventing COPD and its progression to lung cancer. METHODS: The active components and potential targets of chenpi were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Disease-associated targets of COPD and lung cancer were collected in the Gene Cards and TTD database. The component-target network and PPI network were constructed using the Cytoscape 3.8.0 software. David database was used for GO and KEGG enrichment analysis. The main active components were verified by using the autodock Vina 1.1.2 software. Mouse lung cancer with COPD was induced by cigarette smoking (CS) combined with urethane injection to confirm preventing the effect of hesperetin (the candidate compound of chenpi) on COPD progression to lung cancer and its underlying mechanisms. RESULTS: The network analysis revealed that the key active components of chenpi (nobiletin, naringenin, hesperetin) regulate five core targets (AKT1, TP53, IL6, VEGFA, MMP9). In addition, 103 potential pathways of chenpi were identified. Chenpi can prevent COPD and its progression to lung cancer by getting involved in the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking indicated that hesperetin had better binding activity for core targets. In mouse lung cancer with COPD, treatment with hesperetin dose-dependently improved not only lung tissue injury in COPD but also carcinoma lesions in lung cancer. Meanwhile, hesperetin could suppress the protein expression of AKT1, IL6, VEGFA, MMP9 and up-regulate the protein expression of TP53, and thus reduced the risk of COPD progression to lung cancer. CONCLUSION: Hesperetin is a candidate compound of chenpi that helps in preventing COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53.
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Xuefu Zhuyu Decoction (XFZY) is an ancient compound widely used in the treatment of coronary heart disease. However, its efficacy evaluation is not complete and its mechanism of action is not clear enough. In an attempt to address these problems, the efficacy was evaluated by meta-analysis and the mechanism was elucidated by the network pharmacology method. We systematically searched relevant studies in PubMed, Chinese National Knowledge Infrastructure Database (CNKI), Cochrane Library, Wanfang Data, and other databases from 2007 to 2019. The association between XFZY treatment and CHD was estimated by risk ratio (RR) and corresponding 95% confidence intervals (95% CIs). The compounds and the potential protein targets of XFZY were obtained from TCMSP, and active compounds were selected according to their oral bioavailability and drug similarity. The potential genes of coronary heart disease were obtained from TTD, OMIM, and GeneCards. The potential pathways related to genes were determined by GO and KEGG pathway enrichment analyses. The compound-target and compound-target-pathway networks were constructed. Molecular docking validates the component and the target. A total of 21 studies including 1844 patients were enrolled in the present meta-analysis, indicating that XFZY has a greater beneficial on total effect (fixed effect RR = 1.30; 95% Cl: 1.24-1.36; P=0.82; I 2 = 0.0%) and electrocardiogram efficacy (fixed effect RR = 1.40; 95% Cl: 1.26-1.56; P=0.96; I 2 = 0.0%) compared with the control group. A total of 1342 components in XFZY were obtained, among which, 241 were chosen as bioactive components. GO and KEGG analyses got top 10 significantly enriched terms and 10 enriched pathways. The C-T network included 192 compounds and 3085 targets, whereas the C-T-P network included 10 compounds, 109 targets, and 5 pathways. There was a good binding activity between the components and the targets. XFZY has the curative effect on coronary heart disease, and its mechanism is related to 10 compounds, 10 core targets, and 5 pathways.
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Assessment of microbial viability plays a key role in human health protection. Optical imaging based on fluorescent dyes is a simple and convenient way to assess microbial viability. However, it is still a challenge to obtain stable, nontoxic and low-cost dyes. Herein, we prepared a nitrogen and phosphorus co-doped carbon nanodots (N, P-CDs) via a one-step solvothermal method. The prepared CDs possess plenty of functional groups and exhibit high stability, good biocompatibility, excellent photoluminescent and low toxicity. Especially, the properties of high quantum yield (89.9%) and highly negative surface charge (-41.9 mV) make the prepared N, P-CDs ideal materials for microbial differentiation. Compared with commercial dyes, our CDs are more stable, cost less, which can rapidly distinguish dead microorganisms from living ones with higher specificity.
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Bactérias/crescimento & desenvolvimento , Corantes Fluorescentes/química , Fungos/crescimento & desenvolvimento , Viabilidade Microbiana , Nanoestruturas/química , Pontos Quânticos , Bactérias/classificação , Bactérias/isolamento & purificação , Carbono/química , Fungos/classificação , Fungos/isolamento & purificação , Células HeLa , Humanos , Nitrogênio/química , Imagem Óptica , Fósforo/químicaRESUMO
BACKGROUND: Lung cancer remains the most common cause of cancer-related deaths, with a high incidence and mortality in both sexes worldwide. Chemoprevention has been the most effective strategy for lung cancer prevention. Thus, exploring novel and effective candidate agents with low toxicity for chemoprevention is essential and urgent. Houttuynia cordata Thunb. (Saururaceae) (H. cordata), which is a widely used herbal medicine and is also popularly consumed as a healthy vegetable, exhibits anti-inflammatory, antioxidant and antitumor activity. However, the chemopreventive effect of H. cordata against benzo(a)pyrene (B[a]P)-initiated lung tumorigenesis and the underlying mechanism remain unclear. METHODS: A B[a]P-stimulated lung adenocarcinoma animal model in A/J mice in vivo and a normal lung cell model (BEAS.2B) in vitro were established to investigate the chemopreventive effects of H. cordata and its bioactive compound 2-undecanone against lung tumorigenesis and to clarify the underlying mechanisms. RESULTS: H. cordata and 2-undecanone significantly suppressed B[a]P-induced lung tumorigenesis without causing obvious systemic toxicity in mice in vivo. Moreover, H. cordata and 2-undecanone effectively decreased B[a]P-induced intracellular reactive oxygen species (ROS) overproduction and further notably protected BEAS.2B cells from B[a]P-induced DNA damage and inflammation by significantly inhibiting phosphorylated H2A.X overexpression and interleukin-1ß secretion. In addition, H. cordata and 2-undecanone markedly activated the Nrf2 pathway to induce the expression of the antioxidative enzymes heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO-1). Nrf2 silencing by transfection with Nrf2 siRNA markedly decreased the expression of HO-1 and NQO-1 to diminish the reductions in B[a]P-induced ROS overproduction, DNA damage and inflammation mediated by H. cordata and 2-undecanone. CONCLUSIONS: H. cordata and 2-undecanone could effectively activate the Nrf2-HO-1/NQO-1 signaling pathway to counteract intracellular ROS generation, thereby attenuating DNA damage and inflammation induced by B[a]P stimulation and playing a role in the chemoprevention of B[a]P-induced lung tumorigenesis. These findings provide new insight into the pharmacological action of H. cordata and indicate that H. cordata is a novel candidate agent for the chemoprevention of lung cancer.
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Antineoplásicos Fitogênicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Houttuynia/química , Cetonas/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Humanos , Espaço Intracelular/metabolismo , Cetonas/química , Masculino , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. Modern pharmacological studies and clinical practices indicate that AR possesses various biological functions, including potent immunomodulation, antioxidant, anti-inflammation and antitumor activities. To date, more than 200 chemical constituents have been isolated and identified from AR. Among them, isoflavonoids, saponins and polysaccharides are the three main types of beneficial compounds responsible for its pharmacological activities and therapeutic efficacy. After ingestion of AR, the metabolism and biotransformation of the bioactive compounds were extensive in vivo. The isoflavonoids and saponins and their metabolites are the major type of constituents absorbed in plasma. The bioavailability barrier (BB), which is mainly composed of efflux transporters and conjugating enzymes, is expected to have a significant impact on the bioavailability of AR. This review summarizes studies on the phytochemistry, pharmacology and pharmacokinetics on AR. Additionally, the use of AR as a personalized medicine based on the BB is also discussed, which may provide beneficial information to achieve a better and more accurate therapeutic response of AR in clinical practice.
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Astrágalo/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Medicina de Precisão , Animais , Biomarcadores , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Compostos Fitoquímicos/farmacocinética , Extratos Vegetais/farmacocinética , Medicina de Precisão/métodos , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Astragali radix (Huang Qi, HQ), a well-known Chinese herbal medicine, is widely coadministered with many other drugs for treating diseases. The potential herb-drug interactions (HDIs) possibly occur during the combination therapy. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the crucial targets that mediate the production of HDIs. We previously observed that HQ and its three main bioactive compounds, including Astragaloside IV (AS-IV), calycosin (CS) and formononetin (FMNT), could significantly induce the expression of P-gp and BCRP in HepG2 cells in vitro. However, their modulations on the function of P-gp and BCRP remain unknown; their impact on these two proteins expression in vivo is not clear; the exact regulatory mechanism has also not yet been explored. AIM OF THE STUDY: This study aimed to investigate the impact of HQ, AS-IV, CS and FMNT on P-gp and BCRP in vivo, and the exact regulatory mechanism involved. The effects of HQ and these compounds on the function of P-gp and BCRP were also studied. MATERIALS AND METHODS: Wild-type C57BL/6 mice and nuclear factor E2-related factor-2 knockout (Nrf2-/-) C57BL/6 mice were orally treated with HQ, AS-IV, CS or FMNT. The protein levels of P-gp and BCRP in the liver of mice were measured by using Western blot and immunohistochemistry. The mRNA levels were measured by using real-time PCR. The activation of the drugs on the antioxidant response element (ARE)-luciferin activity was studied by using reporter assay in a stably transfected HepG2-C8 cells. The efflux activity of P-gp and BCRP in HepG2 cells were tested by using flow cytometer with typical probes. RESULTS: HQ, AS-IV, CS and FMNT significantly upregulated the P-gp and BCRP expression in the liver of wild-type mice. The induction was significantly reversed in the Nrf2-/- mice. HQ and these compounds significantly increased the Nrf2 expression in wild-type mice. HQ and these compounds also markedly enhanced the ARE-luciferin activity and promoted the nuclear translocation of Nrf2 in cells. Besides, HQ and these compounds significantly enhanced the efflux activity of P-gp and BCRP, and increased the intracellular ATP levels. CONCLUSIONS: Our results proved that HQ and its main bioactive compounds could induce the P-gp and BCRP expression through the activation of the Nrf2-mediated signaling pathway. HQ and these compounds also significantly enhanced the efflux activity of P-gp and BCRP, and the increased intracellular ATP levels were likely involved in the increased P-gp and BCRP function. These results suggested that potentially HDIs likely occurred when HQ was used concomitantly with other drugs that are substrates of P-gp and BCRP.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Isoflavonas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Trifosfato de Adenosina/metabolismo , Animais , Astragalus propinquus , Neoplasias da Mama/metabolismo , Células Hep G2 , Interações Ervas-Drogas , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genéticaRESUMO
BACKGROUND: Fuzi, which is the processed lateral roots of Aconitum carmichaeli Debx. (Ranunculaceae), is a traditional herbal medicine that is well known for its excellent pharmacological effects and acute toxicity. Aconitum alkaloids are responsible for its pharmacological activity and toxicity. Although a large number of studies on Fuzi have been reported, no comprehensive review on its pharmacokinetics has yet been published. PURPOSE: This paper seeks to present a comprehensive review regarding the phytochemistry, pharmacokinetic features and toxicity of Fuzi. The regulation of drug-metabolizing enzymes (DMEs) and efflux transporters (ETs) by Fuzi is also concluded. Additionally, the use of Fuzi as a personalized medicine based on the bioavailability barrier (BB), which mainly comprises DMEs and ETs, is discussed. METHODS: All available information on Fuzi was collected by searching for key words in PubMed, ScienceDirect, CNKI, Google Scholar, Baidu Scholar, and Web of Science. RESULTS: Aconitum alkaloids, which mainly include diester-diterpene alkaloids (DDAs), monoester-diterpene alkaloids (MDAs) and unesterified-diterpene alkaloids (UDAs), could be detected after Fuzi ingestion in vivo. The Aconitum alkaloids are rapidly absorbed in the intestine and extensively distributed in the body. DMEs, especially CYP3A4/5, are responsible for various types of metabolic reactions of the Aconitum alkaloids. ETs, including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), are involved in the efflux of the DDAs and MDAs. The kidney is the most important organ involved in the excretion of the Aconitum alkaloids. DDAs are the main toxic compounds present in Fuzi, and their acute toxicity is mainly due to their effects on the voltage-dependent sodium channels. Furthermore, Fuzi can substantially regulate DMEs and ETs. CONCLUSIONS: The toxicity of DDAs is acute. However, further investigations are necessary to determine the exact toxicological mechanisms. The significant impact of Fuzi on DMEs and ETs suggests that the co-administration of Fuzi with drugs that are substrates of DMEs and/or ETs may cause herb-drug interactions (HDIs). The BB network controlled exposure to the Aconitum alkaloids in vivo. Polymorphisms of DMEs and ETs in different individuals contribute to the differences in the efficacy and toxicity of Fuzi ingestion. In the future, the use of Fuzi as personalized medicine based on the BB network is necessary and practical to achieve ideal therapeutic efficacy with minimal toxicity.
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Diterpenos/química , Diterpenos/farmacocinética , Aconitum/química , Alcaloides/química , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Diterpenos/toxicidade , Medicamentos de Ervas Chinesas , Interações Ervas-Drogas , Humanos , Inativação Metabólica/efeitos dos fármacos , Fitoterapia/métodos , Extratos Vegetais/química , Medicina de Precisão , Distribuição TecidualRESUMO
BACKGROUND: Aconitum alkaloids from Aconitum species are often used to treat arthritis and rheumatic diseases but have the drawback of high toxicity. Identifying their pharmacokinetic behaviour is important for the safe clinical application of Aconitum species. Efflux transporters (ETs), including P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), have important functions in regulating the pharmacokinetic behaviours of drugs and in herb-herb or herb-drug interactions (HDIs). The Aconitum alkaloids regulate P-gp expression and function, but their effects on MRP2 and BCRP expression remain unknown. PURPOSE: To determine the effects of three Aconitum alkaloids, aconitine (AC), benzoylaconine (BAC), and aconine, on MRP2 and BCRP. METHODS: The levels of the protein and mRNA expression of MRP2 and BCRP in vivo and in vitro were measured via Western blotting and real-time PCR, respectively. Fluorescence signals of MRP2 and BCRP were detected via confocal fluorescence microscopy. A reporter assay using HepG2-C8 cells, which were generated by transfecting plasmids containing the antioxidant response element (ARE)-luciferin gene into HepG2 cells, was used to examine the ARE-luciferin activity. The transport activities of MRP2 and BCRP were tested via flow cytometry using substrate probes. RESULTS: The Aconitum alkaloids significantly up-regulated MRP2 and BCRP expression, accompanied by a marked increase in nuclear factor E2-related factor-2 (Nrf2) expression in the jejunum, ileum, and colon of FVB mice, in the order ACâ¯<â¯BACâ¯<â¯aconine. In the in vitro model, the Aconitum alkaloids increased MRP2 and BCRP expression in Caco-2 and LS174T cells, in the order ACâ¯<â¯BACâ¯<â¯aconine. Additionally, these alkaloids promoted the translocation of Nrf2 from the cytoplasm to the nucleus and significantly increased ARE-luciferin activity in HepG2-C8 cells. Luteolin, a potent inhibitor of Nrf2, markedly prevented MRP2 and BCRP expression from being induced by the three Aconitum alkaloids. The efflux activity of MRP2 was also significantly increased in cells receiving the same treatment. CONCLUSIONS: The tested Aconitum alkaloids significantly increased the expression of MRP2 and BCRP by activating the Nrf2-mediated signalling pathway and enhanced the efflux activity of MRP2. The potential for herb-herb interactions or HDIs exists when Aconitum species are co-administered with substrate drugs that are transported via MRP2 and BCRP. Therefore, the Aconitum alkaloids may be used as quality indicators for the herbs of Aconitum species.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aconitum/química , Alcaloides/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aconitina/análogos & derivados , Aconitina/farmacologia , Alcaloides/efeitos adversos , Animais , Elementos de Resposta Antioxidante/efeitos dos fármacos , Células CACO-2 , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos , Proteína 2 Associada à Farmacorresistência Múltipla , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Neoplasias/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Arsenic trioxide (As2O3), a main component of arsenolite which is a common traditional Chinese medicine (TCM) wildly used as a therapeutic agent for more than 2400 years in china, has been accepted as a standard treatment for the patients with acute promyelocytic leukemia (APL) based on the principle in TCM of "using a poison to fight against other poisons or malignancy illnesses". However, it remains unknown that which mechanism is actually responsible for the therapeutic effects against these blood malignancies. AIM OF THE STUDY: The purpose of this study was to explore the actual mechanism that ATO exerts its effects in K562 cells and their initiating cells (K562s). MATERIALS AND METHODS: K562s cells were separated and enriched for CD34+/CD38- cells using magnetic microbeads. Cell proliferation was determined by incorporation of BrdU. Cell apoptosis was evaluated by Annexin-V binding and PI uptake. Autophagy was estimated by acridine orange and immunofluorescence staining of LC3-B and p62. MC colonic formation was used to examine cell self-renew. ROS generation inside living cells was measured by DCFH-DA. Cell differentiation was assessed by the benzidine staining. The SA-ß-gal assay was used to detect cell senescence. Protein expression was examined by western blotting and immunohistochemical staining. RESULTS: K562s cells were stronger in self-renew and resistance to ATO cytotoxicity and starvation-induced apoptosis than K562 cells. Unexpectedly, we found that ATO at a dose of 0.5µM which had no effect on cell proliferation resulted in maximum suppression on self-renew in both cells and maximum starvation-induced apoptosis in K562s cells but minimum starvation-induced apoptosis in K562 cells. Next, we found that ATO no more than 0.5µM selectively induced K562s cell differentiation indicated by benzidine staining, γ-globin and CD235a expression. More importantly, we found that ATO no more than 0.5µM led to opposite efficacy in autophagy between K562 and K562s cells, and the opposite autophagy could induced late-phase senescence in both cells. Finally, we used the optimal dose of ATO to eradicate leukemia cells and obtained a satisfied therapeutic outcomes in vivo. CONCLUSIONS: Our results suggest that the used dose of ATO may determine the fate of cell differentiation senescence or malignant transformation, and the optimal dose of ATO induced opposite efficacy in autophagy between K562 cells and their initiating cells and ultimately leads both cells to late-phase senescence.
Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Óxidos/administração & dosagem , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Feminino , Humanos , Células K562 , Leucemia Mieloide/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Óxidos/farmacologia , Óxidos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Obesidade/complicações , Células 3T3 , Células 3T3-L1 , Adipócitos/citologia , Administração Oral , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Teste de Tolerância a Glucose , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/complicações , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Sobrepeso , Estresse Oxidativo , Fatores de Risco , Transdução de SinaisRESUMO
OBJECTIVE: To investigate whether electro-acupuncture can serve as a method of inducing brain ischaemic tolerance (BIT) by encouraging the expression of glutamate transporter-1 (GLT-1) and suppressing the release of glutamate (Glu). METHODS: Sprague-Dawley (SD) rats were divided into sham, ischaemia and EA groups. EA was performed on dazhui and baihui acupoints and the rat cerebral ischaemia model was achieved by occluding the middle cerebral artery (MCA) for 2 hours, followed by reperfusion. Dialysate was collected from the striatum in vivo to detect the concentration of Glu and the expression of Glutamate Transporter-1 (GLT-1) was examined. The changes of neurological deficit scores were evaluated at 24 hours after reperfusion, while the infarct volumes of brains were then measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: Compared with the ischaemia group, the concentration of Glu decreased and the expression of GLT-1 increased at most of the detective time points in the EA group; the neurological deficit scores were lower and the infarct volumes were smaller in the EA group. CONCLUSION: EA can up-regulate the expression of GLT-1 and inhibit the excessive release of Glu in the striatum in the process of subsequent ischaemic-reperfusion brain injury, which may be one of the mechanisms of inducing BIT and, thus, be neuroprotective for early ischaemic brain injury.