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2.
Pharmacol Res ; 171: 105778, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34298110

RESUMO

The plant Sophora flavescens Ait. has been used in the clinical management of colorectal cancer (CRC). Its constituent compounds, notably the alkaloids matrine, oxymatrine, and sophoridine, have received considerable research attention in experimental models of CRC in vivo and in vitro. This review found that extracts of S. flavescens and/or its constituent compounds have been reported to inhibit CRC cell proliferation by inducing cell-cycle arrest at the G1 phase, inducing apoptosis via the intrinsic pathway, interfering in cancer metabolism, inhibiting metastasis and angiogenesis, regulating senescence and telomeres, regulating the tumour microenvironment and down-regulating cancer-related inflammation. In addition, matrine and oxymatrine reversed multi-drug resistance and enhanced the effects of chemotherapies. These anti-cancer effects were associated with regulation of several cellular signalling pathways including: MAPK/ERK, PI3K/AKT/mTOR, p38MAPK, NF-κB, Hippo/LATS2, TGF-ß/Smad, JAK/STAT3, RhoA/ROC, and Wnt/ ß-catenin pathways. These multiple actions in CRC suggest the alkaloids of S. flavescens may be therapeutic candidates for CRC management. Nevertheless, there remains considerable scope for future research into its flavonoid constituents, the effects of combinations of compounds, and the interaction between these compounds and anti-cancer drugs. In addition, more research is needed to investigate likely drug ligand-receptor interactions for each of the bioactive compounds.


Assuntos
Alcaloides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Quinolizinas/uso terapêutico , Sophora , Animais , Humanos , Fitoterapia , Matrinas
3.
Adv Med ; 2020: 6231751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34189145

RESUMO

OBJECTIVE: Hepatocellular carcinoma is one of the most common diseases that seriously threaten human life and health. In this study, we evaluated the inhibitory effect of tanshinone IIA (Tan IIA) combined with adriamycin (ADM) on human hepatocellular carcinoma and developed a platform to assess the function if Chinese herbal ingredients combined with chemotherapy drugs have synergistic antitumor effects in vivo. METHODS: Established animal model of human hepatocarcinoma HepG2 cell in nude mice. Mice were divided into model control group, Tan IIA group, ADM group, and Tan IIA + ADM group. The changes from general condition, weight, tumor volume, and inhibition rate were observed. The data were gathered from serum AST level and histopathological changes. The content and activity of cytochrome P450 were determined by spectrophotometric analysis. CYP3A4 protein expression was analyzed by western blotting. The binding model crystal structure of Tan IIA and ADM with pregnane X receptor (PXR) was evaluated by Discovery Studio 2.1. RESULTS: A combination of Tan IIA with ADM could improve life quality by relieving ADM toxicity, decreasing tumor volume, declining serum AST level, and improving liner pathological section in tumor-bearing mice. The inhibitory rates of Tan IIA, ADM, and cotreatment were 32.77%, 60.96%, and 73.18%, respectively. The Tan IIA group significantly enhanced the content of cytochrome b5, P450, and erythromycin-N-demethylase activity. CYP3A4 protein expression was enhanced obviously by the Tan IIA + ADM group. Virtual molecular docking showed that both Tan IIA and ADM could be stably docked with the same binding site of PXR but different interactions. CONCLUSIONS: Tan IIA in combination with ADM could improve the life quality in tumor-bearing mice and enhance the antitumor effect. The Tan IIA group increased the concentration of cytochrome P450 enzymes and activity. Combined Tan IIA with ADM could upregulate the CYP3A4 protein expression and make relevant interaction with protein PXR by virtual docking.

4.
Phytomedicine ; 51: 214-225, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30466620

RESUMO

BACKGROUND: The World Health Organization (WHO) reported that colorectal cancer (CRC) was the third most common cancer in men and the second in women, worldwide. Our previous meta-analysis found Sophora flavescens increased tumour response rate in randomised controlled trials of CRC. We hypothesised that its principal constituent matrine had exerted anti-tumour effects. PURPOSE: To elucidate its mechanisms of action we investigated the dose-related anti-tumour effects of matrine on four human CRC cell-lines: LS174T, Caco-2, SW1116 and RKO. In a LS174T xenografted tumour model in nude mice we assessed the effects of matrine and oxaliplatin on tumour volume, weight and morphology. Computer simulated dockings for target proteins were also conducted. METHODS AND DESIGN: Cell viability, cell cycle and apoptosis were measured by Cell Counting Kit-8 and flow cytometry, and Annexin V-FITC/PI double staining assay respectively. Western blot was performed to examine the expression of Bax, Bcl-2 and caspase-3 in the cells. The xenograft model and immunohistochemistry were used to investigate the effect of matrine in vivo. Oxaliplatin was set as positive control. Molecular docking was performed to predict the binding modes of matrine and oxaliplatin with target proteins using CDOCKER algorithm. RESULTS: Matrine inhibited proliferation of cancer cells in a dose- and time-dependent manner. Matrine induced cell-cycle arrest at G1/G0 phase, induced apoptosis and reduced expression of Bcl-2 and caspase-3 while up-regulating Bax and cleaved caspase-3 in the four CRC cells. In vivo, matrine significantly inhibited tumour growth without side effects on physical health compared to the negative (vehicle) control group. Mice in the oxaliplatin group lost vigour, became frail and lost weight. Expression of Bcl-2 in tumour tissue was lower and Bax expression was higher in the matrine-treated groups compared to the negative control. In computer-simulated docking, matrine successfully docked into active sites of Bcl-2 and caspase-3. CONCLUSION: Matrine inhibited growth of colorectal cancer cells in vitro and in vivo. A molecular mechanism was apoptosis induction via effects on Bcl-2, Bax and caspase-3. Moreover, matrine showed minimum side effects and may provide a candidate for the development of new therapies for colorectal cancer.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolizinas/farmacologia , Animais , Células CACO-2 , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais , Humanos , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Sophora/química , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo , beta-Glucanas , Matrinas
5.
BMC Cancer ; 16(1): 899, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27863471

RESUMO

BACKGROUND: The study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers. METHODS: Inhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins. RESULTS: Both tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin. CONCLUSIONS: Tanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs.


Assuntos
Abietanos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Células A549 , Abietanos/química , Abietanos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/metabolismo , Sinergismo Farmacológico , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Microscopia de Fluorescência , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Domínios Proteicos , Fatores de Tempo
6.
Fitoterapia ; 94: 21-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24468191

RESUMO

OBJECTIVE: To investigate the effect of baicalein on side population in human multiple myeloma cell line RPMI 8226 and the underlying molecular mechanisms in vitro and in silico. METHODS: MTT assay was applied to detect the anti-proliferation effect of baicalein. The detection of side population cells is based on the Hoechst 33342 exclusion assay technique and flow cytometric analysis. Western blotting assay was used to explore the expression of ABCG2 protein. Homology modeling and molecular docking were performed with Discovery Studio 2.1. RESULTS: Baicalein decreased both cell viability with IC50=168.5 µM and the proportion of SP cells in a dose-dependent manner. Correspondingly, it significantly decreased the expression level of ABCG2 protein. Baicalein also shared similar binding sites and modes with fumitremorgin C to the protein. CONCLUSIONS: Baicalein possessed novel anticancer properties, such as anti-proliferation and drug efflux inhibition in side population cells, which suggested its potential feature of targeting cancer stem cells of multiple myeloma.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Flavanonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sequência de Aminoácidos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Alinhamento de Sequência , Células da Side Population/efeitos dos fármacos
7.
PLoS One ; 8(7): e68566, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861918

RESUMO

Angiogenesis is crucial for cancer initiation, development and metastasis. Identifying natural botanicals targeting angiogenesis has been paid much attention for drug discovery in recent years, with the advantage of increased safety. Isoliquiritigenin (ISL) is a dietary chalcone-type flavonoid with various anti-cancer activities. However, little is known about the anti-angiogenic activity of isoliquiritigenin and its underlying mechanisms. Herein, we found that ISL significantly inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) at non-toxic concentration. A series of angiogenesis processes including tube formation, invasion and migration abilities of HUVECs were also interrupted by ISL in vitro. Furthermore, ISL suppressed sprout formation from VEGF-treated aortic rings in an ex-vivo model. Molecular mechanisms study demonstrated that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting HIF-1α (Hypoxia inducible factor-1α) proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies further showed that ISL administration could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling, elevated apoptosis ratio and little toxicity effects. Molecular docking simulation indicated that ISL could stably form hydrogen bonds and aromatic interactions within the ATP-binding region of VEGFR-2. Taken together, our study shed light on the potential application of ISL as a novel natural inhibitor for cancer angiogenesis via the VEGF/VEGFR-2 pathway. Future studies of ISL for chemoprevention or chemosensitization against breast cancer are thus warranted.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Chalconas/farmacologia , Neovascularização Patológica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Trifosfato de Adenosina , Animais , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Ethnopharmacol ; 146(1): 40-61, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23286904

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: While there is an increasing number of toxicity report cases and toxicological studies on Chinese herbal medicines, the guidelines for toxicity evaluation and scheduling of Chinese herbal medicines are lacking. AIM: The aim of this study was to review the current literature on potentially toxic Chinese herbal medicines, and to develop a scheduling platform which will inform an evidence-based regulatory framework for these medicines in the community. MATERIALS AND METHODS: The Australian and Chinese regulations were used as a starting point to compile a list of potentially toxic herbs. Systematic literature searches of botanical and pharmaceutical Latin name, English and Chinese names and suspected toxic chemicals were conducted on Medline, PubMed and Chinese CNKI databases. RESULTS: Seventy-four Chinese herbal medicines were identified and five of them were selected for detailed study. Preclinical and clinical data were summarised at six levels. Based on the evaluation criteria, which included risk-benefit analysis, severity of toxic effects and clinical and preclinical data, four regulatory classes were proposed: Prohibited for medicinal usage, which are those with high toxicity and can lead to injury or death, e.g., aristolochia; Restricted for medicinal usage, e.g., aconite, asarum, and ephedra; Required warning label, e.g., coltsfoot; and Over-the-counter herbs for those herbs with a safe toxicity profile. CONCLUSION: Chinese herbal medicines should be scheduled based on a set of evaluation criteria, to ensure their safe use and to satisfy the need for access to the herbs. The current Chinese and Australian regulation of Chinese herbal medicines should be updated to restrict the access of some potentially toxic herbs to Chinese medicine practitioners who are qualified through registration.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Plantas Medicinais/toxicidade , Animais , Austrália , China , Rotulagem de Medicamentos , Medicamentos de Ervas Chinesas/classificação , Medicamentos de Ervas Chinesas/normas , Humanos , Legislação de Medicamentos , Medicina Tradicional Chinesa , Plantas Medicinais/classificação , Testes de Toxicidade
9.
Asian Pac J Cancer Prev ; 14(12): 7179-86, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24460272

RESUMO

BACKGROUND AND AIMS: Scutellaria is one of the most popular traditional Chinese herbal remedies against various human diseases, including cancer. In this study, we examined the active effects of Scutellaria extract and its main flavonoid constituents on the proportion of side population cells within human multiple myeloma cell line RPMI8226 in vitro and explored the potential molecular mechanisms involved. MATERIALS AND METHODS: The contents of flavonoids in ethanolic extract of Scutellaria baicalensis Georgi were determined using high performance liquid chromatography. The antiproliferative effect of the ethanolic extract on RPMI-8226 was determined by CCK assay. Apoptosis was measured by annexin combining with propidium iodide in a flow cytometer. Cell cycle analysis was performed by propidium iodide staining in combination with flow cytometry analysis. Hoechst 33342 exclusion assay was used for the identification of side population within RPMI8226 cells. The expression of ABCG2 protein was assessed by Western blotting assay. RESULTS: The content of major flavonoids constitutents of Scutellaria extract was baicalin (10.2%), wogonoside (2.50%), baicalein (2.29%), and wogonin (0.99%), respectively. The crude Scutellaria extract did not show significant anti-proliferative effect, apoptosis induction and cell cycle arrest in RPMI-8226 within the concentrations of 1-75µg/mL. However, the ethanolic extract, baicalein, wogonin and baicalin reduced the side population cells in RPMI-8226, and data showed that baicalein and wogonin had stronger inhibitory effects. Correspondingly, they also exhibited significant effects on decreasing the expression level of ABCG2 protein in RPMI-8226 in vitro. CONCLUSIONS: Our results for the first time demonstrated a novel mechanism of action for Scutellaria extract and its main active flavonoids, namely targeting SP cells by modulating the expression of ABCG2 protein. This study provides an insight for new therapeutic strategies targeting cancer stem cells of multiple myeloma.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Fitoterapia , Extratos Vegetais/farmacologia , Scutellaria/química , Células da Side Population/efeitos dos fármacos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/metabolismo , Scutellaria baicalensis , Células da Side Population/metabolismo , Células da Side Population/patologia , Células Tumorais Cultivadas
10.
Med Sci Monit ; 18(6): BR229-36, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22648244

RESUMO

BACKGROUND: Osthole (Ost), a natural coumarin derivative, has been shown to inhibit many pro-inflammatory mediators and block voltage-gated Na+ channels. During inflammation, acidosis is an important pain inducer which activates nociceptors by gating depolarizing cationic channels, such as acid-sensing ion channel 3 (ASIC3). The aim of this study was to examine the effects of Ost on nucleus pulposus-evoked nociceptive responses and ASIC3 over-expression in the rat dorsal root ganglion, and to investigate the possible mechanism. MATERIAL/METHODS: Radicular pain was generated with application of nucleus pulposus (NP) to nerve root. Mechanical allodynia was evaluated using von Frey filaments with logarithmically incremental rigidity to calculate the 50% probability thresholds for mechanical paw withdrawal. ASIC3 protein expression in dorsal root ganglions (DRGs) was assessed with Western blot and immunohistochemistry. Membrane potential (MP) shift of DRG neurons induced by ASIC3-sensitive acid (pH6.5) was determined by DiBAC(4) (3) fluorescence intensity (F.I.). RESULTS: The NP-evoked mechanical hyperalgesia model showed allodynia for 3 weeks, and ASIC3 expression was up-regulated in DRG neurons, reaching peak on Day 7. Epidural administration of Ost induced a remarkable and prolonged antinociceptive effect, accompanied by an inhibition of over-expressed ASIC3 protein and of abnormal shift of MP. Amiloride (Ami), an antagonist of ASIC3, strengthened the antinociceptive effect of Ost. CONCLUSIONS: Up-regulation of ASIC3 expression may be associated with NP-evoked mechanical hyperalgesia. A single epidural injection of Ost decreased ASIC3 expression in DGR neurons and the pain in the NP-evoked mechanical hyperalgesia model. Osthole may be of great benefit for preventing chronic pain status often seen in lumbar disc herniation (LDH).


Assuntos
Cumarínicos/farmacologia , Gânglios Espinais/patologia , Disco Intervertebral/patologia , Proteínas do Tecido Nervoso/metabolismo , Nociceptividade/efeitos dos fármacos , Canais de Sódio/metabolismo , Canais Iônicos Sensíveis a Ácido , Analgésicos/farmacologia , Animais , Western Blotting , Cumarínicos/química , Cumarínicos/uso terapêutico , Imunofluorescência , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Disco Intervertebral/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Dor/complicações , Dor/tratamento farmacológico , Dor/patologia , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Fitoterapia , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Ratos , Ratos Sprague-Dawley
11.
Toxicol Ind Health ; 28(3): 195-202, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21730039

RESUMO

OBJECTIVE: To observe the expression of osteopontin (OPN) in hepatocytes of rats fed with corn baked by burning coal from fluorosis areas and a deficiency of calcium/protein intake following fluorosis. METHODS: A total of 48 Wistar rats as objects were randomly assorted into four groups: dose-free fluorine group, which were mainly fed with fluorine-free corn (56% structurally), dose-free fluorine with biased dietary group, which were fed with lower contents of protein (119.41 g/kg) and calcium (0.68 g/kg), high-dose fluorine group (fluorine contents: 104.2 mg/kg), and high-dose fluorine with biased dietary group. After 180 days of cultivation, the contents of fluorine in the bones of rats were tested for the assessment of construction of fluorosis animal model. And the expression of OPN in hepatocytes of rats in different groups was detected with immunohistochemistry and reverse transcription polymerase chain reaction. RESULTS: The present study validated the result that OPN was overexpressed in hepatocytes following fluorosis after oral intake of burning coal-baked corn. OPN was expressed most significantly in high fluorine with biased dietary group, and the high-fluorine group ranked the second most; and dose-free fluorine with biased dietary group ranked the third. The dose-free fluorine group expressed the least OPN. CONCLUSION: Overexpression of OPN in hepatocytes following fluorosis after excess fluorine intake was involved in liver damage process, which was enhanced by deficiency of calcium and protein intake. The results also demonstrated that the development of fluorosis in Guizhou province was correlated with local baking staple corn as a way of excess intake of fluorine and deficiency of calcium/protein intake.


Assuntos
Carvão Mineral , Culinária , Hepatócitos/metabolismo , Osteopontina/biossíntese , Zea mays , Animais , Peso Corporal , Cálcio/deficiência , China , Proteínas Alimentares/administração & dosagem , Modelos Animais de Doenças , Imuno-Histoquímica , Fígado/química , Fígado/metabolismo , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/metabolismo , Osteopontina/análise , Osteopontina/genética , Ratos , Ratos Wistar
12.
Comb Chem High Throughput Screen ; 15(1): 36-80, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21846324

RESUMO

We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.


Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Medicamentos de Ervas Chinesas/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Scutellaria baicalensis/química , Domínio Catalítico/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores Enzimáticos/química , Humanos , Ligantes , Modelos Moleculares , Relação Estrutura-Atividade
13.
Curr Pharm Biotechnol ; 13(9): 1640-704, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22039821

RESUMO

The highly polymorphic human cytochrome P450 2D6 (CYP2D6) metabolizes about 25% of currently used drugs. In this study, we have explored the interaction of a large number of substrates (n = 120) with wild-type and mutated CYP2D6 by molecular docking using the CDOCKER module. Before we conducted the molecular docking and virtual mutations, the pharmacophore and QSAR models of CYP2D6 substrates were developed and validated. Finally, we explored the interaction of a traditional Chinese herbal formula, Fangjifuling decoction, with CYP2D6 by virtual screening. The optimized pharmacophore model derived from 20 substrates of CYP2D6 contained two hydrophobic features and one hydrogen bond acceptor feature, giving a relevance ratio of 76% when a validation set of substrates were tested. However, our QSAR models gave poor prediction of the binding affinity of substrates. Our docking study demonstrated that 117 out of 120 substrates could be docked into the active site of CYP2D6. Forty one out of 117 substrates (35.04%) formed hydrogen bonds with various active site residues of CYP2D6 and 53 (45.30%) substrates formed a strong π-π interaction with Phe120 (53/54), with only carvedilol showing π-π interaction with Phe483. The active site residues involving hydrogen bond formation with substrates included Leu213, Lys214, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, Phe483, and Phe484. Furthermore, the CDOCKER algorithm was further applied to study the impact of mutations of 28 active site residues (mostly non-conserved) of CYP2D6 on substrate binding modes using five probe substrates including bufuralol, debrisoquine, dextromethorphan, sparteine, and tramadol. All mutations of the residues examined altered the hydrogen bond formation and/or aromatic interactions, depending on the probe used in molecular docking. Apparent changes of the binding modes have been observed with the Glu216Asp and Asp301Glu mutants. Overall, 60 compounds out of 130 from Fangjifuling decoction matched our pharmacophore model for CYP2D6 substrates. Fifty four out of these 60 compounds could be docked into the active site of CYP2D6 and 24 of 54 compounds formed hydrogen bonds with Glu216, Asp301, Ser304, and Ala305 in CYP2D6. These results have provided further insights into the factors that determining the binding modes of substrates to CYP2D6. Screening of high-affinity ligands for CYP2D6 from herbal formula using computational models is a useful approach to identify potential herb-drug interactions.


Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Simulação de Acoplamento Molecular/métodos , Domínio Catalítico , Citocromo P-450 CYP2D6/química , Interações Ervas-Drogas , Medicina Herbária/métodos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Medicina Tradicional Chinesa/métodos , Mutação , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Especificidade por Substrato
14.
Xenobiotica ; 41(4): 259-80, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21117944

RESUMO

The pregnane X receptor (PXR) plays a critical role in the regulation of human cytochrome P450 3A4 (CYP3A4) gene. In this study, we investigated the effect of an array of compounds isolated from Chinese herbal medicines on the activity of PXR using a luciferase reporter gene assay in transiently transfected HepG2 and Huh7 cells and on the expression of PXR and CYP3A4 in LS174T cells. Furthermore, molecular docking was performed to investigate the binding modes of herbal compounds with PXR. Praeruptorin A and C, salvianolic acid B, sodium danshensu, protocatechuic aldehyde, cryptotanshinone, emodin, morin, and tanshinone IIA significantly transactivated the CYP3A4 reporter gene construct in either HepG2 or Huh7 cells. The PXR mRNA expression in LS174T cells was significantly induced by physcion, protocatechuic aldehyde, salvianolic acid B, and sodium danshensu. However, epifriedelanol, morin, praeruptorin D, mulberroside A, tanshinone I, and tanshinone IIA significantly down-regulated the expression of PXR mRNA in LS174T cells. All the herbal compounds tested can be readily docked into the ligand-binding cavity of PXR mainly through hydrogen bond and aromatic interactions with Ser247, Gln285, His407, and Arg401. These findings suggest that herbal medicines can significantly regulate PXR and CYP3A4 and this has important implication in herb-drug interactions.


Assuntos
Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Esteroides/genética , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Humanos , Receptor de Pregnano X , RNA Mensageiro/metabolismo , Receptores de Esteroides/metabolismo
15.
Zhong Yao Cai ; 28(9): 819-20, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16450454

RESUMO

OBJECTIVE: In order to enhance the biological availability of emodin inside the body, develop the method of preparing the magnetic nanometer liposome of emodin. METHODS: Used membrane-ultrasound method to prepare the magnetic nanometer liposome of emodin. RESULTS: The particle diameter of the magnetic nanometer liposome of emodin was about 100-300nm, and its envelopment rate was 33.75%. CONCLUSION: It is easy and feasible to use membrane-ultrasound method to make the magnetic nanometer liposome of emodin, and the envelopment rate of emodin is to be further enhanced.


Assuntos
Medicamentos de Ervas Chinesas/química , Emodina/administração & dosagem , Lipossomos/química , Nanoestruturas , Tecnologia Farmacêutica/métodos , Disponibilidade Biológica , Portadores de Fármacos , Emodina/química , Emodina/metabolismo , Magnetismo , Membranas/metabolismo , Tamanho da Partícula , Plantas Medicinais/química , Rheum/química
16.
Zhong Yao Cai ; 25(11): 842-4, 2002 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-15562712

RESUMO

OBJECTIVE: To explore the effect of Dan Shao Tang (DST) in treating simple hematuria of masked nephritis of deficiency of Yin with damp-heat symptom. METHODS: Sixty patients of simple hematuria of masked nephritis of deficiency of Yin with damp-heat symptom were divided into two groups in random, 35 patients in treatment group were treated with Dan Shao Tang and westen medicine, and 25 patients in control group were treated only with western medicine. The effect, change of hematuria and immunity index of the two groups were observed three months later. RESULTS: The total efficiency of treatment group (65.71%) is better than that of control group (36%). Treatment group is obviously better than control group on decreasing hematuria and improving immune function. CONCLUSION: Dan Shao Tang is effective to treatment on simple hematuria of masked nephritis of dificiency of Yin with damp-heat symptom effectively.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hematúria/tratamento farmacológico , Nefrite/tratamento farmacológico , Fitoterapia , Deficiência da Energia Yin/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adolescente , Adulto , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Dipiridamol/administração & dosagem , Dipiridamol/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 22(1): 30-2, 2002 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-12585168

RESUMO

OBJECTIVE: To study the effect of Colquhounia root tablet (CRT) in treating nephrotic syndrome with sequential lipid metabolism disorder (NS-LMD). METHODS: The 96 patients with NS-LMD were randomly divided into two groups, the 60 cases in the treated group treated with CRT and the 36 cases in the control group treated with hormone or cytotoxic medicine. The curative effect and the related indexes were determined before and after treatment. RESULTS: After six months treatment, the general effective rate in the treated group was 88. 33%, which was markedly higher than that in the control group (69.44%, P < 0.05). The levels of the treated group in ameliorating lipid metabolism disorder and renal dysfunction were also higher than those in the control group (P < 0.05). CONCLUSION: CRT could improve NS-LMD, improve renal function, eliminate urinary protein and increase plasma albumin. It is highly effective with low toxicity and safe.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Fitoterapia , Adolescente , Adulto , Idoso , Colesterol/sangue , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/sangue , Síndrome Nefrótica/complicações , Triglicerídeos/sangue
18.
Zhong Yao Cai ; 25(1): 72-5, 2002 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-12583246

RESUMO

OBJECTIVE: To investigate the ameliorative effect on chronic uric acid nephropathy (CUAN) by integrating western and traditional Chinese medicine (IWTCM). METHODS: The 136 CUAN patients were divided into two groups at random, the therapy group of 86 patients were treated by Chinese medicine and allopurinol, and the control group of 50 patients were treated only by allopurinol. The curative effect and the related index such as blood uric acid, renal function, urinary protein, microproteins, blood lipid and hyperviscosity were determined before and after being treated. RESULTS: After three months treatment, the total effective rate in the therapy group (90.7%) was significantly higher (P < 0.01) than that of the control group (56%). The therapy group is also superior to the control group in improving renal function, lipid metabolism and hyperviscosity, decreasing blood uric acid, urinary protein, microproteins in evidence (P < 0.05, P < 0.01). CONCLUSION: IWTCM can obviously improve the ameliorative effect on chronic uric acid nephropathy.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Nefropatias/tratamento farmacológico , Medicina Tradicional Chinesa , Fitoterapia , Ácido Úrico/sangue , Adulto , Idoso , Alopurinol/uso terapêutico , Viscosidade Sanguínea , Quimioterapia Combinada , Feminino , Humanos , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade
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