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1.
J Appl Toxicol ; 40(7): 965-978, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32084673

RESUMO

An ethanol extract complex of Descurainia sophia seeds and Peucedanum praeruptorum roots, called BP10A, has antitumor potential against colorectal cancer. In the present study, we evaluated the 28-day oral toxicity and the genotoxicity of BP10A. The subacute toxicity test was done through oral administration to mice. ICR mice (n = 10) received daily oral BP10A doses of 0, 500, 1000 and 2000 mg/kg for 28 consecutive days. During administration, general clinical signs, food consumption, organ weights, and hematologic, biochemical and histopathological parameters in male and female mice were assessed. No significant adverse effects up to the highest dose (2000 mg/kg) were found. The genotoxicity was evaluated using a battery of tests, including an in vitro bacterial reverse mutation (Ames) test, an in vivo micronucleus test using bone marrow cells in ICR mice and a chromosomal aberration test using CHL/IU cells. BP10A did not show any genotoxic signs in the Ames (up to 5000 µg/plate), micronucleus (up to 5000 mg/kg) and the chromosomal aberration tests (550-1750 µg/mL). Therefore, BP10A was considered safe based on the subacute toxicity and genotoxicity results, indicating that it is a useful pharmaceutical material with no adverse toxicity.

2.
J Ethnopharmacol ; 249: 112381, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31715286

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythia viridissima fruit, one of Forsythiae Fructus (FF) is widely used in traditional medicine to treat diverse diseases-related clinical symptoms, including fever, pain, vomiting, nausea, and abscess. However, the safety of FF has not been fully assessed. AIM OF THE STUDY: In this study, we evaluated the acute oral toxicity and genotoxic potential of an aqueous extract of Forsythia viridissima fruits (EFVF). MATERIALS AND METHODS: For an acute oral toxicity test, male and female SD rats (n = 5) orally received a single dose of 5000 mg/kg EFVF. The genotoxic potential of EFVF was evaluated with a battery of tests, including an in vitro bacterial reverse mutation test using five mutant strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), an in vitro chromosomal aberration test using Chinese hamster lung (CHL/IU) cells, and an in vivo micronucleus test using bone marrow cells in male ICR mice that were orally administered EFVF. All tests were completed in compliance with Organization for Economic Cooperation and Development guidelines and/or regional regulatory standards for toxicity tests. RESULTS: In the acute oral toxicity test, the animals did not show any significant mortality and body weight changes for 14 days following a single dose of EFVF at 5000 mg/kg. There was no evidence of genotoxicity of EFVF based on the results of the in vitro bacterial reverse mutation test (up to 5000 µg/plate), the in vivo micronucleus test (up to 5000 mg/kg), and the in vitro chromosomal aberration test (1100-2500 µg/mL). CONCLUSIONS: We found that EFVF is safe with regard to acute toxicity in rats as well as genotoxicity such as mutagenesis or clastogenesis under the present experimental conditions. These results might support the safety of EFVF as a potential therapeutic material for the traditional use or pharmaceutical development.

3.
BMC Complement Altern Med ; 19(1): 339, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783843

RESUMO

BACKGROUND: The dried fruits of Forsythia suspensa has generally been used to clear heat and detoxify in traditional Korean and Chinese medicine. Oxaliplatin is a first-line treatment chemotherapeutic agent for advanced colorectal cancer, but it induces peripheral neuropathy as an adverse side effect affecting the treatment regimen and the patient's quality of life. The present study was conducted to evaluate the neuroprotective effects of an aqueous extract of F. suspensa fruits (EFSF) on oxaliplatin-induced peripheral neuropathy. METHODS: The chemical components from EFSF were characterized and quantified using the ultra-high performance liquid chromatography-diode array detector system. The cytotoxicities of anticancer drugs in cancer cells and PC12 cells were assessed by the Ez-Cytox viability assay. To measure the in vitro neurotoxicity, the neurite outgrowth was analyzed in the primary dorsal root ganglion (DRG) cells, and neural PC12 cells that were differentiated with nerve growth factor. To evaluate the in vivo neuroprotective activity, the von Frey test was performed in six-week-old male mice (C57BL/6) receiving EFSF (60-600 mg/kg) in the presence of 20-30 mg/kg cumulative doses of oxaliplatin. Thereafter, the mice were euthanized for immunohistochemical staining analysis with an antibody against PGP9.5. RESULTS: EFSF attenuated the cytotoxic activities of the various anticancer drugs in neural PC12 cells, but did not affect the anticancer activity of oxaliplatin in human cancer cells. Oxaliplatin remarkably induced neurotoxicities including cytotoxicity and the inhibited neurite outgrowth of DRG and neural PC12 cells. However, the co-treatment of EFSF (100 µg/ml) with oxaliplatin completely reversed the oxaliplatin-induced neurotoxicity. Forsythoside A, the major component of EFSF, also exerted remarkable neuroprotective effects against the oxaliplatin-induced neurotoxicity. In addition, EFSF (60-200 mg/kg) significantly alleviated the oxaliplatin-induced mechanical allodynia and loss of intra-epidermal nerve fiber to the levels of the vehicle control in the mouse peripheral neuropathy model. CONCLUSIONS: EFSF could be considered a useful herbal medicine for the treatment of peripheral neuropathy in cancer patients receiving chemotherapy with oxaliplatin.


Assuntos
Forsythia , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/toxicidade , Extratos Vegetais/farmacologia , Animais , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuritos/efeitos dos fármacos , Neurotoxinas/toxicidade , Células PC12 , Ratos
4.
Comb Chem High Throughput Screen ; 22(5): 326-332, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31446890

RESUMO

BACKGROUND: Traditionally, Phragmitis rhizoma has been prescribed to relive a fever, vomiting, dysuria, and constipation, and to promote secretion of fluids. In addition, recent studies have reported its efficacy as a diuretic and antiemetic. Our previous study demonstrated that the Phragmitis rhizoma aqueous extract (EPR) ameliorates docetaxel (DTX)-induced myelotoxicity. AIM AND OBJECTIVE: This study was aimed to investigate the effects of EPR on the pharmacokinetics of DTX in Sprague-Dawley rats. MATERIALS AND METHODS: The animals received an intravenous injection of DTX (5 mg/kg) with or without oral EPR (100 mg/kg) pretreatment for 1 or 6 days. The pharmacokinetics of plasma DTX was analyzed using an ultra-performance liquid chromatography-tandem mass spectrometry system, and pharmacokinetic parameters were estimated via noncompartmental analysis. RESULTS: Relative to the control group (DTX alone), EPR pretreatment did not affect significantly the overall profiles of plasma DTX levels. Consecutively pretreated EPR for 6 days slightly altered AUC0-t and Cmax of DTX by 122 and 145.9%, respectively, but these data did not reach the threshold of statistical significance (p > 0.05). CONCLUSION: These results indicate that DTX exposure may not be affected by EPR treatment at the dose level used in this study, suggesting that oral EPR can be used safely when taken with intravenously injected DTX. However, further studies under the stringent conditions are needed when chronic treatment of EPR and anticancer drug.

5.
J Ethnopharmacol ; 241: 112025, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31189082

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: A rhizome of Phragmites communis Trinius has been used in traditional medicine to remove a heat, relieve vomiting and fever, nourish body fluids, and treat diseases like cancers. However, the safety of Phragmitis rhizoma has not yet been fully assessed. AIM OF THE STUDY: The present study evaluated the genotoxicity of an aqueous extract of Phragmitis rhizoma (AEPR). MATERIALS AND METHODS: The genotoxic potential of AEPR was evaluated using both in vitro and in vivo assay systems: a bacterial reverse mutation (AMES) test using auxotrophic mutant strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1537) and Escherichia coli (WP2 uvrA), a chromosomal aberration test using Chinese hamster lung cells, and a micronucleus test using bone marrow cells from male ICR mice subjected to an oral administration of AEPR. All tests were completed in compliance with the OECD guidelines or regional regulatory standards for toxicity study, and Good Laboratory Practice. RESULTS: When compared with the negative control, no genotoxic signs related to the AEPR treatment were observed in the AMES test up to 5000 µg/plate of AEPR and in the chromosomal aberration test up to 500 µg/ml of AEPR regardless of metabolic activation. Repeated oral administration of AEPR up to 5000 mg/kg/day for 2 days did not affect the body weight gains or mortalities of the experimental mice and did not induce any significant changes in the frequency of micronucleated polychromatic erythrocytes. CONCLUSIONS: The present study demonstrated that aqueous extract of Phragmitis rhizoma is safe regarding genotoxicity in an experimental model at least under the conditions tested. Further toxicity assessment in a human clinical study should be done to support the safe use of Phragmitis rhizoma by patients and healthcare providers.


Assuntos
Extratos Vegetais/toxicidade , Poaceae , Animais , Bioensaio , Linhagem Celular , Aberrações Cromossômicas , Cricetinae , Cricetulus , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Fibroblastos/efeitos dos fármacos , Pulmão/citologia , Masculino , Camundongos Endogâmicos ICR , Testes para Micronúcleos , Rizoma , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética
6.
Biomed Pharmacother ; 116: 108987, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31112870

RESUMO

BP10A is a novel two-herb medicine formula, consisting of Descurainiae sophia Semen and Peucedani praeruptorum Radix. This study was done to evaluate the antitumor efficacy of BP10A and its effect on the efficacy of the anticancer drugs oxaliplatin and irinotecan (CPT-11) in a colon tumor xenograft model. Chemical constituents from the ethanol extracts of BP10A were characterized with the ultra-performance liquid chromatography (UPLC) and each constituent was quantified with the UPLC-diode array detector method. Our study showed that BP10A exerted the cytotoxic effects in two colorectal cancer cell lines and its combination treatments with oxaliplatin or CPT-11 remarkably increased the in vitro cytotoxicity of each cancer drug assessed by the Ez-cytox assay. The in vivo antitumor activity of BP10A was evaluated in three colon cancer patient-derived tumor xenograft (PDTX) models with different genetic backgrounds. Oral administration with BP10A (250 and 500 mg/kg, daily) delayed tumor growth by 34-70% in the all PDTX models. Similarly, intraperitoneal injection of oxaliplatin (6 mg/kg) or CPT-11 (20 mg/kg) also suppressed tumor growth by 31.8-60.5% or by 24.3-50.4%, respectively. Furthermore, the combination treatment of BP10A with oxaliplatin or CPT-11 remarkably enhanced the antitumor activity of each anti-cancer drug and delayed tumor growth by 47.1-74.6% or by 74.4-82.9%, respectively. In accordance with the antitumor activity, the Ki-67 expression for tumor cell proliferation and the CD31 for angiogenesis were decreased, and TUNEL staining for tumor cell apoptosis was remarkably increased by the co-treatment of BP10A and the anticancer drugs as well as by each treatment of BP10A, oxaliplatin or CPT-11. Conclusively, BP10A has a strong tumor inhibitory effect against colon cancer and a synergistic effect with anticancer drugs, suggesting that BP10A could be considered as a good therapeutic candidate for the treatment of colon cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Irinotecano/química , Irinotecano/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxaliplatina/química , Oxaliplatina/farmacologia , Fitoterapia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Molecules ; 24(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934631

RESUMO

The dried fruits of Forsythia viridissima have been prescribed to relive fever, pain, vomiting, and nausea in traditional medicine. Oxaliplatin (LOHP) is used to treat advanced colorectal cancer; however, it frequently induces peripheral neuropathies. This study was done to evaluate the neuroprotective effects of an aqueous extract of Forsythia viridissima fruits (EFVF) and its major constituents. Chemical constituents from EFVF were characterized and quantified with the UHPLC-diode array detector method, and three major constituents were identified as arctiin, matairesinol, and arctigenin. The in vitro cytotoxicity was measured by the Ez-cytox viability assay, and the in vivo neuroprotection activity was evaluated by a von Frey test in two rodent animal models that were administered LOHP. EFVF significantly alleviated the LOHP-induced mechanical hypersensitivity in the induction model. EFVF also prevented the induction of mechanical hyperalgesia by LOHP in the pre- and co-treatment of LOHP and EFVF. Consistently, EFVF exerted protective effects against LOHP-induced neurotoxicity as well as inhibited neurite outgrowths in PC12 and dorsal root ganglion cells. Among the major components of EFVF, arctigenin and matairesinol exerted protective effects against LOHP-induced neurotoxicity. Therefore, EFVF may be useful for relieving or preventing LOHP-induced peripheral neuropathy in cancer patients undergoing chemotherapy with LOHP.


Assuntos
Forsythia/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/etiologia , Compostos Fitoquímicos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo
8.
J Ethnopharmacol ; 235: 406-414, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30703490

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lithospermi radix has been prescribed in traditional folk medicine to treat diverse diseases like cancer. AIM OF THE STUDY: The present study assessed the sub-chronic oral toxicity of an aqueous extract of lithospermi radix (WLR) in Fischer 344 rats over a period of 13 weeks. MATERIALS AND METHODS: The chemical compositions of WLR were analyzed using ultra-high performance liquid chromatography (UHPLC). WLR was daily administered to Fischer 344 rats at 0, 500, 1000, and 2000 mg/kg body weights (bw) for 13 weeks via oral gavage. Changes in mortalities, body weights, and intakes of food and water were monitored during the WLR treatment period. Urine was collected and analyzed 12 h before necropsy. Organ weights, hematological parameters, and plasma biochemical parameters were determined along with histopathological examination. RESULTS: When compared with the normal control group, no remarkable toxic signs or parameter variations related with WLR treatment were observed in mortality, body weights, organ weights, food and water consumptions, urinalysis, hematological and plasma biochemical analyses, and histopathological examination. Mortalities observed in one male at 2000 mg/kg bw and three females at 1000 mg/kg bw were not related with WLR treatment because no gross findings of toxicity were observed in both morphological and histological examination. Some significant changes in clinical parameters or histological lesions observed in WLR-treated animals were not related with WLR treatment because the differences were marginal and did not show dose-dependent or directional changes. CONCLUSIONS: Based on these findings, the calculated no-observed-adverse-effect-level (NOAEL) in rats was higher than 2000 mg/kg bw.


Assuntos
Lithospermum/química , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/toxicidade , Testes de Toxicidade Subcrônica , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Masculino , Medicina Tradicional , Nível de Efeito Adverso não Observado , Extratos Vegetais/administração & dosagem , Raízes de Plantas , Ratos , Ratos Endogâmicos F344
9.
BMC Complement Altern Med ; 17(1): 393, 2017 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-28793897

RESUMO

BACKGROUND: A variety of anticancer chemotherapeutics induce adverse side effects including myelotoxicity. Dried roots of Phragmites communis Trinius, Phragmitis rhizoma, have been clinically used in traditional folk medicine to relieve various symptoms like fever. In this study, we evaluated the protective effect of the aqueous extract of Phragmitis rhizoma (EPR) against docetaxel-induced myelotoxicity in vitro and in vivo. METHODS: The in vitro myelo-protective effect of EPR was evaluated using the colony forming unit (CFU) assay with hematopoietic progenitor cells. The in vivo efficacy of EPR was evaluated in myelosuppressed C57BL/6 male mice which were induced by repeated intraperitoneal injections of 30 mg/kg docetaxel for 3 times. EPR was orally administered for 4 days to docetaxel-induced myelosuppressed C57BL/6 male mice which were induced by intraperitoneal injection of 30 mg/kg docetaxel for 3 times: Group 1 (vehicle control, n = 10), Group 2 (docetaxel plus vehicle, n = 10), Group 3 (docetaxel plus EPR 30 mg/kg, n = 10), Group 4 (docetaxel plus EPR 100 mg/kg, n = 10) and Group 5 (docetaxel plus EPR 300 mg/kg, n = 10). Whole blood counts were measured automatically, and immune organs were histologically examined. Expression of immunomodulatory cytokines was measured by quantitative real-time polymerase chain reaction or enzyme-linked immunosorbent assay. The toxicity of EPR itself was evaluated in normal human cell lines including IMR-90, foreskin fibroblast and human umbilical vein endothelial cells. The hepatotoxicity of EPR was predicted by multi-parametric assays involving cell viability, caspase 3/7 activity, GSH contents and LDH leakage using the HepaRG hepatic cell line. RESULTS: Co-treatment of EPR or its major component, p-hydroxycinnamic acid, increased the numbers of hematopoietic CFU counts in the docetaxel-induced in vitro myelotoxicity assay system. The in vitro protective effect of EPR against docetaxel toxicity was replicated in a myelosuppressed animal model: white blood cells, neutrophils, lymphocytes and red blood cells rebounded; bone marrow niche and structural integrity of the thymus were preserved; and the expression of immune-stimulating cytokines including IL3, IL6, SCF and GM-CSF was enhanced. Furthermore, EPR and p-hydroxycinnamic acid promoted the proliferation of primary splenocytes and thymocytes. In the toxicity assays, no remarkable signs related with toxicity were observed in all tested normal human cells and HepaRG. CONCLUSIONS: EPR has the potential to ameliorate docetaxel-mediated myelotoxicity in both in vitro and in vivo models. However, the identification of the responsible active components and the precise underlying myelo-protective mechanism of EPR need to be elucidated before novel drug development using EPR can precede.


Assuntos
Antineoplásicos/efeitos adversos , Medula Óssea/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Extratos Vegetais/farmacologia , Poaceae , Taxoides/efeitos adversos , Animais , Células Sanguíneas , Células da Medula Óssea , Fatores Estimuladores de Colônias/sangue , Docetaxel , Ensaio de Imunoadsorção Enzimática , Fibroblastos , Hematopoese , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-3/sangue , Interleucina-6/sangue , Camundongos Endogâmicos C57BL , Propionatos , Reação em Cadeia da Polimerase em Tempo Real , Rizoma , Baço/efeitos dos fármacos , Fator de Células-Tronco/sangue , Timo/efeitos dos fármacos
10.
BMC Complement Altern Med ; 16(1): 419, 2016 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-27782842

RESUMO

BACKGROUND: Oxaliplatin can induce peripheral neuropathy (OXIPN) as an adverse side effect in cancer patients. Until now, no effective preventive or therapeutic drug has been developed; therefore, the dose-limiting factor of OXIPN is still an obstacle in the use of oxaliplatin to treat cancer patients. In the present study, we report for the first time that the aqueous extract of Lithospermi radix (WLR) can attenuate the OXIPN in both in vitro and in vivo neuropathic models. METHODS: The protective effect of WLR on OXIPN was evaluated in vitro by quantifying nerve growth factor (NGF)-stimulated neurite outgrowth in PC12 cells treated with a combination of oxaliplatin and WLR. The neuroprotective potential of WLR was further confirmed by measuring the changes in nociceptive sensitivities to external mechanical stimuli in neuropathic animals induced by oxaliplatin. Histological and immunohistochemical studies were further done to examine the effect of WLR in mouse spinal cords and footpads. RESULTS: Oxaliplatin-induced neurotoxicity in NGF-stimulated PC12 cells. It could reduce the lengths and branching numbers of neuritis in NGF-stimulated PC12 cells. Co-treatment of WLR rescued the differentiated PC12 cells from the neurotoxicity of oxaliplatin. In a chronic OXIPN animal model, administration of oxaliplatin i.p. induced enhanced nociceptive sensitivity to mechanical stimuli (25.0 to 72.5 % of response rate) along with spinal activation of microglias and astrocytes and loss of intraepidermal nerve fibers in footpads, which is remarkably suppressed by oral administration of WLR (67.5 to 35 % of response rate at the end of experiment). Cytotoxicity of oxaliplatin determined in human cancer cells was not affected irrespective of the presence of WLR. CONCLUSIONS: In conclusion, we demonstrated that WLR can attenuate OXIPN in both in vitro and in vivo experimental models, which may be in part attributed to its anti-inflammatory activity in the spinal cord and its neuroprotective potential in the peripheral nerve system without affecting the anti-tumor potential of oxaliplatin. Therefore, WLR could be considered as a good starting material to develop a novel therapeutic agent targeting OXIPN. However, further studies should be done to elucidate the underlying mechanism such as molecular targets and active constituent(s) in WLR with neuroprotective potential.


Assuntos
Lithospermum/química , Síndromes Neurotóxicas/tratamento farmacológico , Compostos Organoplatínicos/toxicidade , Doenças do Sistema Nervoso Periférico , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Linhagem Celular Tumoral , Gânglios Espinais/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL , Fibras Nervosas/efeitos dos fármacos , Oxaliplatina , Células PC12 , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Extratos Vegetais/química , Substâncias Protetoras/química , Ratos
11.
Environ Toxicol Pharmacol ; 48: 85-93, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27770660

RESUMO

Coniferaldehyde (CA) exerts anti-inflammatory properties by inducing heme oxygenase-1 (HO-1). To define the regulation mechanism by which CA induces a cytoprotective function and HO-1 expression, the up-stream regulations involved in the activation of nuclear transcription factor-erythroid 2-related factor (Nrf)-2/HO-1 pathway were investigated. CA dramatically increased the Nrf-2 nuclear translocation and HO-1 expression. Lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and cell death were down-regulated by CA, which were reversed by inhibition of HO-1 activity. Furthermore, CA specifically enhanced the phosphorylation of protein kinase C (PKC) α/ß II. Selective inhibition of PKC α/ß II using Go6976 or siRNA abolished the CA-induced Nrf-2/HO-1 signaling, and consequently suppressed the cytoprotective activity of CA on the LPS-induced cell death. Together, our results elucidate the regulatory mechanism of PKC α/ß II as the upstream molecule of Nrf-2 required for HO-1 expression during CA-induced anti-inflammatory cytoprotective function in LPS stimulated macrophages.


Assuntos
Acroleína/análogos & derivados , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Macrófagos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Quinase C/metabolismo , Acroleína/isolamento & purificação , Acroleína/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Lipopolissacarídeos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Fosforilação , Proteína Quinase C beta/metabolismo , Proteína Quinase C-alfa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitex/química
12.
BMC Complement Altern Med ; 16: 115, 2016 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-27039295

RESUMO

BACKGROUND: Our previous genome-wide gene expression analysis revealed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors 4 (DR4) and 5 (DR5) are markedly upregulated by the ethanolic extract of D. sohia seeds (EEDS) in A549 TRAIL-refractory cancer cells. In the present study, we investigated whether the EEDS-mediated upregulation of TRAIL death receptors was associated with increased TRAIL-mediated toxicity in A549 cells in vitro. METHODS: Cell proliferation and viability were determined by an automatic cell counter. Gene silencing was performed by introducing small interfering RNA into cells. Expression changes of cellular proteins were determined by western blot analysis. Apoptotic cell death was monitored by western blot analysis. Analysis of variance followed by the post-hoc Dunnett's test was used to compare the data. RESULTS: EEDS treatment increased both mRNA and protein levels of DR4 and DR5 in the TRAIL refractory A549 cells. Co-treatment of A549 cells with sub-lethal dose of EEDS and recombinant TRAIL increased the apoptotic cell death. Upregulation of DR5 by EEDS was mediated by an endoplasmic reticulum stress-induced transcription factor, CCAAT/enhancer-binding protein homologous protein (CHOP), and knockdown of CHOP expression inhibited EEDS-induced DR5 upregulation and abolished the EEDS-associated increase in TRAIL toxicity in A549 cells. CONCLUSIONS: EEDS can sensitize A549 cells to TRAIL cytotoxicity by upregulation of TRAIL death receptors. Our findings suggested that EEDS is a good initial herbal source for the development of an anticancer supplement for anticancer therapeutics associated with TRAIL.


Assuntos
Antineoplásicos/uso terapêutico , Brassicaceae/química , Neoplasias Pulmonares/tratamento farmacológico , Receptores de Morte Celular/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Sementes/química , Fator de Transcrição CHOP/metabolismo , Regulação para Cima
13.
BMC Complement Altern Med ; 15: 441, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26683337

RESUMO

BACKGROUND: Descurainia sophia seeds have a variety of pharmacological functions and been widely used in traditional folk medicine. However, their effects on human drug metabolizing enzyme (DME) activities have not been elucidated. The present study investigated the inhibitory effects of an ethanol extract of D. sophia seeds (EEDS) on human Phase I/II (DMEs) and P-glycoprotein (p-gp) in vitro. METHODS: The enzyme activities of human Phase I (cytochrome P450s, CYPs), Phase II (uridine diphosphate glucuronosyltransferases, UGTs) DMEs, and the drug transporter P-gp were determined in the presence of various concentrations of EEDS using commercially available luminogenic assay systems. The mode of enzyme inhibition and the inhibitory constant (Ki) value of EEDS were graphically determined with Lineweaver-Burk double reciprocal plots and secondary plots, respectively. RESULTS: The enzyme activity assays showed that EEDS moderately inhibited the CYP1A2, CYP2C9, and CYP2C19 isoforms with half maximal inhibitory concentrations (IC50) of 47.3, 25.8, and 38.7 µg/mL, respectively. Graphical analyses with Lineweaver-Burk double reciprocal plots and secondary plots indicated that EEDS competitively inhibited CYP2C9 with a Ki value of 19.8 µg/mL; however, it inhibited CYP2C9 and CYP2C19 in a mixed mode with Ki values of 5.2, and 11.9 µg/mL, respectively. Other Phase I (CYP2C8, CYP2D6, and CYP3A4) and Phase II (UGT1A1 and UGT2B7) enzymes as well as P-gp were weakly or negligibly affected by EEDS with concentrations up to 500 µg/mL. CONCLUSIONS: EEDS is a selective inhibitor of CYP1A2, CYP2C9, and CYP2C19 with moderate enzymatic inhibition. Clinically, full consideration should be given to a potential toxic adverse effect from a herb-drug interaction when drugs that are particularly susceptible to CYP1A2, CYP2C9, or CYP2C19-mediated metabolism are taken together with EEDS. Characterization of metabolic profiles of specific herbal drugs could help consumers and medical specialists to use them safely as a complementary and alternative medicine.


Assuntos
Brassicaceae/química , Inibidores Enzimáticos/química , Extratos Vegetais/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/isolamento & purificação , Glucuronosiltransferase/química , Glucuronosiltransferase/metabolismo , Humanos , Cinética , Desentoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Extratos Vegetais/isolamento & purificação , Sementes/química
14.
BMC Genomics ; 16: 713, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26384484

RESUMO

BACKGROUND: Although the pharmacological activities of the seed extract of Descurainia sophia have been proven to be useful against cough, asthma, and edema, the biologically active components, particularly at the molecular level, remain elusive. Therefore, we aimed to identify the active component of an ethanol extract of D. sophia seeds (EEDS) by applying a systematic genomic approach. RESULTS: After treatment with EEDS, the dose-dependently expressed genes in A549 cells were used to query the Connectivity map to determine which small molecules could closely mimic EEDS in terms of whole gene expression. Gene ontology and pathway analyses were also performed to identify the functional involvement of the drug responsive genes. In addition, interaction network and enrichment map assays were implemented to measure the functional network structure of the drug-responsive genes. A Connectivity map analysis of differentially expressed genes resulted in the discovery of helveticoside as a candidate drug that induces a similar gene expression pattern to EEDS. We identified the presence of helveticoside in EEDS and determined that helveticoside was responsible for the dose-dependent gene expression induced by EEDS. Gene ontology and pathway analyses revealed that the metabolism and signaling processes in A549 cells were reciprocally regulated by helveticoside and inter-connected as functional modules. Additionally, in an ontological network analysis, diverse cancer type-related genes were found to be associated with the biological functions regulated by helveticoside. CONCLUSIONS: Using bioinformatic analyses, we confirmed that helveticoside is a biologically active component of EEDS that induces reciprocal regulation of metabolism and signaling processes. Our approach may provide novel insights to the herbal research field for identifying biologically active components from extracts.


Assuntos
Brassicaceae/química , Glicosídeos Digitálicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sementes/química , Estrofantinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Biologia Computacional , Humanos , Neoplasias Pulmonares/tratamento farmacológico
15.
Biol Pharm Bull ; 38(6): 909-12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26027832

RESUMO

Angiogenesis is the process of new vessel formation from pre-existing blood vasculature and is critical for continuous tumor growth. We previously reported that an ethanolic extract of Gleditsia sinensis thorns (EEGS) and its active constituent, cytochalasin H, have anti-angiogenic activity in vitro and in vivo via suppression of endothelial cell functions. In the present study, EEGS and cytochalasin H were observed to efficiently inhibit tumor growth in an in ovo xenograft model without significant toxicity. We repeatedly observed the anti-tumor and anti-metastatic effects of EEGS in representative animal models. These results suggest that EEGS and its active constituent, cytochalasin H, are potential candidates for the development of anti-angiogenic cancer drugs.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Citocalasinas/uso terapêutico , Gleditsia/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Embrião de Galinha , Citocalasinas/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neovascularização Patológica/tratamento farmacológico , Epiderme Vegetal , Extratos Vegetais/farmacologia
16.
BMC Complement Altern Med ; 15: 42, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25887757

RESUMO

BACKGROUND: Angiogenesis is a general hallmark of cancer; therefore, the inhibition of tumor-derived angiogenesis is considered to be an attractive target in the development of anti-cancer agents. Sa-mi-yeon-geon-tang (SMYGT), a decoction that consists of four natural medicinal products, has been traditionally prescribed in Oriental medicine to treat diverse diseases, including cancer. In the present study, we investigated the anti-angiogenic potential of SMYGT in vitro and in ovo. METHODS: The anti-angiogenic potential of SMYGT was evaluated using conventional in vitro assays with human umbilical vein endothelial cells (HUVECs) and chorioallantoic membrane (CAM) assays with fertilized eggs. The expression changes of pro-angiogenic proteins and intracellular signaling in HUVECs following SMYGT treatment were determined by quantitative polymerase chain reaction, gelatinase zymography, and western blot analysis. RESULTS: SMYGT efficiently inhibited three-dimensional capillary-like tube formation by HUVECs on extracellular matrix supports, as well as new vessel formation on CAMs. SMYGT inhibited cell adhesion to the extracellular matrix and HUVEC cell invasion through Matrigel without affecting cell proliferation, viability, and motility. These anti-angiogenic effects of SMYGT in HUVECs were related to decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metallopeptidase-2 activity. CONCLUSIONS: SMYGT exhibited an anti-angiogenic potential in both in vitro and in ovo experiments, which may partially contribute to its anti-tumor effect in clinical conditions. We suggest that SMYGT may be a promising source material for the development of anti-cancer chemotherapeutics that target angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Patológica , Animais , Capilares/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/irrigação sanguínea , Membrana Corioalantoide/efeitos dos fármacos , Humanos , Técnicas In Vitro , Laminaria , Metaloproteinase 2 da Matriz/metabolismo , Neovascularização Patológica/tratamento farmacológico , Ostrea , Fosforilação , Prunella , Sargassum , Transdução de Sinais/efeitos dos fármacos
17.
BMC Complement Altern Med ; 14: 353, 2014 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-25249371

RESUMO

BACKGROUND: Angiogenesis, which is initiated by certain tumor micro-environmental conditions and diverse protein factors, plays a pivotal role during tumor development and metastasis. Therefore, many efforts have been made to develop effective anti-angiogenic agents as anticancer therapeutics. In the current study, we investigated the anti-angiogenic potential of an ethanol extract of Annona atemoya seeds (EEAA) in vitro and in vivo. METHODS: The anti-angiogenic potential of EEAA was evaluated using various in vitro/in vivo models, including cell proliferation, migration, and tube formation by human umbilical vascular endothelial cells (HUVECs); a Matrigel plug assay; and tumor-induced angiogenesis. The expression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) was investigated using reverse transcription-polymerase chain reaction, immunoassays, and western blotting. RESULTS: EEAA was able to significantly inhibit the angiogenic properties of HUVECs in vitro as well as angiogenic factor-induced blood vessel formation in vivo. EEAA down-regulated the expression of VEGF and HIF-1alpha/2alpha at the mRNA and protein levels, respectively, in cancer cells under hypoxic conditions. CONCLUSIONS: EEAA shows a strong anti-angiogenic potential in both in vitro and in vivo systems, and we suggest that EEAA may be a valuable herbal source for anticancer drug development.


Assuntos
Inibidores da Angiogênese/farmacologia , Annona/química , Extratos Vegetais/farmacologia , Sementes/química , Análise de Variância , Inibidores da Angiogênese/química , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Etanol , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator 1 Induzível por Hipóxia/análise , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Nus , Extratos Vegetais/química , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Biol Pharm Bull ; 37(1): 6-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24172060

RESUMO

Angiogenesis, the process of new vessel formation from the pre-existing blood vasculature, is critical for continuous tumor growth and is considered to be a validated antitumor target. The results of our previous study demonstrate the anti-angiogenic potential of an extract of Gleditsia sinensis thorns, which has been traditionally used in Korean medicine to remedy diverse diseases, including tumors. In the present study, we attempted to identify the active anti-angiogenic constituents of the ethanol extract of G. sinensis thorns (EEGS). By virtue of in vitro activity-guided fractionation using human umbilical vein endothelial cells (HUVEC) primary endothelial cells, chromatographic separation, and NMR spectral analyses, we isolated and identified the potent active constituent, cytochalasin H, a biologically active secondary metabolite of fungi. This unexpected active constituent may have originated from the endophytic fungi, Chaetomium globosum, which naturally populate G. sinensis, the identity of which was determined by analysis of fungal community. Cytochalasin H isolated from the EEGS showed in vitro anti-angiogenic activities such as suppressed cell growth and mobility in HUVEC, and inhibited the pro-angiogenic protein-induced formation of new blood vessels in vivo. The anti-angiogenic effect of cytochalasin H was in part due to reduced expression of pro-angiogenic factor, such as endothelin-1. This is the first report regarding the isolation and identification of cytochalasin H, as an active anti-angiogenic constituent of G. sinensis thorns.


Assuntos
Inibidores da Angiogênese/farmacologia , Citocalasinas/farmacologia , Fungos/química , Gleditsia/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Patológica , Extratos Vegetais/farmacologia , Inibidores da Angiogênese/isolamento & purificação , Células Cultivadas , Chaetomium/química , Citocalasinas/isolamento & purificação , Endófitos/química , Humanos , Extratos Vegetais/química , Estruturas Vegetais
19.
Molecules ; 19(1): 122-38, 2013 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-24366089

RESUMO

A new tetrahydrofuran lignan, (7S,8R,7'S,8'S)-3-methoxy-3',4'-methylenedioxy-7,9'-epoxylignane-4,7',9-triol (1), and 21 known compounds 2-22 were isolated from the roots of Asiasarum heterotropoides by chromatographic separation methods. The structures of all compounds 1-22 were elucidated by spectroscopic analysis including 1D- and 2D-NMR. Fourteen of these compounds (1-3, 7, 10, 12-17, 19, 21, and 22) were isolated from this species in this study for the first time. All of the isolates were evaluated for their anticancer activities using in vitro assays. Among the 22 tested compounds, two (compounds 5 and 7) induced the downregulation of NO production, FOXP3 expression, and HIF-1α transcriptional activity.


Assuntos
Fatores de Transcrição Forkhead , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Traqueófitas/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fatores de Transcrição Forkhead/genética , Humanos , Lignanas/química , Lignanas/farmacologia , Camundongos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Células NIH 3T3 , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Regiões Promotoras Genéticas/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
20.
Nutr Cancer ; 65(8): 1245-53, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24066970

RESUMO

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to possess anticancer activity. Recent studies have also demonstrated that magnolol inhibits cell growth and induces the apoptosis of cancer cells. However, the effects of magnolol on vascular endothelial growth factor (VEGF)-induced angiogenesis in endothelial cells have not been studied. In the present study, we have used human umbilical vein endothelial cells (HUVECs) to investigate the antiangiogenic effect and molecular mechanism of magnolol. Magnolol inhibited the VEGF-induced proliferation, chemotactic motility and tube formation of HUVECs in vitro as well as the vessel sprouting of the aorta ex vivo. Furthermore, magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs. In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Compostos de Bifenilo/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Lignanas/farmacologia , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Magnolia/química , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Crescimento do Endotélio Vascular/metabolismo
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