RESUMEN
Sunbanghwalmyung-eum (SBH) is a traditional herbal medicine that exhibits various pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. In this study, we investigated the systemic anti-obesity effects of an aqueous extract of SBH in the liver, adipose, and muscle tissue from high-fat and high-cholesterol diet (HFHCD)-induced obese C57BL/6J mice. After 6 weeks of an HFHCD, the mice were continuously fed HFHC with oral administration of SBH (100 mg/kg/day), Sim (simvastatin, 5 mg/kg/day, positive control), or water (HFHC only) for another 6 weeks. Our results showed that SBH attenuated the HFHCD-induced body weight gain and fat accumulation in the liver, and improved plasma lipid levels, such as those of triglycerides (TGs), blood total cholesterol (TC), and low-density lipoprotein (LDL-c). SBH and Sim inhibited the inflammation accompanied by obesity via decreasing inflammatory cytokine interleukin (IL)-1ß, tumor necrosis factor α (TNFα), and monocyte chemoattractant protein 1 (MCP1). Moreover, SBH downregulated the expression of protein levels of adipogenic-related factors, including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in the liver, adipose, and muscle tissue. The SBH and Sim treatment also significantly upregulated the phosphorylation of AMP-activated protein kinase α (AMPKα) in the liver and hormone-sensitive lipase (HSL) in the adipose tissue. Overall, the effects of SBH on HFHCD-induced obesity were similar to or more potent than those of simvastatin. These results indicated that SBH has great potential as a therapeutic herbal medicine for obesity.
Asunto(s)
Fármacos Antiobesidad , Hiperlipidemias , Proteínas Quinasas Activadas por AMP/metabolismo , Adipogénesis , Tejido Adiposo/metabolismo , Animales , Fármacos Antiobesidad/uso terapéutico , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Colesterol/metabolismo , Dieta Alta en Grasa , Hiperlipidemias/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , PPAR gamma/metabolismo , Extractos Vegetales/uso terapéutico , Simvastatina/farmacología , Agua/metabolismoRESUMEN
This study aimed to evaluate the genotoxic potential of the fruit and seed powder, fruit puree, and aqueous extracts of Morinda citrifolia (Rubiaceae, noni). The genotoxic potential of the noni substances was evaluated using in vitro Ames, in vitro chromosomal aberration, and in vivo micronucleus tests. All test procedures were conducted per Organization for Economic Cooperation and Development guidelines, and good laboratory practice. None of the noni fruit test substances showed genotoxic signs up to 5000 and 2000 µg/plate in the Ames and micronucleus tests, respectively. In the chromosomal aberration test, neither the fruit puree nor aqueous extract showed structural and numerical aberrations up to 5000 and 4650 µg/mL, respectively, irrespective of metabolic activation, in both 6 h and 24 h treatment groups. The safe ranges of noni fruit and seed powders were up to 2500 and 2100 µg/mL, respectively, in the 6 h treatment group and up to 1600-4100 and 370-450 µg/mL, respectively, in both 6 h and 24 h treatment groups in the presence of metabolic activation. Noni fruit and seeds were safe in terms of genotoxicity under our experimental conditions. Our data are the first to provide valuable genotoxic information on Morinda citrifolia.
RESUMEN
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.
Asunto(s)
Antineoplásicos/toxicidad , Apiaceae/química , Brassicaceae/química , Cromanos/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Daño del ADN/efectos de los fármacos , Extractos Vegetales/toxicidad , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Animales , Extractos Vegetales/administración & dosificación , Raíces de Plantas/química , Semillas/química , Pruebas de ToxicidadRESUMEN
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.
Asunto(s)
Forsythia , Fármacos Neuroprotectores/farmacología , Oxaliplatino/toxicidad , Extractos Vegetales/farmacología , Animales , Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Frutas/química , Células HCT116 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuritas/efectos de los fármacos , Neurotoxinas/toxicidad , Células PC12 , RatasRESUMEN
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.
Asunto(s)
Docetaxel/farmacocinética , Extractos Vegetales/farmacología , Poaceae/química , Rizoma/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Cromatografía Líquida de Alta Presión , Docetaxel/administración & dosificación , Docetaxel/sangre , Docetaxel/toxicidad , Extractos Vegetales/administración & dosificación , Poaceae/anatomía & histología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
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⯵g/ml of AEPR regardless of metabolic activation. Repeated oral administration of AEPR up to 5000â¯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.
Asunto(s)
Extractos Vegetales/toxicidad , Poaceae , Animales , Bioensayo , Línea Celular , Aberraciones Cromosómicas , Cricetinae , Cricetulus , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Fibroblastos/efectos de los fármacos , Pulmón/citología , Masculino , Ratones Endogámicos ICR , Pruebas de Micronúcleos , Rizoma , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Irinotecán/uso terapéutico , Oxaliplatino/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/farmacología , Camptotecina/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Medicamentos Herbarios Chinos/farmacología , Humanos , Irinotecán/química , Irinotecán/farmacología , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Oxaliplatino/química , Oxaliplatino/farmacología , Fitoterapia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Forsythia/química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/etiología , Fitoquímicos/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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 2000â¯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 12â¯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 2000â¯mg/kg bw and three females at 1000â¯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 2000â¯mg/kg bw.
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Lithospermum/química , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/toxicidad , Pruebas de Toxicidad Subcrónica , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Medicina Tradicional , Nivel sin Efectos Adversos Observados , Extractos Vegetales/administración & dosificación , Raíces de Plantas , Ratas , Ratas Endogámicas F344RESUMEN
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.
Asunto(s)
Antineoplásicos/efectos adversos , Médula Ósea/efectos de los fármacos , Ácidos Cumáricos/farmacología , Células Madre Hematopoyéticas/metabolismo , Extractos Vegetales/farmacología , Poaceae , Taxoides/efectos adversos , Animales , Células Sanguíneas , Células de la Médula Ósea , Factores Estimulantes de Colonias/sangre , Docetaxel , Ensayo de Inmunoadsorción Enzimática , Fibroblastos , Hematopoyesis , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-3/sangre , Interleucina-6/sangre , Ratones Endogámicos C57BL , Propionatos , Reacción en Cadena en Tiempo Real de la Polimerasa , Rizoma , Bazo/efectos de los fármacos , Factor de Células Madre/sangre , Timo/efectos de los fármacosRESUMEN
BACKGROUND: KIOM-CRC#BP3B (BP3B) is a novel herbal prescription that is composed of three plant extracts. Our preliminary study identified that BP3B exhibited potent anti-proliferative activity against various types of cancer cell lines in vitro. Because the in vivo anti-tumor effect of BP3B is not evaluated before clinical trial, we want to test it using patient's samples. METHODS: To confirm the in vivo anti-cancer effect of BP3B, we used genetically characterized patient-derived colon tumor xenograft (PDTX) mouse model. Anti-cancer activity was evaluated with apoptosis, proliferation, angiogenesis and histological analysis. RESULTS: Oral administration of BP3B significantly inhibited the tumor growth in two PDTX models. Furthermore, TUNEL assay showed that BP3B induced apoptosis of tumor tissues, which was associated with degradation of PARP and Caspase 8 and activation of Caspase 3. We also observed that BP3B inhibited cancer cell proliferation by down-regulation of Cyclin D1 and induction of p27 proteins. Inhibition of angiogenesis in BP3B-treated group was observed with immunofluorescence staining using CD31 and Tie-2 antibodies. CONCLUSION: These findings indicated that BP3B has a strong growth-inhibitory activity against colon cancer in in vivo model and will be a good therapeutic candidate for treatment of refractory colon cancer.
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Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/fisiopatología , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Ratones , Ratones Desnudos , Plantas Medicinales/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
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Acroleína/análogos & derivados , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Macrófagos/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína Quinasa C/metabolismo , Acroleína/aislamiento & purificación , Acroleína/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Técnicas de Cultivo de Célula , Línea Celular , Supervivencia Celular/efectos de los fármacos , Lipopolisacáridos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Fosforilación , Proteína Quinasa C beta/metabolismo , Proteína Quinasa C-alfa/metabolismo , Transducción de Señal/efectos de los fármacos , Vitex/químicaRESUMEN
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.
Asunto(s)
Lithospermum/química , Síndromes de Neurotoxicidad/tratamiento farmacológico , Compuestos Organoplatinos/toxicidad , Enfermedades del Sistema Nervioso Periférico , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Animales , Línea Celular Tumoral , Ganglios Espinales/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Fibras Nerviosas/efectos de los fármacos , Oxaliplatino , Células PC12 , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Extractos Vegetales/química , Sustancias Protectoras/química , RatasRESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Brassicaceae/química , Neoplasias Pulmonares/tratamiento farmacológico , Receptores de Muerte Celular/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Semillas/química , Factor de Transcripción CHOP/metabolismo , Regulación hacia ArribaRESUMEN
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.
Asunto(s)
Brassicaceae/química , Inhibidores Enzimáticos/química , Extractos Vegetales/química , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/aislamiento & purificación , Glucuronosiltransferasa/química , Glucuronosiltransferasa/metabolismo , Humanos , Cinética , Fase I de la Desintoxicación Metabólica , Fase II de la Desintoxicación Metabólica , Extractos Vegetales/aislamiento & purificación , Semillas/químicaRESUMEN
In the search for novel herbal-based anticancer agents, we isolated a new angular-type pyranocoumarin, (+)-cis-(3'S,4'S)-3'-angeloyl-4'-tigloylkhellactone (1) along with 12 pyranocoumarins (2-13), two furanocoumarins (14, 15), and a polyacetylene (16) were isolated from the roots of Peucedanum praeruptorum using chromatographic separation methods. The structures of the compounds were determined using spectroscopic analysis with nuclear magnetic resonance (NMR) and high-resolution-electrospray ionization-mass spectrometry (HR-ESI-MS). The multidrug-resistance (MDR) reversal and anti-inflammatory effects of all the isolated compounds were evaluated in human sarcoma MES-SA/Dx5 and lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among the 16 tested compounds, two (2 and 16) downregulated nitric oxide (NO) production and five (1, 7, 8, 11, and 13) inhibited the efflux of drugs by MDR protein, indicating the reversal of MDR. Therefore, these compounds may be potential candidates for the development of effective agents against MDR forms of cancer.
Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Apiaceae/química , Extractos Vegetales/farmacología , Piranocumarinas/farmacología , Sarcoma/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antineoplásicos/química , Células Cultivadas , Citocinas/metabolismo , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Raíces de Plantas/química , Piranocumarinas/química , Sarcoma/patología , Neoplasias Uterinas/patologíaRESUMEN
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.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Citocalasinas/uso terapéutico , Gleditsia/química , Fitoterapia , Extractos Vegetales/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Embrión de Pollo , Citocalasinas/farmacología , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neovascularización Patológica/tratamiento farmacológico , Epidermis de la Planta , Extractos Vegetales/farmacologíaRESUMEN
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.
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Inhibidores de la Angiogénesis/farmacología , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Neovascularización Patológica , Animales , Capilares/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Humanos , Técnicas In Vitro , Laminaria , Metaloproteinasa 2 de la Matriz/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Ostrea , Fosforilación , Prunella , Sargassum , Transducción de Señal/efectos de los fármacosRESUMEN
5,3'-Dihydroxy-6,7,4'-trimethoxyflavanone (DHTMF) is one of the constituents of Vitex rotundifolia, a medicinal herb that is used for the treatment of various disorders in China and Korea. In this study we evaluated the antitumor and antiangiogeneic activities of DHTMF. DHTMF significantly suppressed growth and induced apoptosis in lung carcinoma cells in a dose-dependent manner, as indicated by a decrease in Bcl-2 levels and increases in Bax and cleaved caspase-3 levels. In addition, DHTMF treatment significantly reduced the phosphorylation of Akt and mammalian target of rapamycin (mTOR), accompanied by reductions in the protein level of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF), which are key angiogenic molecules in H522 lung cancer cells. Furthermore DHTMF inhibited VEGF-induced angiogenesis, as indicated by reduced expression of CD34, tube formation and migration in human umbilical vein endothelial cells (HUVECs), as well as reduced neovascularization in an in vivo mouse Matrigel plug assay. DHTMF also inhibited phosphorylation of Akt, mTOR, and p70S6K in HUVECs and lung cancer cells. Taken together, our finding indicated that DHTMF inhibits Akt/mTOR signaling and reduces the expression of HIF-1 α and VEGF in tumor cells, which in turns inhibits endothelial cell-mediated angiogenesis. These results suggest that DHTMF inhibits angiogenesis as well as induces apoptosis via the Akt/mTOR pathway and might elicit pharmacological effects that are useful for treatment of lung cancer.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Flavanonas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosforilación , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Despite current advances in diagnostics and medicines, the incidence of lung cancer is increasing and effective treatment is very challenging. Traditional herbal formulae as well as many herbal plant extracts have been recognized as attractive sources for novel multi-targeted therapy of cancer with minimal side effects. METHODS: The ethanol extract of Kilkyung-baeksan (EE-KKBS) and its component herbs were tested for their ability to inhibit cancer growth in several lung cancer cell lines. The effects of EE-KKBS and ethanol extract of Croton tiglium Linné seed (EE-CT) on cell cycle progression were measured by flow cytometric analysis using propidium iodide staining. Western blot analyses were performed to measure the expression profiles of proteins regulating cell cycle checkpoints. RESULTS: EE-KKBS inhibited the growth of lung cancer cells after 24-72 hours treatment. Lung cancer cells treated with either EE-KKBS or EE-CT showed strong G0/G1 cell cycle arrest. The expressions of p21 and p27, two key regulators of G1 cell cycle checkpoint, were significantly upregulated upon treatment with EE-KKBS and EE-CT. CONCLUSION: EE-KKBS exerted its cytostatic activity through regulating G1 cell cycle checkpoint in lung cancer cells, and this activity is mainly mediated by one of its component herbs, seeds of Croton tiglium. Collectively, our data suggest that EE-KKBS could be a novel candidate for adjuvant therapy for lung cancer.