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3.
Int Immunopharmacol ; 78: 106047, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31816576

RESUMO

Isosteroid alkaloids, natural products from Fritillariae Cirrhosae Bulbus, are well known for its antitussive, expectorant, anti-asthmatic and anti-inflammatory properties. However, the anti-inflammatory effect and its mechanism have not been fully explored. In this study, the anti-inflammatory activitives and the potential mechanisms of five isosteroid alkaloids from F. Cirrhosae Bulbus were investigated in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells. The pro-inflammatory mediators and cytokines were measured by Griess reagent, ELISA and qRT-PCR. The expression of MAPKs was investigated by western blotting. Treatment with the five isosteroid alkaloids in appropriate concentrations could reduce the production of nitric oxide (NO), tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in supernatant, and suppressed the mRNA expressions of TNF-α and IL-6. Meanwhile, the five isosteroid alkaloids significantly inhibited the phosphorylated activation of mitogen activated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase (ERK1/2), p38 MAPK and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). These results demonstrated that isosteroid alkaloids from F. Cirrhosae Bulbus exert anti-inflammatory effects by down-regulating the level of inflammatory mediators via mediation of MAPK phosphorylation in LPS-induced RAW264.7 macrophages, thus could be candidates for the prevention and treatment of inflammatory diseases.

4.
Fitoterapia ; 140: 104434, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760067

RESUMO

Fritillaria cirrhosa bulbus is a Chinese folk herb famous for its antitussive, expectorant, anti-asthma and anti-inflammatory properties, and is widely used to treat respiratory diseases. However, the impacts of F. cirrhosa bulbus on oxidative stress are still unkown. In the present study, we investigated the potential effect and mechanism of six isosteroid alkaloids with different chemical structures from F. cirrhosa bulbus on protection against cigarette smoke-induced oxidative stress in RAW264.7 macrophages. The results showed that six isosteroid alkaloids reduced reactive oxygen species (ROS) production, elevated glutathione (GSH) level and promoted heme oxygenase (HO-1) expression, which is in association with induction of NF-E2-related factor 2 (Nrf2) nuclear translocation and up-regulation of Nrf2 expression. Among these alkaloids, verticinone, verticine, imperialine-3-ß-D-glucoside, delavine and peimisine exhibited more potent effect against CSE-induced oxidative stress than that of imperialine. These findings for the first time demonstrated that F. cirrhosa bulbus may play a protective role in cellular oxidative stress by activating Nrf2-mediated antioxidant pathway. Furthermore, the differences in antioxidant effects of these alkaloids were compared, as well as the corresponding structure-activity relationships were preliminarily elucidated. This suggested that F. cirrhosa bulbus might be a promising therapeutic treatment for the prevent of oxidative stress-related diseases.


Assuntos
Alcaloides/farmacologia , Fritillaria/química , Estresse Oxidativo/efeitos dos fármacos , Fumaça/efeitos adversos , Alcaloides/isolamento & purificação , Animais , Glutationa/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Plantas Medicinais/química , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Produtos do Tabaco
5.
J Ethnopharmacol ; 238: 111853, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954613

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fritillariae Bulbus ("Beimu" in Chinese) is a famous traditional Chinese medicine used to treat cough, expectoration and asthma for more than 2000 years, which belongs to the Fritillaria genus in Liliaceae family. Bulbs of Fritillaria cirrhosa D.Don (BFC) and bulbs of Fritillaria pallidiflora Schrenk (BFP) are two important drugs of Beimu. Due to the significant similarities in their outward appearance characters and chemical profiles, BFC has often been adulterated with BFP in Chinese Traditional Medicine markets. AIM OF THE STUDY: This study aims to compare the oral acute toxicity and the traditional pharmacological activities including antitussive, expectorant and anti-inflammatory effects between the extract of BFC and BFP, to clear and definite if the BFP can be used as a substitute of the BFC in the application of traditional medicine. MATERIALS AND METHODS: The extracts were prepared through refluxing with 80% ethanol solvent. For the acute toxicity tests, graded doses of BFP extracts and the maximum dose of BFC extracts were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. For the pharmacological activities tests, graded doses of BFP and BFC extracts were administered orally to mice. To observe the effects relieving cough, expelling phlegm and lessening the ear swelling of BFC extracts and BFP extracts through ammonia liquor inducing cough, phenol red apophlegmating in mice and the xylene-induced auricular swelling of mouse, respectively. RESULTS: In the acute toxicity study, the LD50 value of BFP in mice was calculated to be 213.57 g/kg body weight, and the maximum feasible dose (MFD) value of BFC in mice was 452.14 g/kg. Histopathological analysis has shown inflammatory cells infiltration and cells edema in liver, multinucleated giant cell proliferation in spleen, perivascular exudate and hemorrhage in lung, glomerulus atrophy in kidney of mice after oral administrations of BFP extracts. But only liver cells edema was observed in BFC group. Both BFC extract and BFP extract significantly increased latent period of cough and inhibited cough frequency in mice induced by ammonia. Besides, the two extracts also obviously enhanced mice's tracheal phenol red output in expectorant assessment and inhibited the development of ear edema in anti-inflammatory evaluation assay. CONCLUSION: To summarize, the BFP has the significant similarities in morphological characteristics, chemical profiles and traditional pharmacological activities compared with the BFC. The result of this study provide some valid scientific support for using BFP as a plant substitute of the BFC, but considering the toxicity of BFP is much higher than BFC, we don't recommend long-term oral administration of BFP or exceeding recommended dosage of Chinese Pharmacopoeia 2015.


Assuntos
Anti-Inflamatórios , Antitussígenos , Tosse/tratamento farmacológico , Edema/tratamento farmacológico , Expectorantes , Fritillaria , Extratos Vegetais , Administração Oral , Animais , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Antitussígenos/uso terapêutico , Antitussígenos/toxicidade , Expectorantes/uso terapêutico , Expectorantes/toxicidade , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Raízes de Plantas , Baço/efeitos dos fármacos , Baço/patologia , Testes de Toxicidade Aguda
6.
Planta Med ; 81(10): 821-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26132855

RESUMO

The bulbs of plants belonging to the Fritillaria cirrhosa-group have been used as antitussive and expectorant herbs in traditional Chinese medicine for thousands of years. In this study, we isolated two isomers of verticinone and imperialine, steroidal alkaloids belonging to the cevanine group, from bulbs of Fritillaria wabuensis, which is a part of the Fritillaria cirrhosa group, and investigated their anti-inflammatory effects and relative mechanisms on lipopolysaccharide-stimulated RAW 264.7 macrophages. Our results clearly demonstrate that verticinone or imperialine could dose-dependently inhibit nitric oxide production and also suppress inducible nitric oxide synthase and cyclooxygenase-2 expressions. In addition, verticinone or imperialine suppress the production of pro-inflammatory cytokines in a dose dependent manner, such as tumor necrosis factor-α and interleukin-1ß. The effect of verticinone and imperialine on the activation of nuclear factor-kappaB was also evaluated. The phosphorylation of nuclear factor-kappaB stimulated with LPS is also down-regulated by verticinone or imperialine in a concentration dependent manner, which coincided with the inhibition of phosphorylation forms of inhibitory kappaB-α, a crucial inhibitory factor of nuclear factor-kappaB. Generally, the anti-inflammatory effects and mechanisms of verticinone and imperialine are mediated by the inhibition of the nuclear factor-kappaB activation signaling pathway. According to the results of our researches, verticinone and imperialine may present great potentials to be developed as therapeutics for inflammatory diseases.


Assuntos
Cevanas/farmacologia , Fritillaria/química , Mediadores da Inflamação/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Tubérculos/química , Fator de Necrose Tumoral alfa/metabolismo
7.
J Ethnopharmacol ; 153(1): 258-67, 2014 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24583069

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima, a traditional Chinese medicinal herb, endemic to Yunnan Province is widely used to treat cough, asthma, expectorant, esophageal cancer, gastric cancer, lung cancer, and hepatocellular carcinoma. The aim of this study was to evaluate in vitro and in vivo anti-hematologic neoplasm potential of the ethanolic extract of this herb (crude ethanolic extract of Marsdenia tenacissima, CME) and by using different assays to elucidate its possible mechanism of action. MATERIALS AND METHODS: The cytotoxicity of CME on tumor cells and peripheral blood mononuclear cells (PBMCs) was evaluated using MTT and apoptosis assays. We also tested the effect of CME on colony formation inhibition and cell cycle distribution of tumor cells. The protein expressions of Cyclin D1, Bax, Bcl-2, caspase-3 and caspase-9 were detected through Western blotting. In vivo anti-tumor effect was evaluated by measuring tumor volume changes, measuring tumor weight, evaluation of tumor microvessel density (MVD) and TUNEL staining by using immunohistochemistry staining in tumor models of nude mice. RESULTS: Marsdenia tenacissima ethanolic extract exhibited effects of proliferation inhibition and induction of apoptosis on human hematologic neoplasm tumor cells in vitro, as well as hematologic neoplasm growth in vivo. CONCLUSION: This study clearly indicated that the ethanolic extract of Marsdenia tenacissima displayed strong anti-tumor effects against hematologic neoplasm cells and could induce tumor cells apoptosis in vitro and in vivo, and also had a significant anti-angiogenic effect in vivo against tumor cell apoptosis. Its multi-mechanism of action might be associated with the cell cycle (G0/G1) arrest, induction of apoptosis through up-regulation protein expressions of Bax, caspase-9 and caspase-3 genes and down-regulation of the expressions of Cyclin D1 and Bcl-2 genes, a decrease in tumor microvessel density and an increase of TUNEL-positive cells in vivo. These findings provided the molecular theoretical basis of clinical application.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Etanol/química , Neoplasias Hematológicas/patologia , Humanos , Marcação In Situ das Extremidades Cortadas , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Marsdenia/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regulação para Cima/efeitos dos fármacos
8.
Food Chem Toxicol ; 66: 278-85, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24518540

RESUMO

Rheum emodi has been used as an edible and medicinal plant in Tibet and Kashmir for a long period of time, while safety evaluation of this plant has not yet been investigated. In this study, acute and subchronic oral toxicity studies of aqueous extract of R. emodi (AERE) rhizome were conducted in SD rats. Animals were treated with a single dose of 1000, 2000, 4000 or 10,000 mg/kg of AERE in the acute toxicity. In subchronic oral toxicity, animals were randomly divided into four groups (10 rats/sex/group) and received doses of 0, 1000, 2000, and 4000 mg/kg/d of AERE for 90 days. Daily clinical observations, weekly measurement of body weight and food consumption were conducted. Blood and urine were collected on days 91 to measure changes. At necropsy, selected organs were weighed and recorded, and histological examination was performed. During the subchronic oral toxicity study, no mortality, obvious treatment-related clinical signs and urinalysis parameters were observed. Differences in weight gain, food consumption, hematology, biochemistry, relative organ weight and histopathology examinations between the treated group and the control group were not considered treatment-related. Our results indicated that the no-observed-adverse-effect level (NOAEL) for AERE was 4000 mg/kg/d in both genders.


Assuntos
Extratos Vegetais/toxicidade , Rheum/química , Rizoma/química , Animais , Feminino , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade Subcrônica
9.
Planta Med ; 80(1): 29-38, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24338554

RESUMO

Tenacissoside C, a natural bioactive compound of C21 steroidal saponins, was isolated and purified from air-dried stems of Marsdenia tenacissima. In the present study, the MTT assay showed that tenacissoside C exhibited obvious cytotoxicity in K562 cells with IC50 values of 31.4, 22.2, and 15.1 µM for 24, 48, and 72 h, respectively. Flow cytometry analysis indicated that the antiproliferative activity induced by tenacissoside C might be executed via G0/G1 cell cycle arrest and proapoptosis in K562 cells. Western blotting analysis elucidated that: A) Tenacissoside C induced K562 cell cycle (G0/G1) arrest via downregulating cycline D1 protein expression; and B) Tenacissoside C induced K562 cell apoptosis via the mitochondrial pathway by downregulating Bcl-2 and Bcl-xL protein expression, upregulating Bax and Bak protein expression, and activating caspase-9 and caspase-3. In vivo, significant tumor growth inhibition activity of tenacissoside C was observed in K562 cell-bearing nude mice, accompanied by a significant antiangiogenic effect in vivo against K562 cells (a marked decrease in MVD) and associated with enhanced apoptotic cell death (TUNEL staining assay in vivo), both in dose-dependent manners. The treatment with tenacissoside C did not significantly affect body mass and macroscopic examination of the organs in this mouse tumor model.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Marsdenia/química , Fitosteróis/farmacologia , Saponinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclina D1/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Células K562/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Proteína bcl-X/metabolismo
10.
Nat Prod Res ; 25(12): 1161-70, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21740281

RESUMO

There have, so far, been no papers about the detoxification effects on morphine-dependent animals of a mixture of cis-sec-butyl-1-propoenyl disulphide and trans-sec-butyl-1-propoenyl disulphide (SBD), which is isolated from crude essential oil of Ferula sinkiangensis K.M. Shen, a Chinese traditional herbal medicine. Naloxone-precipitated abstinent morphine-dependent models and naturally abstinent morphine-dependent models were used to evaluate the detoxification effects of intraperitoneal injection of SBD. In addition, the writhing test for mice was used to assess the anti-nociceptive effects of SBD, and the spontaneous activity test was used to verify the sedative effects of SBD. Acute toxicity tests of the SBD in mice were performed and the LD50 values were calculated. The results indicated that SBD can inhibit the abstinent syndromes, and that SBD had good anti-nociceptive and sedative effects.


Assuntos
Medicamentos de Ervas Chinesas/química , Ferula/química , Óleos Voláteis/química , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Sulfetos/farmacocinética , Sulfetos/toxicidade , Animais , Inativação Metabólica , Dose Letal Mediana , Macaca mulatta , Camundongos , Medição da Dor , Ratos , Ratos Sprague-Dawley , Sulfetos/isolamento & purificação , Testes de Toxicidade Aguda
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