RESUMEN
Using the model of cyclophosphamide (CP)-induced immunosuppression in C57BL/6 mice, the hepatotropic effects of a conjugate of betulonic acid with 9-(4-methylpiperazin-1-ylmethyl)-2-(1,2,3-triazolyl) oreozelone (BABC) have been studied. In the liver of treated animals the expression of genes for cytochromes (CYP 1A1, CYP 1A2, CYP 3A44, CYP 2B10, CYP 2C29, CYP 17A1), PPARA, and cytokines (TNF-α, IL-1ß, IL-12α, IL-10) and the relative levels of NF-κB p65, GST-π, and NAT-1 proteins were determined. On day six after administration of the compound and CP to animals a significant (3.2-fold) increase in the expression of the CYP 2B10 as compared to the control group was observed. Treatment of mice with the compound and CP also caused a 2.4-fold increase in the mRNA level of the pro-inflammatory TNF-α gene as compared to the group of animals receiving CP. Administration of the studied compound to intact animals was accompanied by a 2.5-fold increase in the IL-1ß expression and a 1.8-fold decrease in the IL-10 expression as compared to the control group. An increase in the expression of pro-inflammatory cytokine genes in the liver of animals treated with the compound was accompanied by an increase in the content of NF-κB p65 (by 1.6 times), as well as an increase in the relative amount of NAT-1 protein (by 2.7 times) as compared to control animals.
Asunto(s)
Ácido Betulínico , Ácido Oleanólico , Factor de Necrosis Tumoral alfa , Animales , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/genética , Interleucina-10 , FN-kappa B , CiclofosfamidaRESUMEN
The immunomodulatory activity of a betulonic acid-based compound with furocoumarin (BABCF; 2-azido, 9-N-methylpiperazinomethyl oreozelone) has been investigated. Male C57BL/6 mice (aged 3 months) treated with the cytostatic agent cyclophosphamide (CP) and intact individuals served as experimental models. The expression of genes was studied in bone marrow (IL-12, IL-10, IL-1ß, TNF-α, TGF-ß, M-CSF, GM-CSF) or in the suspension of peritoneal cells (IL-12, IL-10; as the injection site). The surface markers of T-lymphocytes (CD3, CD4, and CD8) in fractions of venous blood mononuclear cells (MNCs) were determined by means of flow cytometry using antibodies. Histological and morphometric studies were performed to assess the impact of CP and BABCF on the thymus. BABCF caused a pronounced (about 3-fold) increase in relative expression of the GM-KSF gene. BABCF caused a local increase in the expression of IL-12 in the peritoneal cavity cells and restored the relative content of T-lymphocytes in the blood of CP-treated mice treated affecting mainly CD3âºCD4⺠lymphocytes. This substance reduced the tissue density of the thymic cortex and thymic medulla in CP-treated mice. Thus, results of this study suggest that BABCF exhibits a stimulating effect on the cellular link of immunity and promotes maintenance of the number of T-lymphocytes in the blood due to their migration from the central organs of the immune system.
Asunto(s)
Interleucina-10 , Factor de Necrosis Tumoral alfa , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Anticuerpos , CiclofosfamidaRESUMEN
Antianxiety action of diterpene alkaloid songorine was studied using Vogel conflict test. Songorine in a dose of 0.25 mg/kg demonstrated high anxiolytic activity comparable to that of phenazepam and produced no sedative effect.
Asunto(s)
Alcaloides/farmacología , Ansiolíticos/farmacología , Diterpenos/farmacología , Estrés Psicológico/tratamiento farmacológico , Aconitum/química , Alcaloides/aislamiento & purificación , Animales , Ansiolíticos/aislamiento & purificación , Conducta Animal/efectos de los fármacos , Benzodiazepinas/farmacología , Conflicto Psicológico , Diterpenos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos CBA , Estrés Psicológico/fisiopatologíaRESUMEN
We studied the role of intracellular signaling molecules PI3K, ÐÐÐ K ERK1/2, and Ñ38 in stimulation of realization of the growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Inhibitors of PI3K, ERK1/2 and Ñ38 canceled the increase in proliferative activity of progenitor cells, the blockers of ERK1/2 and Ñ38 reduced the intensity of progenitor cell differentiation.
Asunto(s)
Alcaloides/farmacología , Sistema de Señalización de MAP Quinasas/fisiología , Células Madre Mesenquimatosas/efectos de los fármacos , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/enzimología , División Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Ensayo de Unidades Formadoras de Colonias , Flavonoides/farmacología , Imidazoles/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células Madre Mesenquimatosas/enzimología , Ratones , Ratones Endogámicos CBA , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Modelos Biológicos , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/fisiologíaRESUMEN
We studied the role of NF-κB/IKK-mediated signaling in the stimulation of growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Specific NF-κB inhibitor oridonin abolished activation of proliferation and differentiation of progenitor cells. Aurothiomalate, a selective blocker of IKK-2, also suppressed mitotic activity of fibroblast precursors, but had no effect on the rate of the differentiation.
Asunto(s)
Alcaloides/farmacología , Quinasa I-kappa B/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , FN-kappa B/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Diterpenos de Tipo Kaurano/farmacología , Tiomalato Sódico de Oro/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Ratones , Modelos Biológicos , FN-kappa B/antagonistas & inhibidores , Medicina RegenerativaRESUMEN
The reaction of betulonic acid chloride with 4-amino-2,2,6,6-tetramethylpeperidine-1-oxyl, 3-amino-2,2,5,5-tetramethylpyrrolidine-1-oxyl and 3-aminomethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl gave corresponding triterpenoid amides. It was found that new derivatives exhibit cytotoxic activity against tumor cells CEM-13, U-937, MT-4. CCID50 value for most activity compound--N-[3-oxolup-20(29)-en-30-yl]-(2,2,6,6-tetramethylpiperidine-4-yl)-1-oxyl--was 5.7-33.1 microM.
Asunto(s)
Amidas/síntesis química , Ácido Oleanólico/análogos & derivados , Terpenos/síntesis química , Amidas/química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Ácido Oleanólico/síntesis química , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Marcadores de Spin , Terpenos/química , Terpenos/farmacologíaRESUMEN
The current paper presents research results related to antiarrhythmic activity of halogen-containing derivatives of lappaconitine. Lappaconitine derivatives with iodine, chlorine or bromine substituting the anthranilate moiety at C-5` position were shown in vivo and in vitro to exhibit a more (Br, I) or less (Cl) pronounced antiarrhythmic activity in the models of calcium chloride- and adrenaline-induced arrhythmias as compared with the reference compound lappaconitine. The intensity of antiarrhythmic action depending on halogen substituent was found to be expressed by the following order: Cl < I < Br.
Asunto(s)
Aconitina/análogos & derivados , Antiarrítmicos/química , Antiarrítmicos/farmacología , Halógenos/química , Frecuencia Cardíaca/efectos de los fármacos , Aconitina/química , Aconitina/farmacología , Animales , Modelos Animales de Enfermedad , Humanos , Estructura Molecular , RatasRESUMEN
Accessible triterpenoids of ursane and lupane series, the flavonoid dihydroquercetin and their synthetic derivatives with polar substituentss were tested in vitro for inhibition of collagenase 1 (MMP-1) in UVB irradiation assay. Ursolic acid and uvaol disuccinate were the most active inhibitors in the ursane series. In the lupane series, the best inhibition was manifested by carboxymethyl ester of betulonic acid and betulin succinates. Down- regulation of MMP-1 by dihydroquercetin and its synthetic derivatives surpassed the activity of a standard (retinoic acid).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quercetina/análogos & derivados , Envejecimiento de la Piel/efectos de los fármacos , Triterpenos/farmacología , Antiinflamatorios no Esteroideos/química , Línea Celular , Fibroblastos/efectos de los fármacos , Humanos , Interleucina-8/antagonistas & inhibidores , Queratinocitos/efectos de los fármacos , Metaloproteinasa 1 de la Matriz , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Quercetina/química , Quercetina/farmacología , Tretinoina/química , Tretinoina/farmacología , Triterpenos/química , Rayos Ultravioleta , Ácido UrsólicoRESUMEN
Pinusolide (1), a known platelet-activating factor (PAF) receptor binding antagonist, was synthesized from lambertianic acid (2), a labdane-type diterpene readily accessible in multigram quantities from the Siberian pine tree. It was shown that 1 not only decreases the proliferation activity of tumor cells at relatively low concentrations but specifically induces apoptosis at 100 microM via the mitochondrial pathway in the Burkitt lymphoma cell line BJAB. Also, using primary lymphoblasts and leukemic cells from children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), a significant DNA fragmentation in pinusolide-treated cells could be detected in an ex vivo apoptosis assay.