RESUMEN
In recent years, many alkaloids of plant origin have attracted great attention due to their diverse range of biological properties including anti-hyperglycemic, anti-oxidant, anti-inflammatory, anti-diabetic and anti-tumor activity. Herein, the pyranocarbazole alkaloids were isolated from leaves of Murraya koenigii and their anti-cancer potential was investigated in different cancer cell lines. Among all tested compounds, murrayazoline and O-methylmurrayamine A demonstrated potent anti-cancer activity against DLD-1 colon cancer cells with the IC50 values of 5.7µM and 17.9µM, respectively, without any non-specific cytotoxicity against non-cancer HEK-293 and HaCaT cells. Further, studies of pure compounds revealed that the anti-cancer activity of compounds corresponds with altered cellular morphology, cell cycle arrest in G2/M phase, reactive oxygen species level and mitochondrial membrane depolarization of colon cancer cells. In addition, these compounds activated caspase-3 protein and upregulated Bax/Bcl-2 protein expression ratio leading to induction of caspase-dependent apoptosis in DLD-1 cells. These event induced by carbazole alkaloids also coincides with downregulation of Akt/mTOR suggesting downstream targeting of cell survival pathway. Thus, our in vitro studies not only provided scientific basis of the use of M. koenigii leaves in the traditional Indian Ayurveda medicines, but also expands possibilities of medicinal uses of M. koenigii leaves against colon cancer. Particularly, these findings will help in further investigating murrayazoline and O-methylmurrayamine A or their improvised derivatives as new therapeutics for the treatment of colon cancer.
Asunto(s)
Apoptosis , Carbazoles/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Regulación hacia Abajo , Mitocondrias/metabolismo , Murraya/química , Hojas de la Planta/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Carbazoles/química , Carbazoles/farmacología , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Regulación hacia Abajo/efectos de los fármacos , Humanos , Espacio Intracelular/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Fosforilación/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Murraya koenigii (L.) Spreng. is an important medicinal plant used traditionally as an antiemetic, antidiarrhoeal agent and blood purifier and as a medicine for a variety of ailments. This study investigated the effects of ethanolic extract of M. koenigii (MK) on diabetes-associated insulin resistance induced in mice by chronic low-dose injection of dexamethasone. RESULTS: Mice treated with dexamethasone exhibited hyperglycaemia and impaired glucose tolerance. Treatment with MK reduced the extent of dexamethasone-induced hyperglycaemia and decreased insulin resistance as indicated by improved glucose tolerance and increased insulin-stimulated AKT phosphorylation in skeletal muscle tissue. Further evaluation in clonal skeletal muscle cell lines suggested that MK increased glucose uptake in L6 skeletal muscle cells by increasing cell surface GLUT4 density via an AKT-mediated pathway. CONCLUSION: MK can ameliorate dexamethasone-induced hyperglycaemia and insulin resistance in part by increasing glucose disposal into skeletal muscle.
Asunto(s)
Glucemia/metabolismo , Intolerancia a la Glucosa/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Resistencia a la Insulina , Murraya , Fibras Musculares Esqueléticas/efectos de los fármacos , Fitoterapia , Animales , Dexametasona , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/inducido químicamente , Transportador de Glucosa de Tipo 4/metabolismo , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Insulina/sangre , Masculino , Ratones , Fibras Musculares Esqueléticas/metabolismo , Fosforilación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Obesity is a result of adipocyte hypertrophy followed by hyperplasia. It is a risk factor for several metabolic disorders such as dyslipidemia, type-2 diabetes, hypertension, and cardiovascular diseases. Coagulanolides, particularly coagulin-L isolated from W. coagulan has earlier been reported for anti-hyperglycemic activity. In this study, we investigated the effect of coagulin-L on in vitro models of adipocyte differentiation including 3T3-L1 pre-adipocyte, mouse stromal mesenchymal C3H10T1/2 cells and bone marrow derived human mesenchymal stem cells (hMSCs). Our results showed that, coagulin-L reduces the expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), the major transcription factors orchestrating adipocyte differentiation. Detailed analysis further proved that early exposure of coagulin-L is sufficient to cause significant inhibition during adipogenesis. Coagulin-L inhibited mitotic clonal expansion (MCE) by delayed entry in G1 to S phase transition and S-phase arrest. This MCE blockade was caused apparently by decreased phosphorylation of C/EBPß, modulation in expression of cell cycle regulatory proteins, and upregulation of Wnt/ß-catenin pathway, the early stage regulatory proteins of adipogenic induction. Taken together all evidences, a known anti-hyperglycemic agent coagulin-L has shown potential to inhibit adipogenesis significantly, which can be therapeutically exploited for treatment of obesity and metabolic syndrome.
Asunto(s)
Adipogénesis/efectos de los fármacos , Proteína alfa Potenciadora de Unión a CCAAT/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Withania , Witanólidos/farmacología , Células 3T3-L1 , Animales , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Ratones , Mitosis/efectos de los fármacos , Obesidad/tratamiento farmacológico , PPAR gamma/antagonistas & inhibidores , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Células Madre/efectos de los fármacos , Witanólidos/uso terapéutico , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Wrightia tomentosa Roem. & Schult. (Apocynaceae) is known in the traditional medicine for anti-cancer activity along with other broad indications like snake and scorpion bites, renal complications, menstrual disorders etc. However, the anti-cancer activity of this plant or its constituents has never been studied systematically in any cancer types so far. AIM OF THE STUDY: To evaluate the anti-cancer activities of the ethanolic extract of W. tomentosa and identified constituent active molecule(s) against breast cancer. MATERIAL AND METHODS: Powdered leaves of W. tomentosa were extracted with ethanol. The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa were tested for its anti-proliferative and pro-apoptotic effects in breast cancer cells MCF-7 and MDA-MB-231. RESULTS: The ethanolic extract, subsequent hexane fractions and fraction F-4 of W. tomentosa inhibited the proliferation of human breast cancer cell lines, MCF-7 and MDA-MB-231. The fraction F-4 obtained from hexane fraction inhibited proliferation of MCF-7 and MDA-MB-231 cells in concentration and time dependent manner with IC50 of 50 µg/ml and 30 µg/ml for 24 h, 28 µg/ml and 22 µg/ml for 48 h and 25 µg/ml and 20 µg/ml for 72 h respectively. The fraction F-4 induced G1 cell cycle arrest, reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and subsequent apoptosis. Apoptosis is indicated in terms of increased Bax/Bcl-2 ratio, enhanced Annexin-V positivity, caspase 8 activation and DNA fragmentation. The active molecule isolated from fraction F-4, oleanolic acid and urosolic acid inhibited cell proliferation of MCF-7 and MDA-MB-231 cells at IC50 value of 7.5 µM and 7.0 µM respectively, whereas there is devoid of significant cell inhibiting activity in non-cancer originated cells, HEK-293. In both MCF-7 and MDA-MB-231, oleanolic acid and urosolic acid induced cell cycle arrest and apoptosis as indicated by significant increase in Annexin-V positive apoptotic cell counts. CONCLUSION: Our results suggest that W. tomentosa extracts has significant anti-cancer activity against breast cancer cells due to induction of apoptosis pathway. Olenolic and urosolic acid are important constituent molecules in the extract responsible for anti-cancer activity of W. tomentosa.
Asunto(s)
Antineoplásicos/farmacología , Apocynaceae , Ácido Oleanólico/farmacología , Extractos Vegetales/farmacología , Triterpenos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Etanol/química , Células HEK293 , Humanos , L-Lactato Deshidrogenasa/metabolismo , Hojas de la Planta , Solventes/química , Ácido UrsólicoRESUMEN
The ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemic hamsters. Activity guided isolation resulted in identification of antidyslipidemic compounds ß-AA and ß-AP. Compounds ß-AA and ß-AP decrease the levels of LDL by 36% and 44%, and increase the HDL-C/TC ratio by 49% and 28%, respectively, at a dose of 10mg/kg. In addition, the isolated compounds ß-AA and ß-AP showed significant HMG-CoA-reductase inhibition, which was further established by docking studies.
Asunto(s)
Apocynaceae/química , Dislipidemias/tratamiento farmacológico , Hipolipemiantes/farmacología , Ácido Oleanólico/análogos & derivados , Animales , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Cricetinae , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Dislipidemias/etiología , Dislipidemias/metabolismo , Hidroximetilglutaril-CoA Reductasas/química , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Mesocricetus , Modelos Moleculares , Estructura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Hojas de la Planta/química , Plantas Medicinales/químicaRESUMEN
The natural Cassane and norcassane diterpenes are biosynthetic rearrangement products of Pimarane precursor in the biosynthetic pathway of diterpenes. Their distribution is highly restricted to various genera of Fabaceae family (especially to Caesalpinia genus). A comprehensive account of the structural diversity (322 structures, 114 references) is given in this review along with biological activities of cassane and norcassane diterpenes up to September 2011.
Asunto(s)
Diterpenos/química , Diterpenos/farmacología , Fabaceae/química , Abietanos/metabolismo , Caesalpinia/química , Diterpenos/metabolismo , Plantas Medicinales/químicaRESUMEN
The anticancer potential of Xylopia aethiopica fruit extract (XAFE), and the mechanism of cell death it elicits, was investigated in various cell lines. Treatment with XAFE led to a dose-dependent growth inhibition in most cell lines, with selective cytotoxicity towards cancer cells and particularly the human cervical cancer cell line C-33A. In this study, apoptosis was confirmed by nuclear fragmentation and sub-G(0)/G(1) phase accumulation. The cell cycle was arrested at the G(2)/M phase with a decreased G(0)/G(1) population. A semi-quantitative gene expression study revealed dose-dependent up-regulation of p53 and p21 genes, and an increase in the Bax/Bcl-2 ratio. These results indicate that XAFE could be a potential therapeutic agent against cancer since it inhibits cell proliferation, and induces apoptosis and cell cycle arrest in C-33A cells.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Xylopia , Antineoplásicos Fitogénicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Frutas , Fase G2/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Proteínas Nucleares/metabolismo , Extractos Vegetales/farmacología , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Neoplasias del Cuello Uterino/metabolismoRESUMEN
Skeletal muscle is the major site of postprandial glucose disposal and augmenting glucose uptake into this tissue may attenuate insulin resistance that precedes type 2 diabetes mellitus. Here, we investigated the effect of pongamol, an identified lead molecule from the fruits of Pongamia pinnata, on glucose uptake and GLUT4 translocation in skeletal muscle cells. In L6-GLUT4myc myotubes treatment with pongamol significantly promoted both glucose transport and GLUT4 translocation to the cell surface in a concentration-dependent manner, without changing the total amount of GLUT4 protein and GLUT4 mRNA, effects that were also additive with insulin. Cycloheximide treatment inhibited the effect of pongamol on GLUT4 translocation suggesting the requirement of new protein synthesis. The pongamol-induced increase in GLUT4 translocation was completely abolished by wortmannin, and pongamol significantly potentiated insulin-mediated phosphorylation of AKT (Ser-473). We conclude that pongamol-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane, driven by a PI-3-K/AKT dependent mechanism.
Asunto(s)
Benzofuranos/farmacología , Frutas/química , Glucosa/metabolismo , Millettia/química , Fibras Musculares Esqueléticas/efectos de los fármacos , Extractos Vegetales/farmacología , Androstadienos/farmacología , Animales , Línea Celular , Membrana Celular/metabolismo , Cicloheximida/farmacología , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Insulina/farmacología , Fibras Musculares Esqueléticas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transcripción Genética , WortmaninaRESUMEN
AIM OF THE STUDY: To identify pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits. MATERIAL AND METHODS: Streptozotocin-induced diabetic rats and hyperglycemic, hyperlipidemic and hyperinsulinemic db/db mice were used to investigate the antihyperglycemic activity of pongamol and karangin isolated from the fruits of Pongamia pinnata. RESULTS: In streptozotocin-induced diabetic rats, single dose treatment of pongamol and karanjin lowered the blood glucose level by 12.8% (p<0.05) and 11.7% (p<0.05) at 50mg /kg dose and 22.0% (p<0.01) and 20.7% (p<0.01) at 100mg/kg dose, respectively after 6h post-oral administration. The compounds also significantly lowered blood glucose level in db/db mice with percent activity of 35.7 (p<0.01) and 30.6 (p<0.01), respectively at 100mg/kg dose after consecutive treatment for 10 days. The compounds were observed to exert a significant inhibitory effect on enzyme protein tyrosine phosphatase-1B (EC 3.1.3.48). CONCLUSION: The results showed that pongamol and karangin isolated from the fruits of Pongamia pinnata possesses significant antihyperglycemic activity in Streptozotocin-induced diabetic rats and type 2 diabetic db/db mice and protein tyrosine phosphatase-1B may be the possible target for their activity.
Asunto(s)
Benzofuranos/farmacología , Benzopiranos/farmacología , Frutas/química , Hipoglucemiantes/farmacología , Millettia/química , Células 3T3-L1 , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratones , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Extractos Vegetales/análisis , Proteína Fosfatasa 2C , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
The review covers the phytochemistry and pharmacology of furanoflavonoids describing 291 compounds and containing 228 references.
Asunto(s)
Flavonoides/química , Flavonoides/farmacología , Furanos/química , Furanos/farmacología , Plantas Medicinales/química , Estructura MolecularRESUMEN
Five new flavonoid C-glucosides, 6-hydroxy-2-(4-hydroxybenzyl)-benzofuran-7-C-beta-d-glucopyranoside (1), 3-(alpha-methoxy-4-hydroxybenzylidene)-6-hydroxybenzo-2(3H)-furanone-7-C-beta-d-glucopyranoside (2), 2-hydroxy-2-p-hydroxybenzyl-3(2H)-6-hydroxybenzofuranone-7-C-beta-d-glucopyranoside (4), 8-(C-beta-d-glucopyranosyl)-7,3',4'-trihydroxyflavone (5) and 1,2-bis(2,4-dihydroxy,3-C-glucopyranosyl)-ethanedione (6) and two known compounds C-beta-d-glucopyranosyl-2,6-dihydroxyl benzene (7) and sesquiterpene (8), were isolated from an aqueous extract of the heartwood of Pterocarpus marsupium. The structure has been established using spectroscopic data.
Asunto(s)
Flavonoides/química , Medicina Ayurvédica , Pterocarpus/química , Flavonoides/aislamiento & purificación , Glucósidos/química , Glucósidos/aislamiento & purificación , Conformación Molecular , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
Fruits of Pongamia pinnata afforded four new furanoflavonoids, pongapinnol A-D (1-4), and a new coumestan, pongacoumestan (5) along with thirteen known compounds 6-18. Compounds 16 and 17 are isolated for the first time from this plant. The structures of isolated compounds were elucidated on the basis of spectroscopic data interpretation.