RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The Moutan cortex (MC), the root bark of Paeonia suffruticosa Anderws (Paeoniaceae), has been historically employed in traditional herbal medicine for addressing women's ailments by replenishing kidney Yin. AIM OF THE STUDY: We aimed to explore if paeonol, an active constituent of MC, could ameliorate neuropsychiatric symptoms, such as anxiety, depression, and cognitive impairments, associated with post-menopausal syndrome (PMS) in an ovariectomized (OVX) mouse model. MATERIALS AND METHODS: The experimental design comprised 6 groups, including a sham group, OVX group, paeonol administration groups (3, 10 or 30 mg/kg, p.o.), and an estradiol (E2)-treated positive control group. Behavioral tests including the open field, novel object recognition, Y-maze, elevated plus-maze, splash, and forced swimming tests were conducted. In addition, we investigated the effets of paeonol on the phosphorylated levels of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), as well as on the expression levels of G protein-coupled receptor (GPR30) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus. RESULTS: Paeonol treatment (10 and 30 mg/kg, p.o.) effectively reversed the cognitive decline in OVX mice, measured by the novel object recognition and Y-maze tests, similar to that in the positive control group. Additionally, it alleviated anxiety- and depressive-like behaviors, as evaluated by the elevated plus-maze test, splash test, and forced swimming test. Paeonol restored GPR30 expression levels in the prefrontal cortex and hippocampus, mirroring the effects of E2 administration. Furthermore, it reversed the reduced expression levels of the PI3K-Akt-mTOR signaling pathway in the prefrontal cortex and hippocampus and increased BDNF expression in the hippocampus of OVX mice. CONCLUSION: This research suggests that paeonol would be beneficial for alleviating PMS-associated cognitive impairment, anxiety and depression.
Assuntos
Acetofenonas , Fator Neurotrófico Derivado do Encéfalo , Pós-Menopausa , Camundongos , Humanos , Feminino , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipocampo , Serina-Treonina Quinases TOR/metabolismo , Mamíferos/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. AIM OF THE STUDY: We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. MATERIALS AND METHODS: OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17ß-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK-3ß), ß-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. RESULTS: EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3ß, and ß-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. CONCLUSION: These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3ß/ß-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.
Assuntos
Artemisia annua , Proteínas Proto-Oncogênicas c-akt , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Glicogênio Sintase Quinase 3 beta , beta Catenina/metabolismo , Sinaptofisina , Pós-Menopausa , MAP Quinases Reguladas por Sinal Extracelular/metabolismoRESUMO
Although C17 polyacetylenes from Panax ginseng exhibit cytotoxic properties against various tumor cells, there have been few experiments on epithelial ovarian carcinoma cells. This study aimed to investigate the cytotoxic effects of C17 polyacetylenes from P. ginseng against ovarian cancer cell lines. Four unreported (1-4) and fifteen known (5-19) C17 polyacetylenes were obtained from the roots of P. ginseng using repeated chromatography (open column, MPLC, and preparative HPLC). The chemical structures of all the compounds were determined by analyzing their spectroscopic data (NMR, IR, and optical rotation) and HR-MS. The structures of new polyacetylenes were elucidated as (3S,8S,9R,10R)-(-)-heptadeca-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (1), (3S,8S,9R,10R)-(-)-heptadeca-1-en-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (2), (-)-haptadeca-9,10-epoxy-8-methoxy-4,6-diyne-3,11-diol (3), and (3R,9R,10R)-(+)-3-acetoxy-9,10-dihydroxyheptadeca-1-en-4,6-diyne (4), named ginsenoynes O, P, and Q, and 3-acetyl panaxytriol, respectively. Subsequently, in vitro experiments on A2780 and SKOV3 human epithelial ovarian carcinoma cells were performed to assess the cytotoxic properties of the isolates. Among the isolates, panaquinquecol 4 (15) exhibited the most remarkable cytotoxic effects on both human ovarian cancer cells A2780 (IC50 value of 7.60 µM) and SKOV3 (IC50 value of 27.53 µM). Therefore, C17 polyacetylenes derived from P. ginseng may warrant further investigation for their therapeutic potential in epithelial ovarian cancer.
Assuntos
Neoplasias Ovarianas , Panax , Humanos , Feminino , Panax/química , Carcinoma Epitelial do Ovário , Polímero Poliacetilênico , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Poli-Inos/farmacologia , Poli-Inos/química , Raízes de Plantas/químicaRESUMO
Rhizomes of Cyperus rotundus have been widely used as a traditional medicine in Asia for the treatment of gynecological diseases. However, there is no scientific evidence demonstrating the effect of C. rotundus rhizomes on endometriosis, which is characterized by the adhesion of endometrial tissues outside the uterus, resulting in chronic and severe pelvic pain. The aim of this study was to investigate the effects of Cyperi rhizoma extract (CRE) on cell adhesion and the expression of pain-related factors (neurotrophins) in endometriotic cells, and to elucidate the underlying molecular mechanisms. CRE inhibited the adhesion of human endometriotic 12Z cells to peritoneal mesothelial Met5A cells using by adhesion assays. The mRNA expression of adhesion molecules [P-cadherin and matrix metalloproteinase (MMP)-2] was downregulated by CRE treatment. In addition, CRE significantly inhibited the mRNA expression of neurotrophins (BDNF, NGF, NT-3 and NT-4/5) in 12Z cells. Moreover, Akt overexpression markedly neutralized the inhibition of cell adhesion by CRE and expression of neurotrophins in 12Z cells. Furthermore, it was found that CRE suppressed NF-kB activation through the Akt pathway. These data suggest that CRE exerts anti-endometriotic activities by the inhibition of cell adhesion and neurotrophin expression, through the negative regulation of the Akt and NF-kB pathways in endometriotic cells.
Assuntos
Cyperus/química , Endometriose , NF-kappa B , Extratos Vegetais , Proteínas Proto-Oncogênicas c-akt , Adesão Celular , Células Cultivadas , Endometriose/complicações , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Feminino , Humanos , Dor , Extratos Vegetais/farmacologia , Rizoma/química , Transdução de SinaisRESUMO
PURPOSE: Osteoporosis is a metabolic skeletal disease characterized by bone loss and an increased risk of fractures. This study aimed to investigate the therapeutic effect of Agastache rugosa on postmenopausal osteoporosis and elucidate its mechanisms in modulating the bone status. METHODS AND RESULTS: In the osteoblast differentiation process with MC3T3-E1 pre-osteoblasts, ethanol extract of Agastache rugosa (EEAR) and its compounds increased the expression of the proteins and genes of the osteoblast differentiation-related markers such as Runt-related transcription factor 2 (RUNX2) and ß-catenin along with the elevation of calcium deposits. An ovariectomized mouse model was utilized to determine the impact of EEAR extract on postmenopausal osteoporosis. Twelve weeks of AR treatment suppressed the loss of bone strength, which was observed through micro-computed tomography. AR elevated osteogenic markers in the bone marrow cells, and collagen type 1 alpha 1 in the distal femoral bone. The results of the 16S rRNA gene sequencing analysis of cecal gut microbiomes demonstrated that AR reversed the ovariectomy-induced changes in the gut microbiomes. CONCLUSION: Ethanol extract of Agastache rugosa has a therapeutic effect on postmenopausal osteoporosis via bone morphogenic protein, transforming growth factor ß, and Wnt signaling pathway. It also increases the diversity of gut microbiota. Therefore, these data suggest that EEAR could be a potential candidate to treat postmenopausal osteoporosis.
Assuntos
Agastache/química , Microbioma Gastrointestinal/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Etanol/química , Feminino , Microbioma Gastrointestinal/genética , Camundongos Endogâmicos C57BL , Osteoblastos/fisiologia , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/microbiologia , Ovariectomia , Extratos Vegetais/química , RNA Ribossômico 16S , Via de Sinalização Wnt/efeitos dos fármacos , Microtomografia por Raio-XRESUMO
Codonopsis lanceolata roots have been widely used in Korean cuisine and traditional medicine. This study aimed to investigate the antimetastatic effects of lancemaside A, a major triterpenoid saponin, isolated from the roots of C. lanceolata, in human ovarian cancer cells. Lancemaside A significantly suppressed the migration and invasion and the expression of matrix metalloproteinases (MMPs)-2 and -9 in ovarian cancer A2780 and SKOV3 cells. Treatment with lancemaside A generated reactive oxygen species (ROS) in ovarian cancer cells. However, treatment with anti-oxidant N-acetyl-L-cysteine (NAC) significantly negated the anti-invasive activity of lancemaside A. Additionally, lancemaside A activated p38 MAP kinase, which is mediated by ROS generation. This is the first study, to our knowledge, to reveal that lancemaside A isolated from the roots of C. lanceolata exerts antimetastatic activity through inhibition of MMP expression and cancer cell invasion via activation of the ROS-mediated p38 pathway.
Assuntos
Codonopsis/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/patologia , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos Fitogênicos , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Humanos , Saponinas/isolamento & purificação , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3',4'-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.
Assuntos
Antineoplásicos Fitogênicos , Apoptose/efeitos dos fármacos , Isoflavonas , Millettia/química , Neoplasias Ovarianas/tratamento farmacológico , Sementes/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular , Feminino , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Isoflavonas/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologiaRESUMO
Two new aryltetralin lactone lignans, petasitesins A and B were isolated from the hot water extract of the leaves of butterbur (Petasites japonicus) along with six known compounds. The chemical structures of lignans 1 and 2 were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Petasitesin A and cimicifugic acid D showed significant inhibitory effects on the production of both prostaglandin E2 (PGE2) and NO in RAW264.7 macrophages. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were inhibited by compound 1 in RAW264.7 cells. Furthermore, compounds 1 and 3 exhibited strong affinities with both iNOS and COX-2 enzymes in molecular docking studies.
Assuntos
Anti-Inflamatórios/farmacologia , Lignanas/farmacologia , Petasites , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Lignanas/análise , Lignanas/química , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Células RAW 264.7RESUMO
Chrysanthemum boreale is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from C. boreale (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, ß-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. ß- Caryophyllene induced G1 cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21CIP1/WAF1 and p27KIP1. These results indicate that ß-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Chrysanthemum/química , Neoplasias Pulmonares/metabolismo , Sesquiterpenos Policíclicos/farmacologia , Células A549 , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Óleos Voláteis/farmacologiaRESUMO
The roots of Aucklandia lappa have been used in traditional medicine in Asia to treat inflammation and diseases associated with pain, including endometriosis. The aim of this study was to investigate the anti-endometriotic effect of dehydrocostus lactone, an active compound in A. lappa roots, using human endometriotic cells and macrophages stimulated by these cells. Dehydrocostus lactone induced apoptotic cell death in 12Z human endometriotic cells. Dehydrocostus lactone stimulated the activation of caspase-3, -8, and -9, while caspase inhibitors significantly reversed the dehydrocostus lactone-induced cell death in 12Z cells. In addition, dehydrocostus lactone decreased the production of PGE2 and neurotrophins (BDNF, NGF, NT3, and NT4/5), which are regarded as endometriosis-associated pain factors in human endometriotic cells. Moreover, dehydrocostus lactone inhibited the expression of M2 markers (CD206, and Trem-2), IL-10, VEGF, and MMP-2/-9 in endometriosis-associated macrophages (EAMs). Furthermore, dehydrocostus lactone inhibited the Akt and NFκB pathways in both endometriotic cells and EAMs. Taken together, our findings suggest that dehydrocostus lactone, an active compound of A, lappa, has anti-endometriotic activities via induction of apoptosis and downregulation of pain factors in endometriotic cells and inhibition of the alternative activation of EAMs.
Assuntos
Apoptose/efeitos dos fármacos , Endometriose/tratamento farmacológico , Endometriose/imunologia , Endométrio/citologia , Lactonas/farmacologia , Lactonas/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Fitoterapia , Raízes de Plantas/química , Saussurea/química , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Caspases/metabolismo , Linhagem Celular , Dinoprostona/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Lactonas/isolamento & purificação , Lectinas Tipo C/metabolismo , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Medicina Tradicional , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Sesquiterpenos/isolamento & purificação , Estimulação QuímicaRESUMO
Two tetrahydrofurofurano lignans (1 and 2), four phenylpropanoids (3â»6), and two alkamides (7 and 8) were isolated from the EtOAc-soluble fraction of the roots of Asarum sieboldii. The chemical structures of the isolates were identified by analysis of spectroscopic data measurements, and by a comparison of their data with published values. The isolates (1, 2, 4â»8) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780 and SKOV3) and immortalized ovarian surface epithelial cells (IOSE80PC) using a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Of the isolates, (-)-asarinin (1) exhibited the most potent cytotoxicity to both A2780 and SKOV3 cells. A propidium iodide/annexin V-fluorescein isothiocyanate (V-FITC) double staining assay showed that (-)-asarinin (1) induces apoptotic cell death in ovarian cancer cells. In addition, (-)-asarinin (1) increased the activation of caspase-3, caspase-8, and caspase-9 in ovarian cancer cells. Pretreatment with caspase inhibitors attenuated the cell death induced by (-)-asarinin (1). In conclusion, our findings show that (-)-asarinin (1) from the roots of A. sieboldii may induce caspase-dependent apoptotic cell death in human cancer cells.
Assuntos
Antineoplásicos/farmacologia , Asarum/química , Caspases/metabolismo , Dioxóis/farmacologia , Lignanas/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Dioxóis/isolamento & purificação , Ativação Enzimática , Feminino , Humanos , Lignanas/isolamento & purificação , Estrutura Molecular , Neoplasias Ovarianas/enzimologia , Relação Estrutura-AtividadeRESUMO
Apios americana is an important food crop producing edible tubers with high nutritional and medicinal values and is widely cultivated in many countries. Despite its usefulness, research on its secondary metabolites and biological activities has been limited. In the present study, a new coumaronochromone, (2 R,3 S)-3,7,4'-trihydroxy-5-methoxycoumaronochromone (1), and two new isoflavone glucosides, 7,2',4'-trihydroxy-5-methoxyisoflavone-4'- O-ß-d-glucopyranoside (3) and 5,7,4'-trihydroxyisoflavone-7- O-ß-d-gentiotrioside (5), were isolated from the tubers of A. americana via chromatographic separation. Seventeen known compounds (2, 4, and 6-20) were also obtained from this plant part. The chemical structures of 1, 3, and 5 were determined by the interpretation of spectroscopic data. The absolute structure of the new compound 1 was established from experimental and calculated electronic circular dichroism spectra. This is the first study to determine the absolute configuration of a 3-hydroxycoumaronochromone derivative. The potential anti-inflammatory activity of the 20 isolates obtained was evaluated by measuring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Among the isolates, seven compounds (1, 3, 6-8, 15, and 20) showed substantial inhibition of nitric oxide production in RAW 264.7 cells, with the most active being compound 1 (IC50 value of 0.38 ± 0.04 µM).
Assuntos
Fabaceae/química , Macrófagos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Extratos Vegetais/farmacologia , Animais , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Células RAW 264.7RESUMO
Two new ß-carboline alkaloids, 1-acetyl-4-methoxy-8-hydroxy-ß-carboline (1) and 1-acetyl-4,8-dimethoxy-ß-carboline (2), together with 10 known compounds; seven ß-carboline alkaloids (3-9), two canthin-6-one alkaloids (10 and 11), and one quassinoid (12) were isolated from the stems of Picrasma quassioides. The structure of the new compounds 1 and 2 were determined by spectroscopic analyses including 1D- and 2D-NMR and HRMS interpretation. All the isolates (1-12) were evaluated for their cytotoxicity against human ovarian carcinoma A2780 and SKOV3 cell lines using MTT assays. Of the isolates, compounds 5-7 exhibited the most potent cytotoxicity on both A2780 and SKOV3 cell lines in vitro.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Carbolinas/farmacologia , Picrasma/química , Extratos Vegetais/farmacologia , Caules de Planta/química , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carbolinas/química , Carbolinas/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The stem bark of Ailanthus altissima is used in traditional medicine in Asia to treat a variety of diseases, including cancer. The aim of this study was to identify compounds with tumoricidal activity from A. altissima stem bark and to investigate their mechanisms of action. Among the 13 compounds isolated from the ethyl acetate fraction of A. altissima stem bark, the ß-carboline alkaloid 9-hydroxycanthin-6-one had potent cytotoxicity in all three ovarian cancer cell types examined. 9-Hydroxycanthin-6-one induced apoptosis through the activation of caspases-3, -8, and -9. 9-Hydroxycanthin-6-one increased the intracellular levels of reactive oxygen species (ROS), and pre-treatment with the antioxidant N-acetyl-l-cysteine (NAC) attenuated the pro-apoptotic activity of 9-hydroxycanthin-6-one. Additionally, 9-hydroxycanthin-6-one was found to decrease the expressions of MCP-1 and RANTES, major determinants of macrophage recruitment at tumor sites, in ovarian cancer cells. Treatment with 9-hydroxycanthin-6-one inhibited the levels of M2 phenotype markers and some cancer-promoting factors, such as MMP-2, MMP-9, and VEGF, in macrophages educated in ovarian cancer conditioned medium. Taken together, these data suggest that 9-hydroxycanthin-6-one isolated from A. altissima stem bark induces apoptosis in human ovarian cancer cells through the caspase- and ROS-dependent pathways and inhibits the activation of tumor-associated macrophages.
Assuntos
Ailanthus/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Macrófagos/metabolismo , Acetilcisteína/farmacologia , Ailanthus/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/farmacologia , Inibidores de Caspase/farmacologia , Caspases/química , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocinas/genética , Quimiocinas/metabolismo , Feminino , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Casca de Planta/química , Casca de Planta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Canthin-6-one (CO) alkaloids possess various biological activities, including antibacterial, antitumor, antifungal, and antiviral activities. However, their anti-inflammatory effects and underlying molecular mechanisms are poorly characterized. This study aimed to investigate the anti-inflammatory effects of CO and its derivative 5-(1-hydroxyethyl)-canthin-6-one (5-HCO), isolated from the stem barks of Ailanthus altissima in lipopolysaccharide (LPS)-stimulated macrophages. CO (1 and 5 µM) and 5-HCO (7.5 and 15 µM) significantly inhibited the LPS-induced expression of inducible nitric oxide synthase. In addition, CO (1 and 5 µM) and 5-HCO (15 µM) markedly suppressed the production of prostaglandin E2 (PGE2) and expression of cyclooxygenase-2, a key enzyme in PGE2 synthesis, in LPS-stimulated macrophages. Moreover, CO treatment significantly reduced monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) expression, whereas 5-HCO inhibited MCP-1, but not TNF-α expression. Both CO and 5-HCO inhibited the phosphorylation of inhibitor kappa B and transcriptional activation of nuclear factor kappa B (NF-κB) in LPS-stimulated macrophages. In addition, CO, but not 5-HCO, markedly reduced Akt phosphorylation. Taken together, these data suggest that CO, but not 5-HCO with a hydroxyethyl moiety on the D ring, has potent anti-inflammatory activity in LPS-stimulated macrophages through the downregulation of both the NF-κB and the Akt pathway.
Assuntos
Ailanthus/química , Alcaloides/farmacologia , Anti-Inflamatórios/farmacologia , Carbolinas/farmacologia , Alcaloides Indólicos/farmacologia , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Carbolinas/química , Carbolinas/isolamento & purificação , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismoRESUMO
The flower bud of Syzygium aromaticum (clove) has been used for centuries as a spice and herbal medicine. The biological activities of kumatakenin, a flavonoid that has recently been isolated from cloves, are poorly characterized. In the present study, the anticancer effects of kumatakenin in human ovarian cancer cells and tumor-associated macrophages (TAMs) were investigated. We found that kumatakenin exhibited significant cytotoxic activity in human ovarian cancer cells, SKOV3 and A2780. A propidium iodide and Annexin V-FITC staining assay showed that kumatakenin induces apoptosis in ovarian cancer cells. Kumatakenin treatment increased the activity of caspase-3, -8, and -9, and caspase inhibitors attenuated kumatakenin-induced SKOV3 cell death. In addition, kumatakenin was found to reduce the expressions of MCP-1 and RANTES, which are major determinants of macrophage recruitment at tumor sites in ovarian cancer cells. Moreover, kumatakenin inhibited the expression of M2 markers and cancer-promoting factors, including IL-10, MMP-2/-9, and VEGF, in macrophages stimulated by the ovarian cancer cells. In conclusion, these results suggest that kumatakenin shows anticancer activities by inducing apoptosis of ovarian cancer cells and inhibiting the alternative activation of TAM.
Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Macrófagos/efeitos dos fármacos , Neoplasias Ovarianas/fisiopatologia , Syzygium/química , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Macrófagos/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Pueraria flowers have been used as a vegetable and an ingredient for tea and jelly. In this study, we investigated the effects of Pueraria flower extract (PFE) on endometriosis, a common gynaecological disease characterised by local sterile inflammation of peritoneal cavity. PFE suppressed the adhesion of human endometriotic cells 11Z and 12Z to human mesothelial Met5A cells. In addition, PFE significantly inhibited the migration of 11Z and 12Z cells as shown by woundhealing and transwell migration assays. PFE reduced the protein and mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9 in endometriotic cells. Moreover, extracellular signalregulated kinase (ERK)1/2 was activated by PFE treatment, and an ERK1/2 inhibitor, PD98059, significantly inhibited PFE-inhibited cell migration in endometriotic cells. Furthermore, PFE significantly suppressed endometriotic lesion formation in a mouse model. These data suggest that Pueraria flower is a potential anti-endometriotic agent for the inhibition of endometriotic cell adhesion, migration, and MMP expression.
Assuntos
Endometriose/tratamento farmacológico , Endométrio/efeitos dos fármacos , Flores/química , Extratos Vegetais/farmacologia , Pueraria/química , Animais , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Endométrio/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Flavonoides/farmacologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
A new acetophenone, 2,4,6-trihydroxy-3-methylacetophenone-2-O-ß-d-glucoside (1), together with 21 known compounds; one acetophenone (2), four chromone glycosides (3-6), six phenylpropanoids (7-12), six sesquiterpenoids (13-18), two triterpenoids (19 and 20), one sterol (21), and one tannin (22) were isolated from the flower buds of Syzygium aromaticum (cloves). The structure of the new compound 1 was determined by spectroscopic analyses including 1D-, 2D-NMR and HRMS interpretation. Among the isolates, one acetophenone (2), three phenylpropanoids (10-12), and one sesquiterpenoid (13) were isolated from the flower buds of S. aromaticum for the first time in this study. All the isolates (1-22) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780) using MTT assays. Some of the isolates (5, 6, 9, 15, 17, 19, 20, and 21) showed either moderate or weak cytotoxicity on A2780 cells.
Assuntos
Acetofenonas/química , Antineoplásicos Fitogênicos/química , Flores/química , Glucosídeos/química , Syzygium/química , Acetofenonas/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral/efeitos dos fármacos , Feminino , Glucosídeos/isolamento & purificação , Humanos , Estrutura Molecular , Neoplasias Ovarianas/patologiaRESUMO
Most cancer cells predominantly produce ATP by maintaining a high rate of lactate fermentation, rather than by maintaining a comparatively low rate of tricarboxylic acid cycle, i.e., Warburg's effect. In the pathway, the pyruvate produced by glycolysis is converted to lactic acid by lactate dehydrogenase (LDH). Here, we demonstrated that water extracts from the seeds of Myristica fragrans Houtt. (MF) inhibit the in vitro enzymatic activity of LDH. MF effectively suppressed cell growth and the overall Warburg effect in HT29 human colon cancer cells. Although the expression of LDH-A was not changed by MF, both lactate production and LDH activity were decreased in MF-treated cells under both normoxic and hypoxic conditions. In addition, intracellular ATP levels were also decreased by MF treatment, and the uptake of glucose was also reduced by MF treatment. Furthermore, the experiment on tumor growth in the in vivo mice model revealed that MF effectively reduced the growth of allotransplanted Lewis lung carcinoma cells. Taken together, these results suggest that MF effectively inhibits cancer growth and metabolism by inhibiting the activity of LDH, a major enzyme responsible for regulating cancer metabolism. These results implicate MF as a potential candidate for development into a novel drug against cancer through inhibition of LDH activity.
Assuntos
Proliferação de Células/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Myristica/química , Neoplasias/enzimologia , Neoplasias/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Glucose/metabolismo , Células HT29 , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Desidrogenase/genética , Lactato Desidrogenase 5 , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Extratos Vegetais/química , Sementes/químicaRESUMO
Berberine, a major isoquinoline alkaloid found in medicinal herbs, has been reported to possess anti-inflammatory effects; however, the underlying mechanisms responsible for its actions are poorly understood. In the present study, we investigated the inhibitory effects of berberine and the molecular mechanisms involved in lipopolysaccharide (LPS)-treated RAW 264.7 and THP-1 macrophages and its effects in LPS-induced septic shock in mice. In both macrophage cell types, berberine inhibited the LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) protein expression, but it had no effect on iNOS mRNA transcription. Suppression of LPS-induced iNOS protein expression by berberine occurred via a human antigen R (HuR)-mediated reduction of iNOS mRNA stability. Molecular data revealed that the suppression on the LPS-induced HuR binding to iNOS mRNA by berberine was accompanied by a reduction in nucleocytoplasmic HuR shuttling. Pretreatment with berberine reduced LPS-induced iNOS protein expression and the cytoplasmic translocation of HuR in liver tissues and increased the survival rate of mice with LPS-induced endotoxemia. These results show that the suppression of iNOS protein expression by berberine under LPS-induced inflammatory conditions is associated with a reduction in iNOS mRNA stability resulting from inhibition of the cytoplasmic translocation of HuR.