ABSTRACT
The tuberous roots of Liriope platyphylla (Liriopis Tuber; LT) is traditionally used in Korean Medicine for treating colds, cough, and sputum production. In this study, we investigated the effect of spicatoside A isolated from LT methanol extract on ovalbumin (OVA)-sensitized/challenged asthmatic mice. For induction of allergic asthma, BALB/c mice were sensitized with OVA by an intraperitoneal injection at three times a week, and then challenged into the nasal cavities using a nebulizer. Spicatoside A at dose of 1mg/kg body weight was treated in mice with an oral administration once daily for a week during OVA challenge. The concentrations of OVA-specific IgE, IL-4, IL-5 and IL-13 were measured in the sera or bronchoalveolar lavage fluids (BALF) of mice by enzyme-linked immunosorbent assay (ELISA). The numbers of total cells, macrophages, lymphocytes, neutrophils and eosinophils were counted in BALFs using Diff-Quik staining, and histopathological changes of lung tissues were observed by hematoxylin and eosin (H&E), Periodic acid Schiff (PAS) and Masson's trichrome staining. The purity of spicatoside A was 98.1% with a white powder (yield: 465.6mg). The treatment of spicatoside A in asthmatic mice significantly decreased the production of allergic mediator, OVA-specific IgE and Th2 cytokines, IL-4, IL-5 and IL-13 in sera and BALF. The numbers of inflammatory cells such as macrophages, lymphocytes, neutrophils and eosinophils in BALF of asthmatic mice were significantly reduced by the treatment of spicatoside A. Furthermore, the treatment of spicatoside A in asthmatic mice inhibited the structural damages of lung tissues with thickened bronchiolar epithelium and infiltration of inflammatory cells, the accumulation of mucus by the goblet cells hyperplasia and collagen in the bronchioles. These results suggest that spicatoside A of LT has a preventive effect on allergic asthma through the inhibition of lung inflammation and allergic response.
Subject(s)
Asthma/chemically induced , Liriope Plant/chemistry , Ovalbumin/pharmacology , Saponins/pharmacology , Animals , Asthma/metabolism , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Disease Models, Animal , Immunoglobulin E/metabolism , Inflammation/metabolism , Lung/drug effects , Lung/metabolism , Male , Mice , Mice, Inbred BALB CABSTRACT
The antitumor activity of spicatoside A (1), a steroidal saponin isolated from the tuber of Liriope platyphylla, and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. Compound 1 induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with 1 for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1 (LAMP 1), and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase (MAPK) signaling, and increasing p53 levels. However, a prolonged exposure to 1 resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide (PI)-positive cell population. Apoptosis induced by 1 was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly-ADP-ribose polymerase (PARP). Further study revealed that cleavage of beclin 1 by caspases plays a critical role in the 1-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of 1 in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of 1 as a novel candidate in the treatment of human colorectal cancer cells.
Subject(s)
Autophagy/drug effects , Liliaceae/chemistry , Saponins/pharmacology , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins , Beclin-1 , Cell Proliferation/drug effects , Colorectal Neoplasms , HCT116 Cells , Humans , Membrane Proteins , Mice , Mitogen-Activated Protein Kinases/metabolism , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Saponins/chemistry , Saponins/isolation & purification , Signal Transduction/drug effectsABSTRACT
Cimicifugae rhizoma has been widely used as a traditional herbal medicine to treat inflammation and menopausal symptoms. In this study, we found that some of the triterpenoidal saponins purified from the ethanol extract of Cimicifugae rhizoma dramatically induced histamine release. The structure-related induction of mast cell degranulation by them and the mechanism of action were determined. ß-Hexosaminidase release in HMC-1 cells was increased in a concentration-dependent manner, with maximal 6.5- and 8.5-fold increases, by 200 µg/mL 24-epi-7,8-didehydrocimigenol-3-O-xyloside (comp 1) and cimigenol 3-O-beta-d-xyloside (comp 4) compared with those treated with phorbol 12-myristate 13-acetate and A23187 (PMACI), respectively. However, ß-hexosaminidase release was not changed by 7,8-dihydrocimigenol (comp 3), or 23-OAc-shengmanol-3-O-xyloside (comp 7). These triterpenoidal saponins changed neither the intracellular Ca(2+ )level nor the activation of PKC, both of which play essential roles in histamine release. However, cromolyn and ketotifen, membrane stabilizers, effectively inhibited the ß-hexosaminidase release induced by comp 1 or comp 4 by 39 and 45%, respectively. Collectively, xylose on the cimigenol-related backbone among triterpene glycosides isolated from Cimicifugae rhizoma may play an important role in activating mast cells and induction of degranulation partly via membrane destabilization of mast cells.
Subject(s)
Calcium Signaling/drug effects , Cell Degranulation/drug effects , Cimicifuga/chemistry , Mast Cells/immunology , Saponins/pharmacology , Triterpenes/pharmacology , Animals , Calcium Signaling/immunology , Cell Degranulation/immunology , Cell Line, Tumor , Humans , Rats , Saponins/chemistryABSTRACT
We demonstrate that chikusetsusaponin IVa methyl ester (CME), a triterpenoid saponin from the root of Achyranthes japonica, has an anticancer activity. We investigate its molecular mechanism in depth in HCT116 cells. CME reduces the amount of ß-catenin in nucleus and inhibits the binding of ß-catenin to specific DNA sequences (TCF binding elements, TBE) in target gene promoters. Thus, CME appears to decrease the expression of cell cycle regulatory proteins such as Cyclin D1, as a representative target for ß-catenin, as well as CDK2 and CDK4. As a result of the decrease of the cell cycle regulatory proteins, CME inhibits cell proliferation by arresting the cell cycle at the G0/G1 phase. Therefore, we suggest that CME as a novel Wnt/ß-catenin inhibitor can be a putative agent for the treatment of colorectal cancers.
Subject(s)
Cell Cycle/drug effects , Cell Nucleus/metabolism , Oleanolic Acid/analogs & derivatives , Saponins/pharmacology , beta Catenin/metabolism , Base Sequence , Cell Line , DNA Primers , Esters/chemistry , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Protein Transport , Reverse Transcriptase Polymerase Chain Reaction , Saponins/chemistryABSTRACT
Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-ß-stimulated cell viability, migration, and invasion and decreased TGF-ß-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.
Subject(s)
Bone Resorption/drug therapy , Bone Resorption/etiology , Breast Neoplasms/pathology , Furans/therapeutic use , Lignin/therapeutic use , Osteoblasts/pathology , Osteoclasts/pathology , Animals , Benzodioxoles/chemistry , Benzodioxoles/pharmacology , Benzodioxoles/therapeutic use , Breast Neoplasms/complications , Breast Neoplasms/drug therapy , Cell Line, Tumor , Female , Furans/chemistry , Furans/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lignans/chemistry , Lignans/pharmacology , Lignans/therapeutic use , Lignin/chemistry , Lignin/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Osteoblasts/drug effects , Osteoblasts/metabolism , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteoprotegerin/genetics , Osteoprotegerin/metabolism , Parathyroid Hormone-Related Protein/biosynthesis , RANK Ligand/genetics , RANK Ligand/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
The aim of the present study was to determine the effect of Tanshinone IIA (Tan IIA) on endoplasmic reticulum (ER) stress-induced insulin resistance in L6 myotubes and db/db mice. ER stress markers, RNA-activated protein kinase-like ER resident kinase (PERK), JNK, and AMPK activity were determined in tunicamycin-treated L6 myotubes. Insulin resistance was monitored using glucose uptake assays in vitro and blood glucose levels in vivo. Tan IIA clearly suppressed the phosphorylations of PERK and JNK and potentiated insulin-mediated Akt phosphorylation as well as glucose uptake via AMPK activation under ER stress. Furthermore, these effects are completely abrogated by siRNA-mediated knockdown of AMPK or LKB1. In addition, Tan IIA reduced blood glucose levels and body weights in db/db mice without altering food intake. These findings suggest that Tan IIA enhances insulin sensitivity and improves glucose metabolic disorders by increasing AMPK activity and attenuating ER stress-induced insulin resistance.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Abietanes/pharmacology , Drugs, Chinese Herbal/pharmacology , Endoplasmic Reticulum Stress/drug effects , Hypoglycemic Agents/pharmacology , Insulin Resistance , Animals , Cell Line , Male , Mice , Mice, Inbred C57BL , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/enzymology , Tunicamycin/pharmacologyABSTRACT
Liriope platyphylla has been reported to possess various biological activities, including anti-asthma, anti-inflammation, anti-diabetes, and neuriotogenic properties. In this study, we evaluated the effects of prosapogenin III isolated from the roots of L. platyphylla (Liriopis Tuber) on inflammatory responses in lipopolysaccharide (LPS) stimulated RAW264.7 mouse macrophages. We investigated LPS-induced production/expression of inflammatory mediators such as nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxigenase-2 (COX-2), and proinflammatory cytokines, including interleukin-1ß (IL-1ß) and interleukin (IL)-6 in RAW264.7 cells. We also performed Western blot analysis for determination of the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK), and nuclear translocation of nuclear factor-κB (NF-κB) in LPS-stimulated cells. Treatment with prosapogenin III resulted in significant inhibition of NO production in LPS-stimulated Raw264.7 cells through suppression of iNOS expression. Treatment with prosapogenin III resulted in a significant decrease in expressions of COX-2, IL-1ß, and IL-6 through down-regulation of their mRNA or protein in LPS-stimulated cells. In addition, treatment with prosapogenin III resulted in potently inhibited phosphorylation of three MAPKs, including ERK1/2, p38, and JNK in LPS-stimulated cells. Treatment with prosapogenin III also resulted in suppression of the nuclear translocation of NF-κB in LPS-stimulated cells. These results indicate that prosapogenin III of Liriopis Tuber has anti-inflammatory effects in activated macrophages through inhibition of production of inflammatory mediators by blockade of the MAPK/NF-κB pathway.
Subject(s)
Liriope Plant/chemistry , Saponins/pharmacology , Animals , Blotting, Far-Western , Cyclooxygenase 2/metabolism , Cytokines/immunology , Cytokines/metabolism , Dinoprostone/metabolism , Extracellular Signal-Regulated MAP Kinases/analysis , Inflammation/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Interleukin-6/pharmacology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Mice , Mitogen-Activated Protein Kinase Kinases/analysis , Molecular Structure , NF-kappa B/immunology , NF-kappa B/metabolism , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Phosphorylation/drug effects , Plant Roots/chemistry , Signal Transduction/drug effectsABSTRACT
In this study, luteolin-7-O-glucoside (L7G), an herbal medicine isolated from Ailanthus altissima, inhibited 5-lipoxygenase (5-LOX)-dependent leukotriene C(4) (LTC(4)) production in bone marrow-derived mast cells (BMMCs) in a concentration-dependent manner with an IC(50) of 3.0 µM. To determine the action mechanism of L7G, we performed immunoblotting for cytosolic phospholipase A(2) (cPLA(2)) and mitogen-activated protein kinases (MAPKs) following c-kit ligand (KL)-induced activation of BMMCs with or without L7G. Inhibition of LTC(4) production by L7G was accompanied by a decrease in cPLA(2) phosphorylation, which occurred via the extracellular signal-regulated protein kinase-1/2 (ERK1/2) and p38 and c-Jun N-terminal kinase (JNK) pathways. In addition, L7G also attenuated mast cell degranulation in a dose-dependent manner (IC(50), 22.8 µM) through inhibition of phospholipase Cγ1 (PLCγ1) phosphorylation. Our results suggest that the anti-asthmatic activity of L7G may be mediated in part via the inhibition of LTC(4) generation and mast cell degranulation.
Subject(s)
Bone Marrow Cells/drug effects , Cell Degranulation/drug effects , Flavones/pharmacology , Glucosides/pharmacology , Leukotriene C4/antagonists & inhibitors , Mast Cells/drug effects , Mitogen-Activated Protein Kinases/metabolism , Phospholipase C gamma/metabolism , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , Leukotriene C4/biosynthesis , Mast Cells/cytology , Mast Cells/metabolism , Mice , PhosphorylationABSTRACT
To find anti-inflammatory compounds from the tuberous roots of Dioscorea batatas, we isolated 6-hydroxy-2,4,7-trimethoxyphenanthrene (batatasin I) from the dichloromethane (CH(2)Cl(2)) fraction of this plant. Batatasin I inhibited both the generation of prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)) and degranulation reaction in mouse bone marrow-derived mast cells (BMMCs). This compound inhibited cyclooxygenase-2 (COX-2) dependent PGD(2) generation in a dose dependent manner, with IC(50) values of 1.78 µM. Western blotting probed with specific anti-COX-2 antibodies showed that the decrease in the quantity of the PGD(2) generation was accompanied by a decrease in the COX-2 protein level. In addition, this compound also inhibited the production of 5-lipoxygenase (5-LOX) dependent LTC(4) in a dose dependent manner (IC(50), 1.56 µM). Batatasin I also inhibited the mast cell degranulation reaction (IC(50), 6.7 µM) in BMMCs. This result indicates that batatasin I could be developed as an anti-inflammatory agent through further investigation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Bone Marrow Cells/drug effects , Cell Degranulation/drug effects , Dioscorea/chemistry , Eicosanoids/antagonists & inhibitors , Mast Cells/drug effects , Phenanthrenes/pharmacology , Plant Roots/chemistry , Animals , Anti-Inflammatory Agents/isolation & purification , Eicosanoids/biosynthesis , Leukotrienes/biosynthesis , Male , Mice , Mice, Inbred BALB C , Phenanthrenes/isolation & purificationABSTRACT
Previously, we reported the cognitive enhancing effects of oroxylin A in unimpaired mice and its memory ameliorating activity in various memory impaired mice. To elucidate the mechanism mediating the cognitive effects of oroxylin A, this study examined the consequences of oroxylin A administration on neurogenesis in the hippocampal dentate gyrus using immunostaining for 5-bromo-2-deoxyuridine (BrdU) incorporation. In addition, we determined whether the new cells adopted a neuronal or glial fate by examining the co-localization of BrdU staining with neuronal or glial markers. Administration of oroxylin A in a dose-dependent and time-dependent manner increased the number of BrdU-incorporating cells. Moreover, the percentage of BrdU-incorporating cells co-localized with neuronal markers, neuronal nuclei, was significantly increased by the oroxylin A administration. These results suggest that the increased neurogenesis induced by the administration of oroxylin A could be, at least in part, associated with its positive effects on cognitive processing.
Subject(s)
Dentate Gyrus/physiology , Flavonoids/pharmacology , Neurogenesis/drug effects , Animals , Bromodeoxyuridine/metabolism , Cell Proliferation/drug effects , Dentate Gyrus/drug effects , Male , Mice , Mice, Inbred ICRABSTRACT
Papyriflavonol A (PapA), a prenylated flavonoid (5,7,3',4'-tetrahydroxy-6,5'-di-(r,r-dimethylallyl)-flavonol), was isolated from the root barks of Broussonetia papyriferra. Our previous study showed that PapA has a broad-spectrum antimicrobial activity against pathogenic bacteria and fungi. In this study, the mode of action of PapA against Candida albicans was investigated to evaluate PapA as antifungal agent. The minimal inhibitory concentration (MIC) values were 10~25 microgram/ml for C. albicans and Saccharomyces cerevisiae, gram-negative bacteria (Escherichia coli and Salmonella typhimurium) and gram-positive bacteria (Staphylococcus epidermidis and Staphylococcus aureus). The kinetics of cell growth inhibition, scanning electron microscopy, and measurement of plasma membrane florescence anisotrophy revealed that the antifungal activity of PapA against C. albicans and S. cerevisiae is mediated by its ability to disrupt the cell membrane integrity. Compared with amphotericin B, a cell membrane disrupting polyene antibiotic, the hemolytic toxicity of PapA was negligible. At 10~25 microgram/ml of MIC levels for the tested strains, the hemolysis ratio of human erythrocytes was less than 5%. Our results suggest that PapA could be a therapeutic fungicidal agent having a broad spectrum antimicrobial agent.
Subject(s)
Antifungal Agents/pharmacology , Broussonetia/chemistry , Candida albicans/drug effects , Flavonols/pharmacology , Plant Extracts/pharmacology , Anti-Infective Agents/isolation & purification , Anti-Infective Agents/pharmacology , Antifungal Agents/isolation & purification , Bacteria/drug effects , Bacteria/growth & development , Candida albicans/growth & development , Erythrocytes/drug effects , Flavonols/isolation & purification , Fungi/drug effects , Fungi/growth & development , Humans , Microbial Sensitivity Tests , Plant Extracts/isolation & purification , Plant Roots/chemistryABSTRACT
Mulberry (Morus alba L.) root bark (MRB) was extracted using methanol and the extracts were subjected to tests of anti-inflammatory effects. The ethyl acetate fraction demonstrated the best anti-inflammatory effects. Purified compounds, sanggenon B, albanol B and sanggenon D, showed inhibitory effects on NO production in LPS-stimulated RAW264.7 cells and albanol B demonstrated the best anti-inflammatory effects. Regarding the underlying molecular mechanisms, further investigations showed that treatments with Albanol B reduced production of pro-inflammatory cytokines and decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These results would contribute to development of novel anti-inflammatory drugs from MRB.
Subject(s)
Anti-Inflammatory Agents/isolation & purification , Morus/chemistry , Plant Bark/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Benzofurans/isolation & purification , Chromones/isolation & purification , Cyclooxygenase 2 Inhibitors/isolation & purification , Cyclooxygenase 2 Inhibitors/pharmacology , Flavonoids/isolation & purification , Mice , Nitric Oxide Synthase Type II/antagonists & inhibitors , Plant Extracts/chemistry , Plant Extracts/pharmacology , RAW 264.7 CellsABSTRACT
Previously, we reported that an ethanol extract of Ailanthus altissima has antiinflammatory activity in an ovalbumin (OVA)-sensitized murine asthmatic model. To determine the biological compounds from this plant, luteolin-7-O-glucoside (L7G) was isolated and its antiasthmatic activity was evaluated in an in vivo murine asthmatic model. L7G (10 to 100 mg/kg, per os (p.o.)) reduced the amount of eosinophil infiltration in bronchoalveolar lavage (BAL) fluid in a dose-dependent manner. In comparison, dexamethasone (5 mg/kg, p.o.), which was used as a positive control, also strongly inhibited the number of infiltrating eosinophils. L7G inhibited both the prostaglandin E(2) (PGE(2)) and serum immunoglobulin E level in BAL fluid in a dose-dependent manner. In addition, L7G inhibited the transcript profiles of interleukin (IL)-4, IL-5, and IL-13 mRNA expression levels in the murine asthma model, as determined using reverse transcription-polymerase chain reaction (RT-PCR). These results suggest that the antiasthmatic activity of L7G in OVA-induced lung inflammation may occur in part via the downregulation of T helper 2 cytokine transcripts as well as the inhibition of PGE(2) production.
Subject(s)
Ailanthus/immunology , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Cytokines/antagonists & inhibitors , Dinoprostone/antagonists & inhibitors , Glucosides/therapeutic use , Luteolin/therapeutic use , Ovalbumin/administration & dosage , Th2 Cells/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Asthma/immunology , Asthma/pathology , Cytokines/biosynthesis , Dinoprostone/biosynthesis , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/immunology , Female , Glucosides/isolation & purification , Luteolin/isolation & purification , Mice , Mice, Inbred BALB C , Ovalbumin/toxicity , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
In order to establish the antiallergic properties of Schisandra fructus and Magnolia flos, several compounds isolated from these plants were tested for 5-lipoxygenase (5-LOX) inhibitory activity in vitro, for the first time. The compounds including schizandrins, schisandrols, gomisins, fargesin, eudesmin and lirioresinol B dimethyl ether, inhibited 5-LOX-catalysed leukotriene production from A23187-treated rat basophilic leukemia (RBL-1) cells at concentrations of 1-100 microm. In particular, constituents such as schisandrol A and gomisins showed potent inhibitory activity (IC(50)s < 10 microm) on 5-LOX-catalysed leukotriene production, but were much less active on cyclooxygenase-2-catalysed prostaglandin E(2) and inducible nitric oxide-catalysed NO production. These compounds have the potential to be developed as novel antiallergic agents and may contribute to the antiallergic pharmacological use of these plant materials in Chinese medicine.
Subject(s)
Anti-Allergic Agents/pharmacology , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/pharmacology , Magnolia/chemistry , Plant Extracts/pharmacology , Schisandra/chemistry , Animals , Anti-Allergic Agents/isolation & purification , Cell Line, Tumor , Cyclooctanes/isolation & purification , Cyclooctanes/pharmacology , Cyclooxygenase 2/metabolism , Dinoprostone/biosynthesis , Flowers , Fruit , Inhibitory Concentration 50 , Leukotrienes/biosynthesis , Lignans/isolation & purification , Lignans/pharmacology , Lipoxygenase Inhibitors/isolation & purification , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/metabolism , Plant Extracts/chemistry , RatsABSTRACT
Cimiside E was isolated from the Cimicifuga heracleifolia Komarov extract, which has been previously demonstrated to possess apoptotic action on gastric cancer cells. The IC(50) value of cimiside E on gastric cancer cells for 24 h was 14.58 microM. The mechanism of apoptosis was further elucidated through western blot, RT-PCR, morphology, Annexin V-FITC/PI staining and cell cycle analysis. Cell cycle arrest was induced by cimiside E in S phase at a lower concentration (30 microM) and G2/M phase at higher concentrations (60 and 90 microM). Cimiside E mediated apoptosis through the induction of the caspase cascade for both the extrinsic and intrinsic pathways. These findings suggest that cimiside E may be an effective chemopreventive agent against cancer.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cimicifuga/chemistry , DNA Fragmentation/drug effects , Saponins/pharmacology , Stomach Neoplasms/pathology , Triterpenes/pharmacology , Annexin A5/metabolism , Antineoplastic Agents, Phytogenic/isolation & purification , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Fas Ligand Protein/metabolism , Humans , Reverse Transcriptase Polymerase Chain Reaction , Saponins/isolation & purification , Triterpenes/isolation & purification , fas Receptor/metabolismABSTRACT
The role of cell adhesion molecules has been studied extensively in the process of inflammation, and these molecules are critical components of carcinogenesis and cancer metastasis. This study investigated the effect of tanshinone I derived from the traditional herbal medicine, Salvia miltiorrhiza Bunge, on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-alpha (TNF-alpha)-stimulated endothelial cells. Furthermore, this study investigated the effect of tanshinone I on cancer growth, invasion and angiogenesis on human breast cancer cells MDA-MB-231, both in vitro and in vivo. Tanshinone I dose dependently inhibited ICAM-1 and VCAM-1 expressions in human umbilical vein endothelial cells (HUVECs) that were stimulated with TNF-alpha for 6 h. Pretreatment with tanshinone I significantly reduced adhesion of either monocyte U937 or MDA-MB-231 cells to HUVECs. Interestingly, the inhibitory effect of tanshinone I on monocyte and cancer cell adhesion to HUVECs was mimicked by transfection with ICAM-1 and VCAM-1 small interfering RNA. In addition, tanshinone I effectively inhibited TNF-alpha-induced production of vascular endothelial growth factor (VEGF) and VEGF-mediated tube formation in HUVECs. Tanshinone I also inhibited TNF-alpha-induced VEGF production in MDA-MB-231 cells and migration of MDA-MB-231 cells through extracellular matrix. Additionally, reduction of tumor mass volume and decrease of metastasis incidents by tanshinone I were observed in vivo. In conclusion, this study provides a potential mechanism for the anticancer effect of tanshinone I on breast cancer cells, suggesting that tanshinone I may serve as an effective drug for the treatment of breast cancer.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/drug therapy , Intercellular Adhesion Molecule-1/physiology , Phenanthrenes/pharmacology , Vascular Cell Adhesion Molecule-1/physiology , Abietanes , Angiogenesis Inhibitors/pharmacology , Animals , Breast Neoplasms/pathology , Cell Adhesion/drug effects , Cell Communication , Cell Proliferation/drug effects , Endothelial Cells/cytology , Female , Humans , Intercellular Adhesion Molecule-1/analysis , Mice , Neoplasm Invasiveness , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/analysisABSTRACT
Smooth muscle cell (SMC) migration plays an important role in normal angiogenesis and is relevant to disease-related vascular remodeling in conditions such as brain arteriovenous malformations, pulmonary hypertension, arteriosclerosis, and restenosis after angioplasty. In this present study, we showed that tanshinone IIA, the major lipid-soluble pharmacological constituent of Salvia miltiorrhiza BUNGE, inhibits human aortic smooth muscle cell (HASMC) migration and MMP-9 activity. Tanshinone IIA significantly inhibited IkappaBalpha phosphorylation and p65 nuclear translocation through inhibition of AKT phosphorylation. Tanshinone IIA inhibited TNF-alpha-induced ERK and c-jun phosphorylation, but not other MAPKs such as JNK and p38. Tanshinone IIA also inhibited NF-kappaB and AP-1 DNA-binding. Moreover, tanshinone IIA inhibited the migration of TNF-alpha-induced HASMCs. Our results provide evidence that tanshinone IIA has multiple effects in the inhibition of HASMC migration and may offer a therapeutic approach to block HASMC migration.
Subject(s)
Matrix Metalloproteinase Inhibitors , Myocytes, Smooth Muscle/drug effects , Phenanthrenes/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Abietanes , Aorta/cytology , Cell Movement/drug effects , Drugs, Chinese Herbal/chemistry , Humans , Matrix Metalloproteinase 9/metabolism , Salvia miltiorrhizaABSTRACT
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Wnt signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types.
Subject(s)
Breast Neoplasms/drug therapy , Cell Proliferation/drug effects , Drugs, Chinese Herbal/therapeutic use , Estrogen Receptor alpha/metabolism , Flavanones/therapeutic use , Animals , Apoptosis/drug effects , Breast Neoplasms/chemistry , Breast Neoplasms/genetics , Caspases/drug effects , Caspases/metabolism , Cyclin D1/genetics , Cyclin D1/metabolism , Estrogen Receptor alpha/genetics , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Tumor Cells, Cultured/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Oroxylin A is a flavonoid that is found in the roots of Scutellaria baicalensis Georgi. The aim of this study was to characterize the effects of oroxylin A on the memory impairments and pathological changes induced by Abeta(25-35) peptide in mice. The ameliorating effect of oroxylin A on memory impairment was investigated using passive avoidance and Y-maze tasks and pathological changes were identified by immunostaining and western blotting. Abeta(25-35) peptide (5nmol) was administered by intracerebroventricular injection. In the acute treatment study, a single dose of oroxylin A (5mg/kg, p.o.) treated 1h before behavioral tests was found to significantly reverse Abeta(25-35)-induced cognitive impairments based on passive avoidance and Y-maze task findings (P<0.05). Moreover, these acute effects of oroxylin A were blocked by diazepam (1mg/kg, i.p.), a GABA(A)/benzodiazepine binding site agonist (P<0.05). On the other hand, our subchronic studies revealed that oroxylin A (1 or 5mg/kg/day, p.o.) for 7 days ameliorated the memory impairment induced by Abeta(25-35) peptide. Moreover, Abeta(25-35)-induced increases in GFAP (an astroglia marker) and OX-42 (a microglia marker), and increases in iNOS positive cells in the hippocampus were found to be attenuated by subchronic oroxylin A (1 or 5mg/kg/day, i.p., P<0.05). In addition, reductions in the immunoreactivity and protein level of ChAT (a cholinergic neuronal cell marker) in the CA3 hippocampal area induced by Abeta(25-35) peptide were also attenuated by oroxylin A. Furthermore, lipid peroxidation induced by Abeta(25-35) was also reduced by oroxylin A. These results suggest that the amelioration of Abeta(25-35) peptide-induced memory impairment by oroxylin A is mediated via the GABAergic neurotransmitter system after a single administration, or by reductions in Abeta(25-35) peptide-induced astrocyte and microglia activations, iNOS expression, lipid peroxidation, and increased cholinergic neurotransmission after subchronic administration.
Subject(s)
Amyloid beta-Peptides , Enzyme Inhibitors/administration & dosage , Flavonoids/administration & dosage , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Peptide Fragments , Analysis of Variance , Animals , Behavior, Animal/drug effects , CD11b Antigen/metabolism , Diazepam/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Exploratory Behavior/drug effects , Free Radical Scavengers/metabolism , GABA Modulators/pharmacology , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Lipid Peroxidation/drug effects , Male , Maze Learning/drug effects , Memory Disorders/pathology , Mice , Mice, Inbred ICR , Reaction Time/drug effectsABSTRACT
Danshen (Salvia miltiorrhiza Bunge) is a herb that has been widely and successfully used for treating inflammatory diseases in clinics in Asia. The relatively abundant tanshinones, tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone, have been isolated from Danshen. These tanshinones are the major diterpenes isolated from Danshen, and show cytotoxic effects on cell lines derived from human carcinomas of the colon, ovary, lung, mouth, and breast. Recently, anti-cancer activities of tanshinone IIA have been reported, which suggest that the structurally similar tanshinone I may possess similar cytotoxic effects on tumor cells. We investigated the effect of tanshinone I on the induction of apoptosis in human breast cancer cells (MCF-7 and MDA-MB-231) in vitro. Tanshinone I inhibited cell proliferation of MCF-7 and MDA-MB-231 cells in a dose- and time-dependent manner, as assayed by MTT. In addition, TUNEL assay and flow cytometry showed that tanshinone I significantly induced apoptosis in MCF-7 and MDA-MB-231 cells. The induction of apoptotic cell death was mediated by the activation of caspase 3, the downregulation of the level of the anti-apoptotic protein, Bcl-2, and the upregulation of the level of the pro-apoptotic protein, Bax. Taken together, these results reveal a potential mechanism for the anti-cancer effect of tanshinone I on human breast cancer cells, and suggest that tanshinone I may serve as an effective adjunctive reagent in the treatment of human breast cancer.