Platycodin D Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis by Blocking the Activation of Mitogen-Activated Protein Kinases and the Production of Interleukin-8.

Platycodin D is a major constituent in the root of Platycodon grandiflorum and has diverse pharmacologic activities, including anti-inflammatory, anti-allergic, and antitumor activities. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are potent angiogenic factors and contribute to tumor angiogenesis by directly and indirectly promoting angiogenic processes, including the proliferation, adhesion, migration, and tube formation of endothelial cells. Here, we found that platycodin D at noncytotoxic concentrations inhibited VEGF-induced proliferation, adhesion to the extracellular matrix proteins fibronectin and vitronectin, chemotactic motility, and tube formation of human umbilical vein endothelial cells (HUVECs). Platycodin D reduced the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) and the secretion of IL-8 in VEGF-stimulated HUVECs. Moreover, platycodin D inhibited tube formation and the phosphorylation of ERK and p38 in IL-8-stimulated HUVECs. The in vitro anti-angiogenic activity of platycodin D was confirmed by in vivo experimental models. Platycodin D inhibited the formation of new blood vessels into mouse Matrigel plugs with VEGF or IL-8. In mice injected with MDA-MB-231 human breast cancer cells, orally administered platycodin D inhibited tumor growth, the number of CD34 [Formula: see text]vessels, and the expression of VEGF and IL-8. Taken together, platycodin D directly and indirectly prevents VEGF-induced and IL-8-induced angiogenesis by blocking the activation of mitogen-activated protein kinases (MAPKs). Platycodin D may be beneficial for the prevention or treatment of tumor angiogenesis and angiogenesis-related human diseases.

Xanthorrhizol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Modulating Akt/eNOS Signaling and the NF-[Formula: see text]B-Dependent Expression of Cell Adhesion Molecules.

Angiogenesis plays a crucial role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration are critical steps in tumor angiogenesis. Here, we investigated the anti-angiogenic activity of xanthorrhizol, a sesquiterpenoid isolated from the Indonesian medicinal plant Curcuma xanthorrhiza. Xanthorrhizol at noncytotoxic concentrations inhibited the proliferation, migration, and formation of capillary-like tubes in VEGF-treated human umbilical vein endothelial cells (HUVECs). Xanthorrhizol inhibited the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin in VEGF-treated HUVECs. The expression and transcriptional activity of NF-[Formula: see text]B were downregulated by xanthorrhizol in VEGF-treated HUVECs. Furthermore, xanthorrhizol significantly inhibited VEGF-induced angiogenesis in the chorioallantoic membrane of fertilized eggs and Matrigel plugs subcutaneously injected into mice. Xanthorrhizol inhibited tumor volume and tumor-derived angiogenesis in mice inoculated with breast cancer cells. The in vitro and in vivo anti-angiogenic activities of xanthorrhizol were as potent as those of curcumin, a well-known anticancer agent derived from C. longa. Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-[Formula: see text]B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.

Platycarya strobilacea leaf extract inhibits tumor necrosis factor-α production and bone loss induced by Porphyromonas gingivalis-derived lipopolysaccharide.

OBJECTIVE: Remodeling of alveolar bone is controlled by osteoclast-mediated bone resorption and osteoblast-induced bone formation. LPS of Porphyromonas gingivalis, a major causative agent of periodontitis, produces proinflammatory cytokines in host immune cells, which thereby triggers osteoclastogenesis and leads to alveolar bone resorption. We investigated the anti-periodontitis potential of Platycarya strobilacea leaf extract (PLE), which is used as a traditional medicine in Asian countries. DESIGN: TNF-α levels in cell culture media were measured using a commercially available enzyme-linked immunosorbent assay kit. Osteoclast differentiation was observed by tartrate-resistant acid phosphatase staining, and the expression levels of osteoclastogenic genes were measured by quantitative real-time PCR. Bone-resorbing activity was confirmed by the resorption pit formation, gelatin zymographic, and the cathepsin K activity assays. Osteogenic differentiation was confirmed with an ALP activity assay and alizarin red S staining. RESULTS: PLE treatment inhibited the production of TNF-α in P. gingivalis LPS-stimulated RAW264.7 macrophages. In bone marrow-derived macrophages serving as osteoclast precursors, PLE treatment blocked RANKL-induced osteoclastogenesis and gene expression levels of the osteoclastogenic transcription factor NFATc1, DC-STAMP for osteoclast fusion, and cathepsin K for osteoclast activity. In addition, PLE treatment reduced the formation of resorption pits and the secretion of MMP 9 and cathepsin K from the differentiated osteoclasts. Furthermore, PLE treatment induced osteogenesis by increasing ALP activity and calcium content in preosteoblastic cells. CONCLUSION: PLE inhibits P. gingivalis LPS-induced TNF-α production and bone resorption and induces bone formation. PLE may be a beneficial agent to promote oral health by inhibiting periodontitis-induced alveolar bone loss.

Artemisia annua extract prevents ovariectomy-induced bone loss by blocking receptor activator of nuclear factor kappa-B ligand-induced differentiation of osteoclasts.

The activities of osteoclasts and osteoblasts are balanced to maintain normal bone density. Many pathological conditions cause osteoclastic bone resorption in excess of osteoblastic bone formation, resulting in osteoporosis. We found that oral administration of Artemisia annua ethanol extract (AaE) or major components, artemisinin and arteannuin B, to ovariectomized (OVX) mice prevented bone loss, as verified by examining three-dimensional images and bone morphometric parameters derived from microcomputed tomography analysis, as well as serum levels of bone turnover markers and proinflammatory cytokines. The administered doses were not toxic to the liver or kidney and showed promising effects that were comparable to those of 17ß-estradiol treatment. At non-cytotoxic concentrations, AaE and active components, artemisinin, artemisinic acid, and arteannuin B, potently inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis and the formation of osteoclast-mediated resorption pits. Furthermore, AaE, artemisinin, and arteannuin B remarkably reduced the expression of the c-Fos and NFATc1 transcription factors, which play critical roles in RANKL-induced osteoclast differentiation. Taken together, the in vivo anti-osteoporotic activity of AaE may be derived from the anti-osteoclastic and anti-bone resorptive activities of its active components. AaE has beneficial applications for the prevention and inhibition of osteoporosis and osteoclast-mediated bone diseases.

Methanol Extract of Holarrhena antidysenterica Inhibits the Growth of Human Oral Squamous Cell Carcinoma Cells and Osteoclastogenesis of Bone Marrow Macrophages.

Oral squamous cell carcinoma (OSCC) frequently invades mandibular bone, and outcomes for treatment with surgical resection are typically poor, ultimately resulting in death. Holarrhena antidysenterica L. (Apocynaceae), distributed throughout Sri Lanka and India, has been used as a folk remedy to treat various diseases. Treatment with methanol extract of H. antidysenterica bark (HABE) inhibited cell viability and BrdU incorporation and induced apoptotic cell death in Ca9-22 gingival and HSC-3 tongue SCC cells. Flow cytometric analysis indicated that HABE treatment preferentially induces apoptotic cell death via increasing the sub-G1 peak in Ca9-22 cells and cell cycle arrest at the G1 phase in HSC-3 cells. HABE treatment in the presence of zVAD-fmk, a pan-caspase inhibitor, rescued cell viabilities in both OSCC cell lines. The ratio of Bax to Bcl-2 increased with reductions in the Bcl-2 protein expression, and the activation of caspase 3 and subsequent cleavage of PARP was detected in HABE-treated Ca9-22 and HSC-3 cells. Furthermore, HABE treatment at noncytotoxic concentrations inhibited osteoclast formation in RANKL-stimulated bone marrow macrophages. Taken together, HABE possesses the inhibitory activity on the growth of OSCC cells and antiosteoclastogenic activity. Therefore, HABE may be a promising alternative and complementary agent for preventing and treating OSCC.

Liensinine and Nuciferine, Bioactive Components of Nelumbo nucifera, Inhibit the Growth of Breast Cancer Cells and Breast Cancer-Associated Bone Loss.

Once breast cancer cells grow aggressively and become lodged in the skeleton through migration and invasion, they interact with bone microenvironment and accelerate much more tumor growth and bone destruction. We investigated whether liensinine and nuciferine, major active components in Nelumbo nucifera (lotus), could prevent breast cancer cell-mediated bone destruction. Liensinine and nuciferine inhibited the growth of MDA-MB-231 and MCF-7 human breast cancer cells by inducing apoptosis and inhibiting proliferation via cell cycle arrest. Liensinine treatment led to the increased Bax/Bcl-2 ratio, activation of caspase-3, and subsequent cleavage of PARP. Liensinine also displayed significant inhibition on the migration and invasion of both MDA-MB-231 and MCF-7 human breast cancer cells compared with nuciferine. In addition, liensinine and nuciferine inhibited the receptor activator of nuclear factor kappa-B ligand- (RANKL-) induced osteoclast differentiation in mouse bone marrow macrophage cells and mature osteoclast-mediated bone resorption. Furthermore, oral administration of liensinine reduced the osteolysis in nude mice with intratibial injection of MDA-MB-231 cells. Collectively, liensinine and nuciferine may be promising candidates for preventing and treating breast cancer bone metastasis and the resulting osteolytic bone loss by targeting both cancer cells and osteoclasts. Liensinine has more potent anticancer and antibone resorptive activities than nuciferine.

The Inhibitory Effects of Forsythia Koreana Extracts on the Metastatic Ability of Breast Cancer Cells and Bone Resorption by Osteoclasts.

BACKGROUND: Breast cancer is the most common malignant disease in women. The patients with advanced breast cancer develop metastasis to bone. Bone metastasis and skeletal-related events by breast cancer are frequently associated with the invasiveness of breast cancer cells and osteoclasts-mediated bone resorption. Forsythia koreana is used in oriental traditional medicine to treat asthma, atopy, and allergic diseases. The aim of this study was to evaluate the inhibitory effects of F. koreana extracts on the invasion of breast cancer cells and bone resorption by osteoclasts. METHODS: Cell viability was measured by an MTT assay and the migration and invasion of MDA-MB-231 cells were detected by a Boyden chamber assay. The formation of osteoclasts and pit was detected using tartrate-resistant acid phosphatase staining and calcium phosphate-coated plates, respectively. The activities of matrix metalloproteinases (MMPs) and cathepsin K were evaluated by gelatin zymography and a cathepsin K detection kit. RESULTS: The fruit and leaf extracts of F. koreana significantly inhibited the invasion of MDA-MB-231 cells at noncytotoxic concentrations. The fruit extract of F. koreana reduced the transforming growth factor ß1-induced migration, invasion and MMPs activities of MDA-MB-231 cells. In addition, the fruit, branch, and leaf extracts of F. koreana also inhibited the receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and osteoclast-mediated bone-resorbing activity by reducing the activities of MMPs and cathepsin K. CONCLUSIONS: The extracts of F. koreana may possess the potential to inhibit the breast cancer-induced bone destruction through blocking invasion of breast cancer cells, osteoclastogenesis, and the activity of mature osteoclasts.

Type I saikosaponins a and d inhibit osteoclastogenesis in bone marrow-derived macrophages and osteolytic activity of metastatic breast cancer cells.

Many osteopenic disorders, including a postmenopausal osteoporosis and lytic bone metastasis in breast and prostate cancers, are linked with a hyperosteoclast activity due to increased receptor activator of nuclear factor kappa-B ligand (RANKL) expression in osteoblastic/stromal cells. Therefore, inhibition of RANKL-induced osteoclastogenesis and osteoclast-induced bone resorption is an important approach in controlling pathophysiology of these skeletal diseases. We found that, of seven type I, II, and III saikosaponins isolated from Bupleurum falcatum, saikosaponins A and D, type I saikosaponins with an allyl oxide linkage between position 13 and 28 and two carbohydrate chains that are directly attached to the hydroxyl groups in position 3, exhibited the most potent inhibition on RANKL-induced osteoclast formation at noncytotoxic concentrations. The stereochemistry of the hydroxyl group at C16 did not affect their activity. Saikosaponins A and D inhibited the formation of resorptive pits by reducing the secreted levels of matrix metalloproteinase- (MMP-) 2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Additionally, saikosaponins A and D inhibited mRNA expression of parathyroid hormone-related protein as well as cell viability and invasion in metastatic human breast cancer cells. Thus, saikosaponins A and D can serve as a beneficial agent for the prevention and treatment of osteoporosis and cancer-induced bone loss.

Chemopreventive and Anticancer Activities of Allium victorialis var. platyphyllum Extracts.

BACKGROUND: Allium victorialis var. platyphyllum is an edible perennial herb and has been used as a vegetable or as a Korean traditional medicine. Allium species have received much attention owing to their diverse pharmacological properties, including antioxidative, anti-inflammatory, and anticancer activities. However, A. victorialis var. platyphyllum needs more study. METHODS: The chemopreventive potential of A. victorialis var. platyphyllum methanol extracts was examined by measuring 12-O-tetra-decanoylphorbol 13-acetate (TPA)-induced superoxide anion production in the differentiated HL-60 cells, TPA-induced mouse ear edema, and Ames/Salmonella mutagenicity. The apoptosis-inducing capabilities of the extracts were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, 4',6-diamidino-2-phenylindole staining, and the DNA fragmentation assay in human colon cancer HT-29 cells. Antimetastatic activities of the extracts were also investigated in an experimental mouse lung metastasis model. RESULTS: The methanol extracts of A. victorialis var. platyphyllum rhizome (AVP-R) and A. victorialis var. platyphyllum stem (AVP-S) dose-dependently inhibited the TPA-induced generation of superoxide anion in HL-60 cells and TPA-induced ear edema in mice, as well as 7,12-dimethylbenz[a]anthracene (DMBA) and tert-butyl hydroperoxide (t-BOOH) -induced bacterial mutagenesis. AVP-R and AVP-S reduced cell viability in a dose-related manner and induced apoptotic morphological changes and internucleosomal DNA fragmentation in HT-29 cells. In the experimental mouse lung metastasis model, the formation of tumor nodules in lung tissue was significantly inhibited by the treatment of the extracts. CONCLUSIONS: AVP-R and AVP-S possess antioxidative, anti-inflammatory, antimutagenic, proapoptotic, and antimetastatic activities. Therefore, these extracts can serve as a beneficial supplement for the prevention and treatment of cancer.

Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts.

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.

The inhibitory effect of roasted licorice extract on human metastatic breast cancer cell-induced bone destruction.

The aim of this study was to determine whether the ethanol extract of roasted licorice (rLE) could inhibit breast cancer-mediated bone destruction. rLE treatment reduced the viability of MDA-MB-231 human metastatic breast cancer cells but did not show any cytotoxicity in hFOB1.19 human osteoblastic cells and murine bone marrow-derived macrophages (BMMs). rLE inhibited expression and secretion of receptor activator of nuclear factor κB ligand (RANKL) as well as the mRNA and protein expression of cyclooxygenase-2 in osteoblastic cells exposed to the conditioned medium of breast cancer cells. rLE dramatically inhibited RANKL-induced osteoclastogenesis in BMMs, thereby reducing osteoclast-mediated pit formation. Moreover, treatment with licochalcone A and isoliquiritigenin as the active components, whose contents are increased by the roasting process, remarkably suppressed RANKL-induced osteoclast formation in BMMs, respectively. Furthermore, orally administered rLE substantially blocked tumor growth and bone destruction in mice inoculated with breast cancer cells in the tibiae. Serum levels of tartrate-resistant acid phosphatase and C-terminal cross-linking telopeptide of type I collagen and trabecular bone morphometric parameters were reversed to almost the same levels as the control mice by the rLE treatment. In conclusion, rLE may be a beneficial agent for preventing and treating bone destruction in patients with breast cancer.

Xanthorrhizol induces apoptosis through ROS-mediated MAPK activation in human oral squamous cell carcinoma cells and inhibits DMBA-induced oral carcinogenesis in hamsters.

Xanthorrhizol, a natural sesquiterpenoid compound isolated from Curcuma xanthorrhiza Roxb, has been known to inhibit the growth of human colon, breast, liver and cervical cancer cells. In this study, xanthorrhizol decreased cell viability, induced apoptosis and decreased the level of full-length PARP in SCC-15 oral squamous cell carcinoma (OSCC) cells. A decrease in cell viability and PARP degradation was not prevented by treatment with the caspase inhibitor Z-VAD-fmk in xanthorrhizol-treated cells. Xanthorrhizol treatment elevated intracellular Ca(2+) and ROS levels in SCC-15 cells. Treatment with a Ca(2+) chelator, EGTA/AM, did not affect xanthorrhizol- induced cytotoxicity, but cell viability was partly recovered by treatment with endogenous antioxidant, GSH, or hydroxy radical trapper, MCI-186. Furthermore, the viability of xanthorrhizol-treated SCC-15 cells was significantly restored by treatment with SB203580 and/or SP600125 but not significantly by PD98059 treatment. Xanthorrhizol-induced activation of p38 MAPK and JNK was blocked by MCI-186. Finally, xanthorrhizol suppressed the number of tumors in buccal pouches and increased the survival rate in hamsters treated with 7,12-dimethylbenz[a]anthracene. In conclusion, xanthorrhizol may induce caspase-independent apoptosis through ROS-mediated p38 MAPK and JNK activation in SCC-15 OSCC cells and prevent chemical-induced oral carcinogenesis. Therefore, xanthorrhizol seems to be a promising chemopreventive agent.

Extract of Magnoliae Flos inhibits ovariectomy-induced osteoporosis by blocking osteoclastogenesis and reducing osteoclast-mediated bone resorption.

Bone homeostasis is maintained by a balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteoporosis occurs when osteoclast activity surpasses osteoblast activity. Pro-inflammatory cytokines stimulate osteoclast differentiation and activity by increasing production of macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL). In this study, we investigated whether Magnoliae Flos (MF), one of the most commonly used Chinese medicinal herbs for managing rhinitis, sinusitis and headache, could effectively inhibit osteoporosis. In ovariectomized (OVX) mice compared to sham mice, the body weight increased and serum levels of alkaline phosphatase (ALP), tartrate resistant acid phosphatase 5b, calcium, and osteocalcin were significantly elevated. However, orally administrated MF extract substantially inhibited the increased body weight and serum levels of bone turnover markers, without any evidence of tissue toxicity. MF extract treatment significantly reversed the morphometric parameters of ovariectomy-induced bone loss, including trabecular bone volume, thickness, number, separation, and bone density, to almost the same levels of the sham mice. Furthermore, MF extract reduced the RANKL-mediated osteoclast differentiation and bone resorption by inhibiting the activities of matrix metalloproteinases (MMPs) and cathepsin K in mouse bone marrow macrophages. MF extract appeared to increase ALP activity in murine osteoblastic cells. Taken together, MF extract may be a beneficial supplement for the blockade of osteoporosis progression, particularly for the management of postmenopausal osteoporosis.

Discovery of artemisinin-glycolipid hybrids as anti-oral cancer agents.

Novel artemisinin-glycolipid hybrids were directly synthesized from 12ß (C-C)-type deoxoartemisinin and glycolipid and exhibited exceptional in vitro anticancer activity, particularly against the oral carcinoma cancer cell lines, respectively. The artemisinin-glycolipid hybrids, with effective concentrations under 20 µM, demonstrated better anticancer activity than either artemisinin or glycolipid alone and showed five times more anti-oral cancer activity than either cisplatin or paclitaxel.

Buddlejasaponin IV induces cell cycle arrest at G2/M phase and apoptosis in immortalized human oral keratinocytes.

Buddlejasaponin IV (BS-IV), a major component of Pleurospermum kamtschaticum, exerts antiinflammatory and cytotoxic effects against cancer cells. The study investigated whether BS-IV could prevent oral carcinogenesis by inhibiting the growth of immortalized human oral keratinocytes (IHOKs). BS-IV reduced cell viability and induced cell cycle arrest at G2/M phase and apoptotic morphological changes in IHOKs. BS-IV inhibited the levels of cyclin B1, Cdc2 and Cdc25C, but enhanced Chk2 phosphorylation. The increased levels of pRb and p21 protein and the activation of p53 were also noted in BS-IV-treated IHOKs. In addition, BS-IV induced cytochrome c release from mitochondria by reducing antiapoptotic Bcl-2 levels and increasing pro-apoptotic Bax levels. BS-IV treatment resulted in the activation of caspase-9 and caspase-3. PARP cleavage was also clearly observed in the BS-IV-treated IHOKs. Furthermore, the expression of the Fas death receptor and Fas ligand was induced and procaspase-8 level was suppressed by BS-IV treatment. Taken together, BS-IV treatment inhibited the growth of IHOK cells via the induction of p53-dependent cell cycle arrest at the G2/M phase and apoptosis via both mitochondrial-dependent and death receptor-mediated pathways. Thus, BS-IV can be considered an excellent candidate for a chemopreventive agent to block the progression of HPV-induced oral carcinogenesis.

Cornus kousa F.Buerger ex Miquel increases glucose uptake through activation of peroxisome proliferator-activated receptor γ and insulin sensitization.

AIM OF THE STUDY: Cornus kousa F.Buerger ex Miquel, an oriental medicinal plant, has been traditionally used for the treatment of hyperglycemia, but its molecular mechanism remains unknown. The goal of this study was to investigate the peroxisome proliferator-activated receptor γ (PPARγ) ligand-binding activity of Cornus kousa and to determine the effects of Cornus kousa on insulin sensitization in 3T3-L1 cells for the treatment of type 2 diabetes. MATERIALS AND METHODS: PPARγ luciferase transactivation assay was used to evaluate the PPARγ ligand-binding activity of Cornus kousa leaf extract. Western blot analysis, oil Red O staining, and glucose uptake assay were performed to evaluate PPARγ agonistic activity and insulin sensitizing effects of Cornus kousa leaf extract (CKE) in 3T3-L1 cells. RESULTS: CKE increased PPARγ ligand-binding activity in a dose-dependent manner. In addition, CKE enhanced adipogenesis and the expression of PPARγ target proteins, including glucose transporter 4 (GLUT4) and adiponectin, as well as proteins involved in adipogenesis, including PPARγ and CCAAT/enhancer binding protein α (C/EBPα) in 3T3-L1 adipocytes. Furthermore, CKE led to significant induction of glucose uptake and stimulated insulin signaling, but not to activation of AMP-activated protein kinase (AMPK) signaling. The enhanced glucose uptake by CKE were abolished by treatment with bisphenol a diglycidyl ether (BADGE), a PPARγ antagonist, or LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), but not by compound C, an AMPK inhibitor. CONCLUSION: Consistent with the high PPARγ ligand-binding activity, CKE increased glucose uptake through PPARγ activation and insulin signaling. These results suggest that CKE could have pharmacological effects for the treatment of hyperglycemia and type 2 diabetes.

Decursin and decursinol from Angelica gigas inhibit the lung metastasis of murine colon carcinoma.

The principal objective of the present study was to evaluate the antimetastatic activity of decursin and decursinol isolated from Angelica gigas. Decursin and decursinol inhibited the proliferation and invasion of CT-26 colon carcinoma cells. The expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in cells and the activities in the culture medium were also reduced by decursin and decursinol treatment. In CT-26 cells, the extracellular signal-regulated kinase (ERK) inhibitor inhibited cell proliferation, invasion and MMP-9 expression, and the c-Jun N-terminal kinase (JNK) inhibitor suppressed the expression of both MMPs, as well as cell proliferation and cell invasion. The phosphatidylinositol-3 kinase (PI3K) inhibitor reduced only the expression of MMP-2. In addition, the invasion of CT-26 cells was inhibited by the treatment with anti-MMP-9 antibody, rather than anti-MMP-2 antibody. These results indicate that MMP-9 expression via ERK and JNK plays a critical role for the invasion of CT26 cells. Decursin and decursinol downregulated ERK and JNK phosphorylation. Moreover, oral administration of decursin and decursinol reduced the formation of tumor nodules in the lungs and the increase in lung weight caused by CT-26 metastases. Therefore, both decursin and decursinol may be beneficial antimetastatic agents, targeting MMPs and their upstream signaling molecules.

Red ginseng saponin extract attenuates murine collagen-induced arthritis by reducing pro-inflammatory responses and matrix metalloproteinase-3 expression.

Ginseng, the root of Panax ginseng C. A. MEYER, has been used as a food product and medicinal ingredient. In this study, we assessed the anti-arthritic effects of red ginseng saponin extract (RGSE), including ginsenosides Rg3, Rk1 and Rg5 as major components, on a murine type II collagen (CII)-induced arthritis (CIA), which is a valid animal model of human arthritis. Oral administration of RGSE at 10 mg/kg reduced the clinical arthritis score and paw swelling in the CIA mice, and inhibited joint space narrowing and histological arthritis, illustrating the severity of synovial hyperplasia, inflammatory cell infiltration, pannus formation, and erosion of cartilage. RGSE inhibited the expression of matrix metalloproteinase-3 and nitrotyrosine formation, and recovered the expression of superoxide dismutase in the joints of the CIA mice. Orally administered RGSE also reduced the levels of serum tumor necrosis factor-alpha and interleukin-1beta in the CIA mice. CII- or lipopolysaccharide-stimulated cytokine production, in addition to CII-specific proliferation, was reduced in the spleen cells of the RGSE-treated CIA mice, as compared with those from vehicle-treated CIA mice. Furthermore, RGSE administration protected against CIA-induced oxidative tissue damage by restoring the increased malondialdehyde levels and the decreased glutathione levels and catalase activities almost to control levels. Therefore, RGSE may be a beneficial supplement which can improve human arthritis.

Anti-inflammatory effects of licorice and roasted licorice extracts on TPA-induced acute inflammation and collagen-induced arthritis in mice.

The anti-inflammatory activity of licorice (LE) and roasted licorice (rLE) extracts determined in the murine phorbol ester-induced acute inflammation model and collagen-induced arthritis (CIA) model of human rheumatoid arthritis. rLE possessed greater activity than LE in inhibiting phorbol ester-induced ear edema. Oral administration of LE or rLE reduced clinical arthritis score, paw swelling, and histopathological changes in a murine CIA. LE and rLE decreased the levels of proinflammatory cytokines in serum and matrix metalloproteinase-3 expression in the joints. Cell proliferation and cytokine secretion in response to type II collagen or lipopolysaccharide stimulation were suppressed in spleen cells from LE or rLE-treated CIA mice. Furthermore, LE and rLE treatment prevented oxidative damages in liver and kidney tissues of CIA mice. Taken together, LE and rLE have benefits in protecting against both acute inflammation and chronic inflammatory conditions including rheumatoid arthritis. rLE may inhibit the acute inflammation more potently than LE.

Decursin and decursinol inhibit VEGF-induced angiogenesis by blocking the activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase.

The root of Angelica gigas Nakai contains two major coumarins, which have been previously identified as decursin and decursinol. Decursin has been demonstrated to exhibit potent anti-cancer activity both in vitro and in vivo. In this study, we found that decursin and decursinol at non-cytotoxic doses inhibited the VEGF-induced proliferation, migration, and capillary-tube formation of HUVECs. Moreover, decursin and decursinol suppressed microvessel formation on chorioallantoic membranes in fertilized eggs and into mouse Matrigel plugs. The oral administration of decursin and decursinol also reduced VEGF-induced angiogenesis in Matrigel. Furthermore, decursin and decursinol reduced the phosphorylation of ERK and JNK, but not p38 MAPK, in VEGF-stimulated HUVECs. Taken together, our results reveal that decursin and decursinol inhibit VEGF-induced angiogenesis by reducing the activation of ERK and JNK in HUVECs, and possess potent in vivo anti-angiogenic activity, coupled with the advantage of oral dosing. Thus, these compounds may have the potential for the treatment of cancers dependent on VEGF-induced vascularization.