Ampelopsin

1 Larix sp. 2 Mahonia sp. 3 Pinus sp. 4 Salix sp. 5 Syzygium sp.

Dihydromyricetin is a potent inhibitor with an IC50 of 48 μM on dihydropyrimidinase. Dihydromyricetin can activate autophagy through inhibiting mTOR signaling. Dihydromyricetin suppresses the formation of mTOR complexes (mTORC1/2).

In Vitro:Dihydromyricetin, a flavonol, significantly inhibits the catalytic activities of dihydropyrimidinase toward both the natural substrate dihydrouracil and xenobiotic substrate 5-propyl-hydantoin. Dihydromyricetin exhibits a significant inhibitory effect on the activities of dihydropyrimidinase for both substrates, even more than Myricetin does. The IC50 values of Dihydromyricetin for dihydropyrimidinase determined from the titration curves using Dihydrouracil and 5-propyl-hydantoin are 48±2 and 40±2 μM, respectively[1]. Dihydromyricetin (DHM) supplementation significantly reverses the increased phosphorylation of mTOR at Ser2448 (p-mTOR) during D-gal administration, which suggests that Dihydromyricetin can activate autophagy through inhibiting mTOR signaling[2].

In Vivo:Changes in learning and memory capacity in rats administrated normal control group, D-gal group, D-gal+Dihydromyricetin (100 mg/kg) group, D-gal+Dihydromyricetin (200 mg/kg) group assessed by morris water maze (MWM) (n=10 per group). Dihydromyricetin (DHM) treatment significantly shortens the escape latency when compared with D-gal-induced model group[2].

References:
[1]. Huang CY. Inhibition of a Putative Dihydropyrimidinase from Pseudomonas aeruginosa PAO1 by Flavonoids and Substrates of Cyclic Amidohydrolases. PLoS One. 2015 May 19;10(5):e0127634. [2]. Kou X, et al. Ampelopsin attenuates brain aging of D-gal-induced rats through miR-34a-mediated SIRT1/mTORsignal pathway. Oncotarget. 2016 Nov 15;7(46):74484-74495. [3]. Chang H, et al. Ampelopsin suppresses breast carcinogenesis by inhibiting the mTOR signalling pathway. Carcinogenesis. 2014 Aug;35(8):1847-54.

Ampelopsin sodium exhibits antitumor effects against bladder carcinoma in orthotopic xenograft models.[Pubmed:22241170]

Anticancer Drugs. 2012 Jul;23(6):590-6.

The aim of this study was to establish xenograft models of tumor in mice bladder and evaluate the antitumor efficacy of Ampelopsin sodium (Amp-Na). A total of 2x10 human bladder carcinoma EJ cells and murine sarcoma 180 cells were instilled into the bladder of BALB/c nu/nu mice and Swiss mice after preconditioning to establish the tumor model. Mice bearing orthotopic tumors were treated with Amp-Na by intravenous, intraperitoneal, or intravesical instillation. In addition, the pharmacokinetics property of Amp-Na was investigated in normal BALB/c mice. Our results showed that Amp-Na was excreted mainly through the urine, where it existed at a high concentration. Amp-Na significantly inhibited the proliferation of EJ and sarcoma 180 cells both in vivo and in vitro and this can be at least partially attributed to the cell cycle arrest induced by Amp-Na. This study suggests that the use of Amp-Na is an attractive chemotherapeutic modality for bladder cancer patients.

Ampelopsin suppresses breast carcinogenesis by inhibiting the mTOR signalling pathway.[Pubmed:24861637]

Carcinogenesis. 2014 Aug;35(8):1847-54.

The mammalian target of rapamycin (mTOR), which is a master regulator of cellular catabolism and anabolism, plays an important role in tumourigenesis and progression. In this study, we report the chemopreventive effect of the dietary compound Ampelopsin (AMP) on breast carcinogenesis in vivo and in vitro, which acts by inhibiting the mTOR signalling pathway. Our study indicates that AMP treatment effectively suppresses 1-methyl-1-nitrosourea (MNU)-induced breast carcinogenesis in rats and inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P)-induced cellular carcinogenesis. Additionally, AMP inhibits the growth of breast cancer cells in vitro and in vivo. The activity of mTOR kinase was found to be significantly increased in a time-dependent manner during chronic breast carcinogenesis, and this increase can be suppressed by AMP co-treatment. AMP also effectively suppresses mTOR activity in breast cancer MDA-MB-231 cells. We also demonstrated that AMP is an effective mTOR inhibitor that binds to one site on the mTOR target in two ways. Further studies confirmed that AMP inhibits the activation of Akt, suppresses the formation of mTOR complexes (mTORC)1/2 by dissociating regulatory-associated protein of mTOR and rapamycin-insensitive companion of mTOR and, consequently, decreases the activation of the downstream targets of mTOR, including ribosomal p70-S6 kinase, ribosomal protein S6, eukaryotic translation initiation factor 4B and eukaryotic translation initiation factor 4E-binding protein 1. These finding suggest that AMP is a bioactive natural chemopreventive agent against breast carcinogenesis and is an effective mTOR inhibitor that may be developed as a useful chemotherapeutic agent in the treatment of breast cancer.

[Reversal effect and its mechanism of ampelopsin on multidrug resistance in K562/ADR cells].[Pubmed:19624024]

Zhongguo Zhong Yao Za Zhi. 2009 Mar;34(6):761-5.

OBJECTIVE: To investigate the inhibitory effect of Ampelopsin (AMP) combined with adriamycin (ADR) on growth of human leukemia multidrug resistant cell line K562/ADR. METHOD: MTT assay was used to detect the effect of AMP on the cytotoxicity of ADR. Jin's formula was used to analyze the effect of combined drug therapy. The expression of P-glycoprotein (P-gp) on cell membrane of K562/ADR was detected using PE-labeled antibody. Flow cytometry was used to determine the influence of AMP on the intracellular accumulation of ADR. RESULT: AMP at the concentration of 1.25 to 5 mg x L(-1) could significantly reverse the multidrug resistance (MDR) to ADR in K562/ADR cells. Co-administration of 1.25 mg x L(-1) AMP and low concentrations of ADR showed an antagonistic effect, while there was an additional to synergistic effect when the concentration of AMP was above 2.5 mg x L(-1). AMP could decrease the expression of P-gp in a concentration-dependent manner and increase the intracellular accumulation of ADR in K562/ADR cells. CONCLUSION: AMP could increased the cytotoxicity and the intracellular accumulation of chemotherapeutic drugs in MDR associated tumor cells through inhibiting the efflux of drugs by P-gp. AMP may be a promising MDR modulator.

Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-kappaB signaling pathways.[Pubmed:22193240]

Int Immunopharmacol. 2012 Jan;12(1):278-87.

Ampelopsin (AMP), a plant flavonoid, has potent anti-inflammatory properties in vitro and in vivo. The molecular mechanisms of Ampelopsin on pharmacological and biochemical actions of RAW264.7 macrophages in inflammation have not been clearly elucidated yet. In the present study, non-cytotoxic level of Ampelopsin significantly inhibited the release of nitric oxide (NO) and pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha in a dose-dependent manner. Consistent with NO inhibition, Ampelopsin suppressed lipopolysaccharide (LPS)-induced expression of inducible NO synthase (iNOS) by inhibiting nuclear factor kappaB (NF-kappaB) activation, which highly correlated with its inhibitory effect on IkappaB kinase (IKK) phosphorylation, IkappaB phosphorylation and NF-kappaB nuclear translocation. Further study demonstrated that Ampelopsin suppressed LPS-induced activation of Akt without effecting mitogen-activated protein kinases (MAPKs) phosphorylation. A pharmacological inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt pathway, LY294002, abrogated IKK/IkappaB/NF-kappaB-mediated iNOS gene expression. Finally, we certificated that Ampelopsin reduced reactive oxygen species (ROS) accumulation and an anti-oxidant N-acetyl-L-cysteine (NAC) significantly repressed LPS-induced PI3K/Akt phosphorylation and the downstream IKK/IkappaB activation. NAC thereby inhibited LPS-induced iNOS expression and NO production. The present results suggest that the anti-inflammatory effect of Ampelopsin is due to inhibiting the interconnected ROS/Akt/IKK/NF-kappaB signaling pathways.

Ampelopsin inhibits H(2)O(2)-induced apoptosis by ERK and Akt signaling pathways and up-regulation of heme oxygenase-1.[Pubmed:22144097]

Phytother Res. 2012 Jul;26(7):988-94.

Oxidative stress plays an important role in neurodegenerative disorders. Ampelopsin, a flavonoid abundant in Rattan tea (Ampelopsis grossedentata), is a potent antioxidant and its neuroprotective effect against H(2)O(2)-induced apoptosis in PC12 cells is investigated here for the first time. It was found that treatment of cells with Ampelopsin for 1 h significantly reduced the loss of vitality, LDH release and apoptosis and inhibited the formation of reactive oxygen species (ROS). Ampelopsin was able to prevent the activation of p38 induced by H(2)O(2). In addition, up-regulation of heme oxygenase-1 (HO-1) expression by Ampelopsin was shown to be both dose- and time-dependent. Mechanically, HO-1 expression induced by Ampelopsin was found to be due to activation of the ERK and Akt signaling pathways, because it was almost completely blocked by the specific inhibitors of ERK and Akt. These results suggest that Ampelopsin increases cellular antioxidant defense through activation of the ERK and Akt signaling pathways, which induces HO-1 expression and thereby protects PC12 cells from H(2)O(2)-induced apoptosis.

[Anti-invasive and anti-metastatic effect of ampelopsin on melanoma].[Pubmed:12703989]

Ai Zheng. 2003 Apr;22(4):363-7.

BACKGROUND & OBJECTIVE: The authors had firstly reported that Ampelopsin possess anticancer effects on several human cancer cell lines in vitro and on transplant mouse B16 melanoma in vivo. In order to further explore its antitumor effect, the authors designed this study to investigate the effect of Ampelopsin on invasion and metastasis of B16 melanoma in vivo and in vitro. METHODS: B16 cells were injected into C57BL/6 mouse via tail lateral vein, and subsequently formed an experimental pulmonary metastasis. Ampelopsin was administered at 3 dosages by intraperitoneal injection daily for 18 days from the day before cell injection. The B16 mouse melanoma cells were treated with Ampelopsin for 3 days. The effect of Ampelopsin on invasion, migration,and adhesion of B16 melanoma cells were evaluated using Transwell chambers attached with polycarbonate filters and reconstituted basement membrane (Matrigel). RESULTS: The number of metastases in the mice that were given Ampelopsin at the dosages of 150, 200, and 250 mg/kg significantly reduced as compared to the control (P< 0.05), and the inhibition rates were 30.97%, 40.58%, and 61.16%, respectively. The ability of the Ampelopsin treated B16 cells to invade the reconstituted basement membrane decreased significantly (P< 0.01), and the inhibition rates were 36.06%, 59.58%, and 79.09% for Ampelopsin at 20, 40, and 80 micromol/L, respectively. Ampelopsin can also inhibit B16 cells migration,and the inhibition rates were 51.59%, 56.51%, and 66.75% for Ampelopsin at 20, 40, and 80 micromol/L, respectively (P< 0.01). The ability of adhesion of the B16 cells with fibronectin, laminin, or Matrigel decreased significantly. CONCLUSION: Ampelopsin has anti-invasive and anti-metastatic effects on B16 melanoma.

Hepatoprotective activity of tocha, the stems and leaves of Ampelopsis grossedentata, and ampelopsin.[Pubmed:15630194]

Biofactors. 2004;21(1-4):175-8.

Hepatoprotective effect of the leaves and stems of Ampelopsis grossedentata together with its main constituent, Ampelopsin, were examined on D-galactosamine induced liver injury in rats. The diet containing 50% ethanolic extract (1%) and Ampelopsin (0.1%) markedly suppressed the increase of LDH, ALT, AST, alpha-tocopherol levels and GSG/GSSH caused by GalN treatment. These results suggested that Ampelopsin from Tocha acted to prevent the oxidative stress in vivo that may have been due to active oxygen species formed by a macrophage by the action of GalN.

Dihydromyricetin is a potent inhibitor with an IC50 of 48 μM on dihydropyrimidinase. Dihydromyricetin can activate autophagy through inhibiting mTOR signaling. Dihydromyricetin suppresses the formation of mTOR complexes (mTORC1/2).

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