Hypoglycemic effects of mountain caviar extract and inhibitory mechanism of saponins, including momordin Ic, on glucose absorption.

Mountain caviar is a fruit of Kochia scoparia that contains momordin Ic as a major saponin constituent. Its extract (MCE) has been shown to suppress blood glucose elevations in the human oral glucose tolerance test (OGTT) as well as increases in blood glucose in OGTT, gastric emptying (GE), and glucose incorporation in the small intestine in rats. However, the effects of MCE and momordin Ic on glucose absorption in mice and these action mechanisms have not been examined for more than 2 decades. Therefore, we herein investigated the effects of MCE, its saponin fraction, and momordin Ic on blood glucose elevations in mice. Mouse blood glucose elevation tests were performed on carbohydrate-loaded mice. The mountain caviar saponin fraction significantly delayed blood glucose elevations in glucose-, sucrose-, and soluble starch-loaded mice. In glucose-loaded mice, the saponin fraction, MCE, and momordin Ic significantly suppressed rapid glucose elevations after glucose loading, but not sucrose loading. A mouse GE study was performed by loading with glucose and phenolphthalein solution. Momordin Ic and MCE strongly suppressed mouse GE. Intestinal glucose absorption was evaluated by the incorporation of 2-deoxyglucose (2-DG) into Caco-2 cell layers and mouse duodenum wall vesicles. The results obtained showed that momordin Ic inhibited the incorporation of 2-DG into Caco-2 cells and mouse duodenum vesicles. Collectively, these results suggest that MCE, particularly the principal saponin, momordin Ic, preferably suppressed glucose-induced blood glucose elevations and delayed carbohydrate-induced glucose elevations in mice. The underlying mechanism was found to involve the suppression of GE and intestinal glucose absorption.

Epidermal growth factor receptor as a potential target of momordin Ic to promote apoptosis of cholangiocarcinoma cells.

OBJECTIVES: Strategies that induce apoptosis of malignant cells are recognized as effective cancer treatments. This study evaluated the apoptosis-inducing ability of momordin Ic against cholangiocarcinoma (CCA) cells and the respective underlying mechanisms. METHODS: Quantification of apoptotic cells was performed using Annexin V/7-AAD double dye staining followed by flow cytometry. The effect of momordin Ic on the expression of epidermal growth factor receptor (EGFR) and its downstream signalling molecules was determined via Western blot analysis. The RT2 Profiler PCR Array was used to determine the expression of cell death-associated genes. Expression levels of apoptosis-related proteins were examined using an apoptosis antibody array. KEY FINDINGS: Momordin Ic potently limited the ability of CCA cells to thrive by promoting apoptotic cell death. This apoptosis-inducing activity was accompanied with suppression of expression of EGFR, p-EGFR, c-Myc and other downstream EGFR signalling-related molecules. Additional molecular analyses demonstrated that momordin Ic modified the expression profile of cell death-associated genes in CCA cells. Moreover, significant upregulation of apoptosis-activating proteins and downregulation of apoptosis-inhibiting protein were also observed after exposure to momordin Ic. CONCLUSIONS: These results suggest that momordin Ic has a potential therapeutic opportunity for CCA treatment by acting as an EGFR suppressant.

Momordin Ic induces G0/1 phase arrest and apoptosis in colon cancer cells by suppressing SENP1/c-MYC signaling pathway.

Momordin Ic (MI) is a natural pentacyclic triterpenoid enriched in various Chinese natural medicines such as the fruit of Kochia scoparia (L.) Schrad. Studies have shown that MI presents antitumor properties in liver and prostate cancers. However, the activity and potential mechanisms of MI against colorectal cancer remain elusive. Here, we showed that MI inhibited cell proliferation with G0/1 phase cell cycle arrest in colon cancer cells. Moreover, it was observed that MI increased apoptosis compared to untreated cells. Further investigation showed that the SUMOylation of c-Myc was enhanced by MI and led to the down-regulated protein level of c-Myc, which is involved in regulating cell proliferation and apoptosis. SENP1 has been demonstrated to be critical for the SUMOylation of c-Myc. Meanwhile, knockdown of SENP1 by siRNA abolished the effects of MI on c-Myc level and cell viability in colon cancer cells. Together, these results revealed that MI exerted an anti-tumor activity in colon cancer cells via SENP1/c-Myc signaling pathway. These finding provide an insight into the potential of MI for colon cancer therapy.

Natural triterpenoid saponin Momordin Ic suppresses HepG2 cell invasion via COX-2 inhibition and PPARγ activation.

We previously reported that Momordin Ic, a natural triterpenoid saponin from the fruit of Kochia scoparia (L.) Schrad., exerts good anti-invasive activity on liver cancer partly by altering E-cadherin, VCAM-1, ICAM-1 and MMP-9. The JNK and p38-MAPK pathways differentially altered the four molecules to some extent. However, MMP-9, which is greatly suppressed by Momordin Ic, was affected by neither p38-MAPK nor JNK. Therefore, we further investigated how other signals previously found to regulate cell growth, such as COX-2 and PPARγ, function in the process of cell invasion by western blot. The results demonstrated that COX-2 and PPARγ play a significant role in Momordin Ic-inhibited cell invasion. However, COX-2 only regulated E-cadherin and ICAM-1. PPARγ was not involved in VCAM-1alteration but was significant for the expressions of other proteins. Akt, a kinase upstream of COX-2 and PPARγ, did not influence ICAM-1 but directly mediated the expression of E-cadherin, VCAM-1 and MMP-9. Momordin Ic weakens HepG2 cell invasion through PPARγ activation and COX-2 inhibition. These findings provide evidence for the anti-invasion mechanism of Momordin Ic.

Suppressive effects of Momordin Ic on HepG2 cell migration and invasion by regulating MMP-9 and adhesion molecules: Involvement of p38 and JNK pathways.

Momordin Ic was previously found to induce liver cancer cell apoptosis and autophagy. To further elucidate the anti-cancer activity of Momordin Ic, we analyzed the suppressive effects of Momordin Ic on cell migration and invasion. We also investigated the mechanisms associated with MMP-9, adhesion molecules and signaling transductions. The results demonstrated that Momordin Ic effectively prevented cell attachment, migration and invasion. E-cadherin, mediation of homotypic adhesion was induced while VCAM-1 and ICAM-1 and MMP-9 were inhibited. Momordin Ic influenced phosphorylations of p38, JNK and Erk with VEGF. p38 effectively regulated expressions of E-cadherin, VCAM-1 and ICAM-1. JNK greatly contributed to E-cadherin alteration. Erk hardly modified E-cadherin, VCAM-1, ICAM-1 and MMP-9 although Erk phosphorylation decreased by Momordin Ic. These results revealed Momordin Ic prevent cell invasion by inhibiting VCAM-1, ICAM-1, MMP-9 but inducing E-cadherin expression via p38 and JNK pathways. Thus momordin Ic may be a promising candidate with anti-cancer bioactivity.

Quantification Analysis and In Vitro Anti-Inflammatory Effects of 20-Hydroxyecdysone, Momordin Ic, and Oleanolic Acid from the Fructus of Kochia scoparia.

BACKGROUND: The fructus of Kochia scoparia Schrader (Chenopodiaceae) is a traditional herbal medicine that has been used for treating gonorrhea and dermatitis. OBJECTIVE: We investigated the anti-inflammatory activities of three marker compounds, including 20-hydroxyecdysone, momordin Ic, and oleanolic acid, from the fructus of K. scoparia. MATERIALS AND METHODS: The simultaneous analysis of three components was performed using high-performance liquid chromatography and high-performance thin-layer chromatography. We evaluated the anti-inflammatory effects of the nine marker compounds by determining their anti-inflammatory activities in the murine macrophage cell line RAW 264.7. RESULTS: Among three marker compounds, momordin Ic, but not 20-hydroxyecdysone and oleanolic acid, had inhibitory effects on the production of inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS-treated RAW264.7 macrophages. The effects of three marker compounds on prostaglandin E2(PGE2) were also evaluated. All three compounds significantly reduced PGE2 production in LPS-treated cells. CONCLUSIONS: We suggest that momordin Ic is the most potent phytochemical of the fructus of K. scoparia as an anti-inflammatory agent. SUMMARY: Simultaneous analysis of three phenylpropanoids in the Kochia scoparia was established using HPLC-PDA systemThe momordin Ic had inhibitory effects on production of inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS-treated RAW264.7 macrophagesThe momordin Ic, 20-hydroxyecdysone, and oleanolic acid significantly reduced PGE2 production in LPS-treated cells. Abbreviations used: HPLC: High-performance liquid chromatography; TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; PGE2: Pro-inflammatory mediator prostaglandin E2; LPS: Lipopolysaccharide.

A selective and sensitive method based on UPLC-MS/MS for quantification of momordin Ic in rat plasma: application to a pharmacokinetic study.

A selective and sensitive method was developed and validated based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This method was applied to quantify momordin Ic in rat plasma. Chromatographic separation was performed on a Hypersil GOLD HPLC C18 column (150mm×4.6mm, 5µm) using an isocratic mobile phase of acetonitrile/water (80:20, v/v) at a flow rate of 0.6mL/min. An electrospray ionization source was applied and operated in negative ion mode; selected reaction monitoring (SRM) mode was used for quantification by monitoring the precursor-to-product ion transitions of m/z 763.4→m/z 455.3 for momordin Ic, and m/z 649.4→m/z 487.3 for IS. Calibration curves showed good linearity over the range of 22.0-2200ng/mL for momordin Ic in rat plasma. The developed method was applied to a pharmacokinetic study of momordin Ic in rats after single intravenous doses at 0.52, 1.56, and 4.67mg/kg. The elimination half-life (t1/2) values were 1.22±0.39, 1.14±0.10, and 1.83±0.39h, respectively. The plasma concentration at 2min (C2min) and area under the curve (AUC) for the intravenous doses of momordin Ic were approximately dose proportional.