Effect of Angelica gigas Nakai Ethanol Extract and Decursin on Human Pancreatic Cancer Cells.

Pancreatic cancer (PC) is one of the most severe cancers, and its incidence and mortality rates have steadily increased in the past decade. In this study, we demonstrate the effect of Angelica gigas Nakai extract on pancreatic ductal adenocarcinoma cells. We prepared A. gigas Nakai ethanol extract (AGE) using roots of A. gigas Nakai and detected its active compound decursin from AGE by ultra-performance liquid chromatography analysis. AGE and decursin significantly decreased viability and colony formation of PANC-1 and MIA PaCa-2 cells. AGE and decursin induced G0/G1 phase arrest through downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). Caspase-3-dependent apoptosis of PANC-1 cells was promoted by AGE and decursin. Additionally, nontoxic concentrations of AGE and decursin treatment could suppress matrix metalloproteinase (MMP)-2 and MMP-9 expression and activity by inhibiting p38 phosphorylation. Taken together, this study demonstrates that AGE and decursin have potential properties to be considered in PC treatment.

Arctigenin Inhibits Adipogenesis by Inducing AMPK Activation and Reduces Weight Gain in High-Fat Diet-Induced Obese Mice.

Although arctigenin (ARC) has been reported to have some pharmacological effects such as anti-inflammation, anti-cancer, and antioxidant, there have been no reports on the anti-obesity effect of ARC. The aim of this study is to investigate whether ARC has an anti-obesity effect and mediates the AMP-activated protein kinase (AMPK) pathway. We investigated the anti-adipogenic effect of ARC using 3T3-L1 pre-adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). In high-fat diet (HFD)-induced obese mice, whether ARC can inhibit weight gain was investigated. We found that ARC reduced weight gain, fat pad weight, and triglycerides in HFD-induced obese mice. ARC also inhibited the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα) in in vitro and in vivo. Furthermore, ARC induced the AMPK activation resulting in down-modulation of adipogenesis-related factors including PPARγ, C/EBPα, fatty acid synthase, adipocyte fatty acid-binding protein, and lipoprotein lipase. This study demonstrates that ARC can reduce key adipogenic factors by activating the AMPK in vitro and in vivo and suggests a therapeutic implication of ARC for obesity treatment. J. Cell. Biochem. 117: 2067-2077, 2016. © 2016 Wiley Periodicals, Inc.

Anti-adipogenic effect of Glycoside St-E2 and Glycoside St-C1 isolated from the leaves of Acanthopanax henryi (Oliv.) Harms in 3T3-L1 cells.

Acanthopanax henryi (Oliv.) Harms has been used in the treatment of arthritis, rheumatism, and abdominal pain. This study evaluated whether natural compounds isolated from the leaves of A. henryi (Oliv.) Harms could inhibit adipocyte differentiation by regulating transcriptional factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). AMP-activated protein kinase (AMPK) activity was also evaluated. Among the several compounds isolated from the leaves of A. henryi (Oliv.) Harms, Glycoside St-C1 and Glycoside St-E2 significantly decreased lipid accumulation and the expressions of PPARγ and C/EBPα. Glycoside St-C1 and Glycoside St-E2 were found to activate AMPK when they regulated PPARγ and C/EBPα. Results confirmed that Glycoside St-C1 and Glycoside St-E2 isolated from the leaves of A. henryi (Oliv.) Harms can inhibit adipogenesis through the AMPK-PPARγ-C/EBPα mechanism. Thus, this study suggests that Glycoside St-C1 and Glycoside St-E2 have a therapeutic effect due to activation of the AMPKα.

Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, ß-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Effects of Ixeris dentata water extract and caffeic acid on allergic inflammation in vivo and in vitro.

BACKGROUND: Ixeris dentata Nakai has been used for the treatment of mithridatism, calculous, indigestion, pneumonia, hepatitis, and tumors in Korea, China, and Japan. However, the effect of a water extract of Ixeris dentata (ID) and its molecular mechanism on allergic inflammation has not been elucidated. In this study, we attempted to evaluate the effects of ID and its major compound caffeic acid on allergic inflammation in vivo and in vitro. METHODS: ID was applied to 2, 4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis (AD)-like skin lesion mice and immune cell infiltration, cytokine production, and the activation of mitogen-activated protein kinases (MAPKs) were investigated. Moreover, the effect of ID on compound 48/80-induced anaphylactic shock was investigated in a mouse model. The human keratinocyte cell line (HaCaT cells) and human mast cells (HMC-1) were treated with ID or caffeic acid to investigate the effects on the production of chemokines and proinflammatory cytokines and on the activation of MAPKs. RESULTS: ID inhibited the serum levels of IgE and interleukin (IL)-1ß in DNFB-induced AD-like skin lesion mouse models and suppressed anaphylactic shock in the mouse models. ID and caffeic acid inhibited the production of chemokines and adhesion molecules in HaCaT cells. In addition, ID reduced the release of tumor necrosis factor-α and IL-8 via the inhibition of MAPKs phosphorylation in HMC-1 cells. CONCLUSIONS: These results suggest that ID is a potential therapeutic agent for allergic inflammatory diseases, including dermatitis.

Saikosaponin D Inhibits Lung Metastasis of Colorectal Cancer Cells by Inducing Autophagy and Apoptosis.

Saikosaponin D (SSD), derived from Bupleurum falcatum L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies have investigated the anti-tumor effects of SSD on cancer in multiple organs. However, its role in colorectal cancer (CRC) remains unclear. Therefore, this study aimed to elucidate the suppressive effects of SSD on CRC cell survival and metastasis. SSD reduced the survival and colony formation ability of CRC cells. SSD-induced autophagy and apoptosis in CRC cells were measured using flow cytometry. SSD treatment increased LC3B and p62 autophagic factor levels in CRC cells. Moreover, SSD-induced apoptosis occurred through the cleavage of caspase-9, caspase-3, and PARP, along with the downregulation of the Bcl-2 family. In the in vivo experiment, a reduction in the number of metastatic tumor nodules in the lungs was observed after the oral administration of SSD. Based on these results, SSD inhibits the metastasis of CRC cells to the lungs by inducing autophagy and apoptosis. In conclusion, SSD suppressed the proliferation and metastasis of CRC cells, suggesting its potential as a novel substance for the metastatic CRC treatment.

Extract of Isatidis Radix Inhibits Lipid Accumulation in In Vitro and In Vivo by Regulating Oxidative Stress.

Isatidis Radix (IR), the root of Isatis tinctoria L. belonging to Brassicaceae, has been traditionally used as a fever reducer. Although some pharmacological effects, such as anti-diabetes, anti-virus, and anti-inflammatory, have been reported, there is no study on the anti-obesity effect of IR. This study used 3T3-L1 cells, human mesenchymal adipose stem cells (hAMSCs), and a high-fat diet (HFD)-induced obese mouse model to confirm the anti-adipogenic effect of IR. Intracellular lipid accumulation in 3T3-L1 cells and hAMSCs was decreased by IR treatment.IR extract especially suppressed reactive oxygen species (ROS) production through a cluster of differentiation 36 (CD36)-AMP-activated protein kinase (AMPK) pathway. Consequently, the expressions of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT-enhancer-binding proteins alpha (C/EBPα), and fatty acid synthesis (FAS) were inhibited by IR extract. In addition, ß-oxidation-related genes were also decreased by treatment of IR extract. IR inhibited weight gain through this cascade in the HFD-induced obese mouse model. IR significantly suppressed lipid accumulation in epididymal white adipose tissue (eWAT). Furthermore, the administration of IR extract decreased serum free fatty acid (FFA), total cholesterol (TC), and LDL cholesterol, suggesting that it could be a potential drug for obesity by inhibiting lipid accumulation.

Dehydroevodiamine inhibits lung metastasis by suppressing survival and metastatic abilities of colorectal cancer cells.

BACKGROUND: Despite the rising 5-year survival rate of colorectal cancer (CRC) patients, the survival rate decreases as the stage progress, and a low survival rate is highly associated with metastasis. PURPOSE: The purpose of our study is to investigate the effect of dehydroevodiamine (DHE) on the lung metastasis of CRC and the proliferation of CRC cells. STUDY DESIGN: Cell death was confirmed after DHE treatment on several CRC cell lines. The mechanism of cell cytotoxicity was found using flow cytometry. After that, the expression of the proteins or mRNAs related to the cell cytotoxicity was confirmed. Also, anti-metastatic ability of DHE in CRC cells was measured by checking the expression of Epithelial to Mesenchymal Transition (EMT) markers. Lung metastasis mouse model was established, and DHE was administered orally for 14 days. RESULTS: DHE suppressed the viability of HCT116, CT26, SW480, and LoVo cells. DHE treatment led to G2/M arrest via a reduction of cyclin B1/CDK1 and caspase-dependent apoptosis. It also induced autophagy by regulating LC3-II and beclin-1 expression. Additionally, migration and invasion of CRC cells were decreased by DHE through regulation of the expression of EMT markers. Oral administration of DHE could inhibit the lung metastasis of CT26 cells in an in vivo model. CONCLUSION: Our study demonstrated that DHE has a potential therapeutic effect on colorectal cancer metastasis.

The Medical Needs and Characteristics of Cancer and Progressive Neurologic Disease Patients Who Use Home-Based Medical Care in Korea: A Retrospective Study for 2011-2020.

OBJECTIVES: To investigate the needs and characteristics of patients with cancer and neurologic disorders requiring home-based medical care (HBMC). DESIGN: Retrospective observational study. SETTING AND PARTICIPANTS: Patients receiving HBMC on discharge from a tertiary hospital in Korea during 2011-2020. METHODS: Patients were classified into 3 disease groups: cancer, progressive neurologic disorders (NR), and others. Characteristics and medical needs were assessed in each disease group. Medical needs were categorized based on functional items requiring support or management at the time of registration: respiratory, feeding, urinary system, drain tube, central catheter, wound, medication, and other. Patients with multiple medical needs were assigned to multiple categories. Patients who used HBMC for more than 3 months were defined as long-term users; their characteristics were evaluated in the same way. RESULTS: Of the total 655 patients, 47.0% (308) had cancer and 17.3% (113) were NR patients. Among all patients, 78.8% were partially dependent (44.0%) or completely dependent (34.8%) in daily activities, and there were more dependent patients in the NR group (80.5%) than cancer (26.6%). Patients with cancer needed central catheter management the most (43.5%), followed by wound care (36.7%), feeding support (35.1%), and drain tube management (22.1%). NR patients required feeding support the most (80.5%), followed by respiratory support (43.4%), wound care (41.6%), and urinary system support (19.5%). Of all patients, 30.2% (198) were long-term users (NR, 37.9%; cancer, 35.4%). Long-term users were common among patients who needed respiratory support (59.4%), feeding support (48.75), and urinary system support (34.6%). CONCLUSIONS AND IMPLICATIONS: Homebound patients with cancer and progressive neurologic disorders need medical services at home after discharge. Patients who need feeding and respiratory support usually use HBMC for more than 3 months. Further studies are needed to design an optimal HBMC that continuously provides medical services to patients with serious illnesses living at home.

Gomisin A Alleviates Obesity by Regulating the Phenotypic Switch between White and Brown Adipocytes.

Although gomisin A (GA) alleviates cancer and inflammation, its anti-obesity effect and the underlying mechanism have not yet been elucidated. Therefore, in this study, we aimed to elucidate the anti-obesity effects of GA by investigating the phenotypic changes involved in the browning and whitening of adipocytes. Here, obesity was induced to C57BL/6J mice using a high-fat diet (HFD). We administrated GA and checked weight changes for 12 weeks. We found that GA decreased the weight of weight gain, epididymal white adipose tissue (eWAT), and liver in the mice. In addition, the administration of GA elevated the levels of high-density lipoprotein (HDL)-cholesterol in the mice serum. Moreover, even after 12 weeks of treatment with GA, it did not cause any hepatic and renal toxicity. However, we found that GA induced the browning of eWAT and inhibited the whitening of brown adipose tissue. We further confirmed the anti-obesity mechanism of GA using 3T3-L1 cells, the human adipose mesenchymal stem cells (hAMSCs), and primary brown adipocytes (BAs) in vitroexperiments. We found that GA suppressed adipogenesis via the activation of AMP-activated protein kinase (AMPK). Furthermore, GA-induced browning by increasing the expression levels of uncoupling protein 1 (UCP1) in hAMSCs. The results of our study indicate that GA can inhibit weight gain by regulating the phenotypic changes involved in the browning and whitening of adipose tissues, which makes it a potential therapeutic agent for the treatment of obesity.

Inhibitory Effect of Gallotannin on Lung Metastasis of Metastatic Colorectal Cancer Cells by Inducing Apoptosis, Cell Cycle Arrest and Autophagy.

Colorectal cancer (CRC) is the second most common cause of cancer death in the world, and metastatic CRC is a major cause of cancer death. Gallotannin (GT), a polyphenolic compound, has shown various biological effects such as anti-oxidant, anti-inflammatory, antimicrobial, and antitumor effects. However, the effects of GT on metastatic CRC cells are not completely understood. This study aimed to investigate the anti-metastatic effect of GT and the underlying mechanisms on metastatic CRC cells. Oral administration of GT suppressed the lung metastasis of metastatic CRC cells in the experimental mouse model. GT decreased the viability of metastatic CRC cell lines, including CT26, HCT116, and SW620, by inducing apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest through inactivation of CDK2/cyclin A complex, and autophagic cell death through up-regulation of LC3B and p62 levels. GT regulated PI3K/AKT/mTOR and AMPK signaling pathways, which are critical for the development and maintenance of cancer. Additionally, non-cytotoxic concentrations of GT can suppress migration and invasion of CRC cells by inhibiting the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and epithelial-mesenchymal transition by downregulating the expression of mesenchymal markers including snail, twist, and vimentin. In conclusion, GT prevented colorectal lung metastasis by reducing survival and inhibiting the metastatic phenotypes of CRC cells.

The Extract of Arctium lappa L. Fruit (Arctii Fructus) Improves Cancer-Induced Cachexia by Inhibiting Weight Loss of Skeletal Muscle and Adipose Tissue.

BACKGROUND: Cachexia induced by cancer is a systemic wasting syndrome and it accompanies continuous body weight loss with the exhaustion of skeletal muscle and adipose tissue. Cancer cachexia is not only a problem in itself, but it also reduces the effectiveness of treatments and deteriorates quality of life. However, effective treatments have not been found yet. Although Arctii Fructus (AF) has been studied about several pharmacological effects, there were no reports on its use in cancer cachexia. METHODS: To induce cancer cachexia in mice, we inoculated CT-26 cells to BALB/c mice through subcutaneous injection and intraperitoneal injection. To mimic cancer cachexia in vitro, we used conditioned media (CM), which was CT-26 colon cancer cells cultured medium. RESULTS: In in vivo experiments, AF suppressed expression of interleukin (IL)-6 and atrophy of skeletal muscle and adipose tissue. As a result, the administration of AF decreased mortality by preventing weight loss. In adipose tissue, AF decreased expression of uncoupling protein 1 (UCP1) by restoring AMP-activated protein kinase (AMPK) activation. In in vitro model, CM increased muscle degradation factors and decreased adipocytes differentiation factors. However, these tendencies were ameliorated by AF treatment in C2C12 myoblasts and 3T3-L1 cells. CONCLUSION: Taken together, our study demonstrated that AF could be a therapeutic supplement for patients suffering from cancer cachexia.

Gomisin A ameliorates metastatic melanoma by inhibiting AMPK and ERK/JNK-mediated cell survival and metastatic phenotypes.

BACKGROUND: Gomisin A (G.A), a lignan compound extracted from the fruits of Schisandra chinensis, is known to exert anti-tumor effects on hepatocarcinoma and colorectal cancer cells. Suppression of proliferation and metastatic abilities of cancer cells are some effective cancer treatment methods. PURPOSE: The objective of this study is to investigate the effects of G.A on metastatic melanoma, and the mechanism by which it affects metastatic melanoma. STUDY DESIGN: The anti-proliferative and anti-metastatic effects of G.A were observed in in vitro and in vivo. METHODS: WST assay and flow cytometry were conducted to investigate the effect of G.A on proliferation, cell cycle arrest, and apoptosis in metastatic melanoma cell lines. Migration and invasion abilities of G.A-treated melanoma cells were observed by wound healing and invasion assays. RESULTS: G.A (25-100 µM) decreased the viability of melanoma cells by inducing cell cycle arrest and apoptosis. These anti-proliferative effects of G.A were found to be mediated by AMPK, ERK, and JNK activation. G.A (5-20 µM) decreased the migration and invasion of melanoma cells by suppressing epithelial-mesenchymal transition (EMT). Consequently, G.A (2-50 mg/kg) inhibited lung metastasis by suppressing EMT and inducing cell cycle arrest and apoptosis in melanoma cells. CONCLUSION: These results conclude that G.A has the potential to reduce metastatic melanoma through its anti-proliferative and anti-metastatic effects.

Catalytic reaction system for rapid selective oxidation of alkyl sulphide.

Highly efficient catalytic reaction systems are developed to rapidly and selectively oxidize 2-chloroethyl ethyl sulfide (CEES). In the systems, precursors containing bromide(s) and nitrate anions are chosen for the development of cyclic catalytic loop and the effect of acids on the selective oxidation of CEES are investigated by the addition of several homogeneous acid catalysts. The experimental results reveal that addition of acid results in a higher concentration of tribromide, which is reported as a key component for the observed activity in the catalytic solution. As a consequence, a dramatic improvement in catalytic activity is observed, especially when the molar amount of acid is controlled to be more than twice the initial concentration of tribromide. For the efficient design of a catalytic system, heterogeneous acid catalysts possessing different ratios of Brønsted to Lewis acid sites are also considered. Compared to reaction systems catalysed by homogeneous acids, similar reaction behaviour is observed for the reaction with Amerlyst-15, while those with other heterogeneous catalysts, containing Lewis or mixed acid sites in their structure, exhibits an adverse effect of selective sulfoxidation, mainly due to the adsorption of anions onto Lewis sites and consequential deconstruction of the catalytic loop.

Mechanistic reaction model for oxidation of sulfur mustard simulant by a catalytic system of nitrate and tribromide.

A new metal-free catalytic reaction system is developed to selectively oxidize 2-chloroethyl ethyl sulfide (CEES), a surrogate of sulfur mustard. The combination of two catalytic precursors, tribromide and nitrate, allows a rapid sulfoxidation of CEES even at ambient conditions. The kinetic behaviours at various reaction conditions are investigated to identify the most probable reaction pathways of the development of catalytic loop and the overall reaction steps of CEES sulfoxidation. The mechanistic study demonstrates that the catalytic loop does not require an addition of mineral acid or water, which is common in most other reaction systems. Incomplete catalytic systems with one precursor are also examined to uncover the complex network of sulfoxidation in the catalytic reaction system. The results reveal that the complex between CEES and bromine is a reactive intermediate, bromosulfonium, which can be further catalysed and converted into sulfoxide by nitrate. Based on the proposed reaction mechanism, a predictive kinetic model fully describing most reaction behaviours is developed.

Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells.

BACKGROUND: Colorectal cancer (CRC) is one of the diseases with high prevalence and mortality worldwide. In particular, metastatic CRC shows low probability of surgery and lacks proper treatment. In this study, we conducted experiments to investigate the inhibitory effect of betulin against metastatic CRC and related mechanisms. METHODS: Water-soluble tetrazolium assay was used to determine the effect of betulin on metastatic CRC cell viability. Flow cytometry and TUNEL assay were performed to confirm whether betulin can induce apoptosis, autophagy, and cell cycle arrest. A lung metastasis mouse model was employed to estimate the anti-metastatic effect of betulin. RESULTS: betulin decreased viability of metastatic CRC cells, including CT26, HCT116, and SW620 cell lines. Through PI3K/Akt/mTOR inactivation, betulin induced AMPK-mediated G0/G1 phase arrest and autophagy of CT26 and HCT116 cells. In addition, betulin occurred caspase-dependent apoptosis via the mitogen-activated protein kinase signaling pathway in metastatic CRC cells. Moreover, orally administered betulin significantly inhibited metastasis of CT26 cells to the lung. CONCLUSION: Our results demonstrate the anti-metastatic effect and therapeutic potential of betulin in metastatic CRC treatment.

Galla Rhois water extract inhibits lung metastasis by inducing AMPK­mediated apoptosis and suppressing metastatic properties of colorectal cancer cells.

Galla Rhois is a commonly used medicine in East Asia for the treatment of several diseases. However, the effects of Galla Rhois on the metastasis of colorectal cancer (CRC) and the underlying molecular mechanisms have not been studied. We investigated the anti­metastatic properties of Galla Rhois water extract (GRWE) on metastatic CRC cells. The effect of GRWE on the viability of colon 26 (CT26) cells was evaluated using WST­8 assay. Annexin V assay and western blot analysis were performed to elucidate the underlying molecular mechanisms involved in apoptosis. GRWE suppressed viability of CT26 cells by inducing apoptosis through the cleavage of caspase­3 and PARP, downregulation of caspase­8, caspase­9, Bcl­2 and Bcl­xL, and upregulation of Bax. Metastatic phenotypes such as epithelial­mesenchymal transition (EMT), migration, and invasion of CRC cells were investigated by real­time reverse transcription polymerase chain reaction, wound healing assay, and matrigel invasion assay, respectively. Non­cytotoxic concentrations of GRWE inhibited EMT in CRC cells by regulating the expression of EMT markers. GRWE attenuated cell migration and invasion through the inhibition of matrix metalloproteinase (MMP)­2 and MMP­9 activity. Moreover, GRWE suppressed colorectal lung metastasis in vivo, suggestive of its potential application for the treatment of colorectal metastasis.

Effect of Korean Red Ginseng extract on colorectal lung metastasis through inhibiting the epithelial-mesenchymal transition via transforming growth factor-ß1/Smad-signaling-mediated Snail/E-cadherin expression.

BACKGROUND: In colorectal cancer (CRC), 40-60% of patients develop metastasis. The epithelial-mesenchymal transition (EMT) is a pivotal and intricate process that increases the metastatic potential of CRC. The aim of this study was to investigate the effect of Korean Red Ginseng extract (RGE) on colorectal metastasis through inhibition of EMT and the metastatic abilities of CRC cells. METHODS: To investigate the effect of RGE on the metastatic phenotypes of CRC cells, CT26 and HT29 cells were evaluated by using an adhesion assay, a wound-healing assay, an invasion assay, zymography, and real-time reverse transcription-polymerase chain reaction. Western-blot analysis was conducted to elucidate the molecular mechanisms of RGE, which showed an inhibitory effect on the transforming growth factor-ß1 (TGF-ß1)-induced EMT in HT29 cells. Additionally, the antimetastatic effect of RGE was evaluated in a mouse model of lung metastasis injected with CT26 cells. RESULTS: RGE decreased the adhesion and migration ability of the CT26 cells and TGF-ß1-treated HT29 cells. The invasion ability was also reduced by RGE treatment through the inhibition of matrix metalloproteinase-9 expression and activity. Moreover, RGE suppressed the TGF-ß1-induced EMT via TGF-ß1/Smad-signaling-mediated Snail/E-cadherin expression in HT29 cells and lung tissue in CT26 tumor-bearing mice. CONCLUSION: Our results demonstrated that RGE inhibited colorectal lung metastasis through a reduction in metastatic phenotypes, such as migration, invasion, and the EMT of CRC cells.

Rubrofusarin-6-ß-gentiobioside inhibits lipid accumulation and weight gain by regulating AMPK/mTOR signaling.

BACKGROUND: Although rubrofusarin-6-ß-gentiobioside (RFG), which is a component of Cassiae tora seed, could likely regulate hyperlipidemia, its anti-obesity effect and related mechanism have not been elucidated. PURPOSE: The aim of this study was to examine whether RFG can ameliorate obesity and the mechanism of lipid accumulation regulated by RFG. STUDY DESIGN: In in vitro experiments, we confirmed the anti-adipogenic effect of RFG using 3T3-L1 cells and human adipose mesenchymal stem cells (hAMSCs). To confirm the anti-obesity effect, High-Fat Diet (HFD)-induced obese mice were selected as a model. METHODS: We investigated anti-adipogenic effects of RFG using MTS assay, Oil Red O Staining, real-time RT-PCR, western blot analysis, and immunofluorescence staining. The anti-obesity effect of RFG was confirmed in HFD-induced mice model using hematoxylin and eosin staining and serum analysis. RESULTS: RFG inhibited lipid accumulation in 3T3-L1 cells and hAMSCs by reducing expression of mammalian targets of rapamycin (mTOR), peroxisome proliferator-activated receptor (PPAR)γ, and CCAAT-enhancer binding protein (C/EBP)α. RFG phosphorylated AMP-activated protein kinase (AMPK) in a liver kinase B (LKB) 1-independent manner. Moreover, the anti-adipogenic effect of RFG was blocked by AMPK inhibitor. These results suggest that RFG inhibits lipid accumulation via AMPK signaling. Furthermore, RFG reduced the body weight, size of epididymal white adipose tissue (eWAT), and fatty liver in the mice. RFG also suppressed levels of adipogenic factors PPARγ, C/EBPα, FAS, LPL, and aP2) by activating AMPK in the eWAT and liver. CONCLUSION: RFG can ameliorate obesity, and thus, could be used as a therapeutic agent for treating obesity.

Rosmarinic Acid Activates AMPK to Inhibit Metastasis of Colorectal Cancer.

Rosmarinic acid (RA) has been used as an anti-inflammatory, anti-diabetic, and anti-cancer agent. Although RA has also been shown to exert an anti-metastatic effect, the mechanism of this effect has not been reported to be associated with AMP-activated protein kinase (AMPK). The aim of this study was to elucidate whether RA could inhibit the metastatic properties of colorectal cancer (CRC) cells via the phosphorylation of AMPK. RA inhibited the proliferation of CRC cells through the induction of cell cycle arrest and apoptosis. In several metastatic phenotypes of CRC cells, RA regulated epithelial-mesenchymal transition (EMT) through the upregulation of an epithelial marker, E-cadherin, and the downregulation of the mesenchymal markers, N-cadherin, snail, twist, vimentin, and slug. Invasion and migration of CRC cells were inhibited and expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were decreased by RA treatment. Adhesion and adhesion molecules such as ICAM-1 and integrin ß1 expressions were also reduced by RA treatment. In particular, the effects of RA on EMT and MMPs expressions were due to the activation of AMPK. Moreover, RA inhibited lung metastasis of CRC cells by activating AMPK in mouse model. Collectively, these results proved that RA could be potential therapeutic agent against metastasis of CRC.