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Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

PURPOSE: Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer. METHODS: COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10-/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. RESULTS: WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10-/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC). CONCLUSIONS: WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated early colon cancer in mice.

BACKGROUND/OBJECTIVES: The objective of this study was to investigate the effects of vitamin C on inflammation, tumor development, and dysbiosis of intestinal microbiota in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced inflammation-associated early colon cancer mouse model. MATERIALS/METHODS: Male BALB/c mice were injected intraperitoneally with AOM [10 mg/kg body weight (b.w)] and given two 7-d cycles of 2% DSS drinking water with a 14 d inter-cycle interval. Vitamin C (60 mg/kg b.w. and 120 mg/kg b.w.) was supplemented by gavage for 5 weeks starting 2 d after the AOM injection. RESULTS: The vitamin C treatment suppressed inflammatory morbidity, as reflected by disease activity index (DAI) in recovery phase and inhibited shortening of the colon, and reduced histological damage. In addition, vitamin C supplementation suppressed mRNA levels of pro-inflammatory mediators and cytokines, including cyclooxygenase-2, microsomal prostaglandin E synthase-2, tumor necrosis factor-α, Interleukin (IL)-1ß, and IL-6, and reduced expression of the proliferation marker, proliferating cell nuclear antigen, compared to observations of AOM/DSS animals. Although the microbial composition did not differ significantly between the groups, administration of vitamin C improved the level of inflammation-related Lactococcus and JQ084893 to control levels. CONCLUSION: Vitamin C treatment provided moderate suppression of inflammation, proliferation, and certain inflammation-related dysbiosis in a murine model of colitis associated-early colon cancer. These findings support that vitamin C supplementation can benefit colonic health. Long-term clinical studies with various doses of vitamin C are warranted.

ANOVA and the variance homogeneity assumption: Exploring a better gatekeeper.

Valid use of the traditional independent samples ANOVA procedure requires that the population variances are equal. Previous research has investigated whether variance homogeneity tests, such as Levene's test, are satisfactory as gatekeepers for identifying when to use or not to use the ANOVA procedure. This research focuses on a novel homogeneity of variance test that incorporates an equivalence testing approach. Instead of testing the null hypothesis that the variances are equal against an alternative hypothesis that the variances are not equal, the equivalence-based test evaluates the null hypothesis that the difference in the variances falls outside or on the border of a predetermined interval against an alternative hypothesis that the difference in the variances falls within the predetermined interval. Thus, with the equivalence-based procedure, the alternative hypothesis is aligned with the research hypothesis (variance equality). A simulation study demonstrated that the equivalence-based test of population variance homogeneity is a better gatekeeper for the ANOVA than traditional homogeneity of variance tests.

Regulation of Inflammation by Sucrose Isomer, Turanose, in Raw 264.7 Cells.

Increased sugar consumption has been proposed to be a risk factor for obesity-related metabolic disorders. The objective of this study was to investigate the anti-inflammatory effect of turanose in Raw 264.7 macrophages. Turanose (3-O-α-D-glucosyl-D-fructose), an isomer of sucrose, naturally exists in honey. For these studies, macrophages were treated with total glucose (Glu), 50% Glu/50% turanose (T50), 25% Glu/75% turanose (T75), and 100% turanose (T100), each with a total concentration of 25 mM in cell media. Expressions of inflammatory enzymes and cytokines were analyzed. Cell viability was not affected in the turanose treated groups compared to the Glu group. Lipopolysaccharide and glucose-induced nitric oxide production, protein expression of inducible nitric oxide synthase, COX-2, and superoxide dismutase 2, and mRNA expression levels of interleukin (IL)-1ß and IL-18 were significantly suppressed by turanose treatment. These results demonstrate that turanose exerts anti-inflammatory effects in vitro, and possesses potential to serve therapeutic functional sweetener for testing in vivo and in clinical trials.

Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells.

Neuroblastoma (NB) originates from immature neuronal cells and currently has a poor clinical outcome. NB cells possess cancer stem cells (CSCs) characteristics that facilitate the initiation of a tumor, as well as its metastasis. Human bitter taste receptors, referred to as TAS2Rs, are one of five types of basic taste receptors and they belong to a family of G-protein coupled receptors. The recent finding that taste receptors are expressed in non-gustatory tissues suggest that they mediate additional functions distinct from taste perception. While it is generally admitted that the recognition of bitter tastes may be associated with a self-defense system to prevent the ingestion of poisonous food compounds, this recognition may also serve as a disease-related function in the human body. In particular, the anti-cancer stemness and invasion effects of TAS2Rs on NB cells remain poorly understood. In the present study, endogenous expression of TAS2R8 and TAS2R10 in SK-N-BE(2)C and SH-SY5Y cells was examined. In addition, higher levels of TAS2R8 and TAS2R10 expression were investigated in more differentiated SY5Y cells. Both TAS2Rs were up-regulated following the induction of neuronal cell differentiation by retinoic acid. In addition, ectopic transfection of the two TAS2Rs induced neurite elongation in the BE(2)C cells, and down-regulated CSCs markers (including DLK1, CD133, Notch1, and Sox2), and suppressed self-renewal characteristics. In particular, TAS2RS inhibited tumorigenicity. Furthermore, when TAS2Rs was over-expressed, cell migration, cell invasion, and matrix metalloproteinases activity were inhibited. Expression levels of hypoxia-inducible factor-1α, a well-known regulator of tumor metastasis, as well as its downstream targets, vascular endothelial growth factor and glucose transporter-1, were also suppressed by TAS2Rs. Taken together, these novel findings suggest that TAS2Rs targets CSCs by suppressing cancer stemness characteristics and NB cell invasion, thereby highlighting the chemotherapeutic potential of bitter taste receptors.

Xylobiose, an Alternative Sweetener, Ameliorates Diabetes-Related Metabolic Changes by Regulating Hepatic Lipogenesis and miR-122a/33a in db/db Mice.

Type 2 diabetes is a major public health concern worldwide. Xylobiose (XB) consists of two molecules of d-xylose and is a major disaccharide in xylooligosaccharides that are used as prebiotics. We hypothesized that XB could regulate diabetes-related metabolic and genetic changes via microRNA expression in db/db mice. For six weeks, C57BL/KsJ-db/db mice received 5% XB as part of the total sucrose content of their diet. XB supplementation improved glucose tolerance with reduced levels of OGTT AUC, fasting blood glucose, HbA1c, insulin, and HOMA-IR. Furthermore, XB supplementation decreased the levels of total triglycerides, total cholesterol, and LDL-C. The expression levels of miR-122a and miR-33a were higher and lower in the XB group, respectively. In the liver, expressions of the lipogenic genes, including, fatty acid synthase (FAS), peroxisome proliferator activated receptor γ (PPARγ), sterol regulatory element-binding protein-1C (SREBP-1C), sterol regulatory element-binding protein-2 (SREBP-2), acetyl-CoA carboxylase (ACC), HMG-CoA reductase (HMGCR), ATP-binding cassette transporter G5/G8 (ABCG5/8), cholesterol 7 alpha-hydroxylase (CYP7A1), and sterol 12-alpha-hydroxylase (CYP8B1), as well as oxidative stress markers, including superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPX), and catalase, were also regulated by XB supplementation. XB supplementation inhibited the mRNA expressions levels of the pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1, as well as phosphorylation of c-Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK), p38 mitogen-activated protein kinases (MAPK), and extracellular signal-regulated kinases 1/2 (ERK1/2). These data demonstrate that XB exhibits anti-diabetic, hypolipogenic, and anti-inflammatory effects via regulation of the miR-122a/33a axis in db/db mice.

Retinoic acid receptor ß enhanced the anti-cancer stem cells effect of ß-carotene by down-regulating expression of delta-like 1 homologue in human neuroblastoma cells.

Neuroblastoma (NB) is childhood malignancy that retains characteristics of cancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. ß-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC. Treatment with BC or retinoic acid (RA) upregulated RARß mRNA expression in two NB cell lines. Inhibition of RARß using siRNA up-regulated gene expression of delta-like 1 homologue (DLK1), a marker of CSCs. To understand the molecular mechanisms of RARß-mediated inhibition of DLK1, four retinoic acid receptor elements (RAREs) were identified in the promoter of DLK1. Chromatin immunoprecipitation assays indicated that RARß bound directly to a RARE in the DLK1 promoter region. Knock-down of RARß also increased the self-renewal capacity of NB cells, which was suppressed by BC. Taken together, this study provided evidence that the therapeutic anti-CSC effects of BC depend on RARß and its ability to interact with and down-regulate the CSCs marker, DLK1.

Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness.

Walnut has been known for its health benefits, including anti-cardiovascular disease and anti-oxidative properties. However, there is limited evidence elucidating its effects on cancer stem cells (CSCs) which represent a small subset of cancer cells that provide resistance against chemotherapy. This study aimed to evaluate the anti-CSCs potential of walnut phenolic extract (WPE) and its bioactive compounds, including (+)-catechin, chlorogenic acid, ellagic acid, and gallic acid. In the present study, CD133⁺CD44⁺ cells were isolated from HCT116 cells using fluorescence-activated cell sorting (FACS) and then treated with WPE. As a result, survival of the CD133⁺CD44⁺ HCT116 cells was inhibited and cell differentiation was induced by WPE. In addition, WPE down-regulated the CSC markers, CD133, CD44, DLK1, and Notch1, as well as the ß-catenin/p-GSK3ß signaling pathway. WPE suppressed the self-renewal capacity of CSCs. Furthermore, the WPE exhibited stronger anti-CSC effects than its individual bioactive compounds. Finally, the WPE inhibited specific CSC markers in primary colon cancer cells isolated from primary colon tumor. These results suggest that WPE can suppress colon cancer by regulating the characteristics of colon CSCs.

D-Xylose as a sugar complement regulates blood glucose levels by suppressing phosphoenolpyruvate carboxylase (PEPCK) in streptozotocin-nicotinamide-induced diabetic rats and by enhancing glucose uptake in vitro.

BACKGROUND/OBJECTIVES: Type 2 diabetes (T2D) is more frequently diagnosed and is characterized by hyperglycemia and insulin resistance. D-Xylose, a sucrase inhibitor, may be useful as a functional sugar complement to inhibit increases in blood glucose levels. The objective of this study was to investigate the anti-diabetic effects of D-xylose both in vitro and stretpozotocin (STZ)-nicotinamide (NA)-induced models in vivo. MATERIALS/METHODS: Wistar rats were divided into the following groups: (i) normal control; (ii) diabetic control; (iii) diabetic rats supplemented with a diet where 5% of the total sucrose content in the diet was replaced with D-xylose; and (iv) diabetic rats supplemented with a diet where 10% of the total sucrose content in the diet was replaced with D-xylose. These groups were maintained for two weeks. The effects of D-xylose on blood glucose levels were examined using oral glucose tolerance test, insulin secretion assays, histology of liver and pancreas tissues, and analysis of phosphoenolpyruvate carboxylase (PEPCK) expression in liver tissues of a STZ-NA-induced experimental rat model. Levels of glucose uptake and insulin secretion by differentiated C2C12 muscle cells and INS-1 pancreatic ß-cells were analyzed. RESULTS: In vivo, D-xylose supplementation significantly reduced fasting serum glucose levels (P < 0.05), it slightly reduced the area under the glucose curve, and increased insulin levels compared to the diabetic controls. D-Xylose supplementation enhanced the regeneration of pancreas tissue and improved the arrangement of hepatocytes compared to the diabetic controls. Lower levels of PEPCK were detected in the liver tissues of D-xylose-supplemented rats (P < 0.05). In vitro, both 2-NBDG uptake by C2C12 cells and insulin secretion by INS-1 cells were increased with D-xylose supplementation in a dose-dependent manner compared to treatment with glucose alone. CONCLUSIONS: In this study, D-xylose exerted anti-diabetic effects in vivo by regulating blood glucose levels via regeneration of damaged pancreas and liver tissues and regulation of PEPCK, a key rate-limiting enzyme in the process of gluconeogenesis. In vitro, D-xylose induced the uptake of glucose by muscle cells and the secretion of insulin cells by ß-cells. These mechanistic insights will facilitate the development of highly effective strategy for T2D.

Compositional analysis of walnut lipid extracts and properties as an anti-cancer stem cell regulator via suppression of the self-renewal capacity.

Colon cancer is a leading cause of cancer-related deaths worldwide. Effects of walnut (Juglans regia L.) lipid extracts (WLEs) on the self-renewal capacity of cancer stem cells (CSCs) in colon cancer were investigated. The dominant component of WLEs was α-linoleic acid (64.6%), followed by α-linolenic acid (14.6%), and oleic acid (12.6%). A higher concentration of γ-tocopherol (37.1%) was also present than of α-tocopherol (0.6%). CD133+CD44+CSCs treated with WLEs showed inhibition of colony formation and sphere formation, indicating a decrease in the self-renewal capacity. Treatment with WLEs also resulted in down-regulation of protein levels, including Notch1, phospho-GSK3ß (p-GSK3ß), and ß-catenin, which are associated with CSCs and the self-renewing capacity. WLEs rich in essential fatty acids and γ-tocopherol can exert therapeutic actions on colon cancer via targeting of CSCs.

Dietary Patterns and Their Associations with the Diet Quality Index-International (DQI-I) in Korean Women with Gestational Diabetes Mellitus.

The aim of this study was to examine dietary pattern, nutritional intake, and diet quality of Korean pregnant women with gestational diabetes mellitus (GDM). Between October 2008 and May 2012, 166 pregnant women diagnosed with GDM completed a questionnaire and dietary intake was assessed using a 3-day food record. Blood pressure, fasting plasma glucose, and glycated hemoglobin (HbA1c) concentrations were measured and oral glucose tolerance test (OGTT) was performed. Two major dietary patterns ("carbohydrate and vegetable" and "western" patterns) were identified through factor analysis. Dietary pattern scores for each dietary pattern were categorized into tertiles. The dietary quality index-international (DQI-I) was used to measure overall diet quality. Subjects with higher carbohydrate and vegetable pattern scores reported less physical activity (p < 0.05) and have higher diastolic blood pressure levels (p = 0.05). After adjusting for age and energy intake, higher carbohydrate and vegetable pattern scores were associated with higher sodium intakes (p = 0.02), but lower intakes of fat (p = 0.002) and other micronutrients. On the other hand, higher western pattern scores were associated with higher fat intake (p = 0.0001), but lower intakes of sodium (p = 0.01) and other micronutrients. Higher scores for both dietary patterns were associated with lower scores in the moderation category of the DQI-I (p < 0.0001). HbA1c and fasting plasma glucose levels were significantly lower among participants with high DQI-I than those with low DQI-I (p < 0.05). The study findings suggest that many Korean women with GDM do not consume nutritionally adequate or balanced diets, regardless of dietary pattern.

Intestinal anti-inflammatory activity of Sasa quelpaertensis leaf extract by suppressing lipopolysaccharide-stimulated inflammatory mediators in intestinal epithelial Caco-2 cells co-cultured with RAW 264.7 macrophage cells.

BACKGROUND/OBJECTIVES: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Previously, Sasa quelpaertensis leaves have been shown to mediate anti-inflammation and anti-cancer effects, although it remains unclear whether Sasa leaves are able to attenuate inflammation-related intestinal diseases. Therefore, the aim of this study was to investigate the anti-inflammatory effects of Sasa quelpaertensis leaf extract (SQE) using an in vitro co-culture model of the intestinal epithelial environment. MATERIALS/METHODS: An in vitro co-culture system was established that consisted of intestinal epithelial Caco-2 cells and RAW 264.7 macrophages. Treatment with lipopolysaccharide (LPS) was used to induce inflammation. RESULTS: Treatment with SQE significantly suppressed the secretion of LPS-induced nitric oxide (NO), prostaglandin E2 (PGE2), IL-6, and IL-1ß in co-cultured RAW 264.7 macrophages. In addition, expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and tumor necrosis factor (TNF)-α were down-regulated in response to inhibition of IκBα phosphorylation by SQE. Compared with two bioactive compounds that have previously been identified in SQE, tricin and P-coumaric acid, SQE exhibited the most effective anti-inflammatory properties. CONCLUSIONS: SQE exhibited intestinal anti-inflammatory activity by inhibiting various inflammatory mediators mediated through nuclear transcription factor kappa-B (NF-kB) activation. Thus, SQE has the potential to ameliorate inflammation-related diseases, including IBD, by limiting excessive production of pro-inflammatory mediators.

Sasa quelpaertensis leaf extract suppresses dextran sulfate sodium-induced colitis in mice by inhibiting the proinflammatory mediators and mitogen-activated protein kinase phosphorylation.

Sasa quelpaertensis leaves exert anti-inflammatory and anticarcinogenic effects, although it remains unclear whether these leaves can suppress inflammation-related intestinal diseases. This study hypothesized that Sasa quelpaertensis leaf extract (SQE) exerts a protective effect against inflammation in a dextran sulfate sodium (DSS)-induced colitis mouse model. Therefore, colon tissues of DSS-induced colitis mice that were treated with SQE were assayed for levels of proinflammatory markers, mitogen-activated protein kinase signaling, and activation of nuclear factor κB. For this purpose, mice were pretreated with SQE (100 mg/kg or 300 mg/kg body weight) by gavage for a 2-week period. Mice then received either SQE or sulfasalazine (100 mg/kg body weight) with 2.5% DSS in drinking water for 7 days twice daily and 7 days of tap water ad libitum between DSS treatment. Treatment with SQE was found to attenuate the severity of DSS-induced colitis, as assessed by disease activity index scores, shrinkage of colon length, and histopathologic changes. SQE reduced DSS-induced proliferation in distal colon tissues. It also significantly suppressed levels of tumor necrosis factor-α in serum and colon tissues, nitric oxide synthase, cyclooxygenase, and levels of phosphorylated c-Jun N-terminal kinases, p38, extracellular-signal-regulated kinases 1/2, and IκBα in colon tissues. To our knowledge, this is the first study to demonstrate that SQE supplementation can exert an anti-inflammatory effect on experimental chronic colitis.

Β-carotene inhibits neuroblastoma tumorigenesis by regulating cell differentiation and cancer cell stemness.

Neuroblastoma (NB) is the most common extracranial solid cancer in young children and malignant NB cells have been shown to possess cancer stem cell (CSC) characteristics. Thus, the successful elimination of CSCs represents a strategy for developing an effective preventive and chemotherapeutic agent. CSCs are characterized by differentiation and tumorigenicity. ß-Carotene (BC) has been associated with many anticancer mechanisms, although the efficacy of BC on CSCs remains unclear. In the present study, the effects of BC on tumor cell differentiation and tumorigenicity was investigated using a xenograft model. Mice were pretreated with BC for 21 days, then received a subcutaneous injection of SK-N-BE(2)C cells. Both tumor incidence and tumor growth were significantly inhibited for mice that received BC supplementation compared to the control group. Treatment with BC has also been shown to induce tumor cell differentiation by up-regulating differentiation markers, such as vimentin, peripherin, and neurofilament. Conversely, BC treatment has been shown to significantly suppress tumor stemness by down-regulating CSC markers such as Oct 3/4 and DLK1. BC treatment also significantly down-regulated HIF1-α expression and its downstream target, vascular endothelial growth factor (VEGF). Taken together, these results suggest that BC is a potential chemotherapeutic reagent for the treatment of NB, and mediates this effect by regulating the differentiation and stemness of CSCs, respectively.

Effects of plant-based Korean food extracts on lipopolysaccharide-stimulated production of inflammatory mediators in vitro.

BACKGROUND/OBJECTIVES: The traditional Korean diet is plant-based and rich in antioxidants. Previous studies have investigated the potential health benefits of individual nutrients of Korean foods. However, the cumulative effects of a Korean diet on inflammation remain poorly understood. Therefore, the aim of this study was to investigate the anti-inflammatory effects of a plant-based Korean diet. MATERIALS/METHODS: Using data from the Fifth Korean National Health and Nutrition Examination Survey, 75 individual plant food items were selected which represent over 1% of the total diet intake of the Korean diet. These items were classified into ten different food groups, and the vegetable (Veg) and fruit (Fruit) groups were studied based on their high antioxidant capacity. For comparison, a mixture of all ten groups (Mix) was prepared. To produce a model of inflammation with which to test these Veg, Fruit, and Mix plant-based Korean food extracts (PKE), RAW264.7 macrophages were treated with lipopolysaccharide (LPS). RESULTS: Levels of nitric oxide (NO) and prostaglandin E2 (PGE2), as well as protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were found to be lower following PKE treatment. Furthermore, PKE treatment was found to suppress tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) via the nuclear transcription factor kappa-B (NF-κB) signaling pathway. Overall, the Mix group exhibited the greatest anti-inflammatory effects compared with Veg and Fruit PKE group. CONCLUSIONS: Inhibition of LPS-induced pro-inflammatory mediators by the PKE tested was found to involve an inhibition of NF-kB activation. Moreover, PKE tested have the potential to ameliorate various inflammation-related diseases by limiting the excessive production of pro-inflammatory mediators.

Combination of Sasa quelpaertensis Nakai leaf extract and cisplatin suppresses the cancer stemness and invasion of human lung cancer cells.

Lung cancer is the leading cause of cancer death worldwide, and most chemotherapeutic drugs have limited success in treating this disease. Furthermore, some drugs show undesirable side effects due to the enrichment of cancer stem cells (CSCs) that are present, leading to resistance to conventional chemotherapy and tumor relapse. CSCs possess self-renewal characteristics, aggressive tumor initiating activity, and ability to facilitate tumor metastasis. Therefore, development of nontoxic agents that can potentiate chemotherapy and eliminate CSCs would be highly desirable. In the present study, we investigated whether Sasa quelpaertensis leaf extracts (SQE) and cisplatin (CIS), individually or in combination, would exert anti-CSC and antimetastatic effect in H1299 and A549 human lung cancer cells. Following these treatments, cell growth, phosphorylation of phosphoinositide-3 kinase, and activation of the mammalian target of rapamycin were inhibited. Decreased serial sphere formation, clonogenicity, and expression of major stem cell markers, such as CD44 and SOX-2, in CD44(+) cancer stem cells were also observed. In addition, inhibition of cell migration and invasion in both cell lines as well as inhibition of matrix metalloproteinase-2 activity and expression were detected. Importantly, the anticancer stemness and antimetastasis effects in each of these assays were greater for the combined treatment with SQE and CIS than with each treatment individually. In conclusion, the data suggest that SQE alone, or in combination with CIS, represents a promising therapeutic strategy for eliminating cancer stemness and cell invasion potential of CSCs, thereby treating and preventing metastatic lung cancer cells.

Sasa quelpaertensis leaf extract improves high fat diet-induced lipid abnormalities and regulation of lipid metabolism genes in rats.

Sasa quelpaertensis is a bamboo leaf that is only grown on Jeju Island in South Korea. It is used as a bamboo tea that is consumed for therapeutic purposes, particularly for its anti-diabetic, diuretic, and anti-inflammatory effects. This study investigated the effect of S. quelpaertensis leaf extract (SQE) on high fat-induced lipid abnormalities and regulation of lipid metabolism-related gene expressions in rats. SQE supplementation significantly decreased the levels of plasma triglycerides, total cholesterol, and low-density lipoprotein cholesterol as well as the atherogenic index. SQE restored levels of plasma high-density lipoprotein cholesterol, which were lowered by a high fat diet. Plasma and cardiac resistin levels were also significantly decreased by SQE supplementation. In adipose tissue, mRNA levels of CAAT/enhancer-binding protein ß (C/EBPß) were suppressed in the SQE group. SQE supplementation decreased the accumulation of lipid droplets, inflammatory cell infiltrations, levels of triglycerides, and total lipids in the liver and effectively down-regulated expression of sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FAS), and uncoupling protein 2 (UCP-2). These results suggest that SQE may be a potential treatment for high fat-related disorders by improving lipid profiles and modulating lipid metabolism.

ß-Carotene inhibits neuroblastoma cell invasion and metastasis in vitro and in vivo by decreasing level of hypoxia-inducible factor-1α.

Neuroblastoma is the most prevalent extracranial solid tumor in childhood and has poor clinical outcome due to its high potential for metastasis. Consequently, an understanding of the mechanisms that modulate cancer cell invasion, migration and metastasis is important for the development of more effective chemotherapeutic agents. While ß-carotene is a vitamin A precursor that has been shown to exert antioxidant and anticancer effects, the anti-metastatic effects of ß-carotene on neuroblastoma cells remain poorly understood. The aim of the present study was to investigate the anti-metastatic effects of ß-carotene on highly malignant SK-N-BE(2)C neuroblastoma cells in vitro and in vivo. Treatment of SK-N-BE(2)C cells with ß-carotene was found to attenuate the migratory and invasive capabilities of the cells. In addition, the enzymatic activity and expression of matrix metalloproteinase (MMP)-2 was suppressed following ß-carotene treatment under both normoxia and hypoxia. To induce metastasis, immunodeficient nude mice were injected with SK-N-BE(2)C cells via the tail vein in vivo. The incidence of liver metastasis and mean tumor volume in mice that were administered ß-carotene was decreased compared to controls. Furthermore, mRNA levels of MMPs, membrane-type (MT) 2 MMP and tissue inhibitors of metalloproteinases in liver tumor tissues were also lower following ß-carotene treatment. Level of hypoxia-inducible factor-1α (HIF-1α) and its downstream targets, vascular endothelial growth factor and glucose transporter 1 (GLUT1), were lower both in vitro and in vivo following ß-carotene treatment. In conclusion, the present study provides the first evidence that ß-carotene may represent an effective chemotherapeutic agent by regulating the invasion and metastasis of neuroblastoma via HIF-1α.

Mulberry leaf extract inhibits invasive potential and downregulates hypoxia-inducible factor-1α (HIF-1α) in SK-N-BE2C neuroblastoma cells.

A neuroblastoma is an extracranial solid tumor diagnosed in childhood. Since tumor metastasis is the main cause of death for most neuroblastoma patients, an understanding of the mechanisms that modulate cancer cell invasion is a key to developing more effective chemotherapeutic agents. In the current study, we examined to determine whether mulberry leaf (ML) extract effectively inhibits the invasion potential of neuroblastoma cells in vitro. ML extract was found to suppress cell invasiveness as well as the activity and expression of matrix metalloproteinase-2 (MMP-2) under both normoxia and hypoxia in neuroblastoma. ML extract downregulated the expression of hypoxia-inducible factor-1α (HIF-1α), a well-known regulator of tumor metastasis, and its downstream targets, vascular endothelial growth factor (VEGF) and glucose transporter-1 (GLUT-1). Taken together, these results suggest that ML extract has chemotherapeutic effects on neuroblastoma cells by regulating invasion potential, thereby controlling the metastasis of neuroblastomas.