S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells.

S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.

Antithrombotic Effect of Artemisia princeps Pampanini Extracts in Vitro and in FeCl3 -Induced Thrombosis Rats.

Extracts of several plants possess antithrombotic effects. Herein, we examined the antithrombotic effects of different extracts of Artemisia princeps Pampanini prepared using distilled water, hot distilled water, 70% ethanol, or subcritical water. The antithrombotic effects were determined using a co-culture system consisting of tumor necrosis factor-alpha (TNF-α)-treated EA.hy926 cells and THP-1 cells. In addition, the coagulation time of plasma collected from healthy volunteers was evaluated in terms of the prothrombin time and activated partial thromboplastin time. A carotid arterial thrombosis model was induced by ferric chloride in Sprague Dawley rats. The rats were treated with either sterile water or three different doses of the subcritical water extract for 2 weeks. The thrombus weight, gene expression of cell adhesion molecules, and histological characteristics were assessed. The results of in vitro studies revealed a significant inhibition in the adhesion of monocytes to EA.hy926 cells stimulated by TNF-α in the subcritical water extract-treated group. We also observed considerable suppression of the occlusion and mRNA expression of cell adhesion molecules in the in vivo experiments. This study suggests that Artemisia princeps Pampanini may have the potential to improve blood coagulation.

The protective effects of Gastrodia elata Blume extracts on middle cerebral artery occlusion in rats.

To investigate the effects of Gastrodia elata Blume (GEB) and 4-hydroxybenzyl alcohol (HBA) on brain damage, GEB or HBA was administered orally for 14 days before middle cerebral artery occlusion (MCAO). After 24 h reperfusion, the proportion of circling was significantly reduced in the GEB (79%) or HBA (69%) group compared to the MCAO group (100%) in the corner test, and the removal time in the adhesive removal test was significantly decreased in the GEB (117 ± 21.0 s) and HBA (101 ± 20.9 s) groups compared to the MCAO group (161 ± 12.6 s). GEB treatment significantly reduced infarct volume compared to the MCAO group. In the GEB and HBA group, necrosis of nerve cells in hippocampus and cortex, expressions of TNF-α and TUNEL positive cells were significantly reduced compared to the MCAO group. These results suggest that GEB and HBA prevents brain damage by anti-inflammatory and anti-apoptotic effects.

Protective effects of Gastrodia elata Blume on acetaminophen-induced liver and kidney toxicity in rats.

An overdose of acetaminophen (AAP) causes hepatic and renal toxicity. This study examined the protective effects of Gastrodia elata Blume (GEB) on hepatic and renal injury induced by AAP. Rats were orally administered distilled water or GEB for 14 days and injected with AAP 1 h after the oral last administration; control rats were administered water without AAP injection. All rats were sacrificed 24 h after AAP injection. The GEB pretreatment group showed decreased necrosis and the expression of pro-inflammatory cytokines in the liver and kidney. TUNEL-positive cells and oxidative stress marker, such as malondialdehyde, were decreased. However, antioxidant enzymes, such as glutathione and superoxide dismutase, were increased. The expression of CYP2E1 and N-acetyl-beta-d-glucosaminidase was decreased in the GEB pretreatment group. This study shows that GEB prevents AAP-induced liver and kidney injury.

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.

Xylobiose Prevents High-Fat Diet Induced Mice Obesity by Suppressing Mesenteric Fat Deposition and Metabolic Dysregulation.

Obesity is a public concern and is responsible for various metabolic diseases. Xylobiose (XB), an alternative sweetener, is a major component of xylo-oligosaccharide. The purpose of this study was to investigate the effects of XB on obesity and its associated metabolic changes in related organs. For these studies, mice received a 60% high-fat diet supplemented with 15% d-xylose, 10% XB, or 15% XB as part of the total sucrose content of the diet for ten weeks. Body weight, fat and liver weights, fasting blood glucose, and blood lipids levels were significantly reduced with XB supplementation. Levels of leptin and adipokine were also improved and lipogenic and adipogenic genes in mesenteric fat and liver were down-regulated with XB supplementation. Furthermore, pro-inflammatory cytokines, fatty acid uptake, lipolysis, and ß-oxidation-related gene expression levels in mesenteric fat were down-regulated with XB supplementation. Thus, XB exhibited therapeutic potential for treating obesity which involved suppression of fat deposition and obesity-related metabolic disorders.

Acute and 13-week subchronic toxicological evaluations of turanose in mice.

BACKGROUND/OBJECTIVES: Turanose, α-D-glucosyl-(1→3)-α-D-fructose, is a sucrose isomer which naturally exists in honey. To evaluate toxicity of turanose, acute and subchronic oral toxicity studies were conducted with ICR mice. MATERIALS AND METHODS: For the acute oral toxicity study, turanose was administered as a single oral dose [10 g/kg body weight (b.w.)]. In the subchronic toxicity study, ICR mice were administered 0, 1.75, 3.5, and 7 g/kg b.w. doses of turanose daily for 13 weeks. RESULTS: No signs of acute toxicity, including abnormal behavior, adverse effect, or mortality, were observed over the 14-day study period. In addition, no changes in body weight or food consumption were observed and the median lethal dose (LD50) for oral intake of turanose was determined to be greater than 10 g/kg b.w. General clinical behavior, changes in body weight and food consumption, absolute and relative organ weights, and mortality were not affected in any of the treatment group for 13 weeks. These doses also did not affect the macroscopic pathology, histology, hematology, and blood biochemical analysis of the mice examined. CONCLUSION: No toxicity was observed in the acute and 13-week subchronic oral toxicology studies that were conducted with ICR mice. Furthermore, the no-observed-adverse-effect level is greater than 7 g/kg/day for both male and female ICR mice.

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.

D-Xylose suppresses adipogenesis and regulates lipid metabolism genes in high-fat diet-induced obese mice.

D-Xylose, a natural pentose, has been reported to reduce postprandial glucose levels, although its effect on lipid metabolism has not been investigated. Therefore, this study hypothesized that d-xylose, as an alternative sweetener, suppresses adipogenesis and lipid metabolism by regulating blood lipid profiles, blood glucose levels, and related gene expression in high-fat diet (HFD)-induced obese mice. Mice were fed a normal diet, a 60% HFD diet, or an HFD with 5% or 10% of the total sucrose content supplemented with d-xylose (Xylo 5 and Xylo 10 diets, respectively). Weight gain, food intake, and serum lipid levels for each group were measured. After 12 weeks, histopathology of liver sections and assays of gene expression related to adipogenesis and lipid metabolism in visceral fat and liver tissues were analyzed. Body weight gain; fasting blood glucose levels; weights of subcutaneous and visceral adipose tissues; and serum biochemical markers, including total cholesterol and low-density lipoprotein cholesterol, low-/high-density lipoprotein, and total cholesterol/high-density lipoprotein, were significantly lowered in the Xylo 5 and Xylo 10 groups. In addition, d-xylose supplementation resulted in the down-regulation of adipogenesis-related genes, including sterol regulatory element-binding protein 1C, fatty acid synthase, adipocyte protein 2, and CCAAT/enhancer-binding protein α in visceral adipose tissues. Histopathologically, Xylo 5 and Xylo 10 supplementation reduced HFD-induced fat accumulation in the liver and decreased expressions of fatty acid synthase and peroxisome proliferator-activated receptor γ. D-Xylose supplementation also enhanced lipid oxidation by increasing expressions of carnitine palmitoyltransferase 1A; cytochrome P450, family 4, subfamily a, polypeptide 10; and acyl-CoA oxidase. In conclusion, our finding suggests that d-xylose may help prevent or attenuate the progression of obesity-related metabolic disorders by alleviating adipogenesis and dyslipidemia and improving lipid oxidation.