Anti-metabolic Syndrome Effects Research Articles

Production and Characterization of Durvillaea antarctica Enzyme Extract for Antioxidant and Anti-Metabolic Syndrome Effects

In this study, three enzyme hydrolysate termed Dur-A, Dur-B, and Dur-C, were produced from Durvillaea antarctica biomass using viscozyme, cellulase, and α-amylase, respectively. Dur-A, Dur-B, and Dur-C, exhibited fucose-containing sulfated polysaccharide from chemical composition determination and characterization by FTIR analyses. In addition, Dur-A, Dur-B, and Dur-C, had high extraction yields and low molecular weights. All extracts determined to have antioxidant activities by DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,20-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt), and ferrous ion-chelating methods. All extracts were also able to positively suppress the activities of key enzymes involved in metabolic syndrome: angiotensin I-converting enzyme (ACE), α-amylase, α-glucosidase, and pancreatic lipase. In general, Dur-B exhibited higher antioxidant and higher anti-metabolic syndrome effects as compared to the other two extracts. Based on the above health promoting properties, these extracts (especially Dur-B) can be used as potential natural antioxidants and natural anti-metabolic syndrome agents in a variety of food, cosmetic, and nutraceutical products for health applications.

In-silico Absorption, Distribution, Metabolism, Elimination and Toxicity profile of 9,12,15-Octadecatrienoic acid (ODA) from Moringa oleifera

9,12,15-Octadecatrienoic acid (ODA) a carboxylic acid composed of 18 carbon atoms and three cis double bonds. ODA is a plant derived essential fatty acid indispensable to the human system. ODA refers to many different structural and conformational isomers, that differ in the position of the double bonds along the backbone and on whether they are in cis ('Z') or trans ('E') conformation. It has been well established that ODA can only be outsourced from food and then converted into eicosa-pentaenoic acid (EPA) and docosa-hexaenoic acid (DHA) in the human system. However, this metabolic process is highly limited and the rate of conversion is influenced by several factors such as dose, gender, and disease. Studies suggest that ODA is associated with reduced risk of fatal ischemic heart disease. Further, higher intake may reduce the risk of sudden death among prevalent myocardial infarction in patients consistent with induced antiarrhythmic effect. ODA significantly reduces blood clots. Traditional usage of ODA is attributed to its cardiovascular-protective, anti-cancer, neuro-protective, anti-osteoporotic, anti-inflammatory, and anti-oxidative properties. Recent pharmacological indicate that ODA has anti-metabolic syndrome, anticancer, anti-inflammatory, anti-oxidant, anti-obesity, neuro-protective, and more specifically involved in the regulation of gut-micro-floral functionalities. Studies, both experimental and clinical trials indicate that ODA has anti-metabolic syndrome effects. In short, ODA is potentially used to treat many diseases, but in-depth ADMET studies are required to firmly re-establish its clinical efficacy and market potential.
 Keywords: ADMET; Moringa oleifera; Secondary Metabolites; Natural Products (NPs); Bioactive Substances; Octadecatrienoic acid (ODA); Eicosa-Pentaenoic Acid (EPA); Docosa-Hexaenoic Acid (DHA)

Isoliquiritigenin Attenuates Adipose Tissue Inflammation and Metabolic Syndrome by Modifying Gut Bacteria Composition in Mice.

Isoliquiritigenin (ILG) has been reported to attenuate adipose tissue inflammation and metabolic disorder; however, the underlying mechanisms remain to be elucidated. The aim of this study is to elucidate whether ILG shows the anti-inflammatory and antimetabolic syndrome effects through gut microbiota modification. Mice are fed a high-fat diet (HFD) with or without ILG for up to 12 weeks. The effect of ILG on body weight, blood glucose level, adipose tissue inflammation, gut barrier function, and gut microbiota composition are investigated. ILG supplementation alleviates HFD-induced obesity, glucose tolerance, and insulin resistance and suppresses inflammatory gene expression in epididymal white adipose tissue (eWAT). Moreover, ILG supplementation modifies gut bacterial composition by increasing the abundance of antimetabolic disease-associated species (e.g., Parabacteroides goldsteinii and Akkemansia muciniphila) and up-regulated genes associated with gut barrier function. Fecal microbiome transplantation (FMT) from ILG-fed donors counteract HFD-induced body and eWAT weight changes, inflammation-related gene expression, glucose tolerance, and insulin resistance, thereby suggesting that ILG-responsive gut bacteria exerts anti-inflammatory and antimetabolic syndrome effects. Alterations in gut bacteria underly the beneficial effects of ILG against adipose tissue inflammation and metabolic disorders. ILG may be a promising prebiotic for the prevention and treatment of metabolic syndrome.

The review of alpha-linolenic acid: Sources, metabolism, and pharmacology.

α-linolenic acid (ALA, 18:3n-3) is a carboxylic acid composed of 18 carbon atoms and three cis double bonds, and is an essential fatty acid indispensable to the human body. This study aims to systematically review related studies on the dietary sources, metabolism, and pharmacological effects of ALA. Information on ALA was collected from the internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library, and Europe PMC using a combination of keywords including "pharmacology," "metabolism," "sources." The following findings are mainly contained. (a) ALA can only be ingested from food and then converted into eicosapentaenoic acid and docosahexaenoic acid in the body. (b) This conversion process is relatively limited and affected by many factors such as dose, gender, and disease. (c) Pharmacological research shows that ALA has the anti-metabolic syndrome, anticancer, antiinflammatory, anti-oxidant, anti-obesity, neuroprotection, and regulation of the intestinal flora properties. (d) There are the most studies that prove ALA has anti-metabolic syndrome effects, including experimental studies and clinical trials. (e) The therapeutic effect of ALA will be affected by the dosage. In short, ALA is expected to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of ALA.

The Influence of Hypericum perforatum L. Addition to Wheat Cookies on Their Antioxidant, Anti-Metabolic Syndrome, and Antimicrobial Properties.

The aim of this study was to characterize wheat cookies enriched with 0.5% and 1.0% of Hypericum perforatum L. (St. John’s wort, SJW) and determine their pro-health properties in vitro after hydrolysis in simulated gastrointestinal conditions. The results indicated that 1.0 SJW was characterized by the highest content of polyphenols, flavonoids, and phenolic acids (2.32 mg mL−1, 4.93 µg mL−1, and 12.35 µg mL−1, respectively). The enriching cookies had no effect on water absorption capacity (WAC) and oil absorption capacity (OAC). After in vitro hydrolysis, the highest peptide content was noted in 1.0 SJW (0.52 mg mL−1), and the bioactive compounds were characterized by high potential bioaccessibility (PAC), but poor bioavailability (PAV). The addition of SJW increased the ACE, α-amylase, and LOX inhibitory effect, but reduced the inhibition of pancreatic lipase. The highest antioxidant activity was noted for 1.0 SJW. The results showed that only 0.5 SJW and 1.0 SJW had slight antimicrobial activity against E. coli ATCC 25922 and B. cereus ATCC 14579 with MIC = 12.5 mg mL−1. Fractions with molecular mass <3.0 kDa were characterized with the highest p-coumaric acid content. The results show that SJW cookies had a higher content of bioactive compounds and more potent anti-metabolic syndrome effects.

Amelioration of metabolic disorders by a mushroom-derived polyphenols correlates with the reduction of Ruminococcaceae in gut of DIO mice

A polyphenolic alkaloid-enriched extract (PAE) was prepared from the fruiting bodies of a wild edible mushroom Sarcodon leucopus. Oral administration of PAE reduced hyperglycemia, hyperlipidemia, hepatic steatosis, and LPS-related inflammation in high fat diet-induced obese (DIO) mice. Furthermore, we show that PAE produces taxonomic and predicted functional changes in the gut microbiome of DIO mice. A significant decrease in the family of Ruminococcaceae, especially the secondary bile acid-producing bacteria of Intestinimonas and Anaerotruncus, is detected in the gut microbiome of PAE-treate mice. Accordingly, reductions of deoxycholic acid and lithocholic acid are found in the feces of PAE-treated DIO mice, which benefits for the intestinal integrity and the reduction of inflammation. A gut microbiota related mechanism for the anti-metabolic syndrome effects of the PAE is proposed. We suppose the polyphenolic alkaloid extract from S. leucopus be a new and beneficial prebiotic regulating glucose and lipid metabolisms.

Bifidobacterium animalis subsp. lactis GCL2505 modulates host energy metabolism via the short-chain fatty acid receptor GPR43.

Short-chain fatty acids (SCFAs), which are metabolites derived from the fermentation of dietary fibre by the gut microbiota, are important for host metabolic health. There is interest in probiotics for their beneficial effects on metabolic disorders, such as obesity, but the underlying mechanisms remain largely unknown. In this study, we evaluated whether Bifidobacterium animalis subsp. lactis GCL2505 (GCL2505), a probiotic strain capable of proliferating and increasing SCFA levels in the gut, exerts anti-metabolic syndrome effects via the SCFA receptor G protein-coupled receptor 43 (GPR43). A GCL2505 treatment suppressed body fat accumulation, improved glucose tolerance, and enhanced systemic fatty acid oxidation in high-fat diet (HFD)-fed wild type (WT) mice, whereas these effects were not observed in HFD-fed Gpr43 knockout (Gpr43−/−) mice. Caecal and plasma acetate levels were elevated by GCL2505 in WT and Gpr43−/− mice, but the negative correlation between plasma acetate levels and body fat accumulation was observed only in WT mice. We further demonstrated that GCL2505 suppressed insulin signalling in the adipose tissue via GPR43. These results suggested that increases in SCFA levels in response to GCL2505 enhance host energy expenditure, which decreases fat accumulation via activated GPR43.

Antimetabolic Syndrome Effect of Phytosome Containing the Combined Extracts of Mulberry and Ginger in an Animal Model of Metabolic Syndrome.

Due to the antimetabolic syndrome effect of mulberry and ginger together with the advantages of the synergistic effect and phytosome encapsulation technique, we hypothesized that phytosome containing the combined extracts of mulberry and ginger (PMG) should be able to manage MetS. PMG was developed and assessed the phenolic content and biological activities associated with the pathophysiology of MetS. The antimetabolic syndrome effect and the possible underlying mechanisms in the animal model of MetS were also assessed. Male Wistar rats induced MetS by subjecting to a 16-week high-carbohydrate high-fat diet. MetS rats were orally given PMG at doses of 50, 100, and 200 mg/kg for 21 days. They were determined metabolic parameter changes in serum, histomorphology changes of adipose tissue, the inflammatory cytokines such as IL-6 and TNF-α, oxidative stress status, PPAR-γ, and HDAC3 in adipose tissue. Our in vitro data showed that PMG increased phenolic contents and biological activities. PMG significantly improved MetS parameters including body weight gain, lipid profiles, plasma glucose, HOMA-IR, and ACE. In addition, the density and size of adipocyte, adiposity index, and weights of adipose tissues were also improved. Moreover, the decrease in TNF-α and IL-6, oxidative stress status, and HDAC3 expression together with the increase in PPAR-γ expression in adipose tissue was also observed. These data suggest that PMG exhibit antimetabolic syndrome and the possible underlying mechanism may be associated partly with the modulation effect on HDAC3, PPAR-γ, and adipose tissue. In addition, PMG also improves oxidative stress and inflammation in MetS. Therefore, PMG can be served as the potential supplement to manage MetS. However, a clinical trial study is essential to confirm this health benefit.

Dihydromyricetin Attenuates Metabolic Syndrome And Improves Insulin Sensitivity By Upregulating Insulin Receptor Substrate-1 (Y612) Tyrosine Phosphorylation In db/db Mice.

PurposeDihydromyricetin (DHM), the main bioactive flavonoid in vine tea, exerts multiple health beneficial effects. This work aimed to identify whether a naturally derived flavonoid product, DHM, can significantly attenuate metabolic syndrome and improve insulin sensitivity.Methods10-week-old db/db mice were randomly assigned to receive the antidiabetic agent metformin (Met, 50 mg/kg BW), DHM (1.0 g and 0.5 g/kg BW) or placebo and were simultaneously fed a high-fat diet for 8 weeks. The general status of the animals was observed and recorded daily, body weight and blood glucose levels were measured weekly, during the experimental period. On day 55, the oral glucose tolerance test (OGTT) was performed. After OGTT, all animals were anesthetized and sacrificed by cervical decapitation. Blood samples were collected in tubes to detect plasma insulin and the biochemical parameters of lipid metabolism. Pancreas histological changes and islet fibrosis were demonstrated by H&E staining and Masson staining, respectively. Moreover, the expression of insulin receptor substrate-1 and phosphorylated insulin receptor substrate-1 in the insulin signaling pathway was detected by Western blot assay.ResultsThe oral administration of DHM (1.0 g and 0.5 g/kg BW) reduced the fasting blood glucose, serum insulin, and glycated hemoglobin levels and the insulin resistance (HOMA-IR) index. Furthermore, DHM intervention decreased body weight and the serum lipid profile. In addition, DHM treatment also markedly decreased the relative abdominal fat weight. Western blot analysis indicated that DHM upregulated the IRS-1 (Y612) tyrosine phosphorylation, improving insulin resistance. Treatment with dihydromyricetin attenuated the progression of insulin resistance and pancreatic fibrosis in fatty db/db mice.ConclusionIn summary, we determined the antimetabolic syndrome effect of DHM in db/db obese mice. DHM upregulates the IRS-1 (Y612) tyrosine phosphorylation, improving insulin resistance. Therefore, DHM is a promising therapeutic candidate for the control of metabolic syndrome.

Anti-Metabolic Syndrome Effects of Fucoidan from Fucus vesiculosus via Reactive Oxygen Species-Mediated Regulation of JNK, Akt, and AMPK Signaling.

Recent studies have reported that dietary fiber improved metabolic syndrome (MetS). However, the effects of fucoidans on MetS were still not clear. In this study, we evaluated the activity of fucoidan from Fucus vesiculosus (FvF) on attenuating MetS and first elucidated the underlying mechanism. In vitro, FvF treatment remarkably lowered the level of reactive oxygen species (ROS) compared with the sodium palmitate (PA)-induced insulin resistance (IR) group. The phosphorylation level of c-Jun N-terminal kinase (JNK) was significantly decreased, while phosphorylation of protein kinase B (pAkt) level increased, compared with that of the HepG2 cells treated with PA. Thus, FvF increased glucose consumption and relieved IR via ROS-mediated JNK and Akt signaling pathways. In addition, these changes were accompanied by the activation of adenosine 5′-monophosphate-ativated protein kinase (AMPK) and its downstream targets (e.g., HMG-CoA reductase (HMGCR), acetyl-CoA carboxylase (ACC), and sterol-regulatory element-binding protein-1c (SREBP-1C)), which improved lipid metabolism in IR HepG2 cells. In vivo, FvF improved hyperglycemia and decreased serum insulin level in mice with MetS. Furthermore, we evaluated the inhibition of glucose transport by in vitro (Caco-2 monolayer model), semi-in vivo (everted gut sac model) and oral glucose tolerance test (OGTT), which indicated that FvF could significantly reduce the absorption of glucose into the blood stream, thus it could improve blood-glucose levels and IR in mice with MetS. Moreover, FvF decreased serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) levels and liver lipid accumulation, while increased the serum high density lipoprotein cholesterol (HDL-C) level in mice with MetS. Therefore, FvF could be considered as a potential candidate for the treatment of MetS by alleviating IR, inhibiting glucose transportation, and regulating lipid metabolism.

1776-P: Gut Microbiota Remodeling and Intestinal FXR Inhibition Mediate the Antimetabolic Syndrome Properties of Gynostemma Pentaphyllum

Gynostemma pentaphyllum (G. pentaphyllum) is widely used as a traditonal chinese medicine with anti-metabolic syndrome properties in Asian countries, however, the critical mechanism with the metabolic benefits of G. pentaphyllum remained unclarified. Herein, we performed metabolomic analysis (LC-MS/MS) of samples from obese mice treated with G. pentaphyllum, and identified 2α-OH-PPD (GP2) may be the principal bioactive constituent responsible for the anti-metabolic syndrome effect of G. pentaphyllum. In mouse model of high fat diet-induced obesity, GP2 prevented diet-induced obesity, along with hepatic steatosis and insulin resistance after 5 weeks treatment. The metabolic benefits of GP2 treatment were abrogated in the antibiotic treated DIO mice, which indicated GP2 improves metabolic syndrome dependent on gut microbiota remodeling. Mechanically, GP2, play as an inhibitor of bile salt hydrolase (BSH) in the gut microbiota, increased the bile acid tauro-α/β-muricholic acid (Tα/βMCA) and tauroursodeoxycholic acid (TUDCA) in the gut through decrease in level of the genus Clostridium, but not the genus Lactobacillus (LefSe Analysis for gut microbiota composition). The expression of FGF-15 and shp gene were dramatically decreased in the ileum, and the expression of pro-glucagon in the L cell and glucose induced GLP-1 secretion were markedly increased in the GP2 treated mice, which were accompanied by farnesoid X receptor (FXR) signaling inhibition in the intestine. Finally, after transplanted the fecal microbiota of mice treated by GP2 into recipient mice pretreated with antibiotics, the mice reflected much more GLP-1 secretion after glucose stimulated and high Tα/βMCA level in the gut than the mice received control microbiota. These results indicated that GP2 as well as G. pentaphyllum improved metabolic syndrome in part through intestinal FXR inhibition induced by gut microbiota remodeling. Disclosure Z. Xie: None. L. Hu: None. J. Li: None. J. Li: None. Funding National Natural Science Foundation of China

Luteolin-Enriched Artichoke Leaf Extract Alleviates the Metabolic Syndrome in Mice with High-Fat Diet-Induced Obesity.

This current study aimed to elucidate the effects and possible underlying mechanisms of long-term supplementation with dietary luteolin (LU)-enriched artichoke leaf (AR) in high-fat diet (HFD)-induced obesity and its complications (e.g., dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease) in C57BL/6N mice. The mice were fed a normal diet, an HFD, or an HFD plus AR or LU for 16 weeks. In the HFD-fed mice, AR decreased the adiposity and dyslipidemia by decreasing lipogenesis while increasing fatty acid oxidation, which contributed to better hepatic steatosis. LU also prevented adiposity and hepatic steatosis by suppressing lipogenesis while increasing biliary sterol excretion. Moreover, AR and LU prevented insulin sensitivity by decreasing the level of plasma gastric inhibitory polypeptide and activity of hepatic glucogenic enzymes, which may be linked to the lowering of inflammation as evidenced by the reduced plasma interleukin (IL)-6, IL-1β, and plasminogen activator inhibitor-1 levels. Although the anti-metabolic syndrome effects of AR and LU were similar, the anti-adiposity and anti-dyslipidemic effects of AR were more pronounced. These results in mice with diet-induced obesity suggest that long-term supplementation with AR can prevent adiposity and related metabolic disorders such as dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.

Effect of Oral Paprika Xanthophyll Intake on Abdominal Fat in Healthy Overweight Humans: A Randomized, Double-blind, Placebo-controlled Study.

Xanthophylls that exist in various vegetables and fruits have beneficial actions, such as antioxidant activity and an anti-metabolic syndrome effect, and daily intake of xanthophylls could play an important role in preventing lifestyle-related diseases. We investigated whether intake of xanthophylls from red paprika could decrease the abdominal fat area in the healthy overweight volunteers with a body mass index (BMI) ranging from 25 to < 30 kg/m2. In a randomized, double-blind, placebo-controlled, parallel-group study, 100 healthy volunteers were assigned to oral administration of paprika xanthophyll capsules (containing 9.0 mg of paprika xanthophylls) or placebo capsules for 12 weeks. The primary endpoint was the effect of paprika xanthophyll intake on the abdominal visceral fat area (VFA) as determined by computed tomography. The secondary endpoints were as follows: 1) changes of the abdominal subcutaneous fat area (SFA), total fat area (TFA), and BMI; 2) changes of lipid metabolism parameters, glucose metabolism parameters, and other blood parameters. After 12 weeks, VFA was smaller in the paprika xanthophyll group than in the placebo group. In the paprika xanthophyll group, there was a significant decrease of SFA, TFA, and BMI after 12 weeks compared with baseline, and the reduction of SFA, TFA, and BMI was significantly greater in the paprika xanthophyll group than in the placebo group. Moreover, total cholesterol and low-density lipoprotein cholesterol decreased significantly in the paprika xanthophyll group, but not in the placebo group. No adverse effects were caused by intake of paprika xanthophyll capsules. Intake of paprika xanthophylls for 12 weeks significantly reduced the abdominal fat area and BMI in healthy overweight volunteers without causing any adverse effects. These findings suggest that paprika xanthophyll is a safe food ingredient that improves lipid metabolism and reduces abdominal fat. UMIN-CTR UMIN000021529.

機能性農産物を使用した弁当のメタボリックシンドロームへの影響を検証するヒト介入ランダム化プラセボ対照比較試験

内臓脂肪を減少させメタボリックシンドローム（MetS）を予防する食品は有用であり，MetS改善作用の評価は，農産物単品にとどまってきたため，日常消費される組み合わせ食品としての有用性の検証が必要である．肥満傾向を有する健常な成人の昼食に，機能性農産物を組み合わせた機能性弁当を継続摂取させ，機能性農産物を使用していないプラセボ弁当を摂取した場合と比較して，腹部内臓脂肪の減少効果について検証した．

Abstract B57: Gnetin C, a novel resveratrol dimer, targets pancreatic cancer metabolism

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is aggressively invasive and treatment-resistant malignancy, and is the fourth leading cause of cancer deaths in the United States. The pancreatic cancer cells alter specific metabolic pathways to meet their tremendous energy and biomass demands which contribute to the progression and dissemination of this disease. More importantly, the oncogenic signaling enables cancer cells to reprogram the cellular metabolism that afford growth and proliferative advantages over normal cells and, thus, may contribute to pancreatic cancer pathophysiology. There is an increasing interest to investigate the oncogenic signaling that controls the metabolic reprogramming of cancer cells. Objectives: Mammalian Target of Rapamycin (mTOR), a central downstream target of Akt, is a highly conserved protein kinase, and is frequent activated in PDAs. Earlier studies reported that mTOR, a master regulator of cell growth and proliferation downstream of oncogenic signaling pathways, controls specific aspects of cellular metabolism through the induction of metabolic gene expression. In our earlier microarray studies, we observed differential expression of genes associated with glucose and lipid metabolic pathways, with concomitant increase in mTOR expression. However, the mechanism and critical link between mTOR and the pancreatic cancer metabolism has not been fully understood. Methodology: In the present study, we evaluated the effectiveness of Melinjo (Indonesian name; Gnetum gnemon L.) seed extract (MSE) and gnetin C (GC), a resveratrol dimer found abundantly in MSE in human (Aspc-1 and PANC-1) and mouse (Pan-02) pancreatic cancer cells. MSE has been reported to exert antioxidant, lipase and amylase inhibition, anti-metabolic syndrome effects and anticancer activities. A recent clinical study reported that MSE decreased serum uric acid and increased HDL cholesterol levels in humans, suggesting that MSE may improve lipid metabolism. To test the anti-tumor activities, pancreatic cancer cells were treated with various concentrations of MSE (0 - 400μg/ml) and GC (0 – 100μM) for 48 h. MTS cell proliferation and apoptotic assays were performed to determine the cell growth inhibition and induction of apoptosis. Trans-resveratrol (RES) that is abundant in grapes and wine was used to compare the effects of GC. Real-time PCR was performed to evaluate the effect of a MSE or GC on mTOR and its downstream targets, as well selected glucose and lipid metabolic pathway genes. Western blot was performed to confirm their expression at the protein level. Results and conclusion: Human (ASPC-1 and PANC-1), and mouse (Pan-02) pancreatic cancer cells treated with MSE, GC and RES showed a dose-dependent decrease in cancer cell proliferation. The IC50 values of MSE, GC and RES related to their anti-proliferative effects revealed that GC, the major metabolite of MSE has superior anti-proliferative properties than resveratrol. Further, flow cytometry analysis showed a pre-G1 peak of apoptosis (&amp;gt;10%) with GC. We observed that GC significantly downregulated mTOR complex, namely (mTORC1 and mTOC2). mTORC1 is a sensor of systemic and local levels of nutrients that regulates cancer cell proliferation and survival. mTORC2 is associated with the ribosome and insulin-stimulated oncogenic PI3K signaling. We also found that GC downregulated p-ribosomal protein S6 (p-RPS6), a downstream target of mTOR that plays important role in both neoplastic and inflammatory processes. In addition, GC also downregulated glycogen synthase kinase 3 alpha and beta (GSK3α and β) that is linked to glycogen metabolism and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), which is associated with lipids and lipoproteins metabolism (cholesterol biosynthesis). Further analysis on key genes of the lipid metabolism is in progress. Given the preliminary evidence that GC has superior anti-proliferative activities and its ability to inhibit mTOR and metabolic/lipid pathway genes can be expected to yield more potent therapies against this deadly disease. The future goal will be to test the potentials of GC on the antitumor efficacy and the effect on metabolic pathway targets in preclinical animal models of pancreatic cancer. Citation Format: Narayanan K. Narayanan, Kazuhiro Kunimasa, Di Tian, Lori Horton, Igor Dolgaev, Adriana Heguy, George Miller, Amit Tiwari, Bhagavathi A. Narayanan. Gnetin C, a novel resveratrol dimer, targets pancreatic cancer metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B57.

Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor γ activation.

An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

Strong Reduction of Low-Density Lipoprotein Receptor/Apolipoprotein E Expressions by Telmisartan in Cerebral Cortex and Hippocampus of Stroke Resistant Spontaneously Hypertensive Rats

Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonistic property to exert not only antihypertensive effect but also antimetabolic syndrome effect. We examined the long-term effect of telmisartan on cholesterol transport-related proteins (low-density lipoprotein receptor [LDL-R]/apolipoprotein E [ApoE]) and microtubule-associated proteins 2 (MAP2) in the brains of stroke resistant spontaneously hypertensive rats (SHR-SRs), which were divided into 3 experiment groups including vehicle group (SHR/Ve), low-dose telmisartan group (SHR/Low, .3 mg/kg/day), and high-dose telmisartan group (SHR/High, 3 mg/kg/day). The numbers of LDL-R- and immuno-ApoE-positive neurons increased in both cerebral cortex and hippocampus of SHR/Ve throughout 6, 12, and 18 months of age, compared with age-matched normotensive Wistar rats. On the other hand, telmisartan significantly reduced the numbers of LDL-R- and ApoE immuno-positive neurons in both cerebral cortex and hippocampus, with similar effectiveness in the SHR/Low group without blood pressure (BP) lowering to BP lowering (SHR/High). The decrease of MAP2-positive neuron in SHR/Ve was recovered by telmisartan in both cerebral cortex and hippocampus. These findings suggest that a long-term treatment with telmisartan directly improved neuronal lipid metabolism in the cerebral cortex and hippocampus of SHR-SR, mainly improving LDL-R and ApoE metabolism (SHR/Low) with a small additive benefit by BP lowering (SHR/High), which could provide a preventative approach in patients with hypertension at risk of Alzheimer disease.

Bifidobacterium breve B-3 exerts metabolic syndrome-suppressing effects in the liver of diet-induced obese mice: a DNA microarray analysis

We previously reported that supplementation with Bifidobacterium breve B-3 reduced body weight gain and accumulation of visceral fat in a dose-dependent manner, and improved serum levels of total cholesterol, glucose and insulin in a mouse model of diet-induced obesity. In this study, we investigated the expression of genes in the liver using DNA microarray analysis and q-PCR to reveal the mechanism of these anti-obesity effects in this mouse model. Administration of B. breve B-3 led to regulated gene expression of pathways involved in lipid metabolism and response to stress. The results indicate that these regulations in the liver are related to the anti-metabolic syndrome effects of B. breve B-3.

Asperuloside stimulates metabolic function in rats across several organs under high-fat diet conditions, acting like the major ingredient of Eucommia leaves with anti-obesity activity.

Eucommia leaves (Eucommia ulmoides Oliver) contain chlorogenic acid (a caffeic acid derivative) and geniposidic acid and asperuloside (ASP), iridoid glucosides used in beverages. We used a metabolic syndrome rat model, produced by feeding a 35% high-fat diet (HFD), to examine potential anti-obesity and anti-metabolic syndrome effects and mechanisms of chronic administration of ASP. These effects were compared with Eucommia leaf extract (ELE), the positive control, which exhibits anti-obesity effects. A total of six rats were studied for 3 months in five groups. ASP suppressed body weight, visceral fat weight, food intake and circulating levels of glucose, insulin and lipids, and increased the plasma adiponectin level in rats on a HFD. These effects are similar to those of ELE, except for the influence on the plasma glucose level. RT-PCR studies showed that ASP (like ELE with known anti-obesity effects) diminished isocitrate dehydrogenase 3α, NADH dehydrogenase flavoprotein 1 (Comp I) mRNA and fatty acid synthase levels (white adipose tissue), increased carnitine palmitoyltransferase 1α and acyl-CoA dehydrogenase, very-long-chain mRNA levels (liver), and increased Glut4, citrate synthase, isocitrate dehydrogenase 3α, succinyl CoA synthase, peroxisomal 3-ketoacyl-CoA thiolase, dihydrolipoamide succinyl transferase and succinate dehydrogenase mRNA levels (skeletal muscle) under HFD conditions. Interestingly, ASP administration resulted in significantly increased mRNA levels of uncoupling protein 1 (UCP1) in the brown adipose tissue of HFD-fed rats; ELE did not affect the expression of UCP1. The increased expression of UCP1 may be negated by many ingredients other than ASP in the ELE. These findings suggest that chronic administration of ASP stimulates anti-obesity and anti-metabolic syndrome activity in HFD-fed rats across several organs, similar to ELE administration; thus, ASP may be an important ingredient of ELE.

칡(Pueraria thunbergiana)추출물 청국장 캡슐의 ob/ob Mice에 대한 항비만 효과

본 연구는 칡청국장 및 칡청국장 캡슐함유 식이가 체중, 지방축적, 지질대사 등에 미치는 효능을 알아보기 위하여 선천성 비만 및 인슐린 비의존성 당뇨병의 모델동물인 ob/ob마우스를 대상으로 정상대조군(NC: 일반식이군), 양성대조군(PC: 2% 청국장함유군), 칡청국장 2% 함유군(AR: 2% 칡청국장), 칡청국장 캡슐군(ARC: 2% 칡청국장 캡슐함유)으로 나누어 10주간 실험하였다. 체중 및 식이효율은 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 감소하였다. 혈청 콜레스테롤, LDL-콜레스테롤, 중성지방, 혈당 및 동맥경화지수는 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 감소하였다. 칡청국장 캡슐군에서 지방간의 전형적인 지방축적의 억제효과를 보였다. 간조직의 SOD, CAT, GST 활성은 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 증가하였다. 이에 칡 추출물 청국장 및 캡슐형태의 투여는 지방함량의 저하효과, 혈당강하효과, 항산화계의 활성도 증가 등의 효과를 통하여 항비만기능이 있으며, 칡청국장 캡슐형의 기능성이 높다는 사실을 확인할 수 있었다.