Kuo-Ping Shen

Eugenosedin-A amelioration of lipopolysaccharide-induced up-regulation of p38 MAPK, inducible nitric oxide synthase and cyclooxygenase-2.

In this study, we investigate the protective effects of eugenosedin‐A on p38 mitogen‐activated protein kinase (MAPK), inflammatory nitric oxide (NO) and cyclooxygenase‐2 (COX‐2) pathways in a rat model of endotoxin shock. Rats were pretreated with eugenosedin‐A, trazodone, yohimbine (1 mg kg−1, i.v.), aminoguanidine or ascorbic acid (15 mg kg−1, i.v.) 30 min before endotoxin challenge. Endotoxaemia was induced by a single i.v. injection of lipopolysaccharide (LPS, 10 mg kg−1). In rats not treated with eugenosedin‐A, LPS increased plasma concentrations of NO and prostaglandin E2 (PGE2), and levels of p38 MAPK, inducible NO synthase (iNOS) and COX‐2 proteins in the liver, lung, aorta and lymphocytes. In the pre‐treated rats, eugenosedin‐A not only inhibited the LPS‐induced NO and PGE2 levels but also attenuated the LPS‐induced increase in p38 MAPK and iNOS levels in the liver, aorta and lymphocytes. Eugenosedin‐A also reduced LPS‐induced COX‐2 proteins in the aorta and lymphocytes. Likewise, aminoguanidine, ascorbic acid, yohimbine and trazodone were also found to decrease NO and PGE2 concentrations after endotoxin challenge. While aminoguanidine and ascorbic acid also attenuated the LPS‐induced increase in p38 MAPK, iNOS and COX‐2 proteins in the aorta and lymphocytes, trazodone and yohimbine inhibited only the increase in p38 MAPK, iNOS and COX‐2 proteins in lymphocytes. Finally, eugenosedin‐A (10−10‐10−8 M) significantly inhibited the biphasic response induced by hydrogen peroxide (10−6‐3 × 10−5 M) in rat denudated aorta. Taken together, the results of this study indicate that eugenosedin‐A, as well as ascorbic acid, can attenuate free‐radical‐mediated aortic contraction and relaxation. It may therefore be able to reduce the damage caused by septic shock by inhibiting formation of p38 MAPK, iNOS, COX‐2 and free radicals.

Eugenosedin-A prevents hyperglycaemia, hyperlipidaemia and lipid peroxidation in C57BL/6J mice fed a high-fat diet

Objectives Eugenosedin‐A is a serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT1b/2a and α1/α2/β1‐adrenoceptor blocker with anti‐oxidative, anti‐inflammatory and free‐radical scavenging activities. Previous reports demonstrated that 5‐HT2a blockers could diminish hyperlipidaemia. This study therefore aimed to investigate the possible uses and mechanisms of eugenosedin‐A and other agents in treating hyperlipidaemia.

Eugenosedin-A prevents high-fat diet increased adhesion molecules through inhibition of MAPK- and p65-mediated NF-κB pathway in rat model

Previous studies have shown eugenosedin‐A, a 5‐HT1B/2A and α1/α2/β1‐adrenergic blocker, is able to decrease cholesterol levels, hyperglycaemia and inflammation in hyperlipidaemic mice induced by high‐fat diet (HFD). The aim of this study is to examine the effects of eugenosedin‐A on the inhibition of adhesion molecules of platelets, the aorta and acyl‐coenzymeA:cholesterol acyltransferase‐1 (ACAT‐1) of macrophages in a hyperlipidaemic rat model.

Low‐Dose Aspirin Ameliorated Hyperlipidemia, Adhesion Molecule, and Chemokine Production Induced by High‐Fat Diet in Sprague‐Dawley Rats

Preclinical Research

Pre-germinated brown rice prevents high-fat diet induced hyperglycemia through elevated insulin secretion and glucose metabolism pathway in C57BL/6J strain mice

This study investigated the effect and mechanism of pre-germinated brown rice (PGBR) prevented hyperglycemia in C57BL/6J mice fed high-fat-diet (HFD). Normal six-week-old mice were randomly divided into three groups. Group 1 was fed standard-regular-diet (SRD) and group 2 was fed HFD for 16 weeks. In group 3, the mice were fed a HFD with its carbohydrate replaced with PGBR for 16 weeks. Comparing the SRD and HFD groups, we found the HFD group had higher blood pressure, higher concentrations of blood glucose and HbA1c. The HFD group had less protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), glucose transporter-4 (GLUT-4) and glucokinase (GCK) and greater expression of glucogen synthase kinase (GSK) in skeletal muscle. The HFD group also had less expression of IR, serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), GCK and peroxisome proliferator-activated receptor γ (PPARγ) in liver. In the HFD + PGBR group, the PGBR could reverse the disorders of blood pressure, blood glucose, HbA1c and increase insulin concentration. PGBR increased the IR, IRS-1, PI3K, Akt, GLUT-1 and GLUT-4 proteins, and ameliorated AMPK, GCK, GSK and PPARγ proteins. Together, PGBR prevented HFD-induced hyperglycemia through improving insulin levels, insulin receptor, glucose transporters and enhancing glucose metabolism.

Suppression of inflammatory response and endothelial nitric oxide synthase downregulation in hyperlipidaemic C57BL/6J mice by eugenosedin-A

Objectives  Eugenosedin‐A has been found to ameliorate high‐fat diet (HFD)‐induced hyperglycaemia and hyperlipidaemia in C57BL/6J mice. This study aimed to investigate the mechanisms of action of eugenosedin‐A on endothelial function and inflammation in hyperlipidaemic mice.

Eugenosedin-A ameliorates hyperlipidemia-induced vascular endothelial dysfunction via inhibition of α1-adrenoceptor/5-HT activity and NADPH oxidase expression

Eugenosedin‐A (Eu‐A) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated. Rats were randomly divided into four groups: two control groups and two treatment groups. The control rats received a regular diet or high fat diet (HFD); the treatment rats fed received an HFD with 5 mg/kg Eu‐A or atorvastatin for 10 weeks. No changes in serotonin levels were observed in the four groups; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu‐A and atorvastatin. In the HFD group, the vascular reactivity was increased by vasoconstrictors (5‐nonyloxytryptamine, 5‐HT, and phenylephrine) and decreased by an endothelium‐dependent vasorelaxant, carbachol. Protein levels of α1‐adrenergic receptors (not 5‐HT1B/2A), reactive oxygen species (ROS) p47phox, p67phox, and gp91phox, and oxidative damage markers 3‐nitrotyrosine (3‐NT) and 4‐hydroxy‐2‐nonenal (4‐HNE) were increased, but endothelial nitric oxide synthase (eNOS), P‐eNOS and vasodilator‐stimulated phosphoprotein phosphorylation (P‐VASP) were decreased. Catalase and superoxide dismutase (SOD‐1 and SOD‐2) proteins were increased, but glutathione peroxidase (GPx) was decreased in the aorta. Eu‐A and atorvastatin reduced vasoconstrictor‐induced aortic contractions that might be related to 5‐HT1B/2A and α1‐adrenergic receptors inhibitory activities. Eu‐A and atorvastatin improved eNOS/P‐eNOS, P‐VASP, GPx, and malondialdehyde (MDA) levels, and decreased ROS and oxidative damage markers. Taken together, we suggest that Eu‐A can ameliorate hyperlipidemia‐induced vascular endothelial dysfunction and oxidative dysregulation.

Hypotensive and antiaggregative effects of eugenosedin-B with serotonin and alpha/beta-adrenoceptor antagonistic activities in rats and human platelets.

Eugenosedin-B is able to block serotonin (5-HT) and α/β receptors and to inhibit platelet aggregation. In Wistar rats, intravenous injections of eugenosedin-B (2.4, 7.2, 12 μmoL/kg) caused a dose-dependent decrease in blood pressure and heart rate. In contrast, intracisternal injection of eugenosedin-B (0.3, 0.03 μmoL) and an α2-antagonist yohimbine (0.03 μmoL) increased blood pressure and heart rate. Eugenosedin-B and yohimbine prevented hypotension induced by intracisternal injection of an α2-agonist clonidine (38 pmol). In in vitro experiments, eugenosedin-B (10−9, 10−8, 10−7 M) competitively antagonized norepinephrine-, clonidine-, and 5-HT (10−8 to 10−4 M)-induced vasocontractions in isolated rat aorta. It also competitively antagonized the isoproterenol (10−8 to 10−4 M)-induced positive inotropic effects in isolated rat atrium. These findings clearly suggest that eugenosedin-B possesses α1, α2, β1, and 5-HT2A receptor blocking activities. In isolated rabbit ear artery sensitized with 16 mM K+, eugenosedin-B antagonized 5-nonyloxytryptamine- and 5-HT-induced vasocontractions, indicating it also blocked 5-HT1B and 5-HT2A receptors. In radioligand-binding experiments, eugenosedin-B had significant binding affinities on α1, α2, β1, 5-HT1B, and 5-HT2A receptors. In human platelets, eugenosedin-B inhibited epinephrine and 5-HT-induced aggregations. It also had competitive binding effects in human platelet with [3H]yohimbine (α2), [3H]ketanserin (5-HT2A). We conclude that hypotensive and vasorelaxant effects of eugenosedin-B can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, α1/2 and β1 receptors, and its ability to reduce platelet aggregation attributed to its blockade of α2 and 5-HT2A receptors.

Pre-germinated brown rice prevented high fat diet induced hyperlipidemia through ameliorating lipid synthesis and metabolism in C57BL/6J mice

Pre-germinated brown rice (PGBR) can ameliorate hyperlipidemia, but the action mechanism is not clear. We focus the mechanisms of PGBR prevented hyperlipidemia. Six-week-old mice were divided into: standard-regular diet (SRD), high-fat diet (HFD) and HFD with PGBR (HFD + PGBR) groups for 16 weeks. The HFD group has higher concentrations of TG, TC, HDL and Non-HDL in the blood, and a higher atherosclerosis index (AI). The TG levels in the liver, and TG, bile acid levels in the feces were enhanced; and the total adipocytokines level in adipose tissue was reduced. The HFD group had higher protein expressions of SREBP-1, SCD-1, FAS, LDLR, and CYP7α1 in the liver. Moreover, the greater expressions of SREBP-1, SCD-1, FAS and the less expressions of PPAR-α and adiponectin were in adipose tissue. In the HFD + PGBR group, the PGBR regulated the levels of TG, TC, HDL, Non-HDL, AI and adipocytokines. PGBR increased more cholesterol and bile acid exhaust in feces. The SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7α1 and PPAR-α proteins in the liver; and the SREBP-1, SCD-1, FAS, PPAR-α and adiponectin proteins in adipose tissue were reversed by PGBR. Taken together, PGBR can improve lipid synthesis and metabolism, and we suggest PGBR is a recommendable food for controlling hyperlipidemia.

Eugenosedin-A improves glucose metabolism and inhibits MAPKs expression in streptozotocin/nicotinamide-induced diabetic rats

This study examined the effects of eugenosedin‐A (Eu‐A) in a streptozotocin (STZ)/nicotinamide‐induced rat model of type II diabetes mellitus (T2DM). Six‐week‐old Sprague–Dawley rats were randomly divided into three groups: (1) RD group, normal rats fed a regular diet (RD), (2) DM group, T2DM rats fed a high‐fat diet, and (3) Eu‐A group, T2DM rats fed a high fat diet plus oral Eu‐A (5 mg/kg/day). After 30 days, the DM group had higher body weight, higher blood glucose and lower insulin levels than the RD group. The DM group also had increased protein expression of glycogen synthase kinase (GSK) in liver and skeletal muscle and decreased protein expression of insulin receptor (IR), insulin receptor substrate‐1 (IRS‐1), IRS‐2, AMP‐activated protein kinase (AMPK), glucose transporter‐4 (GLUT‐4), glucokinase (GCK), and peroxisome proliferator‐activated receptor γ (PPAR‐γ). STZ/nicotinamide‐induced T2DM increased the expression of mitogen‐activated protein kinases (MAPKs: p38, ERK, JNK) and inflammatory p65 protein. In the Eu‐A treated T2DM rats, however, blood glucose was attenuated and the insulin concentration stimulated. Changes in IR, IRS‐1 and IRS‐2 proteins as well as AMPK, GLUT‐4, GCK, GSK, PPAR‐γ, MAPKs, and inflammatory p65 proteins were ameliorated. These results suggested that Eu‐A alleviates STZ/nicotinamide‐induced hyperglycemia by improving insulin levels and glucose metabolism, and inhibiting the MAPKs‐ and p65‐mediated inflammatory pathway.