Pyrogallol-Phloroglucinol-6,6'-Bieckol from Ecklonia cava Improved Blood Circulation in Diet-Induced Obese and Diet-Induced Hypertension Mouse Models.
ABSTRACT: Blood circulation disorders, such as hyperlipidemia and arteriosclerosis, are not easily cured by dietary supplements, but they can be mitigated. Although Ecklonia cava extract (ECE), as dietary supplements, are associated with improving the conditions, there are not many studies verifying the same. In this study, the beneficial effect of ECE and leaf of Ginkgo biloba extract (GBE), which is a well-known dietary supplement, were first confirmed in a diet induced-obese model. Afterwards, 4 phlorotannins were isolated from ECE, and their inhibitory effects on vascular cell dysfunction were validated. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) was selected to be orally administered in two mice models: the diet induced obese model and diet induced hypertension model. After four weeks of administration, the blood pressure of all mice was measured, after which they were subsequently sacrificed. PPB was found to significantly improve blood circulation, including a reduction of adhesion molecule expression, endothelial cell (EC) death, excessive vascular smooth muscle cell (VSMC) proliferation and migration, blood pressure, and lipoprotein and cholesterol levels. Based on the excellent efficacy in diet-induced mouse models of obese and hypertension, our results demonstrate that PPB is a valuable active compound from among the phlorotannins that were isolated and it has the potential to be used in functional foods for improving the blood circulation.
Project description:Advanced glycation end products/receptor for AGEs (AGEs/RAGEs) or Toll like receptor 4 (TLR4) induce vascular smooth muscle cell (VSMC) phenotype changes in osteoblast-like cells and vascular calcification. We analyzed the effect of Ecklonia cava extract (ECE) or pyrogallol-phloroglucinol-6,6-bieckol (PPB) on VSMC phenotype changes and vascular calcification prompted by a high-fat diet (HFD). HFD unregulated RAGE, TLR4, transforming growth factor beta (TGF?), bone morphogenetic protein 2 (BMP2), protein kinase C (PKC), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) signals in the aorta of mice. ECE and PPB restored the increase of those signal pathways. AGE- or palmitate-treated VSMC indicated similar changes with the animal. HFD increased osteoblast-like VSMC, which was evaluated by measuring core-binding factor alpha-1 (CBF?-1) and osteocalcin expression and alkaline phosphatase (ALP) activity in the aorta. ECE and PPB reduced vascular calcification, which was analyzed by the calcium deposition ratio, and Alizarin red S stain was increased by HFD. PPB and ECE reduced systolic, diastolic, and mean blood pressure, which increased by HFD. PPB and ECE reduced the phenotype changes of VSMC to osteoblast-like cells and vascular calcification and therefore lowered the blood pressure.
Project description:Obesity is associated with systemic chronic inflammation, and it induces central leptin resistance which blocks the appetite-suppressing effect of leptin and leptin resistance in adipocytes. In the present study, we evaluated the effects of Ecklonia cava extract (ECE), which contained rich phlorotannins, on inflammation and leptin resistance in the adipose tissue of a diet-induced obese model. Effects of ECE on fat deposition, inflammation, M1/M2 macrophage, and T-cell infiltrations were investigated, and leptin resistance and SOCS3 were also measured in adipose tissue. Furthermore, ECE attenuated the expression of inflammation-related receptors such as TLR4 and RAGE and leptin resistance by reducing SOCS3 expression, increasing expression of leptin receptor in adipose tissue, and increasing lipolysis. ECE showed antiadiposity and anti-inflammatory effects, attenuated leptin resistance, and increased lipolysis in the diet-induced obese model. This study shows that ECE is a suitable dietary supplement candidate for the prevention or treatment of obesity or obesity-associated diseases, especially inflammation-related diseases.
Project description:The hypoxia/reoxygenation (H/R) injury causes serious complications after the blood supply to the kidney is stopped during surgery. The main mechanism of I/R injury is the release of high-mobility group protein B1 (HMGB1) from injured tubular epithelial cells (TEC, TCMK-1 cell), which triggers TLR4 or RAGE signaling, leading to cell death. We evaluated whether the extracts of Ecklonia cava (E. cava) would attenuate TEC death induced by H/R injury. We also evaluated which phlorotannin-dieckol (DK), phlorofucofuroeckol A (PFFA), pyrogallol phloroglucinol-6,6-bieckol (PPB), or 2,7-phloroglucinol-6,6-bieckol (PHB)-would have the most potent effect in the context of H/R injury. We used for pre-hypoxia treatment, in which the phlorotannins from E. cava extracts were added before the onset of hypoxia, and a post- hypoxia treatment, in which the phlorotannins were added before the start of reperfusion. PPB most effectively reduced HMGB1 release and the expression of TLR4 and RAGE induced by H/R injury in both pre- and post-hypoxia treatment. PPB also most effectively inhibited the expression of NF-kB and release of the inflammatory cytokines TNF-? and IL-6 in both models. PPB most effectively inhibited cell death and expression of cell death signaling molecules such as Erk/pErk, JNK/pJNK, and p38/pp38. These results suggest that PPB blocks the HGMB1-TLR4/RAGE signaling pathway and decreases TEC death induced by H/R and that PPB can be a novel target for renal H/R injury therapy.
Project description:Ecklonia cava (E. cava) can alleviate diet-induced obesity in animal models, and phlorotannins contained in E. cava help prevent hypertrophy-induced adipocyte differentiation. Receptor for advanced glycation end-products (RAGE) is well known to induce hypertrophy of visceral fat and to trigger inflammation substantially. While the relationship between RAGE and obesity and inflammation has been well-characterized, few studies describe the effects of phlorotannin on RAGE. In this study, we investigated the anti-obesity effects of pyrogallol-phloroglucinol-6,6-bieckol (PPB)-a single compound from the ethanoic extract of E. cava-mediated by a reduction in the inflammation caused by RAGE and RAGE ligands. In visceral fat, PPB (i) significantly inhibited RAGE ligands, (ii) reduced the expression of RAGE, and (iii) reduced the binding ratio between RAGE and RAGE ligands. Under lower expression of RAGE, RAGE ligands and their cognate binding, the differentiation of macrophages found in visceral fat into M1-type-the pro-inflammatory form of this immune cell-was reduced. As the M1-type macrophage decreased, pro-inflammatory cytokines, which cause obesity, decreased in visceral fat. The results of this study highlight the anti-obesity effects of PPB, with the effects mediated by reductions in RAGE, RAGE ligands, and inflammation.
Project description:It is well known that perivascular fat tissue (PVAT) dysfunction can induce endothelial cell (EC) dysfunction, an event which is related with various cardiovascular diseases. In this study, we evaluated whether Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB), one component of ECE, could attenuate EC dysfunction by modulating diet-induced PVAT dysfunction mediated by inflammation and ER stress. A high fat diet (HFD) led to an increase in the number and size of white adipocytes in PVAT; PPB and ECE attenuated those increases. Additionally, ECE and PPB attenuated: (i) an increase in the number of M1 macrophages and the expression level of monocyte chemoattractant protein-1 (MCP-1), both of which are related to increases in macrophage infiltration and induction of inflammation in PVAT, and (ii) the expression of pro-inflammatory cytokines (e.g., tumor necrosis factor-? (TNF-?) and interleukin (IL)-6, chemerin) in PVAT which led to vasoconstriction. Furthermore, ECE and PPB: (i) enhanced the expression of adiponectin and IL-10 which had anti-inflammatory and vasodilator effects, (ii) decreased HFD-induced endoplasmic reticulum (ER) stress and (iii) attenuated the ER stress mediated reduction in sirtuin type 1 (Sirt1) and peroxisome proliferator-activated receptor ? (PPAR?) expression. Protective effects against decreased Sirt1 and PPAR? expression led to the restoration of uncoupling protein -1 (UCP-1) expression and the browning process in PVAT. PPB or ECE attenuated endothelial dysfunction by enhancing the pAMPK-PI3K-peNOS pathway and reducing the expression of endothelin-1 (ET-1). In conclusion, PPB and ECE attenuated PVAT dysfunction and subsequent endothelial dysfunction by: (i) decreasing inflammation and ER stress, and (ii) modulating brown adipocyte function.
Project description:Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.
Project description:Obesity induces inflammation both in the adipose tissue and the brain. Activated macrophage infiltration, polarization of macrophages to a more inflammatory type (M1), and increased levels of pro-inflammatory cytokines are related to brain inflammation, which induces leptin resistance in the brain. Pyrogallol-phloroglucinol-6,6-bieckol (PPB), a compound from Ecklonia cava, has anti-inflammatory effects. In this study, we evaluated the effects of PPB effect M1 polarization and inflammation and its ability to restore the effects of leptin, such as a decrease in appetite and body weight. We administered PPB to diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice, evaluated macrophage activation, polarization, and changes of inflammatory cytokine level in adipose tissue and brain, and determined the effect of PPB on leptin resistance or leptin sensitivity in the brain. The levels of activated macrophage marker, M1/M2, and pro-inflammatory cytokines were increased in the adipose tissue and brain of DIO and ob/ob mice than control. TLR4 expression, endoplasmic reticulum (ER) stress, and NF-?B expression in the brain of DIO and ob/ob mice were also increased; this increase was related to the upregulation of SOCS3 and decreased phosphorylated STAT3, which decreased leptin sensitivity in the brain. PPB decreased inflammation in the brain, restored leptin sensitivity, and decreased food intake and weight gain in both DIO and ob/ob mice.
Project description:Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins-dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)-had the most potent effect on attenuating leptin resistance. TLR4 and NF-?B expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.
Project description:Obesity and its common association with type 2 diabetes, dyslipidemia, and cardiovascular diseases are worldwide epidemics. Currently, to prevent or treat obesity and associated metabolic disorders, herbal dietary supplements or medicines have attracted more and more attention owing to their relative effectiveness with fewer significant side effects. We investigate the therapeutic effects and underlying mechanisms of Plantago asiatica L. seed extract (PSE) on obesity and associated metabolic disorders in high-fat (HF) diet-induced mice. Our results displayed that PSE did not modify food intake or body weight but decreased abdominal white adipose tissue ratio, white/brown adipocyte size, serum total cholesterol, triglyceride (TG), low density lipoprotein cholesterol, free fatty acid, and hepatic TG concentrations when compared with the HF group. The levels of fasting blood glucose and glucose tolerance were improved in the PSE group when compared with the HF group. Furthermore, PSE upregulated mRNA expressions of peroxisome proliferator activated receptors (PPARs) and target genes related to fatty acid metabolism and energy expenditure in liver and adipose tissue of obese mice when compared with the HF group. PSE treatment effectively improved lipid and glucose metabolism in HF diet-induced obese mice. These effects might be attributed to the upregulation of PPAR signaling.
Project description:In the past, vitamins and minerals were used to cure deficiency diseases. Supplements nowadays are used with the aim of reducing the risk of chronic diseases of which the origins are complex. Dietary supplement use has increased in the UK over recent decades, contributing to the nutrient intake in the population, but not necessarily the proportion of the population that is sub-optimally nourished; therefore, not reducing the proportion below the estimated average requirement and potentially increasing the number at risk of an intake above the safety limits. The supplement nutrient intake may be objectively monitored using circulation biomarkers. The influence of the researcher in how the supplements are grouped and how the nutrient intakes are quantified may however result in different conclusions regarding their nutrient contribution, the associations with biomarkers, in general, and dose-response associations specifically. The diet might be sufficient in micronutrients, but lacking in a balanced food intake. Since public-health nutrition guidelines are expressed in terms of foods, there is potentially a discrepancy between the nutrient-orientated supplement and the quality of the dietary pattern. To promote health, current public-health messages only advocate supplements in specific circumstances, but not in optimally nourished populations.