Date (Phoenix dactylifera L.) seed oil is an agro-industrial waste with biopreservative effects and antimicrobial activity.

Antimicrobial resistant (AMR) infections are a leading health threat globally. Previous literature has underscored the farm-to-fork continuum as a potential focal point for the emergence and spread of AMR. In the present study, date (Phoenix dactylifera L.) seed oil was investigated for its chemical composition and antimicrobial activity against common foodborne pathogens including Escherichia coli O157:H7, Salmonella enteritidis, Salmonella typhimurium, Listeria monocytogenes, and Staphylococcus aureus in vitro, and in ultra-high-temperature (UHT) milk as a food model at storage temperatures of 37 °C (24 h) and 10 °C (7 days). GC-MS analysis of the seed oil revealed 20 compounds, with octadecane (52.2-55.4%) as the major constituent, and the fatty acid analysis revealed 17 fatty acids, with oleic acid (42.3-43.1%) as the main constituent, followed by lauric acid (19.8-20.3%). The antimicrobial activity of date seed oil was determined using the microdilution method. A significant inhibition against gram-negative bacteria was noted in microbiological media and UHT milk, with a log reduction ranging from 4.3 to 6.7 (at 37 °C/24 h) and 5.7 to 7.2 (at 10 °C/7 days), respectively, at oil concentrations ranging between 10 and 15 µl/ml. The oil showed a similar significant inhibitory effect against St. aureus in the microbiological media (2.0-6.0 log reduction), whereas the inhibitory effect against L. monocytogenes was not statistically significant, with a maximum log reduction of 0.64 achieved at a concentration of 10 µl/ml. AFM imaging of the bacteria showed that oil treatment led to morphological changes in the bacteria including the formation of distorted shapes, surface blebs, indentations, stiffness, and swelling. Present findings suggest that date seed oil can be a promising by-product with potential antimicrobial activity and a food preservative.

Fuzhuan brick tea ameliorates hepatic steatosis and steatohepatitis through gut microbiota-derived aryl hydrocarbon receptor ligands in high-fat diet-induced obese mice.

High-fat diet (HFD) induced obesity and its associated conditions, such as hepatic steatosis and steatohepatitis, are major health concerns worldwide. Previous studies have reported the excellent efficiency of Fuzhuan brick tea (FBT) in attenuating HFD-induced obesity and metabolic disorders. In this study, we investigated the effects of FBT on hepatic steatosis and simple steatohepatitis in HFD-induced obese mice, as well as the metabolic function of the gut microbiome using metagenomics and metabolomics. The results showed that FBT ameliorated dyslipidemia, hepatic steatosis and steatohepatitis in HFD-induced obese mice by normalizing the gut microbiota structure and tryptophan metabolism. FBT increased the cecal abundance of aryl hydrocarbon receptor (AhR)-ligand producing bacteria such as Lactobacillus_reuteri and Lactobacillus_johnsonii, at the expense of AhR-ligand consuming bacteria, such as Faecalibaculum_rodentium and Escherichia_coli, and elevated the cecal contents of AhR-ligands such as IAA, IPA, and KYNA. Furthermore, FBT regulated the expressions of AhR and its targeted lipometabolic genes such as Pemt, Fasn, and SREBP-1c, as well as other inflammatory genes including TNF-α, IL-6, and IL-1ß in the liver of mice. Overall, these findings highlight the beneficial effects of FBT on obesity-related hepatic steatosis and steatohepatitis via microbiota-derived AhR signaling.

An olive-derived elenolic acid stimulates hormone release from L-cells and exerts potent beneficial metabolic effects in obese diabetic mice.

Insulin resistance and progressive decline in functional ß-cell mass are two key factors for developing type 2 diabetes (T2D), which is largely driven by overweight and obesity, a significant obstacle for effective metabolic control in many patients with T2D. Thus, agents that simultaneously ameliorate obesity and act on multiple pathophysiological components could be more effective for treating T2D. Here, we report that elenolic acid (EA), a phytochemical, is such a dual-action agent. we show that EA dose-dependently stimulates GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts. In addition, EA induces L-cells to secrete peptide YY (PYY). EA induces a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling. Consistently, inhibition of (PLC) or Gαq ablates EA-stimulated increase of [Ca2+]i and GLP-1 secretion. In vivo, a single dose of EA acutely stimulates GLP-1 and PYY secretion in mice, accompanied with an improved glucose tolerance and insulin levels. Oral administration of EA at a dose of 50 mg/kg/day for 2 weeks normalized the fasting blood glucose and restored glucose tolerance in high-fat diet-induced obese (DIO) mice to levels that were comparable to chow-fed mice. In addition, EA suppresses appetite, reduces food intake, promotes weight loss, and reverses perturbated metabolic variables in obese mice. These results suggest that EA could be a dual-action agent as an alternative or adjuvant treatment for both T2D and obesity.

The metabolic regulation of Fuzhuan brick tea in high-fat diet-induced obese mice and the potential contribution of gut microbiota.

This study investigated the metabolic effects of Fuzhuan brick tea (FBT) in high-fat diet (HFD)-induced obese mice and the potential contribution of gut microbiota. The results showed that FBT ameliorated the HFD-induced glycerophospholipid metabolic aberrance, specifically increased the serum levels of phosphatidylcholines (PCs), lysophosphatidylcholines (LysoPCs), and the ratio of PC to phosphatidylethanolamines (PE). Besides, FBT increased the serum level of gut microbiota-derived aryl hydrocarbon receptor (AhR) ligand, 3-indole propionic acid, as well as the relative abundance of intestinal AhR-ligand producing bacteria such as Clostridiaceae, Bacteroidales_S24-7_group, and Lactobacillaceae. However, the metabolic benefits of FBT were weakened when the gut microbiota were depleted by antibiotic treatment, thereby suggesting that gut microbiota was required for FBT to regulate glycerophospholipid metabolism. Indeed, the metabolites regulated by FBT were significantly correlated with the AhR-ligand producing bacteria. The KEGG pathway enrichment analysis and expressions of AhR target genes indicated that FBT would improve the glycerophospholipid metabolism via the AhR-Pemt signal axis, in which the gut microbiota and their metabolites played pivotal mediators. Overall, FBT could be a functional beverage to improve HFD-induced metabolic disorders in a gut microbiota dependent manner.

Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes.

Protein aggregation is associated with a large number of human protein-misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid (RA) as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC50 = 200-300 nM). Structure-function relationship analysis of RA showed the additive effects of the two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin but rather lead to nontoxic, remodeled protein aggregates. RA has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of RA treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein-misfolding diseases.

The R2R3-MYB transcription factor CsMYB73 negatively regulates l-Theanine biosynthesis in tea plants (Camellia sinensis L.).

l-Theanine, a non-proteinaceous amino acid abundantly present in tea (Camellia sinensis), contributes to the umami flavor of tea and has beneficial effects on human health. While key l-theanine biosynthetic genes have been well documented, their transcriptional regulation remains poorly understood. In this study, we determined the l-theanine contents in tea leaves of two cultivars at three developmental stages and investigated the expression patterns of the l-theanine biosynthetic genes CsGS1 and CsGS2. Additionally, we identified an R2R3-MYB transcription factor, CsMYB73, belonging to subgroup 22 of the R2R3-MYB family. CsMYB73 expression negatively correlated with l-theanine accumulation during leaf maturation. We found that CsMYB73, as a nuclear protein, binds to the promoter regions of CsGS1 and CsGS2 via MYB recognition sequences and represses the transcription of CsGS1 and CsGS2 in tobacco leaves. Collectively, our results demonstrate that CsMYB73 is a transcriptional repressor involved in l-theanine biosynthesis in tea plants. Our findings might contribute to future tea plant breeding strategies.

Fuzhuan Brick Tea Attenuates High-Fat Diet-Induced Obesity and Associated Metabolic Disorders by Shaping Gut Microbiota.

An increasing amount of evidence suggests that the metabolic improvement of high-fat diet (HFD)-induced obese mice by Fuzhuan brick tea (FBT) is associated with gut microbiota. However, the causalities between FBT and gut microbiota have not yet been elucidated and the underlying mechanisms of action remain unclear. To impart direct evidence for the essential role of gut microbiota in the attenuation of obesity by FBT, the effects of FBT on healthy mice and microbiota-depleted mice that were treated with antibiotics were compared in an HFD-induced obesity mouse model. The results showed that FBT dramatically ameliorated obesity, serum lipid parameters, blood glucose homeostasis, hepatic steatosis, adipocyte hypertrophy, and tissue inflammation. However, the microbiota-depleted mice with single bacterium (Escherichia-Shigella) after antibiotic treatment were resistant to FBT-induced antiobesity and metabolic improvement. The beneficial effects of FBT resulted from its shift on gut microbiota composition and structure in mice. HFD-induced increase in the phyla Firmicutes/Bacteroidetes (F/B) ratio was remarkably restored by FBT. Furthermore, FBT-induced increase in abundances of beneficial bacteria Clostridiaceae, Bacteroidales, and Lachnospiraceae and decreases in harmful Ruminococcaceae, Peptococcaceae, Peptostreptococcaceae, and Erysipelotrichaceae were causal antecedents for FBT to reduce obesity and improve metabolic disorders.

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator-activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.-Si, H., Wang, X., Zhang, L., Parnell, L. D., Admed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

The Flavonoid Kaempferol Ameliorates Streptozotocin-Induced Diabetes by Suppressing Hepatic Glucose Production.

In diabetes mellitus, the excessive rate of glucose production from the liver is considered a primary contributor for the development of hyperglycemia, in particular, fasting hyperglycemia. In this study, we investigated whether kaempferol, a flavonol present in several medicinal herbs and foods, can be used to ameliorate diabetes in an animal model of insulin deficiency and further explored the mechanism underlying the anti-diabetic effect of this flavonol. We demonstrate that oral administration of kaempferol (50 mg/kg/day) to streptozotocin-induced diabetic mice significantly improved hyperglycemia and reduced the incidence of overt diabetes from 100% to 77.8%. This outcome was accompanied by a reduction in hepatic glucose production and an increase in glucose oxidation in the muscle of the diabetic mice, whereas body weight, calorie intake, body composition, and plasma insulin and glucagon levels were not altered. Consistently, treatment with kaempferol restored hexokinase activity in the liver and skeletal muscle of diabetic mice while suppressed hepatic pyruvate carboxylase activity and gluconeogenesis. These results suggest that kaempferol may exert antidiabetic action via promoting glucose metabolism in skeletal muscle and inhibiting gluconeogenesis in the liver.

Dietary Flavonoids in the Prevention of T2D: An Overview.

Type 2 diabetes (T2D) is a progressive metabolic disease that is increasing in prevalence globally. It is well established that insulin resistance (IR) and a progressive decline in functional ß-cell mass are hallmarks of developing T2D. Obesity is a leading pathogenic factor for developing IR. Constant IR will progress to T2D when ß-cells are unable to secret adequate amounts of insulin to compensate for decreased insulin sensitivity. Recently, a considerable amount of research has been devoted to identifying naturally occurring anti-diabetic compounds that are abundant in certain types of foods. Flavonoids are a group of polyphenols that have drawn great interest for their various health benefits. Results from many clinical and animal studies demonstrate that dietary intake of flavonoids might be helpful in preventing T2D, although cellular and molecular mechanisms underlying these effects are still not completely understood. This review discusses our current understanding of the pathophysiology of T2D and highlights the potential anti-diabetic effects of flavonoids and mechanisms of their actions.

Mechanisms by which cocoa flavanols improve metabolic syndrome and related disorders.

Dietary administration of cocoa flavanols may be an effective complementary strategy for alleviation or prevention of metabolic syndrome, particularly glucose intolerance. The complex flavanol composition of cocoa provides the ability to interact with a variety of molecules, thus allowing numerous opportunities to ameliorate metabolic diseases. These interactions likely occur primarily in the gastrointestinal tract, where native cocoa flavanol concentration is high. Flavanols may antagonize digestive enzymes and glucose transporters, causing a reduction in glucose excursion, which helps patients with metabolic disorders maintain glucose homeostasis. Unabsorbed flavanols, and ones that undergo enterohepatic recycling, will proceed to the colon where they can exert prebiotic effects on the gut microbiota. Interactions with the gut microbiota may improve gut barrier function, resulting in attenuated endotoxin absorption. Cocoa may also positively influence insulin signaling, possibly by relieving insulin-signaling pathways from oxidative stress and inflammation and/or via a heightened incretin response. The purpose of this review is to explore the mechanisms that underlie these outcomes, critically review the current body of literature related to those mechanisms, explore the implications of these mechanisms for therapeutic utility, and identify emerging or needed areas of research that could advance our understanding of the mechanisms of action and therapeutic potential of cocoa flavanols.

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway.

Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 µM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell-monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase ß and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff-Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.

Dietary supplementation of chinese ginseng prevents obesity and metabolic syndrome in high-fat diet-fed mice.

Obesity and diabetes are growing health problems worldwide. In this study, dietary provision of Chinese ginseng (0.5 g/kg diet) prevented body weight gain in high-fat (HF) diet-fed mice. Dietary ginseng supplementation reduced body fat mass gain, improved glucose tolerance and whole body insulin sensitivity, and prevented hypertension in HF diet-induced obese mice. Ginseng consumption led to reduced concentrations of plasma insulin and leptin, but had no effect on plasma adiponectin levels in HF diet-fed mice. Body temperature was higher in mice fed the ginseng-supplemented diet but energy expenditure, respiration rate, and locomotive activity were not significantly altered. Dietary intake of ginseng increased fatty acid oxidation in the liver but not in skeletal muscle. Expression of several transcription factors associated with adipogenesis (C/EBPα and PPARγ) were decreased in the adipose tissue of HF diet-fed mice, effects that were mitigated in mice that consumed the HF diet supplemented with ginseng. Abundance of fatty acid synthase (FASN) mRNA was greater in the adipose tissue of mice that consumed the ginseng-supplemented HF diet as compared with control or un-supplemented HF diet-fed mice. Ginseng treatment had no effect on the expression of genes involved in the regulation of food intake in the hypothalamus. These data suggest that Chinese ginseng can potently prevent the development of obesity and insulin resistance in HF diet-fed mice.

Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway.

Sulforaphane, a naturally occurring isothiocyanate present in cruciferous vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of sulforaphane at physiological concentrations remain unclear. Here, we report that a sulforaphane concentration as low as 0.5 µM significantly inhibited tumor necrosis factor-α (TNF-α)-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis both in static and under flow conditions. Such physiological concentrations of sulforaphane also significantly suppressed TNF-α-induced production of monocyte chemotactic protein-1 and adhesion molecules including soluble vascular adhesion molecule-1 and soluble E-selectin, key mediators in the regulation of enhanced endothelial cell-monocyte interaction. Furthermore, sulforaphane inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, Inhibitor of NF-κB alpha (IκBα) degradation and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that sulforaphane can inhibit inflammation by suppressing NF-κB signaling. In an animal study, sulforaphane (300 ppm) in a mouse diet significantly abolished TNF-α-increased ex vivo monocyte adhesion and circulating adhesion molecules and chemokines in C57BL/6 mice. Histology showed that sulforaphane treatment significantly prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization, as shown by Verhoeff-van Gieson staining. Immunohistochemistry studies showed that sulforaphane treatment also reduced vascular adhesion molecule-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, sulforaphane at physiological concentrations protects against TNF-α-induced vascular endothelial inflammation, in both in vitro and in vivo models. This anti-inflammatory effect of sulforaphane may be, at least in part, associated with interfering with the NF-κB pathway.

Dietary antiaging phytochemicals and mechanisms associated with prolonged survival.

Aging is well-known an inevitable process that is influenced by genetic, lifestyle and environmental factors. However, the exact mechanisms underlying the aging process are not well understood. Increasing evidence shows that aging is highly associated with chronic increase in reactive oxygen species (ROS), accumulation of a low-grade proinflammatory phenotype and reduction in age-related autophagy, suggesting that these factors may play important roles in promoting aging. Indeed, reduction of ROS and low-grade inflammation and promotion of autophagy by calorie restriction or other dietary manipulation can extend lifespan in a wide spectrum of model organisms. Interestingly, recent studies show that some food-derived small molecules, also called phytochemicals, can extend lifespan in various animal species. In this paper, we review several recently identified potential antiaging phytochemicals that have been studied in cells, animals and humans and further highlight the cellular and molecular mechanisms underlying the antiaging actions by these molecules.

The flavonoid luteolin induces nitric oxide production and arterial relaxation.

PURPOSE: Luteolin, a flavone present in many foods and medicinal plants, may have beneficial effects on various human chronic diseases. In the present study, we investigated the hypothesis that luteolin can directly act on vascular endothelial cells (ECs), leading to nitric oxide (NO) production and subsequent vascular relaxation. METHODS: Rat aortic rings were mounted in organ bath. Luteolin was added cumulatively, and vessel relaxation of rat aortic rings precontracted with phenylephrine (PE) or potassium was recorded. Endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177 and NO production from aortic rings and primary human aortic endothelial cells (HAECs) exposed to luteolin were measured by using Western blot and fluorometric assay, respectively. RESULTS: Luteolin dose-dependently (10-100 µmol/L) elicited relaxation of PE- or potassium-contracted aortic rings. The vasorelaxation effect of luteolin was attenuated by the eNOS inhibitor, N-nitro-L-arginine methyl ester, suggesting that this luteolin action is at least partially mediated by activating eNOS activity. We further found that luteolin dose-dependently (10-100 µmol/L) increased eNOS phosphorylation at Ser1177 (up to 1.9-fold) in isolated rat rings. Consistently, exposure of HAECs to luteolin also increased eNOS phosphorylation and NO production. CONCLUSIONS: Luteolin may be a vascular protective agent by directly acting on vascular ECs to stimulate NO-dependent vascular dilatation.

Recent advances in understanding the anti-diabetic actions of dietary flavonoids.

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic ß-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic ß-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.

Dietary flavonol epicatechin prevents the onset of type 1 diabetes in nonobese diabetic mice.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic ß-cells. Although successful islet transplantation provides a promising treatment, high cost, lack of donor organs, immune-mediated destruction of transplanted islets, and side effects from immunosuppressive drugs greatly limit its uses. Therefore, the search for novel and cost-effective agents that can prevent or ameliorate T1D is extremely important to decrease the burden of T1D. In this study, we discovered that epicatechin (EC, 0.5% in drinking water), a flavonol primarily in cocoa, effectively prevented T1D in nonobese diabetic (NOD) mice. At 32 weeks of age, 66.7% of control mice had overt diabetes, whereas only 16.6% of EC-treated mice became diabetic. Consistently, EC mice had significantly higher plasma insulin levels but lower glycosylated hemoglobin concentrations compared to control mice. EC had no significant effects on food or water intake and body weight gain in NOD mice, suggesting that EC's effect was not due to alterations in these variables. Treatment with EC elevates circulating anti-inflammatory cytokine interleukin-10 levels, ameliorates pancreatic insulitis, and improves pancreatic islet mass. These findings demonstrate that EC may be a novel, plant-derived compound capable of preventing T1D by modulating immune function and thereby preserving islet mass.

Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic ß-cell function.

Type 2 diabetes is a result of chronic insulin resistance and loss of functional pancreatic ß-cell mass. Strategies to preserve ß-cell mass and a greater understanding of the mechanisms underlying ß-cell turnover are needed to prevent and treat this devastating disease. Genistein, a naturally occurring soy isoflavone, is reported to have numerous health benefits attributed to multiple biological functions. Over the past 10 years, numerous studies have demonstrated that genistein has anti-diabetic effects, in particular, direct effects on ß-cell proliferation, glucose-stimulated insulin secretion and protection against apoptosis, independent of its functions as an estrogen receptor agonist, antioxidant, or tyrosine kinase inhibitor. Effects are structure-specific and not common to all flavonoids. While there are limited data on the effects of genistein consumption in humans with diabetes, there are a plethora of animal and cell-culture studies that demonstrate a direct effect of genistein on ß-cells at physiologically relevant concentrations (<10 µM). The effects appear to involve cAMP/PKA signaling and there are some studies that suggest an effect on epigenetic regulation of gene expression. This review focuses on the anti-diabetic effects of genistein in both in vitro and in vivo models and potential mechanisms underlying its direct effects on ß-cells.

Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling.

The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 µM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling.