Natural Products and Diabetes: (-)-Epicatechin and Mechanisms Involved in the Regulation of Insulin Sensitivity.

Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.

( -)-Epicatechin and cardiometabolic risk factors: a focus on potential mechanisms of action.

This review summarizes experimental evidence on the beneficial effects of ( -)-epicatechin (EC) attenuating major cardiometabolic risk factors, i.e., dyslipidemias, obesity (adipose tissue dysfunction), hyperglycemia (insulin resistance), and hypertension (endothelial dysfunction). Studies in humans are revised and complemented with experiments in animal models, and cultured cells, aiming to understand the molecular mechanisms involved in EC-mediated effects. Firstly, an assessment of EC metabolism gives relevance to both conjugated-EC metabolites product of host metabolism and microbiota-derived species. Integration and analysis of results stress the maintenance of redox homeostasis and mitigation of inflammation as relevant processes associated with cardiometabolic diseases. In these processes, EC appears having significant effects regulating NADPH oxidase (NOX)-dependent oxidant production, nitric oxide (NO) production, and energy homeostasis (mitochondrial biogenesis and function). The potential participation of cell membranes and membrane-bound receptors is also discussed in terms of direct molecular action of EC and EC metabolites reaching cells and tissues.

A Decreased Response to Resistin in Mononuclear Leukocytes Contributes to Oxidative Stress in Nonalcoholic Fatty Liver Disease.

BACKGROUND: Deregulation of immune response and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Resistin is a physiological modulator of inflammation and redox homeostasis of different cell types. Increased resistin serum concentration and the direct association between resistin hepatic expression and NAFLD severity suggest that resistin participates in NAFLD pathogenesis. AIMS: To evaluate resistin-induced regulation of redox homeostasis in mononuclear leukocytes from NAFLD patients and controls. METHODS: We evaluated basal and resistin-mediated modulation of reactive oxygen species (ROS) and glutathione content by flow cytometry, and antioxidant enzyme activities by spectrophotometry. RESULTS: Peripheral blood mononuclear cells (PBMC) from NAFLD patients showed higher ROS content and glutathione peroxidase activity and lower glutathione content, superoxide dismutase and glutathione reductase activities than control PBMC. Resistin decreased ROS levels and superoxide dismutase activity and increased glutathione reductase and catalase activities in PBMC from controls but not from patients. Resistin decreased glutathione content in PBMC from control and NAFLD patients, with greater effect on patient cells. Basal and resistin-modulated ROS levels were directly associated with obesity-related risk factors for NAFLD. Hepatic myeloid cells and T-lymphocytes from NAFLD patients showed higher basal ROS content than cells from controls. Resistin decreased ROS levels in hepatic T-lymphocytes from controls but not from patients. CONCLUSIONS: Resistin regulates redox homeostasis in mononuclear leukocytes. A decreased response to resistin in leukocytes from NAFLD patients is associated with an impaired redox homeostasis.

Research trends in flavonoids and health.

Herein we describe, based on some bibliometric data, how the field of research on flavonoids has evolved over the last 25 years. The number of papers on flavonoids has risen in an exponential manner over these years, much faster than other fields on food constituents. This increase appears to be related to the contemporary explosion of interest in healthy foods, supplements and nutraceuticals. It was also probably triggered by large epidemiological studies on fruits and vegetables, and particularly on flavonoids, consumption and incidence of cancer, stroke and coronary heart disease. The widely distributed flavonols constitute the flavonoid subgroup upon which the greatest interest has been focused, followed by flavanols and more recently by anthocyanidins and other related polyphenols such as resveratrol. Research on isoflavones rapidly emerged in the 1990s but plateaued in the 2000s. In the 1990s flavonoids were mainly considered as the active components of medicinal plants, while from 2000 onward, they switched to be mainly regarded as bioactive food ingredients. We envision a continuation in the growth of research for the coming decade focused on clearly demonstrating the importance of flavonoids for human health.

Effects of quercetin on heart nitric oxide metabolism in l-NAME treated rats.

This study investigated the effects of a quercetin-supplemented diet on the biochemical changes installed in the heart of NO-deficient rats in terms of oxidants production and NO bioavailability determinants. Sprague-Dawley rats were subjected to Nω-nitro-l-arginine methyl ester (l-NAME) treatment (360 mg/L l-NAME in the drinking water, 4 d) with or without supplementation with quercetin (4 g/kg diet). l-NAME administration led to increased blood pressure (BP) (30%), decreased nitric oxide synthase (NOS) activity (50%), and increases in NADPH oxidase (NOX)-dependent superoxide anion production (60%) and p47phox protein level (65%). The co-administration of quercetin prevented the increase in BP and the activation of NOX but did not modify the decrease in NOS activity caused by l-NAME. In addition, quercetin affected oxidative stress parameters as glutathione oxidation, and the activities of oxidant detoxifying enzymes superoxide dismutase, glutathione peroxidase, and catalase. Thus, quercetin administration counteracts l-NAME effects on NO bioavailability determinants in vivo, essentially through controlling NOX-mediated superoxide anion production.

(-)-Epicatechin improves insulin sensitivity in high fat diet-fed mice.

Obesity constitutes a major public health concern, being frequently associated with type 2 diabetes (T2D). Evidence from studies in humans and experimental animals suggest that consumption of the flavan-3-ol (-)-epicatechin (EC) and of EC-rich foods may improve insulin sensitivity. To further understand the potential benefits of dietary EC consumption on insulin resistance, this study investigated the capacity of EC supplementation to prevent high fat diet (HFD)-induced insulin resistance in mice. To assess the underlying mechanisms, the effects of HFD and EC consumption on the activation of the insulin cascade and of its negative modulators were evaluated. HFD consumption for 15 w caused obesity and insulin resistance in C57BL/6J mice as evidenced by high fasted and fed plasma glucose and insulin levels, and impaired ITT and GTT tests. This was associated with alterations in the activation of components of the insulin-triggered signaling cascade (insulin receptor, IRS1, ERK1/2, Akt) in adipose and liver tissues. EC supplementation prevented/ameliorated all these parameters. EC acted improving insulin sensitivity in the HFD-fed mice in part through a downregulation of the inhibitory molecules JNK, IKK, PKC and protein tyrosine phosphatase 1B (PTP1B). Thus, the above results suggest that consumption of EC-rich foods could constitute a dietary strategy to mitigate obesity-associated insulin resistance.

In vitro measurements and interpretation of total antioxidant capacity.

BACKGROUND: One of the strategies most commonly used to assess a free radical-antioxidant balance in chemical and biological systems is the determination of the total antioxidant capacity (TAC). A large amount of research has been published using TAC. However, it remains unclear which is the significance of these investigations for understanding the biological importance of free radical reactions. SCOPE OF REVIEW: This review discusses the relevance and limitations of TAC for the assessment of the antioxidant activities present in food and food derivatives, and in body tissues and fluids. MAJOR CONCLUSIONS: TAC determinations are simple, inexpensive, and able to evaluate the capacity of known and unknown antioxidants and their additive, synergistic and/or antagonistic actions, in chemical and biological systems. However, different TAC assays correlate poorly with each other, since each TAC assay is sensitive to a particular combination of compounds, but exclude many others. The TAC values for foods cannot be translated to the in vivo (human) antioxidant defenses, and furthermore, to health effects provided by that food. GENERAL SIGNIFICANCE: Up to date, conclusions that can be drawn from the extensive amount of research done using TAC of foods or populations should not be considered when used for making decisions affecting population health. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.

Procyanidins can interact with Caco-2 cell membrane lipid rafts: involvement of cholesterol.

Large procyanidins (more than three subunits) are not absorbed at the gastrointestinal tract but could exert local effects through their interactions with membranes. We previously showed that hexameric procyanidins (Hex), although not entering cells, interact with membranes modulating cell signaling and fate. This paper investigated if Hex, as an example of large procyanidins, can selectively interact with lipid rafts which could in part explain its biological actions. This mechanism was studied in both synthetic membranes (liposomes) and Caco-2 cells. Hex promoted Caco-2 cell membrane rigidification and dehydration, effects that were abolished upon cholesterol depletion with methyl-ß-cyclodextrin (MCD). Hex prevented lipid raft structure disruption induced by cholesterol depletion/redistribution by MCD or sodium deoxycholate. Supporting the involvement of cholesterol-Hex bonding in Hex interaction with lipid rafts, the absence of cholesterol markedly decreased the capacity of Hex to prevent deoxycholate- and Triton X-100-mediated disruption of lipid raft-like liposomes. Stressing the functional relevance of this interaction, Hex mitigated lipid raft-associated activation of the extracellular signal-regulated kinases (ERK) 1/2. Results support the capacity of a large procyanidin (Hex) to interact with membrane lipid rafts mainly through Hex-cholesterol bondings. Procyanidin-lipid raft interactions can in part explain the capacity of large procyanidins to modulate cell physiology.

Exploring the benefits and challenges of establishing a DRI-like process for bioactives.

Bioactives can be defined as: "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status" (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Reg 69:55821-55822, 2004). Although traditional nutrients, such as vitamins, minerals, protein, essential fatty acids and essential amino acids, have dietary reference intake (DRI) values, there is no such evaluative process for bioactives. For certain classes of bioactives, substantial scientific evidence exists to validate a relationship between their intake and enhanced health conditions or reduced risk of disease. In addition, the study of bioactives and their relationship to disease risk is a growing area of research supported by government, academic institutions, and food and supplement manufacturers. Importantly, consumers are purchasing foods containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects. This conference, Bioactives: Qualitative Nutrient Reference Values for Life-stage Groups?, explored why it is important to have a DRI-like process for bioactives and challenges for establishing such a process.

(-)-Epicatechin reduces blood pressure and improves vasorelaxation in spontaneously hypertensive rats by NO-mediated mechanism.

Studies in humans have found consumption of certain flavanoid-containing foods to be associated with improvement in endothelial function and with reduction of blood pressure (BP). (-)-Epicatechin is a compound representative of the flavanols (a subfamily of flavonoids), abundant in cocoa seeds, which is preserved during the industrialization process to chocolate. The antihypertensive effect of dietary (-)-epicatechin was investigated on spontaneously hypertensive rats (SHRs). Consumption of (-)-epicatechin-supplemented diet (3 g (-)-epicatechin/kg diet) decreased BP in SHR by 27 and 23 mm Hg on days 2 and 6, respectively. On day 6, a 173% increase of nitric oxide synthase (NOS) activity was observed in the aorta of EPI-SHR as compared to nonsupplemented SHR (P < 0.05). Responses to acetylcholine (ACh) were then examined in femoral arteries in the absence and the presence of L-NAME, a nonselective NOS inhibitor, to assess the ACh-mediated relaxation ascribed to NO-dependent and -independent mechanisms. Acetylcholine-induced endothelium-dependent relaxation in the femoral artery was significantly higher in EPI-SHR than in SHR, with a predominance of the NO-dependent component of this relaxation. The endothelium-independent relaxation, assayed by using the NO donor sodium nitroprusside, resulted in nonsignificant difference in the three experimental groups, demonstrating an unaffected function of vascular smooth muscle cells. These results give further support to the concept that (-)-epicatechin can modulate BP in hypertension by increasing NO levels in the vasculature.

Anthocyanin actions at the gastrointestinal tract: Relevance to their health benefits.

Anthocyanins (AC) are flavonoids abundant in the human diet, which consumption has been associated to several health benefits, including the mitigation of cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, and neurological disorders. It is widely recognized that the gastrointestinal (GI) tract is not only central for food digestion but actively participates in the regulation of whole body physiology. Given that AC, and their metabolites reach high concentrations in the intestinal lumen after food consumption, their biological actions at the GI tract can in part explain their proposed local and systemic health benefits. In terms of mechanisms of action, AC have been found to: i) inhibit GI luminal enzymes that participate in the absorption of lipids and carbohydrates; ii) preserve intestinal barrier integrity and prevent endotoxemia, inflammation and oxidative stress; iii) sustain goblet cell number, immunological functions, and mucus production; iv) promote a healthy microbiota; v) be metabolized by the microbiota to AC metabolites which will be absorbed and have systemic effects; and vi) modulate the metabolism of GI-generated hormones. This review will summarize and discuss the latest information on AC actions at the GI tract and their relationship to overall health benefits.

(Poly)phenols and the regulation of NADPH oxidases.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are enzymes that generate superoxide anion (O2•-) and hydrogen peroxide (H2O2), and that are widely distributed in mammalian tissues. Many bioactives, especially plant (poly)phenols are being studied for their capacity to regulate NOXs. The modulation of these enzymes are of central relevance to maintain redox homeostasis and regulate cell signaling. In in vitro and ex vivo assays, and in experimental animal models, different (poly)phenols are able to modulate NOX-dependent generation of O2•- and H2O2. Mechanistically, most of the known effects of (poly)phenols and of their metabolites on NOX1, NOX2, and NOX4, include the modulation of: i) the expression of the different constituent subunits, and/or ii) posttranslational modifications involved in the assembly and translocation of the protein complexes. Very limited evidence is available on a direct action of (poly)phenols on NOX active site (electron-transferring protein). Moreover, it is suggested that the regulation by (poly)phenols of systemic events, e.g. inflammation, is frequently associated with their capacity to regulate NOX activation. Although of physiological significance, more studies are needed to understand the specific targets/mechanisms of NOX regulation by (poly)phenols, and the (poly)phenol chemical structures and moieties directly involved in the observed effects. It should be kept in mind the difficulties of NOX's studies associated with the complexity of NOXs biochemistry and the methodological limitations of O2•- and H2O2 the determinations. Studies relating human ingestion of specific (poly)phenols, with NOX activity and disease conditions, are guaranteed to better understand the health importance of (poly)phenol consumption and the involvement of NOXs as biological targets.

(Poly)phenols and nitrolipids: Relevant participants in nitric oxide metabolism.

Nitric oxide (•NO) is an essential molecule able to control and regulate many biological functions. Additionally, •NO bears a potential toxicity or damaging effects under conditions of uncontrolled production, and because of its participation in redox-sensitive pathways and oxidizing reactions. Several plant (poly)phenols present in the diet are able to regulate the enzymes producing •NO (NOSs). In addition, (poly)phenols are implicated in defining •NO bioavailability, especially by regulating NADPH oxidases (NOXs), and the subsequent generation of superoxide and •NO depletion. Nitrolipids are compounds that are present in animal tissues because of dietary consumption, e.g. of olive oil, and/or as result of endogenous production. This endogenous production of nitrolipids is dependent on the nitrate/nitrite presence in the diet. Select nitrolipids, e.g. the nitroalkenes, are able to exert •NO-like signaling actions, and act as •NO reservoirs, becoming relevant for systemic •NO bioavailability. Furthermore, the presence of (poly)phenols in the stomach reduces dietary nitrite to •NO favoring nitrolipids formation. In this review we focus on the capacity of molecules representing these two groups of bioactives, i.e. (poly)phenols and nitrolipids, as relevant participants in •NO metabolism and bioavailability. This participation acquires especial relevance when human homeostasis is lost, for example under inflammatory conditions, in which the protective actions of (poly)phenols and/or nitrolipids have been associated with local and systemic •NO bioavailability.

(-)-Epicatechin prevents TNFα-induced activation of signaling cascades involved in inflammation and insulin sensitivity in 3T3-L1 adipocytes.

Obesity is major public health concern worldwide and obese individuals exhibit a higher risk of chronic diseases such as type 2 diabetes. Inflammation plays a significant role in metabolic regulation and mounting evidence highlight the contribution of adipose tissue to systemic inflammatory state. Food extracts with a high content of (-)-epicatechin have been found to exert systemic anti-inflammatory actions, however the anti-inflammatory actions of (-)-epicatechin on adipose tissue remain to be determined. The aim of this study was to investigate the capacity of (-)-epicatechin to prevent tumor necrosis alpha (TNFα)-induced activation of cell signals involved in inflammation and insulin resistance (NF-κB, mitogen-activated protein kinases (MAPKs), AP-1, and peroxisome proliferator activated receptor γ (PPARγ)) in differentiated white adipocytes (3T3-L1). TNFα triggered the activation of transcription factors NF-κB and AP-1, and MAPKs ERK1/2, JNK, and p38. (-)-Epicatechin caused a dose (0.5-10 µM)-dependent decrease in TNFα-mediated JNK, ERK1/2, and p-38 phosphorylation, and nuclear AP-1-DNA binding. (-)-Epicatechin also inhibited TNFα-triggered activation of the NF-κB signaling cascade, preventing TNFα-mediated p65 nuclear transport and nuclear NF-κB-DNA binding. (-)-Epicatechin also attenuated the TNFα-mediated downregulation of PPARγ expression and decreased nuclear DNA binding. Accordingly, (-)-epicatechin inhibited TNFα-mediated altered transcription of genes (MCP-1, interleukin-6, TNFα, resistin, and protein-tyrosine phosphatase 1B) involved in inflammation and insulin signaling. In conclusion, (-)-epicatechin can attenuate TNFα-mediated triggering of signaling cascades involved in inflammation and insulin resistance. These findings could be of relevance in the dietary management of obesity and metabolic syndrome.

Curcumin Mitigates TNFα-Induced Caco-2 Cell Monolayer Permeabilization Through Modulation of NF-κB, ERK1/2, and JNK Pathways.

SCOPE: This work studies the capacity of curcumin to inhibit tumor necrosis alpha (TNFα)-induced inflammation, oxidative stress, and loss of intestinal barrier integrity, characterizing the underlying mechanisms. METHODS AND RESULTS: Caco-2 cell monolayers are incubated with TNFα (10 ng mL-1 ), in the absence or presence of curcumin. TNFα causes an increase in interleukin (IL)-6 and IL-8 release, which is inhibited by curcumin in a dose-dependent manner (half-maximal inhibitory concentration (IC50 ) = 3.4 µM for IL-6). Moreover, TNFα leads to: i) increased intercellular adhesion molecule 1 (ICAM-1) and NLRP3 inflammasome expression; ii) increased cell monolayer permeability and decreased levels of tight junction proteins; iii) increased cellular and mitochondrial oxidant production; iv) decreased mitochondrial membrane potential and complex I-III activity; v) activation of redox-sensitive pathways, i.e., nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinases (JNK); and vi) increased myosin light-chain kinase (MLCK) expression and phosphorylation levels of myosin light-chain protein MLC. Curcumin (2-8 µM) inhibits all these TNFα-triggered undesirable outcomes, mostly showing dose-dependent effects. CONCLUSION: The inhibition of NF-κB, ERK1/2, and JNK activation could be in part involved in the capacity of curcumin to mitigate intestinal inflammation, oxidant production, activation of redox-sensitive pathways, and prevention of monolayer permeabilization. These results support an action of dietary curcumin in sustaining gastrointestinal tract physiology.

Cyanidin and delphinidin restore colon physiology in high fat diet-fed mice: Involvement of TLR-4 and redox-regulated signaling.

Consumption of high fat diets (HFD) mimics a modern or "Western style" diet pattern and can impair intestinal barrier integrity, leading to endotoxemia and associated unhealthy conditions. This study investigated if supplementation with an anthocyanin (cyanidin and delphinidin glucosides)-rich extract (CDRE) could revert or mitigate HFD-induced alterations of colonic physiology in part through the regulation of Toll-Like Receptor 4 (TLR-4)- and redox-regulated signaling. C57BL/6J male mice were fed for 4 weeks with a control or an HFD. Then, mice were divided in four groups fed either control or HFD, or these diets supplemented with CDRE for the subsequent 4 weeks. After 8 weeks on the HFD we observed in the colon: i) disruption of tight junction structure and function; ii) increased TLR-4 expression; iii) increased NADPH oxidase NOX1 expression, and iv) activation of redox-sensitive and TLR-4-triggered pathways, i.e. NF-κB, ERK1/2, JNK1/2, PI3K/Akt. All these events were prevented or reverted by CDRE supplementation. Supporting the relevance of CDRE-mediated downregulation of TLR-4 on its colon beneficial effect; in vitro (Caco-2 cell monolayers), cyanidin, delphinidin and their metabolites protocatechuic and gallic acid, mitigated lipopolysaccharide (LPS)-induced monolayer permeabilization by restoring tight junction structure and dynamics and preventing lipid/protein oxidation. The CDRE also mitigated HFD-mediated alterations in parameters of goblet cell differentiation and function, including the downregulation of markers of goblet cell differentiation (Klf4), and intestinal mucosa healing (Tff3). Results show that a short-term supplementation with cyanidin and delphinidin, protect from HFD-induced alterations in colon physiology in part through the modulation of TLR-4- and redox-regulated signaling.

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice.

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.

A randomized placebo-controlled cross-over study on the effects of anthocyanins on inflammatory and metabolic responses to a high-fat meal in healthy subjects.

This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.

Linking biomarkers of oxidative stress and disease with flavonoid consumption: From experimental models to humans.

Identification of the links among flavonoid consumption, mitigation of oxidative stress and improvement of disease in humans has significantly advanced in the last decades. This review used (-)-epicatechin (EC) as an example of dietary flavonoids, and inflammation, endothelial dysfunction/hypertension and insulin resistance/diabetes as paradigms of human disease. In these pathologies, oxidative stress is part of their development and/or their perpetuation. Evidence from both, rodent studies and characterization of mechanisms in cell cultures are encouraging and mostly support indirect antioxidant actions of EC and EC metabolites in endothelial dysfunction and insulin resistance. Human studies also show beneficial effects of EC on these pathologies based on biomarkers of disease. However, there is limited available information on oxidative stress biomarkers and flavonoid consumption to allow establishing conclusive associations. The evolving discovery of metabolites that could serve as reliable markers of intake of specific flavonoids constitutes a powerful tool to link flavonoid consumption to disease and prevention of oxidative stress in human populations.