(-)-Epicatechin and the comorbidities of obesity.

Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.

Cefdinir Solid Dispersion Composed of Hydrophilic Polymers with Enhanced Solubility, Dissolution, and Bioavailability in Rats.

The aim of this work was to develop cefdinir solid dispersions (CSDs) prepared using hydrophilic polymers with enhanced dissolution/solubility and in vivo oral bioavailability. CSDs were prepared with hydrophilic polymers such as hydroxypropyl-methylcellulose (HPMC; CSD1), carboxymethylcellulose-Na (CMC-Na; CSD2), polyvinyl pyrrolidone K30 (PVP K30; CSD3) at the weight ratio of 1:1 (drug:polymer) using a spray-drying method. The prepared CSDs were characterized by aqueous solubility, differential scanning calorimetry (DSC), powder X-ray diffraction (p-XRD), scanning electron microscopy (SEM), aqueous viscosity, and dissolution test in various media. The oral bioavailability of CSDs was also evaluated in rats and compared with cefdinir powder suspension. The cefdinir in CSDs was amorphous form, as confirmed in the DSC and p-XRD measurements. The developed CSDs commonly resulted in about 9.0-fold higher solubility of cefdinir and a significantly improved dissolution profile in water and at pH 1.2, compared with cefdinir crystalline powder. Importantly, the in vivo oral absorption (represented as AUCinf) was markedly increased by 4.30-, 6.77- and 3.01-fold for CSD1, CSD2, and CSD3, respectively, compared with cefdinir suspension in rats. The CSD2 prepared with CMC-Na would provide a promising vehicle to enhance dissolution and bioavailability of cefdinir in vivo.

Effects of (-)-epicatechin on hepatic triglyceride metabolism.

(-)-Epicatechin (EC) consumption is associated with an improvement of hyperlipemia and other metabolic changes linked to obesity and western-style diets. This work investigated the effects of EC on triglyceride (TG) metabolism both in vivo, where mice were supplemented with EC (2 and 20 mg EC per kg body weight), and in vitro, when human HepG2 hepatocytes were incubated in the presence of EC and the main EC metabolites found in human plasma. Increased hepatic TG levels were only observed after 24 weeks supplementation with EC (20 mg per kg body weight), with a preserved liver structure and absence of inflammation or oxidative stress. EC caused increased expression of diacylglycerol acyltransferases (DGAT2), key enzymes in TG synthesis, and the upregulation of PPARα, which promotes free fatty acid (FFA) oxidation. On the other hand, incubation of HepG2 cells in the presence of high concentrations of EC (1-10 µM) did not affect TG deposition nor DGAT2 expression. In summary, in mouse liver, EC upregulated mechanisms that can neutralize the potential toxicity of FFA, i.e. TG synthesis and FFA ß-oxidation. Results in mouse liver and HepG2 cells stress the safety of EC in terms of TG metabolism and development of hepatopathies in doses within the limits given by a rational time and dose for human consumption.

Using Real-Time Interaction Analysis to Explore Human-Robot Interaction.

Despite the increasing presence of social robots (SRs) in Human-Robot Interaction, there are few studies that quantify these interactions and explore children's attitudes by analyzing real-time data as they communicate with SRs. Therefore, we attempted to explore the interaction between pediatric patients and SRs by analyzing the interaction log collected from real-time. This study is a retrospective analysis of data collected in a prospective study conducted on 10 pediatric cancer patients at tertiary hospitals in Korea. Using the Wizard of Oz method, we collected the interaction log during the interaction between pediatric cancer patients and the robot. Out of the collected data, 955 sentences from the robot and 332 sentences from the children were available for analysis, except for the logs that were missing due to environmental errors. we analyzed the delay time from saving the interaction log and the sentence similarity of the interaction log. The interaction log delay time between robot and child was 5.01 seconds. And the child's delay time averaged 7.2 seconds, which was longer than the robot's delay time of 4.29 seconds. Additionally, as a result of analyzing the sentence similarity of the interaction log, the robot (97.2%) was higher than the children (46.2%). The results of the sentiment analysis of the patient's attitude toward the robot were 73% neutral, 13.59% positive, and 12.42% negative. The observational evaluations of pediatric psychological experts identified curiosity (n=7, 70.0%), activity (n=5, 50.0%), passivity (n=5, 50.0%), sympathy (n=7, 70.0%), concentration (n=6, 60.0%), high interest (n=5, 50.0%), positive attitude (n=9, 90.0%), and low interaction initiative (n=6, 60.0%). This study made it possible to explore the feasibility of interaction with SRs and to confirm differences in attitudes toward robots according to child characteristics. To increase the feasibility of human-robot interaction, measures such as improving the completeness of log records by enhancing the network environment are required.

(-)-Epicatechin exerts positive effects on anxiety in high fat diet-induced obese mice through multi-genomic modifications in the hippocampus.

Obesity is associated with increased occurrence of cognitive and mood disorders. While consumption of high-fat diets (HFD) and associated obesity could have a detrimental impact on the brain, dietary bioactives may mitigate these harmful effects. We previously observed that (-)-epicatechin (EC) can mitigate HFD-induced anxiety-associated behaviors in mice. The aim of our study is to investigate the molecular mechanisms of EC actions in the hippocampus which underlies its anti-anxiety effects in HFD-fed mice using a multi-genomic approach. Healthy eight-week old male C57BL/6J mice were fed for 24 weeks either: (A) a control diet containing 10% total calories from fat; (B) a HFD containing 45% total calories from fat; or (C) the HFD supplemented with 20 mg EC per kg body weight. Hippocampi were isolated for genomic analysis using Affymetrix arrays, followed by in-depth bioinformatic analyses. Genomic analysis demonstrated that EC induced significant changes in mouse hippocampal global gene expression. We observed changes in the expression of 1001 protein-coding genes, 241 miRNAs, and 167 long non-coding RNAs. Opposite gene expression profiles were observed when the gene expression profile obtained upon EC supplementation was compared to the profile obtained after consumption of the HFD. Functionality analysis revealed that the differentially expressed genes regulate processes involved in neurofunction, inflammation, endothelial function, cell-cell adhesion, and cell signaling. In summary, the capacity of EC to mitigate anxiety-related behaviors in HFD-induced obese mice can be in part explained by its capacity to exert complex genomic modifications in the hippocampus, counteracting changes driven by consumption of the HFD and/or associated obesity.

(-)-Epicatechin mitigates anxiety-related behavior in a mouse model of high fat diet-induced obesity.

Mounting evidence demonstrates that consumption of high fat diet (HFD) and subsequent development of obesity leads to alterations in cognition and mood. While obesity can affect brain function, consumption of select dietary bioactives may help prevent obesity-related cognitive decline. This study investigated the capacity of the dietary flavonoid (-)-epicatechin (EC) to mitigate HFD-induced obesity-associated alterations in memory and mood. Healthy 8-week old male C57BL/6J mice were maintained on either a control diet (10 kCal% from fat) or a HFD (45 kCal% from fat) and were supplemented with EC at 2 or 20 mg/kg body weight (B.W.) for a 24 week period. Between week 20 and 22, anxiety-related behavior, recognition memory, and spatial memory were measured. Underlying mechanisms were assessed by measuring the expression of selected genes in the hippocampus and by 16S rRNA sequencing and metabolomic analysis of the gut microbiota. 24 weeks of HFD feeding resulted in obesity, which was not affected by EC supplementation. HFD-associated increase in anxiety-related behavior was mitigated by EC in a dose-response manner and was accompanied by increased hippocampal brain-derived neurotrophic factor (BDNF), as well as partial or full restoration of glucocorticoid receptor, mineralocorticoid receptor and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression. Higher EC dosage (20 mg/kg B.W.) also restored aberrant Lactobacillus and Enterobacter abundance altered by HFD and/or the associated obesity. Together, these results demonstrate how EC mitigates anxiety-related behaviors, revealing a connection between BDNF- and glucocorticoids-mediated signaling. Our findings link changes in the hippocampus and the gut microbiota in a context of HFD-induced obesity and anxiety.

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.

(-)-Epicatechin mitigates high fat diet-induced neuroinflammation and altered behavior in mice.

Obesity is characterized by a condition of low-level chronic inflammation that can lead to altered cognition and behavior. The flavanol (-)-epicatechin (EC) has been shown to have anti-inflammatory actions in mouse models of diet-induced obesity. This study investigated the capacity of dietary EC to mitigate hippocampal inflammation and impaired memory in high fat diet (HFD)-fed mice. Healthy 6 weeks old male C57BL/6J mice (10 mice per group) were fed for 13 weeks either: a control diet (10% total calories from fat), a high fat diet (60% total calories from fat), or the control and high fat diets supplemented with 20 mg EC per kg body weight. Short-term object recognition memory was evaluated by the novel object recognition (NOR) task and spatial memory by the object location memory (OLM) task and the Morris water maze (MWM). After 13 weeks on the dietary treatments, HFD-fed mice developed obesity, which was not affected by EC supplementation. HFD consumption caused metabolic endotoxemia, and increases in parameters of hippocampal inflammation, i.e. mRNA levels of TLR4, Iba-1, and NOX4. All these changes were mitigated by EC supplementation. EC supplementation also significantly improved recognition memory in HFD-fed mice while neither HFD consumption nor EC supplementation affected mouse spatial memory. Overall, EC supplementation prevented short-term recognition memory impairment in HFD-induced obese mice, which could be in part due to the capacity of EC to mitigate metabolic endotoxemia and associated hippocampal inflammation and oxidative stress.

Anti-inflammatory actions of (-)-epicatechin in the adipose tissue of obese mice.

Obesity and type 2 diabetes (T2D) are major public health concerns. Visceral adipose tissue inflammation is considered a significant contributor to obesity-associated T2D development. We previously showed that the flavan-3-ol (-)-epicatechin (EC) can mitigate insulin resistance in mice fed a high fat diet (HFD). This study investigated the capacity of EC to inhibit visceral adipose tissue inflammation occurring as a consequence of HFD consumption in C57BL/6J mice, and characterized the underlying mechanisms. In association with the development of obesity and insulin resistance, HFD consumption caused inflammation in the visceral adipose tissue as evidenced by activation of the pro-inflammatory transcription factor NF-κB and increased tissue levels of the macrophage marker F4/80, tumor necrosis factor alpha (TNFα), and the chemokine MCP-1. EC supplementation mitigated all these events. In addition, we observed activation of the three branches of the unfolded protein response (UPR), and upregulation of NADPH oxidases NOX4 and NOX2 in visceral fat of mice fed HFD. These can account, at least in part, for the associated oxidative stress and activation of the redox sensitive NF-κB. Notably, EC supplementation mitigated this and the release of pro-inflammatory proteins from metabolically stressed adipocytes. Attenuation of adipocyte endoplasmic reticulum (ER) and oxidative stress by EC could contribute to decreased inflammation and improved visceral adipose tissue insulin sensitivity. Our results support the concept that consumption of EC-rich foods could mitigate obesity-associated insulin resistance through attenuation of adipose tissue inflammation.