Showing papers in "Molecular Nutrition & Food Research in 2018"

Safety Aspects of the Use of Quercetin as a Dietary Supplement.

Abstract: The flavonoid quercetin is frequently found in low amounts as a secondary plant metabolite in fruits and vegetables. Isolated quercetin is also marketed as a dietary supplement, mostly as the free quercetin aglycone, and frequently in daily doses of up to 1000 mg d-1 exceeding usual dietary intake levels. The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements. Among the numerous published human intervention studies, adverse effects following supplemental quercetin intake have been rarely reported and any such effects were mild in nature. Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (≥1000 mg) are currently not available. Based on animal studies involving oral quercetin application some possible critical safety aspects could be identified such as the potential of quercetin to enhance nephrotoxic effects in the predamaged kidney or to promote tumor development especially in estrogen-dependent cancer. Furthermore, animal and human studies with single time or short-term supplemental quercetin application revealed interactions between quercetin and certain drugs leading to altered drug bioavailability. Based on these results, some potential risk groups are discussed in the present review.

Propolis from Different Geographic Origins Decreases Intestinal Inflammation and Bacteroides spp. Populations in a Model of DSS-Induced Colitis.

Abstract: Scope Dietary supplementation with polyphenol-rich propolis can protect against experimentally induced colitis. We examined whether different polyphenol compositions of Chinese propolis (CP) and Brazilian propolis (BP) influence their ability to protect against dextran sulfate sodium (DSS)-induced colitis in rats. Methods and results HPLC-DAD/Q-TOF-MS analysis confirmed that polyphenol compositions of CP and BP were dissimilar. Rats were given CP or BP by gavage (300 mg kg-1 body weight) throughout the study, starting 1 week prior to DSS treatment for 1 week followed by 3 d without DSS. CP and BP significantly reduced the colitis disease activity index relative to controls not receiving propolis, prevented significant DSS-induced colonic tissue damage, and increased resistance to DSS-induced colonic oxidative stress as shown by reduced malonaldehyde levels and increased T-AOC levels. CP and BP significantly reduced DSS-induced colonic apoptosis. Colonic inflammatory markers IL-1β, IL-6, and MCP-1 were suppressed by CP and BP, whereas only BP-induced expression of TGF-β. CP, not BP, increased the diversity and richness of gut microbiota populations. Both forms of propolis significantly reduced populations of Bacteroides spp. Conclusions Despite the dissimilar polyphenol compositions of CP and BP, their ability to protect against DSS-induced colitis is similar. Nevertheless, some different physiological impacts were observed.

Kudingcha and Fuzhuan Brick Tea Prevent Obesity and Modulate Gut Microbiota in High-Fat Diet Fed Mice.

Abstract: Scope Kudingcha (KDC) from Ilex kudingcha and Fuzhuan brick tea (FBT) are popular beverages in China, and their preventive and therapeutic roles in metabolic disorders have been reported. However, the relationship between the gut microbiota modulatory effects of KDC and FBT and prevention of obesity is still not clearly understood. Methods and results KDC and FBT are tested individually for their capacities to prevent obesity and modulate the gut microbiota in high-fat diet (HFD) fed C57BL/6J mice. The results show that both KDC and FBT supplementation could modulate oxidative injury, inflammation, lipid metabolism, and reduce HFD induced obesity significantly. Both KDC and FBT could enhance the diversity of gut microbiota. KDC could reduce the relative abundance of Erysipelotrichaceae, while FBT could reduce the ratio of Firmicutes to Bacteroidetes and enhance the relative abundance of Bifidobacteriaceae. Conclusion These findings suggest that KDC and FBT could attenuate features of the metabolic syndrome in HFD-fed mice, which might be due to the modulation of gut microbiota by KDC and FBT.

Sulfated Polysaccharide from Sea Cucumber and its Depolymerized Derivative Prevent Obesity in Association with Modification of Gut Microbiota in High-Fat Diet-Fed Mice

Abstract: Scope Sulfated polysaccharide from sea cucumber (SCSP), Stichopus japonicus, has been shown to prevent diverse diseases, but little is known about its effects on obesity and gut microbiota in mice fed a high-fat diet (HFD). Methods and results Diet-induced obese, BALB/c mice are fed an HFD with or without SCSP and depolymerized SCSP (d-SCSP, 0.004 kcal g-1 ) for 8 weeks. The results show that both SCSP and d-SCSP reduce body weight, fat and liver hypertrophy, insulin resistance, and serum lipid and inflammatory cytokine levels in HFD-fed mice. Moreover, SCSP and d-SCSP not only prevent HFD-induced gut disorder, as indicated by the enriched probiotic Akkermansia and reduce endotoxin-bearing Proteobacteria, but also improve the SCFAs and endotoxin (LPS) levels and gut tissue index. Spearman's correlation analysis reveals that several specific genera are strongly correlated with obesity-related indexes. In addition, the inhibitory effect of d-SCSP on fat accumulation is more effective than that of SCSP, which may be related to their different regulation of the gut microbiota. Conclusions These findings suggest that SCSP can prevent diet-induced obesity and its associated diseases by modulating the gut microbiota and improving microbial metabolites and gut tissue, and its effects can be enhanced by free-radical depolymerization.

Isothiocyanates: Translating the Power of Plants to People

Abstract: Isothiocyanates from cruciferous vegetables have been studied extensively in cells and in animals for their disease preventive and therapeutic effects. However, translating their utility to human populations has been both limited and challenging. Herein, clinical trials employing two isothiocyanates, sulforaphane (SFN; 1-isothiocyanato-4-(methylsulfinyl) butane) and phenethyl isothiocyanate (PEITC; 2-isothiocyanatoethylbenzene) that are isolated principally from broccoli and watercress, respectively, are summarized and discussed. Both of these compounds have been used in small human clinical trials, either within food matrices or as single agents, against a variety of diseases ranging from cancer to autism. Results suggest an opportunity to incorporate them, or more likely preparations derived from their source plants, into larger human disease mitigation efforts. The context for the applications of these compounds and plants in evidence-based food and nutritional policy is also evaluated.

Allergy to Peanut, Soybean, and Other Legumes: Recent Advances in Allergen Characterization, Stability to Processing and IgE Cross-Reactivity

Abstract: Peanut and soybean are members of the Leguminosae family. They are two of the eight foods that account for the most significant food allergies in the United States and Europe. Allergic reactions to other legume species can be of importance in other regions of the world. The major allergens from peanut and soybean have been extensively analyzed and members of new protein families identified as potential marker allergens for symptom severity. Important recent advances concerning their molecular properties or clinical relevance have been made. Therefore, there is increasing interest in the characterization of allergens from other legume species such as lupine, lentil, chickpea, green bean, or pea. As legumes are mainly consumed after thermal processing, knowledge about the effect of such processing on the allergenicity of legumes has increased during the last years. In the present review, recent advances in the identification of allergens from peanut, soybean, lupine, and other legume species are summarized and discussed. An overview of the most recently described effects of thermal processing on the allergenic properties of legumes is provided and the potential IgE cross-reactivity among members of the Leguminosae family is discussed.

BCAA Metabolism and Insulin Sensitivity – Dysregulated by Metabolic Status?

Abstract: Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease.

Allergic risks of consuming edible insects: A systematic review

Abstract: The expected future demand for food and animal-derived protein will require environment-friendly novel food sources with high nutritional value. Insects may be one of such novel food sources. However, there needs to be an assessment of the risks associated with their consumption, including allergic risks. Therefore, we performed a systematic review aiming to analyse current data available regarding the allergic risks of consuming insects. We reviewed all reported cases of food allergy to insects, and studied the possibility of cross-reactivity and co-sensitisation between edible insects, crustaceans and house dust mites. We analysed a total of 25 articles – eight assessing the cross-reactivity/co-sensitisation between edible insects, crustaceans and house dust mite; three characterizing allergens in edible insects and 14 case reports, describing case series or prevalence studies of food allergy caused by insects. Cross-reactivity/co-sensitisation between edible insects and crustaceans seems to be clinically relevant, while it is still unknown if co-sensitisation between house dust mites and edible insects can lead to a food allergy. Additionally, more information is also needed about the molecular mechanisms underlying food allergy to insects, although current data suggest that an important role is played by arthropod pan-allergens such as tropomyosin or arginine kinase. This article is protected by copyright. All rights reserved

Taste and Flavor Perceptions of Glucosinolates, Isothiocyanates, and Related Compounds

Abstract: Brassicaceae plants are renowned for their taste, aroma and trigeminal characteristics; predominantly bitter taste, sulfurous aroma, and pungency. Compounds responsible for these sensations include the glucosinolates (GSLs) and their hydrolysis products, particularly isothiocyanates (ITCs), but also sulfur-containing volatile compounds. This article reviews the relative importance of taste and flavor perceptions resulting from such compounds; collating evidence from papers where findings are based on sensory analytical correlations, and those that have extracted specific compounds prior to sensory evaluation. Where specific GSLs impart bitterness and many ITCs impart pungency, this is clearly not true for all GSLs and ITCs. Designing crop improvement strategies for sensory traits based on total GSL content would be flawed, as it does not consider the relative differences in sensory characteristics of different GSLs and ITCs, nor the contribution from other GSL hydrolysis products. In addition, some Brassicaceae plants are consumed raw, whilst others are cooked; this affects not only the hydrolysis of GSLs, but also the generation and release of sulfides. Therefore, in breeding new plant varieties, it is prudent to consider the individual GSLs, the typical cooking conditions the plant is subjected to, enzyme stability, and resultant composition of both GSL hydrolysis products (including ITCs) and sulfides.

Cruciferous Vegetables, Isothiocyanates, and Bladder Cancer Prevention.

Abstract: Bladder cancer is a significant health burden due to its high prevalence, risk of mortality, morbidity, and high cost of medical care. Epidemiologic evidence suggests that diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Phytochemicals in cruciferous vegetables, such as glucosinolates, which are enzymatically hydrolyzed to bioactive isothiocyanates, are possible mediators of an anticancer effect. In vitro studies have shown inhibition of bladder cancer cell lines, cell cycle arrest, and induction of apoptosis by these isothiocyanates, in particular sulforaphane and erucin. Although not yet completely understood, many mechanisms of anticancer activity at the steps of cancer initiation, promotion, and progression have been attributed to these isothiocyanates. They target multiple pathways including the adaptive stress response, phase I/II enzyme modulation, pro-growth, pro-survival, pro-inflammatory signaling, angiogenesis, and even epigenetic modulation. Multiple in vivo studies have shown the bioavailability of isothiocyanates and their antitumoral effects. Although human studies are limited, they support oral bioavailability with reasonable plasma and urine concentrations achieved. Overall, both cell and animal studies support a potential role for isothiocyanates in bladder cancer prevention and treatment. Future studies are necessary to examine clinically relevant outcomes and define guidelines on ameliorating the bladder cancer burden.

Exosomal MicroRNAs in Milk from Mothers Delivering Preterm Infants Survive in Vitro Digestion and Are Taken Up by Human Intestinal Cells.

Abstract: Scope: This study investigates the ability of preterm milk exosomes to survive gastric/pancreatic digestion, internalization by intestinal epithelia, and the microRNAs (miRNAs) contents. Methods and results: At average infant age 1 week and 6 days, milk is collected from mothers who delivered preterm and term infants (n = 10). Milk is exposed to conditions simulating infant gut digestion. Exosomes are isolated and lysed, and the exposed miRNAs are sequenced. Preterm milk exosomes survive in vitro digestion, and can be taken up by intestinal epithelia. Three hundred and thirty miRNAs are identified as preterm milk exosome miRNAs, and in vitro digestion does not have a pronounced effect on their expression. The abundant miRNAs in preterm milk exosomes are similar to those from term milk. Twenty-one low abundance miRNAs are specifically expressed in preterm milk exosomes compared to early term milk in the current study and what previously is found in mature term milk. Conclusion: These results for the first time reveal the survivability of preterm milk exosomes following simulated gastric/pancreatic digestion. The authors demonstrate the richness of the miRNAs content in these exosomes. The results improve the knowledge of preterm milk biology and the molecular basis by which exosome miRNAs may uniquely affect preterm infants during early development.

Human Milk Oligosaccharides as Promising Antivirals

Abstract: Human milk oligosaccharides (HMOs) are diverse unconjugated carbohydrates that are highly abundant in human breast milk. These glycans are investigated in the context of exhibiting multiple functions in infant growth and development. They seem to provide protection against infectious diseases, including a number of poorly manageable viral infections. Although the potential mechanism of the HMO antiviral protection is rather broad, much of the current experimental work has focused on studying of HMO antiadhesive properties. HMOs may mimic structures of viral receptors and block adherence to target cells, thus preventing infection. Still, the potential of HMOs as a source for new antiviral drugs is relatively unexploited. This can be partly attributed to the extreme complexity of the virus-carbohydrate interactions and technical difficulties in HMO isolation, characterization, and manufacturing procedures. Fortunately, we are currently entering a period of major technological advances that have enabled deeper insights into carbohydrate mediated viral entry, rational selection of HMOs as anti-entry inhibitors, and even evaluation of individual synthetic HMO structures. Here, we provide an up-to-date review on glycan binding studies for rotaviruses, noroviruses, influenza viruses, and human immunodeficiency viruses. We also discuss the preventive and therapeutic potential of HMOs as anti-entry inhibitors and address challenges on the route from fundamental studies to clinical trials.

Green Tea Liquid Consumption Alters the Human Intestinal and Oral Microbiome.

Abstract: Scope GTPs (green tea polyphenols) exert anti‐CRC (colorectal cancer) activity. The intestinal microbiota and intestinal colonization by bacteria of oral origin has been implicated in colorectal carcinogenesis. GT modulates the composition of mouse gut microbiota harmonious with anticancer activity. Therefore, the effect of green tea liquid (GTL) consumption on the gut and oral microbiome is investigated in healthy volunteers (n = 12).

Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis.

Abstract: Scope Necrotizing enterocolitis (NEC) is a leading cause of morbidity and death in preterm infants, occurring more often in formula-fed than breastfed infants. Studies in both rats and humans show that human milk oligosaccharides (HMOs) lower the incidence of NEC, but the mechanism underlying such protection is currently unclear. Methods and results By extracting HMOs from pooled human breastmilk, the impact of HMOs on the intestinal mucin levels in a murine model of NEC are investigated. To confirm the results, the findings are validated by exposing human intestinal epithelial cells and intestinal organoids to HMOs and evaluated for mucin expression. HMO-gavage to pups increases Muc2 levels and decreases intestinal permeability to macromolecular dextran. HMO-treated cells have increased Muc2 expression, decreased bacterial attachment and dextran permeability during challenge by enteric pathogens. To identify the mediators involved in HMO induction of mucins, it is demonstrated that HMOs directly induce the expression of chaperone proteins including protein disulfide isomerase (PDI). Suppression of PDI activity removes the protective effects of HMOs on barrier function in vitro as well as NEC protection in vivo. Conclusions Taken together, the results provide insights to the possible mechanisms by which HMOs protect the neonatal intestine through upregulation of mucins.

Current Insights into the Biological Action of Squalene

Abstract: Squalene is a triterpenic compound found in a large number of plants and other sources with a long tradition of research since it was first reported in 1926. Herein a systematic review of studies concerning squalene published in the last 8 years is presented. These studies have provided further support for its antioxidant, anti-inflammatory, and anti-atherosclerotic properties in vivo and in vitro. Moreover, an antineoplastic effect in nutrigenetic-type treatments, which depends on the failing metabolic pathway of tumors, has also been reported. The bioavailability of squalene in cell cultures, animal models, and in humans has been well established, and further progress has been made in regard to the intracellular transport of this lipophilic molecule. Squalene accumulates in the liver and decreases hepatic cholesterol and triglycerides, with these actions being exerted via a complex network of changes in gene expression at both transcriptional and post-transcriptional levels. Its presence in different biological fluids has also been studied. The combination of squalene with other bioactive compounds has been shown to enhance its pleiotropic properties and might lead to the formulation of functional foods and nutraceuticals to control oxidative stress and, therefore, numerous age-related diseases in human and veterinary medicine.

The Endotoxemia Marker Lipopolysaccharide-Binding Protein is Reduced in Overweight-Obese Subjects Consuming Pomegranate Extract by Modulating the Gut Microbiota: A Randomized Clinical Trial.

Abstract: SCOPE: Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro‐inflammatory status promote cardiovascular risk. However, the modulation of the gut microbiome to prevent endotoxemia in obesity has been scarcely studied. We investigated the association between gut microbiota modulation and plasma lipopolysaccharide‐binding protein (LBP), a surrogate marker of endotoxemia, in overweight‐obese individuals. METHODS AND RESULTS: In a randomized trial, 49 overweight‐obese subjects (body mass index> 27 kg m⁻²) with mild hypelipidemia daily consumed, in a cross‐over fashion, two doses (D1 and D2, lasting 3 weeks each) of pomegranate extract (PE) or placebo alternating with 3 weeks of wash‐out periods. A significant decrease (p < 0.05) of plasma LBP and a marginal decrease (p = 0.054) of high‐sensitivity C‐reactive protein were observed, but only after PE‐D2 administration (656 mg phenolics). 16S rDNA sequencing analyses revealed the increase of microorganisms important for maintaining normal balance of gut microbiota and gut barrier function, particularly Bacteroides, Faecalibacterium, Butyricicoccus, Odoribacter, and Butyricimonas. PE‐D2 also decreased pro‐inflammatory microorganisms including Parvimonas, Methanobrevibacter, and Methanosphaera. Remarkably, plasma LBP reduction was significantly associated (p < 0.05) with both Faecalibacterium and Odoribacter increase and Parvimonas decrease. CONCLUSIONS: Consumption of PE decreased endotoxemia in overweight‐obese individuals by reshaping the gut microbiota, mainly through the modulation of Faecalibacterium, Odoribacter, and Parvimonas.

Antimicrobial Emulsifier-Glycerol Monolaurate Induces Metabolic Syndrome, Gut Microbiota Dysbiosis, and Systemic Low-Grade Inflammation in Low-Fat Diet Fed Mice

Abstract: cope : Glycerol monolaurate (GML) was widely consumed worldwide in food industry, and considered as safe, yet for chronic diseases, supporting scientific data remain sparse. This study was to investigate whether dietary GML induces metabolic syndrome, gut microbiota dysbiosis and systemic low-grade inflammation. Methods and results : GML-induced occurrence of metabolic syndrome, gut microbiota alterations and systemic low-grade inflammation were investigated. Our results demonstrated that GML induced metabolic syndrome by significantly increasing the body weight, weight gain, food intake, body fat, fat droplet size and percentage of epididymal fat, serum triglycerides (TG), LDL and atherogenic index, and decreasing the body muscle ratio, liver weight and HDL, compared to the CON group. Meanwhile, GML significantly changed the β-diversity and composition of gut microbiota and up-regulated the circulating levels of serum LPS, IL-1β, IL-6 and TNF-α. Importantly, GML significantly decreased Akkermansia muciniphila and Lupinus luteus, and increased Bacteroides acidifaciens, Escherichia coli and the microbial DNA abundance of the 10 predicated metabolism pathways involved in carbohydrate, amino acid and lipid metabolism. Conclusion : Our results indicate that the relatively low-dose GML consumption promotes metabolic syndrome, gut microbiota dysbiosis and systemic low-grade inflammation, thereby calling for a reassessment of GML usage. This article is protected by copyright. All rights reserved

Pharmacological and Nutritional Effects of Natural Coumarins and Their Structure-Activity Relationships

Abstract: Coumarins are fused benzene and pyrone ring systems with a wide spectrum of bioactivities, including antitumor, anti-inflammation, antiviral, and antibacterial effects. In this paper, the current development of coumarin-based drugs is introduced, and their structure-activity relationship is discussed by reviewing the relevant literature published in the past 20 years. Coumarin molecules can be customized by the target site to prevent systemic side effects by virtue of structural modification. The ortho-phenolic hydroxyl on the benzene ring has remarkable antioxidant and antitumor activities. Coumarins with aryl groups at the C-4 position have good activities in anti-HIV, antitumor, anti-inflammation, and analgesia. C-3 phenylcoumarins have strong anti-HIV and antioxidant effects. Tetracycline pyranocoumarins can significantly inhibit HIV; osthol structural analogues have antimicrobial activity. Praeruptorin C and its derivatives play an important role in lowering blood pressure and dilating coronary arteries, and khellactone derivatives have significant inhibitory effects on AIDS, cancer, and cardiovascular diseases. It is concluded that the specific site on the core structure of coumarin exhibits one or more activities due to the electronic or steric effects of the substituents. This review is intended to be conducive to rational design and development of more active and less toxic agents with a coumarin scaffold.

Green Tea Polyphenol EGCG Alleviates Metabolic Abnormality and Fatty Liver by Decreasing Bile Acid and Lipid Absorption in Mice

Abstract: Scope The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been shown to ameliorate metabolic abnormalities and fatty liver. The present study investigates the mechanisms of actions of EGCG on bile acid homeostasis and lipid metabolism. Methods Male C57BL/6J mice are fed a low-fat diet, a high-fat western-style diet, or a high-fat western-style diet containing 0.32% EGCG. The effects of the treatments on biochemical parameters, gene expression, and lipidomics are analyzed. Results EGCG treatment significantly reduces body weight gain, mesenteric fat mass, fasting blood glucose, insulin resistance, serum cholesterol, and severity of fatty liver after treatment for 17 weeks, but most of these effects were less apparent at week 33. At week 17, EGCG treatment significantly elevates the mRNA levels of cholesterol 7α-hydroxylase, HMG-CoA reductase, low-density lipoprotein receptor, and scavenger receptor B1, and partially normalizes the high-fat diet induced lipidomic profile. The intestinal bile acid content is significantly decreased by EGCG, while fecal excretion of bile acids, cholesterol, and total lipids are increased. Conclusion EGCG decreases bile acid reabsorption, results in lower intestinal bile acid levels, which further decreases the absorption of lipids. These actions contribute to the alleviation of metabolic abnormalities and fatty liver disease caused by the high-fat diet.

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders

Abstract: Although dietary fatty acids can modulate metabolic and immune responses, the effects of palmitoleic acid (16:1n-7) remain unclear. Since this monounsaturated fatty acid is described as a lipokine, studies with cell culture and rodent models have suggested it enhances whole body insulin sensitivity, stimulates insulin secretion by β cells, increases hepatic fatty acid oxidation, improves the blood lipid profile, and alters macrophage differentiation. However, human studies report elevated blood levels of palmitoleic acid in people with obesity and metabolic syndrome. These findings might be reflection of the level or activity of stearoyl-CoA desaturase-1, which synthesizes palmitoleate and is enhanced in liver and adipose tissue of obese patients. The aim of this review is to describe the immune–metabolic effects of palmitoleic acid observed in cell culture, animal models, and humans to answer the question of whether palmitoleic acid is a plausible nonpharmacological strategy to prevent, control, or ameliorate chronic metabolic and inflammatory disorders. Despite the beneficial effects observed in cell culture and in animal studies, there are insufficient human intervention studies to fully understand the physiological effects of palmitoleic acid. Therefore, more human-based research is needed to identify whether palmitoleic acid meets the promising therapeutic potential suggested by the preclinical research.

Lactobacillus fermentum Improves Tacrolimus-Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling.

Abstract: Scope The aim is to analyze whether the probiotic Lactobacillus fermentum CECT5716 (LC40) can prevent endothelial dysfunction and hypertension induced by tacrolimus in mice. Methods and results Tacrolimus increases systolic blood pressure (SBP) and impairs endothelium-dependent relaxation to acetylcholine and these effects are partially prevented by LC40. Endothelial dysfunction induced by tacrolimus is related to both increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) and uncoupled endothelial nitric oxide synthase (eNOS)-driven superoxide production and Rho-kinase-mediated eNOS inhibition. LC40 treatment prevents all the aortic changes induced by tacrolimus. LC40 restores the imbalance between T-helper 17 (Th17)/regulatory T (Treg) cells induced by tacrolimus in mesenteric lymph nodes and the spleen. Tacrolimus-induced gut dysbiosis, that is, it decreases microbial diversity, increases the Firmicutes/Bacteroidetes (F/B) ratio and decreases acetate- and butyrate-producing bacteria, and these effects are prevented by LC40. Fecal microbiota transplantation (FMT) from LC40-treated mice to control mice prevents the increase in SBP and the impaired relaxation to acetylcholine induced by tacrolimus. Conclusion LC40 treatment prevents hypertension and endothelial dysfunction induced by tacrolimus by inhibiting gut dysbiosis. These effects are associated with a reduction in vascular oxidative stress, mainly through NOX2 downregulation and prevention of eNOS uncoupling, and inflammation possibly because of decreased Th17 and increased Treg cells polarization in mesenteric lymph nodes.

Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses.

Abstract: Inflammation is an innate immune response to noxious stimuli to protect the body from pathogens. Inflammatory responses consist of two main steps: priming and triggering. In priming, inflammatory cells increase expressions of inflammatory molecules, while in triggering, inflammasomes are activated, resulting in cell death and pro-inflammatory cytokine secretion. Inflammasomes are protein complexes comprising intracellular pattern recognition receptors (PRRs) (e.g., nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2), and caspases-4/5/11) and pro-caspase-1 with or without a bipartite adaptor molecule ASC. Inflammasome activation induces pyroptosis, inflammatory cell death, and stimulates caspase-1-mediated secretion of interleukin (IL)-1b and IL-18. Flavonoids are secondary metabolites found in various plants and are considered as critical ingredients promoting health and ameliorating various disease symptoms. Anti-inflammatory activity of flavonoids and underlying mechanisms have been widely studied. This review introduces current knowledge on different types of inflammasomes and their activation during inflammatory responses and discusses recent studies regarding anti-inflammatory roles of flavonoids as suppressors of inflammasomes in inflammatory conditions. Understanding the regulatory effects of flavonoids on inflammasome activation will increase our knowledge of flavonoid-mediated anti-inflammatory activity and provide new insights into the development of flavonoid preparations to prevent and treat human inflammatory diseases.

Chlorogenic Acid Protects Against oxLDL-Induced Oxidative Damage and Mitochondrial Dysfunction by Modulating SIRT1 in Endothelial Cells.

Abstract: Scope Endothelial dysfunction is an important mechanism in the development of atherosclerosis and is thought to be critical for predicting cardiovascular diseases. Previous reports suggested that chlorogenic acid (CGA) is a potent antioxidant and anti-inflammatory compound. The molecular mechanisms underlying the inhibitory effects of CGA on oxLDL-induced oxidative injuries in human endothelial cells are still largely unknown. This study is aimed to test the hypothesis that CGA protects against oxLDL-facilitated oxidative stress by upregulating SIRT1 and to explore the role of AMPK/PGC-1 pathway and mitochondrial biogenesis. Methods and results HUVECs were treated with oxLDL in the presence or absence of CGA pretreatment. Our data indicated that CGA pretreatment increased SIRT1 deacetylase activity levels. In addition, CGA reversed oxLDL-impaired SIRT1 and AMPK/PGC-1 activity and mitigated oxLDL-induced oxidative stress and dysfunction of mitochondrial biogenesis. However, silencing SIRT1, AMPK, and PGC-1 abated the ability of CGA to protect against oxidative stress. Results from the present study also suggested that CGA inhibits oxLDL-induced endothelial apoptosis through modulating SIRT1 and AMPK/PGC-1 function. Conclusion These findings provide new insights into possible molecular mechanisms by which CGA mitigates oxLDL-induced endothelial oxidative stress and mitochondrial dysfunction by activating SIRT1 and modulating the AMPK/PGC-1 signaling pathway.

Gallic Acid and Gallates in Human Health and Disease: Do Mitochondria Hold the Key to Success?

Abstract: Gallic acid and gallate esters are widely used as dietary supplements or additives with clinical significances. Over the last few decades, a large number of publications have been reported stating the antioxidative, antiapoptotic, cardioprotective, neuroprotective, and anticancer properties of gallic acid and gallates, and mostly demonstrated their antioxidative or prooxidative properties influencing the reactive oxygen species (ROS) signaling networks. However, very little focus has been paid to clinical trials, and this restricted their use as a prescribed preventative supplement. Since mitochondria are the principal organelles responsible for ROS generation, we reviewed the existing literature of mitochondria-specific effects of gallates including ROS production, respiration, mitochondrial biogenesis, apoptosis, and the physico-chemical parameters affecting the outcome of gallate supplementation to various health scenarios such as cardiovascular diseases, neurodegeneration, hepatic ailments, or cancers. The major signaling pathways and the molecules targeted by gallic acid and its derivatives have also been discussed with emphasis on mitochondria as the target site. This review provides a better understanding of the effect of gallic acid and gallate esters on mitochondrial functions and in designing effective preventative measures against the onset of various diseases.

Kefir Peptides Prevent Hyperlipidemia and Obesity in High‐Fat‐Diet‐Induced Obese Rats via Lipid Metabolism Modulation

Abstract: Scope Obesity has reached epidemic proportions worldwide. Obesity is a complex metabolic disorder that is linked to numerous serious health complications with high morbidity. The present study evaluated the effects of kefir peptides on high fat diet (HFD)-induced obesity in rats. Methods and results Kefir peptides markedly improved obesity, including body weight gain, inflammatory reactions and the formation of adipose tissue fat deposits around the epididymis and kidney, and adipocyte size. Treating high fat diet (HFD)-induced obese rats with kefir peptides significantly reduced the fatty acid synthase protein and increased the p-acetyl-CoA carboxylase protein to block lipogenesis in the livers. Kefir peptides also increased fatty acid oxidation by increasing the protein expressions of phosphorylated AMP-activated protein kinase, peroxisome proliferator-activated receptor-α, and hepatic carnitine palmitoyltransferase-1 in the livers. In addition, administration of kefir peptides significantly decreased the inflammatory response (TNF-α, IL-1β, and TGF-β) to modulate oxidative damage. Conclusion These results demonstrate that kefir peptides treatment improves obesity via inhibition of lipogenesis, modulation of oxidative damage, and stimulation of lipid oxidation. Therefore, kefir peptides may act as an anti-obesity agent to prevent body fat accumulation and obesity-related metabolic diseases.

Stachyose Improves Inflammation through Modulating Gut Microbiota of High‐Fat Diet/Streptozotocin‐Induced Type 2 Diabetes in Rats

Abstract: Scope The present study is undertaken to assess the effects of stachyose (STS) on type 2 diabetes in rats and changes in the gut microbiota compared to metformin (MET). Methods and results The type 2 diabetic model is successfully established via a high-fat diet /streptozotocin in Wistar rats, and STS or MET is administered for 4 weeks. Blood is collected to analyze biochemical parameters, pancreas for mRNA expression of related gene, and contents of colon for gut microbiota. STS or MET decreases serum LPS, mRNA expression of IL-6, and tumor necrosis factor-α (TNF-α). In addition, STS and MET show a similar shifting of the structure of the gut microbiota and a selective enrichment of key species. At the genus level, STS shows selective enrichment of Phascolarctobacterium, Bilophila, Oscillospira, Turicibacter, and SMB5, but MET demonstrates a selective effect on Sutterella, Prevotella, 02d06, and rc4. The correlation analysis indicates that STS and MET decrease IL-6 and TNF-α and increase Akt/PI3K expression, which are relative to key species of gut microbiota. Conclusion STS decreases pancreatic mRNA expression of IL-6 and TNF-α via key species of gut microbiota. The mechanism of this effect is similar to that of MET.

Dietary intervention modifies DNA methylation age assessed by the epigenetic clock

Abstract: Scope: Alterations in DNA methylation patterns are correlated with aging, environmental exposures and disease pathophysiology; the possibility of reverting or preventing these processes through dietary intervention is gaining momentum. In particular, methyl donors that provide S-adenosyl-methionine for one-carbon metabolism and polyphenols such as flavanols that inhibit the activity of DNA methyltransferases (DNMTs) could be key modifiers of epigenetic patterns. Methods and results: We assessed DNA methylation patterns in publicly available Illumina Infinium 450K methylation datasets from intervention studies with either folic acid + vitamin B12 (GSE74548) or monomeric and oligomeric flavanols (MOF) (GSE54690) in 44 and 13 participants, respectively. Global DNA methylation levels increased in unmethylated regions such as CpG islands and shores following folic acid + vitamin B12 supplementation and decreased in highly methylated regions, including shelves and open-seas following intervention with MOF. After supplementation with folic acid + vitamin B12, epigenetic age, estimated by the Horvath ‘epigenetic clock’ model, was reduced in women with the MTHFR 677CC genotype. Conclusions: The effects of supplementation with folic acid + vitamin B12 and MOF on DNA methylation age are dependent upon gender and MTHFR genotype. Additionally, our findings demonstrate the potential for these dietary factors to modulate global DNA methylation profiles.

Gut Microbiota Interacts with Markers of Adipose Tissue Browning, Insulin Action and Plasma Acetate in Morbid Obesity.

Abstract: cope : To examine the potential relationship among gene expression markers of adipose tissue browning, gut microbiota and insulin sensitivity in humans. Methods and results : Gut microbiota composition and gene markers of browning were analysed in subcutaneous (SAT) and visceral (VAT) adipose tissue from morbidly obese subjects (n = 34). Plasma acetate was measured through 1H NMR and insulin sensitivity using euglycemic hyperinsulinemic clamp. Subjects with insulin resistance showed an increase in the relative abundance (RA) of the phyla Bacteroidetes and Proteobacteria while RA of Firmicutes was decreased. In all subjects, Firmicutes RA was negatively correlated with HbA1c and fasting triglycerides, whereas Proteobacteria RA was negatively correlated with insulin sensitivity. Firmicutes RA was positively associated with markers of brown adipocytes (PRDM16, UCP1 and DIO2) in SAT, but not in VAT. Multivariate regression analysis indicated that Firmicutes RA contributed significantly to SAT PRDM16, UCP1 and DIO2 mRNA variance after controlling for age, BMI, HbA1c or insulin sensitivity. Interestingly, Firmicutes RA, specifically those bacteria belonging to Ruminococcaceae family, was positively associated with plasma acetate levels, which were also linked to SAT PRDM16 mRNA and insulin sensitivity. Conclusion : Gut microbiota composition is linked to adipose tissue browning and insulin action in morbidly obese subjects, possibly through circulating acetate. This article is protected by copyright. All rights reserved

Frataxin-Mediated PINK1-Parkin-Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin.

Abstract: Scope Naturally occurring quercetin has been found to induce mitophagy and prevent nonalcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not. Methods and results Adult male C57BL/J mice were fed a high-fat diet (HFD, 60% of energy from fat) with quercetin (100 mg kg-1 body weight) or not for 10 weeks. Quercetin alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, quercetin blocked mitophagy suppression by HFD based on the increased LC3II, PTEN-induced putative kinase 1 (PINK1) and Beclin1 expressions, as well as decreased p62 levels. Quercetin also improved the Parkin translocation to mitochondria confirmed by immunofluorescence. Specifically, frataxin was lowered in the liver of HFD-fed mice or HepG2 cell incubated with oleate/palmitate but restored by quercetin, and quercetin's regulation of frataxin may depend on p53. Furthermore, lentivirus-mediated stable knockdown of frataxin in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Frataxin was further decreased by free fatty acids in knockdown cells concomitantly with depressed PINK1-Parkin-associated mitophagy, which was partially normalized by quercetin. Conclusion Quercetin alleviated hepatic steatosis by enhancing frataxin-mediated PINK1/Parkin-dependent mitophagy, highlighting a promising preventive strategy and mechanism for NAFLD by quercetin.

Flavonoid-Rich Apple Improves Endothelial Function in Individuals at Risk for Cardiovascular Disease: A Randomized Controlled Clinical Trial

Abstract: cope : The cardioprotective effects of apples are primarily attributed to flavonoids, found predominantly in the skin. This study aimed to determine if acute and/or chronic (4 weeks) ingestion of flavonoid-rich apples improves endothelial function, blood pressure (BP) and arterial stiffness in individuals at risk for CVD. Methods and results : In this randomised, controlled cross-over trial, acute and 4 week intake of apple with skin (high flavonoid apple, HFA) was compared to intake of apple flesh only (low flavonoid apple, LFA) in 30 participants. The primary outcome was endothelial function assessed using flow-mediated dilation (FMD) of the brachial artery, while main secondary outcomes were 24 h ambulatory BP and arterial stiffness. Other outcomes included fasting serum glucose and lipoprotein profile, plasma haem oxygenase-1 (Hmox-1), F2-isoprostanes, flavonoid metabolites, and plasma and salivary nitrate (NO3−) and nitrite (NO2−) concentrations. Compared to LFA control, the HFA resulted in a significant increase in FMD acutely (0.8%, p<0.001) and after 4 weeks chronic intake (0.5%, p<0.001), and in plasma flavonoid metabolites (p<0.0001). Other outcomes were not altered significantly. Conclusion : A lower risk of CVD with higher apple consumption could be mediated by the beneficial effect of apple skin on endothelial function, both acutely and chronically. This article is protected by copyright. All rights reserved