Showing papers in "Journal of Nutritional Biochemistry in 2018"

A critical review on the impacts of β-glucans on gut microbiota and human health.

Abstract: The β-glucans are the glucose polymers present in the cells walls of yeast, fungi and cereals. β-Glucans are the major compositions of various nutritional diets such as oats, barley, seaweeds and mushrooms. Various biological activities of β-glucans have been reported such as anticancer, antidiabetic, anti-inflammatory and immune-modulating effects. The importance of β-glucans in food processing industries such as bread preparation, yogurt and pasta have been well elucidated. In recent findings on food science research gut microbiota plays a significant role and vastly studied for its intermediate role in regulating health. Several reports have suggested that β-glucans should have a significant impact on the gut microbiota changes and in turn on human health. The review was aimed to accumulate the evidence on types of β-glucans, their functional properties and the mechanism by how the β-glucans regulate the gut microbiota and human health. The various in vitro, in vivo and clinical studies, have been summarized, in particular, the changes happening upon the β-glucans supplementation on the gut microbiota. Overall, this review updates the recent studies on β-glucans and gut microbiota and also inputs the demanding questions to be addressed in β-glucans-microbiota research in the future.

Omega-3 fatty acids in obesity and metabolic syndrome: a mechanistic update.

Abstract: Strategies to reduce obesity have become public health priorities as the prevalence of obesity has risen in the United States and around the world. While the anti-inflammatory and hypotriglyceridemic properties of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are well known, their antiobesity effects and efficacy against metabolic syndrome, especially in humans, are still under debate. In animal models, evidence consistently suggests a role for n-3 PUFAs in reducing fat mass, particularly in the retroperitoneal and epididymal regions. In humans, however, published research suggests that though n-3 PUFAs may not aid weight loss, they may attenuate further weight gain and could be useful in the diet or as a supplement to help maintain weight loss. Proposed mechanisms by which n-3 PUFAs may work to improve body composition and counteract obesity-related metabolic changes include modulating lipid metabolism; regulating adipokines, such as adiponectin and leptin; alleviating adipose tissue inflammation; promoting adipogenesis and altering epigenetic mechanisms.

Polysaccharide of Hericium erinaceus attenuates colitis in C57BL/6 mice via regulation of oxidative stress, inflammation-related signaling pathways and modulating the composition of the gut microbiota.

Abstract: Inflammatory bowel disease (IBD) is a disease caused by a dysregulated immune with unknown etiology. Hericium erinaceus (H. erinaceus) is a Chinese medicinal fungus, with the effect of prevention and treatment of gastrointestinal disorders. In this study, we have tested the anti-inflammatory effect of polysaccharide of H. erinaceus (HECP, Mw: 86.67 kDa) in the model of dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. Our data indicated that HECP could improve clinical symptoms and down-regulate key markers of oxidative stresses, including nitric oxide (NO), malondialdehyde (MDA), total superoxide dismutase (T-SOD), and myeloperoxidase (MPO). HECP also suppressed the secretion of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and decreased the expression of related mRNA. Meanwhile, HECP blocked phosphorylation of nuclear factor-κB (NF-κB) p65, NF-κB inhibitor alpha (IκB-α), mitogen-activated protein kinases (MAPK) and Protein kinase B (Akt) in DSS-treated mice. Moreover, HECP reversed DSS-induced gut dysbiosis and maintained intestinal barrier integrity. In conclusion, HECP ameliorates DSS-induced intestinal injury in mice, which suggests that HECP can serve as a protective dietary nutrient against IBD.

Ancient wheat species and human health: biochemical and clinical implications.

Abstract: Wheat is the major staple food in many diets. Based on the increase in worldwide mortality attributable to diet-related chronic diseases, there is an increasing interest in identifying wheat species with greater health potential, more specifically for improved anti-oxidant and anti-inflammatory properties. In particular, ancient varieties (defined as those species that have remained unchanged over the last hundred years) are gaining interest since several studies suggested that they present a healthier nutritional profile than modern wheats. This manuscript reviews the nutritional value and health benefits of ancient wheats varieties, providing a summary of all in vitro, ex vivo, animal and human studies that have thus far been published. Differences in chemical composition, and biochemical and clinical implications of emmer, einkorn, spelt, khorasan and various regional Italian varieties are discussed. Although many studies based on in vitro analyses of grain components provide support to the premise of a healthier nutritional and functional potential of ancient wheat, other in vitro studies performed are not in support of an improved potential of ancient varieties. In the light of existing evidence derived from in vivo experiments, the ancient wheat varieties have shown convincing beneficial effects on various parameters linked to cardio-metabolic diseases such as lipid and glycaemic profiles, as well as the inflammatory and oxidative status. However, given the limited number of human trials, it is not possible to definitively conclude that ancient wheat varieties are superior to all modern counterparts in reducing chronic disease risk.

Short-chain fatty acids suppress food intake by activating vagal afferent neurons.

Abstract: Fermentable carbohydrates including dietary fibers and resistant starch produce short-chain fatty acids (SCFAs), including acetate, propionate and butyrate, through microbial fermentation in the intestine of rodents and humans. Consumption of fermentable carbohydrate and SCFAs suppress food intake, an effect involving the brain. However, their signaling pathway to the brain remains unclear. Vagal afferents serve to link intestinal information to the brain. In the present study, we explored possible role of vagal afferents in the anorexigenic effect of SCFAs. Intraperitoneal (ip) injection of three SCFA molecules (6 mmol/kg) suppressed food intake in fasted mice with the rank order of butyrate > propionate > acetate. The suppressions of feeding by butyrate, propionate and acetate were attenuated by vagotomy of hepatic branch and blunted by systemic treatment with capsaicin that denervates capsaicin-sensitive sensory nerves including vagal afferents. Ip injection of butyrate induced significant phosphorylation of extracellular-signal-regulated kinase 1/2, cellular activation markers, in nodose ganglia and their projection site, medial nucleus tractus solitaries. Moreover, butyrate directly interacted with single neurons isolated from nodose ganglia and induced intracellular Ca2+ signaling. The present results identify the vagal afferent as the novel pathway through which exogenous SCFAs execute the remote control of feeding behavior and possibly other brain functions. Vagal afferents might participate in suppression of feeding by intestine-born SCFAs.

Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development

Abstract: Reduced short-chain fatty acids (SCFAs) have been reported in patients with ulcerative colitis, and increased intake of dietary fiber has shown to be clinically beneficial for colitis. Whether SCFAs suppress tumorigenesis in colitis-associated colorectal cancer remains unknown. The chemopreventive effect of SCFAs in colitis-associated colorectal cancer was evaluated in this study. Model of colitis-associated colorectal cancer in male BALB/c mice was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). SCFAs mix (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) was administered in drink water during the study period. Macroscopic and histological studies were performed to examine the colorectal inflammation and tumorigenesis in AOM/DSS-induced mice treated with or without SCFA mix. The effects of SCFAs mix on colonic epithelial cellular proliferation were also assessed using Ki67 immunohistochemistry and TUNEL staining. The administration of SCFAs mix significantly reduced the tumor incidence and size in mice with AOM/DSS-induced colitis associated colorectal cancer. SCFAs mix protected from AOM/DSS-induced colorectal cancer by improving colon inflammation and disease activity index score as well as suppressing the expression of proinflammatory cytokines including IL-6, TNF-α and IL-17. A decrease in cell proliferation markers and an increase in TUNEL-positive tumor epithelial cells were also demonstrated in AOM/DSS mice treated with SCFAs mix. SCFAs mix administration prevented development of tumor and attenuated the colonic inflammation in a mouse model of colitis-associated colorectal cancer. SCFAs mix may be a potential agent in the prevention and treatment of colitis-associated colorectal cancer.

Supplementation of lycopene attenuates lipopolysaccharide-induced amyloidogenesis and cognitive impairments via mediating neuroinflammation and oxidative stress

Abstract: Neuroinflammation is documented to be the major culprit of Alzheimer's disease. Lycopene (LYC), a fat soluble carotenoid, exhibits neuroprotective function in several neurodegenerative disorders. However, the effects of LYC to countering systemic inflammation-induced amyloidogenesis and memory deficiency remain to be elucidated. In current study, 3-month-old male C57BL/6J mice were treated with 0.03% LYC (w/w, mixed into normal chow) for 5 weeks. The mice were then treated by intraperitoneal injection of LPS (0.25mg/kg) for 9 days. It was found that LYC inhibited LPS-induced memory loss by behavior tests including Y-maze test and Morris water test. Meanwhile, LYC prevented LPS-induced accumulation of Aβ, levels of amyloid precursor protein (APP), and suppressed neuronal β-secretase BACE1 and elevated the expressions of α-secretase ADAM10. Furthermore, LYC down-regulated the expression of IBA-1 (a marker of microglia activation), reduced the levels of inflammatory mediators and inhibited oxidative stress in LPS-treated mice. Moreover, LYC suppressed the phosphorylation of MAPKs, NFκB, and activated Nrf2 signaling pathways in LPS-treated BV2 microglial cells. Therefore, our study indicated that LYC could ameliorate LPS-induced neuroinflammation, oxidative stress, amyloidogenesis and cognitive impairments possibly through mediating MAPKs, NFκB and Nrf2 signaling pathways, indicating that LYC might be a nutritional preventive strategy in neuroinflammation-related diseases such as AD.

Liraglutide modulates gut microbiota and reduces NAFLD in obese mice.

Abstract: Metabolic disorders such as insulin resistance and diabetes are associated with obesity and nonalcoholic fatty liver disease (NAFLD). The aggressive form of a fatty liver disease may progress to cirrhosis and hepatocellular carcinoma. Furthermore, recent studies demonstrated that there is a dysbiosis in the gut microbiota associated with early stages of metabolic disease. Therefore, the identification and repurposing of drugs already used to treat insulin resistance may be an excellent option for other disorders. We evaluated the effect of liraglutide on obesity, NAFLD and gut microbiota modulation in two different animal models of obesity: the ob/ob mice and the high-fat diet (HFD)-fed mice. Liraglutide treatment induced significant weight loss in both obesity models, showed improvements in glycemic parameters and reduced inflammatory cell infiltration in the cecum and the liver. In ob/ob mice, the liraglutide treatment was able to reduce the accumulation of liver fat by 78% and reversed steatosis in the HFD mice. The gut microbiota analysis showed that liraglutide changed the overall composition as well as the relative abundance of weight-relevant phylotypes such as a reduction of Proteobacteria and an increase of Akkermansia muciniphila in the treated HFD group. We show that liraglutide can lead to weight loss and gut microbiota modulations, and is associated with an improvement of NAFLD. Furthermore, by generating a profile of the intestinal microbiota, we compiled a list of potential bacterial targets that may modulate metabolism and induce a metabolic profile that is considered normal or clinically controlled.

Intestinal anti-inflammatory effect of the probiotic Saccharomyces boulardii in DSS-induced colitis in mice: Impact on microRNAs expression and gut microbiota composition

Abstract: The beneficial effects exerted by probiotics in inflammatory bowel disease (IBD) are well known, although their exact mechanisms have not been fully elucidated, and only few studies have focused on their impact on selected miRNAs and the gut microbiota composition. Therefore, our aim was to correlate the intestinal anti-inflammatory activity of the probiotic Saccharomyces boulardii in the dextran sodium sulphate (DSS) model of mouse colitis and the changes induced in miRNA expression and gut microbiota populations. Probiotic was given orally (5×109 CFU) to C57BL/6 mice for 26 days. After 2 weeks, the colitis was induced adding DSS to the drinking water. Mice were scored daily using a Disease Activity Index (DAI). After sacrifice, the colonic specimens were evaluated by determining the expression of inflammatory markers and micro-RNAs by qRT-PCR. Moreover, changes in microbiota populations were evaluated by pyrosequencing. Probiotic ameliorated the colonic damage induced by DSS, as evidenced by lower DAI values and colonic weight/length compared with untreated mice. The treatment modified the colonic expression of different inflammatory markers and the epithelial integrity proteins, and induced changes in micro-RNAs expression. Moreover, microbiota characterization showed that probiotic treatment increased bacterial diversity, thus ameliorating the dysbiosis produced by DSS-colitis. Saccharomyces boulardii exerted intestinal anti-inflammatory effects in DSS-mouse colitis, through the modulation in the immune response, involving modification of altered miRNA expression, being associated to the improvement of the inflammation-associated dysbiosis in the intestinal lumen, which could be of great interest to control the complex pathogenesis of IBD.

Chlorogenic acid improves intestinal barrier functions by suppressing mucosa inflammation and improving antioxidant capacity in weaned pigs.

Abstract: Intestinal barrier plays key roles in maintaining intestinal homeostasis. Inflammation and oxidative damage can severely destroy the intestinal integrity of mammals. Chlorogenic acid (CGA) is a natural polyphenol present in human diet and plants, possessing potent antioxidant and anti-inflammatory activities. This study was conducted to investigate the protective effects of CGA and its molecular mechanisms on intestinal barrier function in a porcine model. Twenty-four weaned pigs were allotted to two groups and fed with a basal diet or a basal diet containing 1000 mg/kg CGA. The results showed that CGA decreased serum D-lactate and diamine oxidase levels, and enhanced the expression and localization of claudin-1 protein in apical intercellular region of small intestinal epithelium. Interestingly, CGA significantly decreased the mucosa histamine and tryptase contents, as well as the tryptase-positive mast cell counts. Moreover, the expression levels of critical inflammation molecules (interleukin-1β, interleukin-6, tumor necrosis factor-α, and nuclear factor-κB) were down-regulated by CGA in jejunal and ileal mucosa. However, the expression levels of inflammation repressors (suppressor of cytokine signaling 1 and toll-interacting protein) were up-regulated by CGA. Importantly, CGA decreased the malondialdehyde content but elevated glutathione peroxidase and catalase content in duodenal and jejunal mucosa. The expression levels of critical molecules in antioxidant signaling (nuclear factor erythroid-derived 2-related factor 2 and heme oxygenase-1) were elevated by CGA in duodenal and jejunal mucosa. These results suggested that CGA could ameliorate intestinal barrier disruption in weaned pigs, which might be mediated by suppressing the TLR4/NF-κB signaling pathway and activating the Nrf2/HO-1 signaling pathway.

Effects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studies

Abstract: Chemotherapy is essential to most patients with gastric cancer and the anticancer drug, irinotecan (CPT-11), and its metabolite, SN-38, an inhibitor of DNA topoisomerase I, are first-line chemotherapies for gastric cancer Quercetin, a flavonoid that is widely found in various vegetables and fruits, has the ability to potentiate the efficacy of anticancer drugs The purpose of this study was to investigate the therapeutic effect of quercetin combined with irinotecan/SN-38 in the AGS human gastric cancer cell line in vitro and in vivo The in vitro study evaluated the efficacy of high-dose SN-38 and quercetin combined with low-dose SN-38 on cell viability, apoptosis, and β-catenin expression Results showed that cell viability and the percentage of apoptosis in combined treatments with quercetin and SN-38 were comparable to treatment with high-dose SN-38 alone AGS cells treated with a high dose of SN-38 exhibited up-regulation of β-catenin protein expression, whereas quercetin-treated cells (either quercetin alone or combined with low-dose SN-38) exhibited lower protein levels of β-catenin In the AGS xenograft mouse model, gene expression of cyclooxygenase-2 and epithelial-mesenchymal transition-related markers, such as Twist1 and ITGβ6, were lower in combined treatments with quercetin and low-dose irinotecan than high-dose irinotecan alone Furthermore, the concentration of angiogenesis-associated factors (vascular endothelial growth factor (VEGF)-A and VEGF-receptor 2) and percentage of Tie2-expressing monocytes was significantly down-regulated in combined treatments with quercetin and irinotecan These results suggest that quercetin may enhance the efficacy of irinotecan/SN-38 in the human AGS cell line

Astaxanthin exerts anti-inflammatory and antioxidant effects in macrophages in NRF2-dependent and independent manners.

Abstract: Although anti-inflammatory effects of astaxanthin (ASTX) have been suggested, the underlying mechanisms have not been fully understood. Particularly, the modulatory action of ASTX in the interplay between nuclear factor E2-related factor 2 (NRF2) and nuclear factor κB (NFκB) to exert its anti-inflammatory effect in macrophages is unknown. The effect of ASTX on mRNA and protein expression of pro-inflammatory and antioxidant genes and/or cellular reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages, bone marrow-derived macrophages (BMDM) from wild-type (WT) and Nrf2-deficient mice, and/or splenocytes and peritoneal macrophages of obese mice fed ASTX. The effect of ASTX on M1 and M2 macrophage polarization was evaluated in BMDM. ASTX significantly decreased LPS-induced mRNA expression of interleukin 6 (Il-6) and Il-1β by inhibiting nuclear translocation of NFκB p65; and attenuated LPS-induced ROS with an increase in NRF2 nuclear translocation, concomitantly decreasing NADPH oxidase 2 expression in RAW 264.7 macrophages. In BMDM of WT and Nrf2-deficient mice, ASTX decreased basal and LPS-induced ROS accumulation. The induction of Il-6 mRNA by LPS was repressed by ASTX in both types of BMDM while Il-1β mRNA was decreased only in WT BMDM. Furthermore, ASTX consumption lowered LPS sensitivity of splenocytes in obese mice. ASTX decreased M1 polarization of BMDM while increasing M2 polarization. ASTX exerts its anti-inflammatory effect by inhibiting nuclear translocation of NFκB p65 and by preventing ROS accumulation in NRF2-dependent and -independent mechanisms. Thus, ASTX is an agent with anti-inflammatory and antioxidant properties that may be used for the prevention of inflammatory conditions.

Cranberries attenuate animal-based diet-induced changes in microbiota composition and functionality: a randomized crossover controlled feeding trial

Abstract: Cranberries have multiple health effects but their impact on gut microbiota has not been examined in randomized controlled feeding trials. We evaluated the relationship between the microbiota and cranberries in the context of an animal-based diet. In a randomized, double-blind, cross-over, controlled design trial, 11 healthy adults consumed for 5 days each a control diet (animal-based diet plus 30 g/day placebo powder) and a cranberry diet (animal-based diet plus 30 g/day freeze-dried whole cranberry powder). The animal-based diet included meats, dairy products, and simple sugars. Stool, urine, and blood samples were obtained before and after each intervention phase. As compared to the pre-control diet, control diet modified 46 taxonomic clades, including an increase in the abundance of Firmicutes and decrease in Bacteroidetes. Moreover, it increased bacteria-derived deoxycholic acid and decreased acetate and butyrate in stool. As compared to the post-intervention phase of control diet, the cranberry diet modified 9 taxonomic clades, including a decrease in the abundance of Firmicutes and increase in Bacteroidetes. Further, the cranberry diet attenuated control diet-induced increase in secondary bile acids and decrease in short-chain fatty acids (SCFA), and increased urinary anthocyanins and bacterially derived phenolic acids. No changes were found in fecal trimethylamine and plasma cytokines. In conclusion, an animal-based diet altered the microbiota composition to a less favorable profile, increased carcinogenic bile acids, and decreased beneficial SCFA. Cranberries attenuated the impact of the animal-based diet on microbiota composition, bile acids, and SCFA, evidencing their capacity to modulate the gut microbiota.

Butyrate from pectin fermentation inhibits intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E-deficient mice

Abstract: Short-chain fatty acids (SCFAs), the major products of dietary fiber fermentation by intestinal microflora, exert beneficial effects on pathogenesis of multiple metabolic diseases. The aim of this study was to determine whether SCFAs from fermentation of pectin (PE), a soluble dietary fiber, prevent the development of atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. Male apoE-/- mice (8-week-old) were fed a high-fat, high-cholesterol diet (HCD; 21% wt/wt fat, 0.15% wt/wt cholesterol) or HCD supplemented with 20% wt/wt PE (HCD+PE) alone or with antibiotics (HCD+PE + A) in drinking water for 12 weeks. Serum lipids and SCFAs concentrations, atherosclerotic lesion area, and intestinal morphology and function were measured. Caco-2 cells were treated with SCFAs to determine whether they affected the expression of genes involved in cholesterol absorption. HCD+PE-treated mice exhibited decreased serum total and low-density lipoprotein cholesterol, and reduced atherosclerotic lesion area compared with HCD mice. These beneficial effects of PE were not observed in the HCD+PE+A group. Incubation of Caco-2 cells with butyrate, but not acetate and propionate, down-regulated the expression of Niemann-Pick C1-Like 1 but up-regulated the ATP-binding cassette transporters G5 and G8 (ABCG5 and G8) at the mRNA level. Butyrate treatment also increased transcriptional activity of liver X receptor in Caco-2 cells. Our data suggest that butyrate from PE intestinal fermentation protects mice from the progression of diet-induced atherosclerosis in apoE-/- mice. These findings suggest a novel mechanism by which dietary fiber may prevent the development of atherosclerosis.

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice.

Abstract: Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects. Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression. Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

Impact of tart cherries polyphenols on the human gut microbiota and phenolic metabolites in vitro and in vivo

Abstract: Tart cherries have been reported to exert potential health benefits attributed to their specific and abundant polyphenol content. However, there is a need to study the impact and fate of tart cherries polyphenols in the gut microbiota. Here, tart cherries, pure polyphenols (and apricots) were submitted to in vitro bacterial fermentation assays and assessed through 16S rRNA gene sequence sequencing and metabolomics. A short-term (5 days, 8 oz. daily) human dietary intervention study was also conducted for microbiota analyses. Tart cherry concentrate juices were found to contain expected abundances of anthocyanins (cyanidin-glycosylrutinoside) and flavonoids (quercetin-rutinoside) and high amounts of chlorogenic and neochlorogenic acids. Targeted metabolomics confirmed that gut microbes were able to degrade those polyphenols mainly to 4-hydroxyphenylpropionic acids and to lower amounts of epicatechin and 4-hydroxybenzoic acids. Tart cherries were found to induce a large increase of Bacteroides in vitro, likely due to the input of polysaccharides, but prebiotic effect was also suggested by Bifidobacterium increase from chlorogenic acid. In the human study, two distinct and inverse responses to tart cherry consumption were associated with initial levels of Bacteroides. High-Bacteroides individuals responded with a decrease in Bacteroides and Bifidobacterium, and an increase of Lachnospiraceae, Ruminococcus and Collinsella. Low-Bacteroides individuals responded with an increase in Bacteroides or Prevotella and Bifidobacterium, and a decrease of Lachnospiraceae, Ruminococcus and Collinsella. These data confirm that gut microbiota metabolism, in particular the potential existence of different metabotypes, needs to be considered in studies attempting to link tart cherries consumption and health.

Polyphenol-rich green tea extract improves adipose tissue metabolism by down-regulating miR-335 expression and mitigating insulin resistance and inflammation.

Abstract: Obesity leads to changes in miRNA expression in adipose tissue, and this modulation is linked to the pathophysiology of the disease. Green tea (GT) is a natural source of polyphenols that have been shown to confer health benefits, particularly preventing metabolic diseases. Here, we investigated if the beneficial effects of GT in obesity results from changes in the miRNA profile in white adipose tissue. GT treatment [500 mg/body weight (BW)/12 weeks] increased energy expenditure of high-fat diet-fed mice (16 weeks), leading to reduced weight gain, decreased adiposity, reduced inflammation and improved insulin sensitivity. These phenotypes were associated with a decrease in the expression of miR-335 in the adipose tissue. miR-335 was up-regulated by TNF-α in adipocytes and, in turn, down-regulated genes involved in insulin signaling and lipid metabolism. On the other hand, GT inhibited TNF-α effect. In conclusion, miR-335 serves as a link between inflammation and impaired metabolism in adipose tissue, providing an important mechanistic insight into the molecular basis underlying GT action during obesity.

Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond.

Abstract: Environmental factors (e.g., malnutrition and physical inactivity) contribute largely to metabolic disorders including obesity, type 2 diabetes, cardiometabolic disease and nonalcoholic fatty liver diseases. The abnormalities in metabolic activity and pathways have been increasingly associated with altered DNA methylation, histone modification and noncoding RNAs, whereas lifestyle interventions targeting diet and physical activity can reverse the epigenetic and metabolic changes. Here we review recent evidence primarily from human studies that links DNA methylation reprogramming to metabolic derangements or improvements, with a focus on cross-tissue (e.g., the liver, skeletal muscle, pancreas, adipose tissue and blood samples) epigenetic markers, mechanistic mediators of the epigenetic reprogramming, and the potential of using epigenetic traits to predict disease risk and intervention response. The challenges in epigenetic studies addressing the mechanisms of metabolic diseases and future directions are also discussed and prospected.

Grape seed procyanidin extract ameliorates lead-induced liver injury via miRNA153 and AKT/GSK-3β/Fyn-mediated Nrf2 activation

Abstract: Lead-induced hepatotoxicity is characterized by an extensive oxidative stress. Grape seed procyanidin extract (GSPE) possesses abundant biological activities. Herein, we investigated the protective role of GSPE against lead-induced liver injury and determined the potential molecular mechanisms. In vivo, rats were treated with/without lead acetate (PbAc) (0.05%, w/v) in the presence/absence of GSPE (200 mg/kg). In vitro, hepatocytes were pretreated with/without GSPE (100 μg/ml) in the presence/absence of PbAc (100 μM). PbAc administration to rats resulted in anemia, liver dysfunction, lead accumulation in the bone and liver, oxidative stress, DNA damage and apoptosis. GSPE significantly attenuated these adverse effects, except lead accumulation in liver. GSPE also decreased the expression of miRNA153 and increased the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and levels of its downstream protein, and protein kinase B (AKT) phosphorylation in PbAc-induced liver injury. In primary hepatocytes treated with PbAc, GSPE increased hepatocyte viability and decreased lactate dehydrogenase release and reactive oxygen species levels. Dietary GSPE attenuated PbAc-induced liver injury in rats via an integrated mechanism associated with the miRNA153 and AKT/glycogen synthase kinase 3 beta/Fyn-mediated Nrf2 activation.

The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice.

Abstract: Titanium dioxide (TiO2) is a common component of orthopedic prosthesis. However, prosthesis wear releases TiO2, which induces inflammation and osteolysis in peri-prosthetic tissues. Quercetin is a flavonoid widely present in human diet, which presents biological activities such as antinociceptive, anti-inflammatory and antioxidant effects. Therefore, the effect of intraperitoneal treatment with quercetin in TiO2-induced arthritis model was evaluated. In the first set of experiments, mice received injection of TiO2 (0.1-3 mg/knee joint) and articular mechanical hyperalgesia, edema and histopathology analysis were performed in a 30 days protocol. The dose of 3 mg of TiO2 showed the most harmful effect, and was chosen to the following experiments. Subsequently, mice received 3 mg of TiO2 followed by post-treatment with quercetin during 30 days. Quercetin (10-100 mg/kg) inhibited in a dose-dependent manner TiO2-induced knee joint mechanical hyperalgesia, edema and leukocyte recruitment and did not induce damage in major organs such as liver, kidney and stomach. The dose of 30 mg/kg was chosen for the subsequent analysis, and reduced histopathological changes such as leukocyte infiltration, vascular proliferation and synovial hyperplasia (pannus formation) on day 30 after TiO2 challenge. The protective analgesic and anti-inflammatory mechanisms of quercetin included the inhibition of TiO2-induced neutrophil and macrophage recruitment, proteoglycan degradation, oxidative stress, cytokine production (TNF-α, IL-1β, IL-6, and IL-10), COX-2 mRNA expression, and bone resorption as well as activation of Nrf2/HO-1 signaling pathway. These results demonstrate the potential therapeutic applicability of the dietary flavonoid quercetin to reduce pain and inflammatory damages associated with prosthesis wear process-induced arthritis.

Anti-inflammatory effects of α-linolenic acid in M1-like macrophages are associated with enhanced production of oxylipins from α-linolenic and linoleic acid.

Abstract: Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA α-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion. We find that ALA treatment leads to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production. Although ALA is known to be converted to longer-chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins. In contrast, we observed profound increases in oxylipins directly derived from ALA. Lipoxygenase products of linoleic acid were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. These results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those used by the long-chain omega-3 fatty acids EPA and DHA. Thus, there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents.

Grape proanthocyanidin-induced intestinal bloom of Akkermansia muciniphila is dependent on its baseline abundance and precedes activation of host genes related to metabolic health

Abstract: We previously showed that C57BL/6J mice fed high-fat diet (HFD) supplemented with 1% grape polyphenols (GP) for 12 weeks developed a bloom of Akkermansia muciniphila with attenuated metabolic syndrome symptoms. Here we investigated early timing of GP-induced effects and the responsible class of grape polyphenols. Mice were fed HFD, low-fat diet (LFD) or formulations supplemented with GP (HFD-GP, LFD-GP) for 14 days. Mice fed HFD-GP, but not LFD-GP, showed improved oral glucose tolerance compared to controls. A. muciniphila bloom occurred earlier in mice fed LFD-GP than HFD-GP; however, timing was dependent on baseline A. muciniphila levels rather than dietary fat. Mice gavaged for 10 days with GP extract (GPE) or grape proanthocyanidins (PACs), each delivering 360 mg PACs/kg body weight, induced a bloom of fecal and cecal A. muciniphila, the rate of which depended on initial A. muciniphila abundance. Grape PACs were sufficient to induce a bloom of A. muciniphila independent of specific intestinal gene expression changes. Gut microbial community analysis and in vitro inhibition of A. muciniphila by GPE or PACs suggest that the A. muciniphila bloom in vivo occurs via indirect mechanisms.

Anthocyanins as a potential pharmacological agent to manage memory deficit, oxidative stress and alterations in ion pump activity induced by experimental sporadic dementia of Alzheimer's type

Abstract: Anthocyanins (ANT) are polyphenolic flavonoids with antioxidant and neuroprotective properties. This study evaluated the effect of ANT treatment on cognitive performance and neurochemical parameters in an experimental model of sporadic dementia of Alzheimer's type (SDAT). Adult male rats were divided into four groups: control (1 ml/kg saline, once daily, by gavage), ANT (200 mg/kg, once daily, by gavage), streptozotocin (STZ, 3 mg/kg) and STZ plus ANT. STZ was administered via bilateral intracerebroventricular (ICV) injection (5 μl). ANT were administered after ICV injection for 25 days. Cognitive deficits (short-term memory and spatial memory), oxidative stress parameters, and acetylcholinesterase (AChE) and Na+-K+-ATPase activity in the cerebral cortex and hippocampus were evaluated. ANT treatment protected against the worsening of memory in STZ-induced SDAT. STZ promoted an increase in AChE and Na+-K+-ATPase total and isoform activity in both structures; ANT restored this change. STZ administration induced an increase in lipid peroxidation and decrease in the level of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the cerebral cortex; ANT significantly attenuated these effects. In the hippocampus, an increase in reactive oxygen species (ROS), nitrite and lipid peroxidation levels, and SOD activity and a decrease in CAT and GPx activity were seen after STZ injection. ANT protected against the changes in ROS and antioxidant enzyme levels. In conclusion, the present study showed that treatment with ANT attenuated memory deficits, protected against oxidative damage in the brain, and restored AChE and ion pump activity in an STZ-induced SDAT in rats.

Kaempferol alleviates palmitic acid-induced lipid stores, endoplasmic reticulum stress and pancreatic β-cell dysfunction through AMPK/mTOR-mediated lipophagy

Abstract: Kaempferol, a natural flavonoid, has the beneficial effects of preserving pancreatic β-cell mass and function, but its action on β-cell lipid metabolism still remains elusive. Recently, autophagy has been reported to play a major role in lipid metabolism in various cell types, but its role in pancreatic β-cell's lipid metabolism is rarely reported. Here, we investigated the role of kaempferol-induced autophagy in inhibition of lipid stores, ER stress and β-cell dysfunction in palmitic acid-challenged RIN-5F cells and isolated pancreatic islets. The lipid-lowering effect of kaempferol was determined by Oil Red O staining, triglyceride assay, BODIPY labeling, RT-PCR and immunoblot analysis of PLIN2 (the lipid droplet coat protein) expression. Further, the involvement of AMPK/mTOR-mediated lipophagy was established by pharmacological and genetic inhibitors of autophagy and AMPK. The co-localization studies of lipid droplets with autophagosomes/lysosomes by BODIPY-MDC-LysoTracker co-staining, LC3/BODIPY labeling and LC3/PLIN2 double immunolabeling further strengthened the findings. Kaempferol treatment exhibited decreased lipid stores and increased co-localization of lipid droplets with autophagosomes and lysosomes in palmitic acid-challenged β-cells. Moreover, inhibition of autophagy led to decreased co-localization and increased lipid droplets accumulation. Kaempferol-induced alleviation of ER stress and β-cell dysfunctions was established by immunoblot analysis of CHOP-10 (a key mediator of cell death in response to ER stress) and insulin content/secretion analysis respectively. Together, these findings suggest that kaempferol prevents ectopic lipid accumulation and ER stress, thus restoring β-cell function through AMPK-mediated lipophagy. The current data implies that kaempferol may be a potential therapeutic candidate to prevent obesity-linked diabetic complications.

Food components with antifibrotic activity and implications in prevention of liver disease.

Abstract: Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.

Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease.

Abstract: The gut-brain axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota and, in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.

Long-Term Treatment with Green Tea Polyphenols Modifies the Gut Microbiome of Female Sprague-Dawley Rats

Abstract: Green tea polyphenols (GTP) have been shown to exert a spectrum of health benefits to animals and humans. It is plausible that the beneficial effects of GTP are a result of its interaction with the gut microbiota. This study evaluated the effect of long-term treatment with GTP on the gut microbiota of experimental rats and the potential linkage between changes of the gut microbiota with the beneficial effects of GTP. Six-month-old Sprague-Dawley rats were randomly allocated into three dosing regimens (0, 0.5%, and 1.5% of GTP) and followed for 6 months. At the end of month 3 or month 6, half of the animals from each group were sacrificed and their colon contents were collected for microbiome analysis using 16S ribosomal RNA and shotgun metagenomic community sequencing. GTP treatment significantly decreased the biodiversity and modified the microbial community in a dose-dependent manner; similar patterns were observed at both sampling times. Multiple operational taxonomic units and phylotypes were modified: the phylotypes Bacteroidetes and Oscillospira, previously linked to the lean phenotype in human and animal studies, were enriched; and Peptostreptococcaceae previously linked to colorectal cancer phenotype was depleted in GTP treated groups in a dose-dependent manner. Several microbial gene orthologs were modified, among which genes related to energy production and conversion were consistently enriched in samples from month 6 in a dose-dependent manner. This study showed that long-term treatment with GTP induced a dose-dependent modification of the gut microbiome in experimental rats, which might be linked to beneficial effects of GTP.

Inulin fiber dose-dependently modulates energy balance, glucose tolerance, gut microbiota, hormones and diet preference in high-fat-fed male rats

Abstract: Inulin, a popular prebiotic fiber, has been reported to promote satiety and fat loss; however, the dose-response effects of inulin on energy balance and diet preference, and whether the metabolic effects are independent of calorie restriction are not well characterized. Therefore, we compared the effects of diets varying in inulin concentrations on food intake, energy expenditure, body composition, gut microbiota and hormones, and assessed whether inulin-induced hypophagia was due to reduced diet preference. In experiment 1, male rats were randomized to six high-fat diet groups: control (CON, 0% inulin), 2.5% inulin (2.5IN), 10% inulin (10IN), 25% inulin (25IN), 25% cellulose (25CE) or pair-fed to 25IN (25PF) for 21 days. We demonstrate that inulin dose-dependently decreased caloric intake and respiratory quotient; improved glucose tolerance; increased the abundance of Bacteroidetes and Bifidobacterium spp.; decreased Clostridium clusters I and IV; increased butyryl-CoA:acetate CoA-transferase in cecum; upregulated peptide YY, cholecystokinin and proglucagon transcripts in the cecum and colon; and increased plasma peptide YY and glucagon-like peptide-1 concentrations. Importantly, unlike 25PF, 25IN attenuated the reduction in energy expenditure associated with calorie restriction and decreased adiposity. In experiment 2, following four training periods, diet preferences were determined. Although 10IN and 25IN decreased caloric intake, and 25CE increased caloric intake, during training, all high-fiber diets were less preferred. Taken together, this work demonstrates that inulin dose-dependently decreased caloric intake, modulated gut microbiota and upregulated satiety hormones, with metabolic effects being largely independent of caloric restriction.

The potential atheroprotective role of plant MIR156a as a repressor of monocyte recruitment on inflamed human endothelial cells.

Abstract: MicroRNAs have become the spotlight of the biological community for more than a decade, but we are only now beginning to understand their functions. The detection of stably expressed endogenous microRNAs in human blood suggests that these circulating miRNAs can mediate intercellular communication. Our previous study reported the surprising finding that exogenous rice MIR168a could regulate liver low-density lipoprotein receptor adapter protein 1 (LDLRAP1) gene expression in mice. Here, we show that plant MIR156a, which is abundantly expressed in dietary green veggies, also stably presents in healthy human serum. Compared with age-matched individuals, decreased levels of MIR156a are observed both in serum and blood vessel of cardiovascular disease (CVD) patients. In vitro studies demonstrate that MIR156a can directly target the junction adhesion molecule-A (JAM-A), which is up-regulated in atherosclerotic lesions from CVD patients. Functional studies show that ectopic expression of MIR156a in human aortic endothelial cells reduces inflammatory cytokine-induced monocytes adhesion by suppressing JAM-A. These findings offer a novel vasoprotective molecular mechanism of green veggies through plant microRNAs.

Vitamin K1 inversely correlates with glycemia and insulin resistance in patients with type 2 diabetes (T2D) and positively regulates SIRT1/AMPK pathway of glucose metabolism in liver of T2D mice and hepatocytes cultured in high glucose.

Abstract: There is no previous study in the literature that has examined the relationship between circulating vitamin K1 (VK1) with glycemic status in type 2 diabetes (T2D). Moreover, scientific explanation for the beneficial role of VK1 supplementation in lowering glycemia in diabetes is yet to be determined. This study for the first time demonstrated that circulating VK1 was significantly lower in T2D patients compared to age-matched control subjects, and VK1 levels in T2D were significantly and inversely associated with fasting glucose and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], which suggest that boosting plasma VK1 may reduce the fasting glucose and insulin resistance in T2D patients. Using high-fat-diet-fed T2D animal model, this study further investigated the positive effect of VK1 supplementation on glucose metabolism and examined the underlying molecular mechanism. Results showed that VK1 supplementation [1, 3, 5 μg/kg body weight (BW), 8 weeks] dose dependently improved the glucose tolerance; decreased BW gain, fasting glucose and insulin, glycated hemoglobin, HOMA-IR and cytokine secretion (monocyte chemoattractant protein-1 and interleukin-6); and regulated the signaling pathway of hepatic glucose metabolism [sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK)/phosphoinositide 3-kinase/phosphatase and tensin homolog/glucose transporter 2/glucokinase/glucose 6 phosphatase], lipid oxidation (peroxisome proliferator-activated receptor alpha/carnitine palmitoyltransferase 1A) and inflammation (nuclear factor kappa B) in T2D mice. Comparative signal silencing studies also depicted the role of SIRT1/AMPK in mediating the effect of VK1 on glucose metabolism, lipid oxidation and inflammation in high-glucose-treated cultured hepatocytes. In conclusion, this study demonstrates that circulating VK1 has a positive effect on lowering fasting glucose and insulin resistance in T2D via regulating SIRT1/AMPK signaling pathway.