Anti-osteoporosis Effect of Fisetin against Ovariectomy Induced Osteoporosis in Rats: In silico, in vitro and in vivo Activity.

Osteoporosis is a bone related disease that is characterised by bone loss that further increases the susceptibility to bone fractures and bone frailty due to disturbances in the micro-architecture of bone tissue. Fisetin (flavonoids) exhibited anti-inflammatory and antioxidative stress effects against various diseases. In this protocol, we make an effort to comfort the anti-osteoporosis effect of fisetin against ovariectomy (OVX) induced osteoporosis. A docking study of fisetin and alendronate on the estrogen (α and ß) and vitamin D receptors was carried out. SaOS-2 (osteoblast like human) cells were used for the estimation of cell proliferation. The OVX induced OVX model was used and three doses of fisetin and alendronate was given to rats till 16 weeks. The hormone levels, bone turnover markers and biochemical parameters were estimated. Fisetin was docked into estrogen (α and ß) and vitamin D receptors, resulting in stable complexes with lower binding scores. Fisetin significantly (p < 0.001) exhibited the induction of cell proliferation against the SaOS-2 cells. OVX induced osteoporosis rats exhibited a suppression of body weight and uterus index, after the Fisetin treatment. Fisetin treatment significantly (p < 0.001) improved the level of bone mineral content (BMC), bone mineral density (BMD) and biochemical parameters such as energy, maximum load, stiffness, young modules, maximum stress and reduced the level of 1,25(OH) 2 D3 and E 2 . Fisetin treatment significantly (p < 0.001) declined the level of phosphorus (P), calcium (Ca) and boosted the level of VitD. Fisetin treatment significantly (p < 0.001) reduced the malonaldehyde (MDA) level and enhanced the glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) level in the bone, intestine and hepatic tissue. Fisetin treatment suppressed the cytokines, RANKL/OPG ratio, receptor activator of nuclear factor-κB ligand (RANKL) and improved the level of osteoprotegerin (OPG). The findings suggest that fisetin could be a beneficial phytoconstituent for the treatment and prevention of postmenopausal osteoporotic complications.

Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis-associated encephalopathy.

BACKGROUND: Fisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis-associated encephalopathy (SAE) remains unclarified. METHODS: Cecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood-brain barrier (BBB) integrity was detected by Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro-inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes. RESULTS: Rats in the CLP group presented increased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase-1 expression and IL-1ß secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase-1 and reduced release of IL-1ß into CNS. CONCLUSION: Collectively, fisetin-blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL-1ß into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.

The effect of monomeric and oligomeric FLAVAnols in patients with type 2 diabetes and microalbuminuria (FLAVA-trial): A double-blind randomized controlled trial.

BACKGROUND & AIMS: Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. METHODS: We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200 mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. RESULTS: Participants (n = 97) were 63.0 ± 9.5 years old; diabetes-duration was 15.7 ± 8.5 years. Median baseline AER was 60 (IQR 20-120) mg/24 h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24 h, p = 0.41) or the control group (0 (-20-10) mg/24 h, p = 0.91). There was no between-group difference in the course of AER over three months (log-transformed data: ß = -0.02 (95%CI -0.23-0.20), p = 0.88), nor in the plasma levels of the endothelial dysfunction markers. CONCLUSION: Daily 200 mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. CLINICAL TRIALS REGISTRATION: NTR4669, www.trialregister.nl.

Dietary dihydromyricetin supplementation enhances antioxidant capacity and improves lipid metabolism in finishing pigs.

Nowadays, chronic diseases have become a potential danger to human health and are highly concerning. Given that pigs are a suitable animal model for human nutrition and metabolism for its similar anatomical and physiological properties to those of humans, this study has used 24 castrated male Duroc × Landrace × Yorkshire (DLY) pigs as experimental subjects to explore the effects of dietary dihydromyricetin (DHM) supplementation on the antioxidant capacity and lipid metabolism. Results showed that dietary 300 and 500 mg DHM kg-1 diet supplementation increased the serum total superoxide dismutase (T-SOD) level, serum and liver reduced glutathione (GSH), muscle catalase (CAT) level and serum high-density lipoprotein cholesterol (HDL-C) level, and reduced the liver malondialdehyde (MDA) level and muscle triglyceride (TG) level in finishing pigs. Western blot analysis showed that dietary DHM supplementation activated the nuclear-related factor 2 (Nrf2) and AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signals. Real-time quantitative PCR analysis showed that dietary DHM supplementation upregulated the mRNA levels of lipolysis and fatty acid oxidation-related genes, and down-regulated the mRNA expression of lipogenesis-related genes in finishing pigs. Together, we provide evidence that dietary DHM supplementation improved the antioxidant capacity and lipid metabolism in finishing pigs.

Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-ß/SMAD3 signaling.

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.

Insights into the role of diet and dietary flavanols in cognitive aging: results of a randomized controlled trial.

With the world's population aging, age-related memory decline is an impending cognitive epidemic. Assessing the impact of diet on cognitive aging, we conducted a controlled, randomized, parallel-arm dietary intervention with 211 healthy adults (50-75 years) investigating effects of either a placebo or 260, 510 and 770 mg/day of cocoa flavanols for 12-weeks followed by 8-weeks washout. The primary outcome was a newly-developed object-recognition task localized to the hippocampus' dentate gyrus. Secondary outcomes included a hippocampal-dependent list-learning task and a prefrontal cortex-dependent list-sorting task. The alternative Healthy Eating Index and a biomarker of flavanol intake (gVLM) were measured. In an MRI substudy, hippocampal cerebral blood volume was mapped. Object-recognition and list-sorting performance did not correlate with baseline diet quality and did not improve after flavanol intake. However, the hippocampal-dependent list-learning performance was directly associated with baseline diet quality and improved after flavanol intake, particularly in participants in the bottom tertile of baseline diet quality. In the imaging substudy, a region-of-interest analysis was negative but a voxel-based-analysis suggested that dietary flavanols target the dentate gyrus. While replication is needed, these findings suggest that diet in general, and dietary flavanols in particular, may be associated with memory function of the aging hippocampus and normal cognitive decline.

Astilbin lowers the effective caffeine dose for decreasing lipid accumulation via activating AMPK in high-fat diet-induced obese mice.

BACKGROUND: Caffeine has an anti-obesity effect, although chronic excessive caffeine consumption also causes caffeinism, which is marked by increased anxiety or depression, amongst other symptoms. The present study aimed to investigate whether the addition of flavonoids such as astilbin can reduce the caffeine dose needed to inhibit obesity. RESULTS: ICR mice (n = 80) were fed with normal diet, high-fat diet (HFD), HFD supplemented with astilbin, caffeine, or astilbin + caffeine for 12 weeks. When diets supplemented with astilbin, 0.3 g kg-1 diet caffeine had the same effect as 0.6 g kg-1 diet caffeine alone, and 0.6 g kg-1 diet caffeine combined with astilbin most effectively inhibited HFD-induced obesity. Astilbin improved the anti-obesity effects of caffeine on lipid accumulation via the activation of AMP-activated protein kinase α (AMPKα). (i) Activated AMPKα decreased lipid biosynthesis by suppressing the activity or mRNA expression of 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element binding protein 1c and its target gene fatty acid synthase. (ii) Activated AMPKα also up-regulated lipolysis by enhancing the expression of adipose triglyceride lipase and increasing the phosphorylation of hormone-sensitive lipase. (iii) Finally, activated AMPKα increased carnitine acyltransferase and acyl-CoA oxidase activities, which further promoted fatty acid ß-oxidation. CONCLUSION: The results obtained in the present study indicate that astilbin may decrease the effective dose of caffeine needed for an anti-obesity effect and also suggest that it suppresses fat accumulation via the activation of AMPK. © 2020 Society of Chemical Industry.

Physicochemical properties of dihydromyricetin and the effects of ascorbic acid on its stability and bioavailability.

BACKGROUND: Dihydromyricetin (DMY) is a natural dihydroflavonol with many bioactive effects. However, the physicochemical properties of DMY related to its bioavailability, especially its stability, are unclear. RESULTS: The effects of pH, temperature, metal ions and ascorbic acid (AA) on the stability of DMY were studied using high-performance liquid chromatography (HPLC). The bioavailability of DMY in the presence and absence of AA was compared. Dihydromyricetin was unstable in weak alkaline solutions, and the degradation was significantly accelerated in the presence of Cu2+ and Fe3+ . The degradation process followed the first-order kinetic model. The degradation rate constant (k) increased with increasing pH and temperature. The remaining DMY was only 49% of its initial concnentration after 4 h in simulated intestinal fluid (SIF) at 37 °C. However, by supplementing with AA, the degradation of DMY was rarely occured within 6 h. The solubility of DMY at pH 3-5 was about 750 µg mL-1 , slightly increasing to 853 µg mL-1 at pH 6. Pharmacokinetic studies showed that the bioavailability of DMY increased from 0.122% to 0.341% by supplementing with AA (10% of DMY). CONCLUSION: The degradation of DMY is one reason for its poor bioavailability. The presence of AA could significantly improve the stability of DMY, and further improve its bioavailability in rats. © 2020 Society of Chemical Industry.

Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer's Disease: A Systematic Review.

Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

Flavanols and triterpenoids from Myrianthus arboreus ameliorate hyperglycaemia in streptozotocin-induced diabetic rats possibly via glucose uptake enhancement and α-amylase inhibition.

Myrianthus arboreus is use traditionally as an antidiabetic agent in Ghana. We reported the in vivo antidiabetic activity of its 70 % ethanol stem bark extract (MAB) which we found to be strongly concentrated in its EtOAc fraction using glucose uptake and enzyme inhibitory assays. The present study sought to investigate the in vivo hypoglycaemic and anti-hyperlipidaemic activity of this ethyl acetate fraction of MAB (MAB-EtOAc, 50 and 100 mg/kg) in streptozotocin (STZ)-induced diabetic rats for 21 days, isolate and evaluate the bioactive constituents responsible for the antidiabetic activity. In silico pharmacokinetic and toxicity properties of the most active compound was also determined. MAB-EtOAc significantly (p < 0.001) reduced the blood glucose levels while normalizing considerably the altered serum lipid parameters of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Chemical investigation of MAB-EtOAc led to the isolation of seven known compounds including three flavanols which are reported for the first time in the plant: epicatechin (1), epigallocatechin (2), dulcisflavan (3), euscaphic acid (4), tormentic acid (5), sitosterol-3-O-ß-d-glucopyranoside (6) and arjunolic acid (7). The compounds markedly inhibited the action of α-amylase and, except for 4 and 6, which stimulated considerably glucose uptake in C2C12 cells. Compounds 2, 3, 5, 6 and 7 which were further evaluated in STZ-induced diabetic rats demonstrated hypoglycaemic and anti-hyperlipidaemic activities which, however, were not comparable with MAB-EtOAc. Compound 3, the most active compound was predicted to be non-toxic, non-mutagenic, has reasonable oral bioavailability and a decent substrate for further drug development. The findings of this study show that the isolated compounds may contribute to the antidiabetic activity of M. arboreus and could serve as marker compounds for the quality control of herbal medicines that would be made from the plant.

Dihydromyricetin Protects the Liver via Changes in Lipid Metabolism and Enhanced Ethanol Metabolism.

BACKGROUND: Excess alcohol (ethanol, EtOH) consumption is a significant cause of chronic liver disease, accounting for nearly half of the cirrhosis-associated deaths in the United States. EtOH-induced liver toxicity is linked to EtOH metabolism and its associated increase in proinflammatory cytokines, oxidative stress, and the subsequent activation of Kupffer cells. Dihydromyricetin (DHM), a bioflavonoid isolated from Hovenia dulcis, can reduce EtOH intoxication and potentially protect against chemical-induced liver injuries. But there remains a paucity of information regarding the effects of DHM on EtOH metabolism and liver protection. As such, the current study tests the hypothesis that DHM supplementation enhances EtOH metabolism and reduces EtOH-mediated lipid dysregulation, thus promoting hepatocellular health. METHODS: The hepatoprotective effect of DHM (5 and 10 mg/kg; intraperitoneal injection) was evaluated using male C57BL/6J mice and a forced drinking ad libitum EtOH feeding model and HepG2/VL-17A hepatoblastoma cell models. EtOH-mediated lipid accumulation and DHM effects against lipid deposits were determined via H&E stains, triglyceride measurements, and intracellular lipid dyes. Protein expression of phosphorylated/total proteins and serum and hepatic cytokines was determined via Western blot and protein array. Total NAD+ /NADH Assay of liver homogenates was used to detect NAD + levels. RESULTS: DHM reduced liver steatosis, liver triglycerides, and liver injury markers in mice chronically fed EtOH. DHM treatment resulted in increased activation of AMPK and downstream targets, carnitine palmitoyltransferase (CPT)-1a, and acetyl CoA carboxylase (ACC)-1. DHM induced expression of EtOH-metabolizing enzymes and reduced EtOH and acetaldehyde concentrations, effects that may be partly explained by changes in NAD+ . Furthermore, DHM reduced the expression of proinflammatory cytokines and chemokines in sera and cell models. CONCLUSION: In total, these findings support the utility of DHM as a dietary supplement to reduce EtOH-induced liver injury via changes in lipid metabolism, enhancement of EtOH metabolism, and suppressing inflammation responses to promote liver health.

Pharmacokinetic, bioavailability and tissue distribution study of astilbin in rats.

OBJECTIVE: The purpose of this study is to reveal the pharmacokinetic profiles of astilbin with various doses in rats and investigate the oral absolute bioavailability and tissue distribution of astilbin after oral administration. METHODS: Wistar rats were orally administered astilbin 12, 24 mg/kg and intravenous administered astilbin 6 mg/kg randomly. The concentration of astilbin in rat plasma and various tissue samples was determined by LC-MS/MS method. Noncompartmental pharmacokinetic parameters including AUC and t1/2 were calculated from plasma concentration-time data of astilbin with the DAS 3.0. KEY FINDINGS: After oral administration of astilbin 12 and 24 mg/kg to rats, the oral absolute bioavailability of astilbin were 1.16 ± 0.695% and 1.27 ± 0.379%; the plasma elimination half-lives (t1/2 ) were 101 ± 35.8 and 109 ± 25.3 min, respectively. Astilbin had a rapid absorption and a wide distribution throughout the whole body except liver and fat following oral administration. Astilbin could penetrate the blood-brain barrier of rat. CONCLUSIONS: The oral absolute bioavailability of astilbin is poor because of the low permeability and solubility. Both oral absorption and clearance of astilbin in rats are rapid after oral administration.

Acute consumption of flavanol-rich cocoa beverage improves attenuated cutaneous microvascular function in healthy young African Americans.

Flavanols have beneficial effects on vascular health and we have recently demonstrated that cerebral vasodilatory capacity in healthy young African Americans (AA) is improved with acute flavanol intake relative to aged-matched Caucasian Americans (CA). However, whether the positive benefits of acute flavanol consumption would also be present in the cutaneous microvascular circulation of AA remains unknown. Thus, we hypothesized that acute consumption of flavanol-rich cocoa (FC) would improve the previously reported reduced cutaneous microvascular responses to local heating in young AA. Seven AA and seven CA participated in this double-blind crossover study. Data were collected on two different days, separated by a minimum of one week. Two intradermal microdialysis membranes were inserted in the forearm and each site was randomly assigned to receive lactated Ringer's solution or NO synthase (NOS) inhibitor. Participants were randomly assigned to consume either a non-flavanol containing (NF) beverage or FC beverage. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flux/mean arterial pressure and normalized as % maximal CVC (%CVCmax). The difference in %CVCmax between the Ringer's site and NOS inhibited site was calculated to assess NO contribution (Δ %CVCmax). In the Ringer's site, acute consumption of FC beverage improved %CVCmax during 39 °C heating when compared to NF beverage in AA (NF: 36 ±â€¯6 vs. FC: 47 ±â€¯5%CVCmax; P < .01) while there was similar %CVCmax during 39 °C heating between beverages in CA (NF: 55 ±â€¯4 vs. FC: 59 ±â€¯5%CVCmax; P = .40). During 39 °C heating, NO contribution was significantly higher with FC beverage than NF beverage in AA (NF: 27 ±â€¯5 vs. FC: 35 ±â€¯4 Δ %CVCmax; P = .03) while there was similar NO contribution between beverages in CA (NF: 42 ±â€¯4 vs. FC: 45 ±â€¯4 Δ %CVCmax; P = .36). This data suggests that acute consumption of FC could be a therapeutic solution to improve an attenuated microvascular function in young AA.

Metabolism, Excretion, and Tissue Distribution of Astilbin-Zein Nanoparticles in Rats.

The excretion, tissue distribution, and metabolic profile of astilbin in rat were studied by HPLC and UPLC-QTOF-MS. Astilbin underwent isomerization in the small intestine, and its four isomers were found in feces. Besides, taxifolin, the aglycone of astilbin, and its further metabolites by gut microbes through hydrogenation, dehydration, and ring-fission were found. The total feces excretion of astilbin was about 14.4% of administration. The forming of zein-caseinate nanoparticles can significantly delay and reduce the feces excretion of astilbin. Astilbin and its isomers were absorbed in their intact form. The main metabolites found in plasma and tissues were the methylated products. Astilbin was rapidly distributed in various tissues including brain and maintained relatively high concentration in heart. Compared with other tissues, significantly higher concentration and longer duration of astilbin were found in the gastrointestinal tract. Astilbin and its isomers were excreted in their intact and methylated form in urine.

Flavanol supplementation protects against obesity-associated increases in systemic interleukin-6 levels without inhibiting body mass gain in mice fed a high-fat diet.

Weight gain and obesity are associated with increased levels of proinflammatory cytokines. Studies have demonstrated the ability of dietary flavanols to reduce the severity of metabolic derangements due to high-fat (HF) feeding. The degree of polymerization of the flavanols appears to play a role in determining the extent of these protective effects. This study evaluated the preventative effects of grape seed and pine bark flavanol supplementation, with significantly different flavanol degree of polymerization, in the context of an HF diet. For 13 weeks, mice were given 35 mg/kg body weight per day grape seed or pine bark as part of an HF diet and compared to mice fed a low-fat diet and control HF diet. All flavanol-supplemented groups and the HF control incurred significantly higher weight gain compared to the lean control, and the grape seed group gained significantly more weight than the HF control. Increased weight gain of treatment groups was likely caused by hyperphagia. Despite lack of improvements to weight gain and glycemic control, it was observed that all flavanol treatment groups were able to significantly reduce interleukin-6 compared to HF control. The grape seed group, which gained the most weight overall, also exhibited the lowest levels of interleukin-6 compared to other groups. Overall, low-dose flavanol extract supplementation, regardless of mean degrees of polymerization, blunted cytokine production despite increased weight gain. This obesity-independent effect suggests flavanols may be used as complementary interventions to ameliorate increased inflammatory tone in the contexts of obesity and diabetes. Furthermore, flavanol-induced hyperphagia may have use for attenuation of cachexia.

Bioavailability Enhancement of Astilbin in Rats through Zein-Caseinate Nanoparticles.

Astilbin-encapsulated zein-caseinate nanoparticles were fabricated through the antisolvent method. The encapsulation and loading efficiency of astilbin in the nanoparticles were determined by high-performance liquid chromatography. The nanoparticles were characterized by particle size, ζ potential, redispersibility, scanning electron microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, and differential scanning calorimetry (DSC). Under the optimal formulation of astilbin, zein, and sodium caseinate with a mass ratio of 1:1:2, the size and ζ potential of the nanoparticles were 152.9 nm and -40.43 mV, respectively, while the encapsulation and loading efficiency of astilbin were 80.1 and 21.8%, respectively. The nanoparticles had good redispersibility in water without a particle size change after freeze drying. The nanoparticles showed a spherical shape with a smooth surface. XRD and DSC analyses showed that astilbin existed in amorphous form in the nanoparticles. The interactions between astilbin and the protein were found, and astilbin was encapsulated in nanoparticles rather than adsorbed. The diffusion of astilbin from nanoparticles was significantly faster than that of astilbin suspensions in both simulated gastric and intestinal fluids. Astilbin was relatively stable in simulated intestinal fluids, and the encapsulation in the nanoparticles showed a slight stability improvement effect. A pharmacokinetic study showed that the absolute bioavailability of astilbin was improved from 0.32 to 4.40% in rats through nanoparticle fabrication.

Estimation of daily intake of flavonoids and major food sources in middle-aged Australian men and women.

Flavonoid consumption has reported health benefits such as reducing cardiovascular disease risk factors, improving endothelial function, and delaying age-related cognitive decline. However, there are little dietary intake data for Australians, which limit our ability to make dietary recommendations to increase intakes to a level where health benefits are seen. The aim of this cross-sectional study was to determine the intake of flavonoids, flavonoid classes, and flavonoid subclasses of 1183 Australians aged 39 to 65 years using a validated 215-item food frequency questionnaire. Based on limited global flavonoid intake data, flavanols are the major dietary flavonoid and are found predominantly in tea and cocoa. As Australians are large tea drinkers, we anticipated that flavanols would be the major flavonoid in the Australian diet. The flavonoid content of foods was determined using a combination of the United States Department of Agriculture Databases and the Phenol-Explorer Database. One-way analysis of variance was undertaken to examine differences between flavonoid intake between men and women. Total flavonoid intake was 626 ±â€¯579 mg/d. Men and women consumed 566 ±â€¯559 mg and 660 ±â€¯588 mg of total flavonoids per day, respectively. Thearubigin accounted for 58% of the flavonoid intake. Women consumed more total flavonoids, thearubigins (both P < .01), anthocyanidins (P < .0001), flavan-3-ols, flavones, and flavonols (all P < .05) than men, whereas men consumed more flavanones than women (P = .01). There was no difference between sexes for the consumption of isoflavones. The data indicated that flavan-3-ols, predominantly thearubigin from tea, were the main flavonoid consumed by Australians. This information contributes to population flavonoid intakes, which should be considered when exploring flavonoid and health relationships.

Regular Intake of a Usual Serving Size of Flavanol-Rich Cocoa Powder Does Not Affect Cardiometabolic Parameters in Stably Treated Patients with Type 2 Diabetes and Hypertension-A Double-Blinded, Randomized, Placebo-Controlled Trial.

Regular cocoa consumption has been shown to improve blood pressure (BP), insulin sensitivity, and lipid levels in patients with type 2 diabetes (T2D), using up to 100 g of chocolate or 54 g of cocoa. These effects, attributed to cocoa flavanols, would be beneficial for patients with T2D if they could be achieved by a usual serving size of flavanol-rich cocoa. Forty-two hypertensive patients with T2D (stable pharmacological treatment, with good adjustment for glucose metabolism, lipids, and BP) ingested capsules with 2.5 g/day of a flavanol-rich cocoa or cocoa-free capsules for 12 weeks in a double-blinded, randomized, placebo-controlled study with parallel group design. Participants had to maintain diet, lifestyle, and medication. Before and after intervention, fasting blood samples were collected; BP and nutritional status were investigated. Cocoa treatment did not affect BP, nor glucose metabolism (glucose, HbA1c, insulin, HOMA-IR) and lipids (triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol). Body weight, fat mass, and nutrient supply remained unchanged. Changes in the placebo group did not occur. Regular intake of a usual serving size of flavanol-rich cocoa does not improve cardiometabolic parameters in stably treated patients with T2D and hypertension. As the medication modulates partly the same targets as cocoa flavanols, future studies should focus on the preventive effect of cocoa against diabetes and other cardiometabolic diseases in individuals with preexisting abnormalities that do not require any pharmacological treatment.

Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial.

Background: Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are composed principally of the monomer (-)-epicatechin (∼20%), with a degree of polymerisation (DP) of 1 (DP1), and oligomeric procyanidins (∼80%, DP2-10). Objective: Our objective was to investigate the relative contribution of procyanidins and (-)-epicatechin to CF intake-related improvements in vascular function in healthy volunteers. Design: In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men (aged 18-35 y) consumed the following once daily for 1 mo: 1) a DP1-10 cocoa extract containing 130 mg (-)-epicatechin and 560 mg procyanidins, 2) a DP2-10 cocoa extract containing 20 mg (-)-epicatechin and 540 mg procyanidins, or 3) a control capsule, which was flavanol-free but had identical micro- and macronutrient composition. Results: Consumption of DP1-10, but not of either DP2-10 or the control capsule, significantly increased flow-mediated vasodilation (primary endpoint) and the concentration of structurally related (-)-epicatechin metabolites (SREMs) in the circulatory system while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1-10 and DP2-10 as compared with the control. Conclusions: CF-related improvements in vascular function are predominantly related to the intake of flavanol monomers and circulating SREMs in healthy humans but not to the more abundant procyanidins and gut microbiome-derived CF catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily to that of (-)-epicatechin. This trial was registered at clinicaltrials.gov as NCT02728466.