stilbenes and hesperetin

Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m(2)), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (-37%, P < 0.05) and total body methylglyoxal-protein glycation (-14%, P < 0.01). It decreased fasting and postprandial plasma glucose (-5%, P < 0.01, and -8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min(-1) ⋅ m(-2), P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (-10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Cell Line; Cross-Over Studies; Female; Glutathione; Glutathione Disulfide; Hep G2 Cells; Hesperidin; Humans; Lactoylglutathione Lyase; Male; Middle Aged; Models, Biological; Obesity; Overweight; Pyruvaldehyde; Resveratrol; Stilbenes; Young Adult

Drug nanosuspension is one of the established methods to improve the bioavailability of poorly soluble drugs. Drug physical properties aspect (morphology, solid state, starting size et al) is a critical parameter determining the production efficiency. Some drug modification approaches such as spray-drying were proved to improve the millability of drug powders. However, the mechanism behind those improved performances is unclear. This study is to systematically investigate the influence of those physical properties.. Five different APIs (active pharmaceutical ingredients) with different millabilities, i.e. resveratrol, hesperetin, glibenclamide, rutin, and quercetin, were processed by standard high pressure homogenization (HPH), wet bead milling (WBM), and a combinative method of spray-drying and HPH.. Smaller starting sizes of certain APIs could accelerate the particle size reduction velocity during both HPH and WBM processes. Spherical particles were observed for almost all spray-dried powders (except spray-dried hesperetin) after spray-drying. The crystallinity of some spray-dried samples such as rutin and glibenclamide became much lower than their corresponding unmodified powders. Almost all spray-dried drug powders after HPH processes could lead to smaller nanocrystal particle size than unmodified APIs.. The modified microstructure instead of solid state after spray-drying explained the potential reason for improved nanosizing efficiency. In addition, the contribution of starting size on the production efficiency was also critical according to both HPH and WBM results.

Topics: Calorimetry, Differential Scanning; Crystallization; Desiccation; Glyburide; Hesperidin; Microscopy, Electron, Scanning; Nanoparticles; Particle Size; Powder Diffraction; Quercetin; Resveratrol; Rutin; Stilbenes; Technology, Pharmaceutical

Systematic screening for optimal formulation composition and production parameters for nanosuspensions consumes a lot of time and also drug material when performed at lab scale. Therefore, a cost-effective miniaturized scale top down approach for nanocrystals production by wet bead milling was developed. The final set-up consisted of 3 magnetic stirring bars placed vertically one over the other in a 2 mL glass vial and agitated by a common magnetic stirring plate. All of the tested actives (cyclosporin A, resveratrol, hesperitin, ascorbyl palmitate, apigenin and hesperidin) could be converted to nanosuspensions. For 4 of them, the particles sizes achieved were smaller than previously reported on the literature (around 90 nm for cyclosporin A; 50 nm for hesperitin; 160 nm for ascorbyl palmitate and 80 nm for apigenin). The "transferability" of the data collect by the miniaturized method was evaluated comparing the production at larger scale using both wet bead milling and high pressure homogenization. Transferable information obtained from the miniaturized scale is minimum achievable size, improvements in size reduction by reduction of beads size, diminution kinetics and potentially occurring instabilities during processing. The small scale batches also allow identification of optimal stabilizer types and concentrations. The batch size is 0.5 mL, requiring approximately 50 mg or 5 mg of drug (5% and 1% suspension, respectively). Thus, a simple, accessible, low-cost miniaturized scale method for the production of pharmaceutical nanocrystals was established.

Topics: Apigenin; Ascorbic Acid; Chemistry, Pharmaceutical; Cyclosporine; Hesperidin; Miniaturization; Nanoparticles; Particle Size; Resveratrol; Stilbenes; Suspensions; Technology, Pharmaceutical

The objective of this study was to investigate the ability of resveratrol and hesperetin to scavenge acrolein at pH 7.4 and 37 °C. About 6.4 or 5.2% of acrolein remained after reaction with resveratrol or hesperetin for 12 h at equimolar concentrations. An acrolein-resveratrol adduct and two acrolein-hesperetin adducts were isolated. Their structures were elucidated using mass and NMR spectroscopy. Acrolein reacted with resveratrol at the C-2 and C-3 positions through nucleophilic addition and formed an additional heterocyclic ring. Two similar monoacrolein-conjugated adducts were identified for hesperetin. Spectroscopic data suggested each acrolein-hesperetin adduct was a mixture of four stereoisomers due to the existence of two chiral carbon atoms. Yield of adducts was low at pH 5.4 but increased at pH 7.4 and 8.4. Higher pH also promoted the formation of diacrolein adducts. Results suggest that resveratrol and hesperetin exert health benefits in part through neutralizing toxic acrolein in vivo.

Topics: Acrolein; Antioxidants; Hesperidin; Hydrogen-Ion Concentration; Molecular Structure; Resveratrol; Stilbenes

Antioxidants possess significant therapeutic potential for the treatment of inflammatory disorders. One such disorder is periodontitis characterised by an antimicrobial immune response, inflammation, and irreversible changes to the supporting structures of the teeth. Recognition of conserved pathogen-associated molecular patterns is a crucial component of innate immunity to Gram-negative bacteria such as Escherichia coli, as well as the periodontal pathogen Aggregatibacter actinomycetemcomitans. In this study, we investigated the antioxidants Phloretin, Silymarin, Hesperetin, and Resveratrol to ascertain whether they altered the production of inflammatory mediators by innately-activated leukocytes. Peripheral blood mononuclear cells were stimulated with lipopolysaccharide purified from Aggregatibacter actinomycetemcomitans, and the production of cytokines, chemokines, and differentiation factors was assayed by enzyme-linked immunosorbent assay, cytometric bead array, and RT-PCR. Significant inhibition of these factors was achieved upon treatment with Phloretin, Silymarin, Hesperetin, and Resveratrol. These data further characterise the potent anti-inflammatory properties of antioxidants. Their ability to inhibit the production of inflammatory cytokines, chemokines, and differentiation factors by a heterogeneous population of leukocytes has clear implications for their therapeutic potential in vivo.

Topics: Aggregatibacter actinomycetemcomitans; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Differentiation; Cells, Cultured; Cytokines; Escherichia coli; Hesperidin; Humans; I-kappa B Proteins; Inflammation; Leukocytes; Leukocytes, Mononuclear; Lipopolysaccharides; Monocytes; Neutrophils; NF-KappaB Inhibitor alpha; Phloretin; Resveratrol; RNA, Messenger; Silymarin; Stilbenes

The reactivity of flavonoids as radical scavengers was investigated under kinetic considerations using radical polymerization of methyl methacrylates initiated by benzoyl peroxide. The number of radicals which are trapped by each molecule of phenol (the stoichiometric factors, n values) decreased in the order of epigallocatechin-3-O-gallate (ECG) (5.5) > catechin (3.5) > resveratrol (2.4) > quercetin (1.9) > n-propylgallate (1.5) > hesperetin (1.0). The inhibition rate constants (k(inh)) (1-3 x 10(3) 1/(mol s)) for the flavonoids were not different from each other, and, therefore, the radical scavenging activity depend on n values. The n values of the fully oxidized flavonoids were estimated from the frontier orbital theory, using PM3 semiempirical molecular orbital calculation. The experimental n values were consistent with the calculated values.

Topics: Catechin; Flavonoids; Free Radical Scavengers; Free Radicals; Hesperidin; Kinetics; Molecular Structure; Polymers; Propyl Gallate; Quercetin; Resveratrol; Stilbenes; Structure-Activity Relationship