Figure 1.
Cyclodextrins enhance the solubility of naringenin.
(a) Complexation of naringenin with cyclodextrins resulted in minimal shift in the compound UV absorption spectrum. (b) Naringenin solubility in water was measured to be 36±1 µM, whereas its soluble fraction increased with the addition of βCD, mβCD, or HPβCD by 132-fold, 526-fold, and 437-fold, respectively.
Table 1.
Naringenin solubility in cyclodextrin solutions.
Figure 2.
HPβCD enhances the bioavailability of naringenin.
(a) 11 mM naringenin, either alone or in a complex with 45 mM HPβCD, was added to the top apical chamber of a Caco-2 model of human intestinal transport. In the presence of HPβCD, the concentration of naringenin was increased in the bottom basal side from 40±20 nM to 510±70 nM, representing an 11-fold enhancement of transport across the Caco-2 monolayer. (b) Phase image of Caco-2 monolayer grown for 21 days on collagen-coated transwell membranes. Barrier resistance remained unchanged during the course of the experiment. (c) Male Sprague-Dawley rats were fed 20 mg/kg body weight naringenin either alone, or as a HPβCD-naringenin complex. Blood samples were collected sequentially and analyzed for naringenin content by LC-MS. HPβCD-naringenin complex had higher oral bioavailability compared to naringenin alone. AUC0-10 of the HPβCD-naringenin complex increased by 7.4-fold (p = 0.005), and maximal concentration, Cmax increased by 14.6-fold (p = 0.002).
Figure 3.
HPβCD-naringenin complex ameliorates the effects of a fat and glucose-rich meal.
(a) Male Sprague-Dawley rats were fasted overnight, and then fed 20 mg/kg body weight naringenin either alone or as a HPβCD-naringenin complex. 30 min later, the rats were administered a meal composed of a suspension of 1 ml/kg olive oil and 1 g/kg glucose. Glucose clearance was measured as the rate of return to normal from maximal concentration (about 65 min). (b) Plasma cholesterol, HDL, triglycerides, and ApoB100 (VLDL) were measured 3.5 hrs after the meal. Cholesterol and HDL levels did not change. Triglyceride levels in rats fed the HPβCD-naringenin complex were elevated, but not significantly (p = 0.24, n = 3). In contrast, plasma levels of ApoB100, the structural protein of VLDL, were significantly 42% lower (p = 0.05, n = 3) than rats given naringenin alone. (c) mRNA abundance of PGC1α increased by 230±100% and 118±60% in skeletal muscle and liver, respectively. Tissue samples were collected 3.5 hrs after the meal.
Figure 4.
Male Sprague-Dawley rats were fed 20 mg/kg body weight naringenin either alone, or as a HPβCD-naringenin complex.
Animals were sacrificed 10 hrs post-treatment and tissue samples were collected and preserved. Representative images of H&E histological preparations from bowel, kidney, and liver are presented. Tissues were evaluated by a blinded pathologist and were judged to be normal with no signs of inflammation or necrosis.
Table 2.
Comprehensive Metabolic Panel of naringenin-treated male Sprague-Dawley rats compared with untreated controls.