OBJECTIVE: The possible interaction of dietary flavonoid intake and sleep on non-alcoholic fatty liver disease (NAFLD) has not been well studied. This study investigated the interaction between dietary flavonoid intake and trouble sleeping on the risk of NAFLD.
METHODS: Three discrete National Health and Nutrition Examination Survey data cycles from 2007 to 2010 and 2017 to 2018 were used. NAFLD was diagnosed by a US Fatty Liver Index ≥30. A sleep questionnaire diagnosed trouble sleeping. Univariate and multivariate logistic regression, restricted cubic spline (RCS) and subgroup analyses were used to evaluate the association between dietary flavonoids, trouble sleeping and NAFLD. We employed the relative excess risk due to interaction, attributable proportion of interaction and synergy index to evaluate additive interactions.
RESULTS: Ultimately, 5056 participants were enrolled, and higher anthocyanidins and flavanones intake was negatively correlated with NAFLD. Conversely, trouble sleeping was positively associated with NAFLD. These correlations remained stable after adjusting for confounders, and there was a sex difference in this relationship. In the RCS model, anthocyanins were negatively non-linearly related to NAFLD, while flavanones showed a negative linear relationship. Moreover, there was a synergistic interplay between low dietary anthocyanin intake and trouble sleeping on the risk of NAFLD. A similar relationship existed for flavanone intake.
CONCLUSIONS: Anthocyanin and flavanone intake were negatively associated, whereas trouble sleeping was positively associated with NAFLD risk. There was a synergistic effect of low anthocyanin intake and trouble sleeping. The same relationship existed for low flavanone intake.

The therapeutic properties of flavonoids are reported to offer cardioprotective benefits against doxorubicin (Dox)-induced cardiotoxicity (DIC). In the current study, we aimed to investigate the prophylactic properties of 7-hydroxyflavanone (7H), a flavonoid with antioxidative properties, against DIC. An in vitro model of DIC was established by exposing H9c2 cardiomyoblasts to Dox for 6 days. Similarly, cells were also co-treated with 7H to assess its ability to mitigate DIC. The data obtained indicate that 7H, as a co-treatment, alleviates Dox-induced oxidative stress by enhancing total glutathione content (p ≤ 0.001) and superoxide dismutase activity (p ≤ 0.001) whilst decreasing ROS (p ≤ 0.001), malondialdehyde production (p ≤ 0.001) and the secretion of interleukin-6 (p ≤ 0.001). The data also showed an improvement in mitochondrial function as shown via enhanced bioenergetics, mitochondrial membrane potential, and PGC1-alpha (p ≤ 0.05) and pAMPK (p ≤ 0.001) expression. The cardioprotective potential of 7H was further highlighted by its ability attenuate Dox-induced caspase 3/7 activity (p ≤ 0.001), apoptosis (p ≤ 0.001) and necrosis (p ≤ 0.05). In conclusion, our findings demonstrated the cardioprotective benefits of 7H and thus suggests that it could be a suitable candidate cardioprotective agent against DIC.

The excessive steroid may cause dyslipidaemia and oxidative insult during femoral head osteonecrosis, inducing bone loss and impairment of the intraosseous blood system. In contrast, bio-flavanone naringin has shown antioxidant, antiresorptive and lipid-lowering bioactivities. The present research is an effort to explore the anti-ON potential of naringin in vivo and in vitro. After a 6-week treatment, the femora were dissected for histological examination following bone mineral density assay by X-ray absorptiometry. Blood samples were examined for coagulation, oxidative stress, lipid transportation and endothelial injury. Marrow samples were cultured and assayed for adipogenic and osteogenic alterations by ALP activity, mineralization, RT-qPCR and western blot analysis. The results showed that naringin exerted a dose-dependent effect on reducing ON incidence, with inhibition of osteoporosis, oxidative stress and dyslipidaemia. The mechanism included the suppression of PPARγ2 for adipogenesis of bone marrow stem cells (BMSCs) and the prevention of oxidative stress in endothelium injury. Naringin may restore steroid-impaired osteogenesis by enhancing the mRNA and protein expression of osteogenic markers in a dose-ascending manner and new bone formation can be found in naringin groups. Taken together, our findings showed that naringin may serve as a prophylactic agent and selective PPARγ modulator for the early-stage ON.

BACKGROUND: Traditional Chinese medicine (TCM) Xiao Jianzhong Tang (XJZ) has a favorable efficacy in the treatment of chronic atrophic gastritis (CAG). However, its pharmacological mechanism has not been fully explained.
OBJECTIVE: The purpose of this study was to find the potential mechanism of XJZ in the treatment of CAG using pharmacocoinformatics approaches.
METHODS: Network pharmacology was used to screen out the key compounds and key targets, MODELLER and GNNRefine were used to repair and refine proteins, Autodock vina was employed to perform molecular docking, Δ Lin_F9XGB was used to score the docking results, and Gromacs was used to perform molecular dynamics simulations (MD).
RESULTS: Kaempferol, licochalcone A, and naringenin, were obtained as key compounds, while AKT1, MAPK1, MAPK14, RELA, STAT1, and STAT3 were acquired as key targets. Among docking results, 12 complexes scored greater than five. They were run for 50ns MD. The free binding energy of AKT1-licochalcone A and MAPK1-licochalcone A was less than -15 kcal/mol and AKT1-naringenin and STAT3-licochalcone A was less than -9 kcal/mol. These complexes were crucial in XJZ treating CAG.
CONCLUSIONS: Our findings suggest that licochalcone A could act on AKT1, MAPK1, and STAT3, and naringenin could act on AKT1 to play the potential therapeutic effect on CAG. The work also provides a powerful approach to interpreting the complex mechanism of TCM through the amalgamation of network pharmacology, deep learning-based protein refinement, molecular docking, machine learning-based binding affinity estimation, MD simulations, and MM-PBSA-based estimation of binding free energy.

This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4\'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and -15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4\'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4\'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro and preclinical studies are needed to confirm these findings.Communicated by Ramaswamy H. Sarma.

Previous research has demonstrated flavonoid intake was closely related to hyperuricemia. The purpose of this study was to examine whether flavonoid intake was associated with serum uric acid and hyperuricemia in U.S. adults.
The study sample consisted of 8,760 participants enrolled in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010. Flavonoid consumption was measured using a two-day recall questionnaire on dietary intake. Hyperuricemia was defined based on the serum uric acid levels, determined as ≥ 7 mg/dL for males and ≥ 6 mg/dL for females. The study utilized multivariate linear regression to determine the correlation between flavonoid consumption and serum uric acid levels. Additionally, analyses involving multivariate logistic regression and restricted cubic splines (RCS) were conducted to evaluate the potential link between flavonoid consumption and hyperuricemia. All analyses were adjusted for possible confounding variables.
The study revealed a negative correlation between serum uric acid levels and elevated levels of anthocyanidins and flavanones, with significant p-trends of < 0.001 and 0.02 respectively. The multivariate analysis showed that anthocyanidins and flavanones intake had a significant negative association with the risk of hyperuricemia, with p-trend value being < 0.001 and 0.01, respectively. Flavan-3-ols, flavonols, and all flavonoids exhibited a non-linear association with the incidence of hyperuricemia, with significant p-nonlinear values of < 0.001, 0.04, and 0.01 respectively.
Our study demonstrated that individuals who follow a diet rich in anthocyanins and flavanones had significantly lower serum uric acid levels and a lower incidence of hyperuricemia.

Cytostatic activity of baicalin, baicalein, and neogalenical drug Chlorophyllipt was studied in vitro on HeLa-v cells. Standard samples of Eucalimin, baicalin, and baicalein, as well as Chlorophyllipt and paclitaxel (reference drug Taxacad) were used. The cell deaths were determined by MTT assay in a Multiskan FC microplate reader with incubator. The effective inhibition concentration (IC50) of the tested substances were: paclitaxel (4.0±0.4 μM)-baicalein (10.5±1.1 μM)-baicalin (16.5±1.7 μM)-sum of euglobals in Chlorophyllipt (24.1±2.5 μM). Chlorophyllipt was found to exhibit cytostatic activity. Cytostatic activity of baicalein, baicalin, and Chlorophyllipt was lower than cytostatic activity of the reference drug by 2.6, 4.1, and 6 times, respectively. The prospects of further evaluation of the synergetic effect of baicalin, baicalein, and chlorophyllipt used in combinations with different cytostatic agents for finding the most effective combination have been shown.

Chronic orange juice intake is associated with reduced risk of cardiovascular disease, however, a large inter-individual variability in response to orange juice for lipid profile and blood pressure has been observed. This heterogeneity in responsiveness could be associated with single nucleotide polymorphism (SNP), which has not been previously addressed. This study aims to investigate the influence of SNP in apolipoprotein E (APOE), apolipoprotein A1 (APOA1), mevalonate (MVK), and lipase lipoprotein (LPL) genes in the biological response after chronic orange juice intake.
Forty-six volunteers ingested 500 mL daily for 60 days and blood pressure and biochemical parameters are measured. Also, SNPs in APOE, APOA1, MVK, and LPL genes are genotyped in the volunteers that are medium/high excretors of flavanone metabolites. Genotypes CC (APOA1), AA, and GG (LPL) are associated with positive health effects of orange juice and the CC (APOE), GG (APOA1), GG, and AA (LPL) genotypes are associated with no effects of orange juice consumption (p < 0.05).
These results identify for the first-time SNP associated with effects of orange juice on lipid levels and blood pressure, results that may provide bases for future precise nutritional recommendations regarding this flavanone-rich food to lower the risk for cardiovascular disease.

Recently, coamorphization and cocrystal technologies are of particular interest in the pharmaceutical industry due to their ability to improve the solubility/dissolution and bioavailability of poorly water-soluble drugs, while the coamorphous system often tends to convert into the stable crystalline form usually crystalline physical mixture of each component during formulation preparation or storage. In this paper, BCS II drug baicalein (BAI) along with nicotinamide (NIC) were prepared into a single homogeneous coamorphous system with a single transition temperature at 42.5 °C. Interestingly, instead of the physical mixture of crystalline BAI and NIC, coamorphous BAI-NIC would transform to its cocrystal form under stress of temperature and humidity. The transformation rate under isothermal condition was temperature-dependent, since the crystallinity of the cocrystal enhanced as the temperature increased. Further mechanic studies showed the activation energy for the transformation under non-isothermal condition was calculated to be 184.52 kJ/mol. Additionally, water vapor sorption tests with further solid characterizations indicated the transformation was faster under higher humidity condition due to the faster nucleation process of cocrystal BAI-NIC. This research not only discovered the mechanism of transformation from coamorphous BAI-NIC to cocrystal form, but also provided an unusual method for cocrystal preparation from its coamorphous form.

α-Glucosidase is among the intestinal epithelial enzymes that produce absorbable glucose in the final stage of glycan catabolism. It leads to an increase in blood glucose levels as a result of high glucose uptake in diabetic patients. However, inhibition of this essential biochemical process can be a useful therapeutic approach to diabetes mellitus (DM). Eriocitrin (ER) is an abundant \"flavanone glycoside\" in citrus fruits with rich antioxidant properties whose effects on α-Glu inhibition in the small intestine remain to be determined. Herein, pH-sensitive microgels (MGs) were designed based on cross-linked methacrylate with acrylamide (AM) and acrylic acid (AAc) (molar ratio 70 : 30 of AAc : AM) as a controlled release system for sustained delivery of ER into the small intestine. The presence of amide and acrylate in MGs and the mechanical resistance were determined using FT-IR spectroscopy, rheology, and viscoelastometry. In vitro experiments showed that MGs could protect ER against diffusion in the gastric location and adjust its release in the intestinal milieu. The intestinal α-Glu activity was inhibited by ER (IC50 value of 12.50 ± 0.73 μM) in an uncompetitive dose-dependent manner. The presence of ER altered the structure of α-Glu and reduced the hydrophobic pockets of the enzyme. Molecular docking analysis along with molecular dynamics simulation displayed that ER-α-Glu formation is directed by hydrogen binding with Asp69, Asp215, Glu411, Asp307, and Tyr347 residues. Moreover, in vivo assessment showed that rat blood glucose concentration decreased after ER administration compared with the control group. The results highlight that ER-loaded-MGs can be considered as a useful releasing strategy in treating DM via α-Glu inhibition.