The aim of our study was to determine the PPARγ agonism and hypoglycemic activity of natural phenolics isolated from Paulownia tomentosa and Morus alba. We started with a molecular docking preselection, followed by in vitro cell culture assays, such as PPARγ luciferase reporter gene assay and PPARγ protein expression by Western blot analysis. The ability of the selected compounds to induce GLUT4 translocation in cell culture and lower blood glucose levels in chicken embryos was also determined. Among the thirty-six plant phenolic compounds, moracin M showed the highest hypoglycemic effect in an in ovo experiment (7.33 ± 2.37%), followed by mulberrofuran Y (3.84 ± 1.34%) and diplacone (3.69 ± 1.37%). Neither moracin M nor mulberrofuran Y showed a clear effect on the enhancement of GLUT4 translocation or agonism on PPARγ, while diplacone succeeded in both (3.62 ± 0.16% and 2.4-fold ± 0.2, respectively). Thus, we believe that the compounds moracin M, mulberrofuran Y, and diplacone are suitable for further experiments to elucidate their mechanisms of action.

• Keywords
• PPARγ, diabetes mellitus, hypoglycemic, natural products, plant phenolics,
• MeSH
• Phenols * chemistry   pharmacology   isolation & purification   MeSH
• Hypoglycemic Agents * chemistry   pharmacology   isolation & purification   MeSH
• Chick Embryo MeSH
• Humans MeSH
• Morus * chemistry   MeSH
• Mice MeSH
• PPAR gamma * agonists   metabolism   genetics   chemistry   MeSH
• Glucose Transporter Type 4 metabolism   genetics   MeSH
• Plant Extracts * chemistry   pharmacology   isolation & purification   MeSH
• Molecular Docking Simulation MeSH
• Animals MeSH
• Check Tag
• Chick Embryo MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phenols * MeSH
• Hypoglycemic Agents * MeSH
• PPAR gamma * MeSH
• Glucose Transporter Type 4 MeSH
• Plant Extracts * MeSH

The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 µg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability.

• Keywords
• MRSA, S. aureus, anti-inflammatory, antibacterial, antioxidant, cytotoxicity, mastitis, nanotechnology, prenylated flavonoids, skin, wound healing,
• MeSH
• Anti-Bacterial Agents pharmacology   MeSH
• Anti-Infective Agents * pharmacology   MeSH
• Antioxidants * pharmacology   MeSH
• Flavonoids pharmacology   MeSH
• Wound Healing MeSH
• Humans MeSH
• Microbial Sensitivity Tests MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Anti-Infective Agents * MeSH
• Antioxidants * MeSH
• Flavonoids MeSH

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

• Keywords
• P-glycoprotein, flavonoids, molecular docking, molecular dynamics, multidrug resistance, natural compounds, structure-based virtual screening,
• Publication type
• Journal Article MeSH