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<p>This study comprehensively evaluated the antidiarrheal potential of phlorizin, a natural dihydrochalcone glycoside abundant in apple peels, using an integrated approach combining network pharmacology, molecular docking, density functional theory (DFT) analyses, antimicrobial assays, and ex vivo spasmolytic evaluations. Network pharmacology identified 52 overlapping targets between phlorizin and diarrhoea-associated genes, significantly enriched in TLR4/NF-κB, PI3K/AKT, and HIF-1 signalling pathways, implicating roles in inflammation regulation, epithelial protection, and cellular metabolism. Molecular docking revealed strong binding affinities of phlorizin with key target proteins including PIK3R1 (− 11.8&#xa0;kcal/mol), SLC2A1/GLUT1 (− 10.3&#xa0;kcal/mol), NF-κB1 (− 6.9&#xa0;kcal/mol), TLR4 (− 6.6&#xa0;kcal/mol), and NOS2 (− 6.4&#xa0;kcal/mol)—stabilized by multiple hydrogen bonds and favourable MMGBSA energies (− 49.14 to − 69.65&#xa0;kcal/mol). DFT analysis (B3LYP-GD3/6-311G(d,p)) demonstrated notable thermodynamic stability (Δ<i>E</i> &lt; 4&#xa0;kcal/mol between conformers), a dipole moment of 10.6 D, and significant charge localisation on hydroxyl oxygens (− 0.55 to − 0.76 e), supporting strong hydrogen bonding and electrostatic interactions within protein binding pockets. Antimicrobial evaluation showed dose-dependent inhibition of <i>Escherichia coli</i> and <i>Bacillus subtilis</i>, with optical density (OD<sub>600</sub>) reductions to 0.23 ± 0.19 and 0.38 ± 0.84, respectively, and inhibition zones up to 2.41 ± 0.26&#xa0;mm at 1000&#xa0;µg/mL, confirming moderate antibacterial activity. Ex vivo spasmolytic assays on isolated chicken ileum demonstrated dose-dependent relaxation against acetylcholine- and histamine-induced contractions, achieving 94.44 ± 0.98% and 90.91 ± 1.45% relaxation at 10&#xa0;mg/mL, with EC<sub>50</sub> values of 4.35 ± 0.96&#xa0;mg/mL and 5.62 ± 0.78&#xa0;mg/mL, respectively. Collectively, these findings highlight phlorizin’s multi-target pharmacological profile, combining anti-inflammatory, antimicrobial, metabolic, and antispasmodic effects. The integration of computational and experimental results supports phlorizin as a thermodynamically stable, selectively binding, and biologically active phytochemical, offering a promising natural alternative for the management of diarrheal diseases, particularly amid rising antibiotic resistance.</p>

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Mechanistic insights into the antidiarrheal action of phlorizin: modulation of TLR4/NF-κB, PI3K/AKT, and HIF-1 signalling with antispasmodic and antimicrobial effects

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Ravi Kushwah,
  • Smita Jain,
  • Meenal Sahu,
  • Chinchu Praisthy LJ,
  • Siddharth Maurya,
  • Taufik Ansari,
  • Mansi,
  • Ashwini Kumar Mishra,
  • Aleksey Kuznetsov

摘要

This study comprehensively evaluated the antidiarrheal potential of phlorizin, a natural dihydrochalcone glycoside abundant in apple peels, using an integrated approach combining network pharmacology, molecular docking, density functional theory (DFT) analyses, antimicrobial assays, and ex vivo spasmolytic evaluations. Network pharmacology identified 52 overlapping targets between phlorizin and diarrhoea-associated genes, significantly enriched in TLR4/NF-κB, PI3K/AKT, and HIF-1 signalling pathways, implicating roles in inflammation regulation, epithelial protection, and cellular metabolism. Molecular docking revealed strong binding affinities of phlorizin with key target proteins including PIK3R1 (− 11.8 kcal/mol), SLC2A1/GLUT1 (− 10.3 kcal/mol), NF-κB1 (− 6.9 kcal/mol), TLR4 (− 6.6 kcal/mol), and NOS2 (− 6.4 kcal/mol)—stabilized by multiple hydrogen bonds and favourable MMGBSA energies (− 49.14 to − 69.65 kcal/mol). DFT analysis (B3LYP-GD3/6-311G(d,p)) demonstrated notable thermodynamic stability (ΔE < 4 kcal/mol between conformers), a dipole moment of 10.6 D, and significant charge localisation on hydroxyl oxygens (− 0.55 to − 0.76 e), supporting strong hydrogen bonding and electrostatic interactions within protein binding pockets. Antimicrobial evaluation showed dose-dependent inhibition of Escherichia coli and Bacillus subtilis, with optical density (OD600) reductions to 0.23 ± 0.19 and 0.38 ± 0.84, respectively, and inhibition zones up to 2.41 ± 0.26 mm at 1000 µg/mL, confirming moderate antibacterial activity. Ex vivo spasmolytic assays on isolated chicken ileum demonstrated dose-dependent relaxation against acetylcholine- and histamine-induced contractions, achieving 94.44 ± 0.98% and 90.91 ± 1.45% relaxation at 10 mg/mL, with EC50 values of 4.35 ± 0.96 mg/mL and 5.62 ± 0.78 mg/mL, respectively. Collectively, these findings highlight phlorizin’s multi-target pharmacological profile, combining anti-inflammatory, antimicrobial, metabolic, and antispasmodic effects. The integration of computational and experimental results supports phlorizin as a thermodynamically stable, selectively binding, and biologically active phytochemical, offering a promising natural alternative for the management of diarrheal diseases, particularly amid rising antibiotic resistance.