Background/objectives Liver fibrosis is the consequence of the wound-healing response of the liver to frequent injury. Calycosin is a flavonoid, which has been documented for its hepatoprotective properties. The aim of this study was to evaluate the hepatoprotective action of calycosin in a model of ethanol-induced liver injury (EILI) in rats. For mechanistic insights, we aimed to measure tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), and hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in liver samples and evaluate the ability of calycosin to bind these pathologic molecules. Methods Network pharmacology and molecular docking were performed for discovering the interacting target proteins. Forty male rats were assigned into five groups: 1) the vehicle, 2) the calycosin per se group, 3) the EILI control group, and 4) and 5) the EILI + calycosin (5 or 10 mg/kg) groups. The liver homogenates were used for ELISA measurement of TNF-α, NF-κB, and HIF-1α. Furthermore, liver specimens were used for histopathological and ultrastructural investigations. Results The network pharmacology study confirmed the role of TNF-α/NF-κB/HIF-1α signaling in EILI, and molecular docking explored the possible interaction between calycosin and these three molecules (docking score = −7.6, −7, and −7.6 kcal/mol). The rat study showed that calycosin was able to attenuate histopathological and ultrastructural changes in rat livers, reduce collagen accumulation, and prevent the increases shown in liver enzyme activities (2.17-fold for ALT and 2.26-fold for AST). Conclusion Thus, these integrated in silico and in vivo studies confirmed the hepatoprotective effect of calycosin against the EILI rat model and provided a mechanistic insight through TNF-α/NF-κB/HIF-1α signaling. Further studies are warranted to fully explore the protective mechanism of calycosin in EILI.
Abeer A. Mohamed, Y. G. Sabry, Amr El-Mistekawy et al.· Frontiers in Pharmacology· 0 citations
Myelotoxicity is a common adverse effect of vincristine and other chemotherapeutic drugs. Hesperetin is a bioactive flavanone with anti-inflammatory activity. This study was planned to examine the hesperetin protecting effect against vincristine induced myelosuppression and splenic inflammation in mice and test whether this effect is mediated through the suppression of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response-88 (MYD88)/nuclear factor-kappa B (NF-κB) signaling pathways.
Bioinformatics tools were used to establish the rationale of the study and molecular docking defined the potential binding of hesperetin to TLR4. Mice were allocated into different experimental groups: Group 1: was the saline mice, Group 2; mice were injected with vincristine (0.1 mg/kg, i. p) for 5 days per week, Group 3; mice received vincristine (as in Group 2) plus hesperetin (100 mg/kg, p. o.) and Group 4; mice received hesperetin (100 mg/kg, p. o.) only; the experiment continued for 2 weeks.
The mouse experiment showed that vincristine produced significant decreases in hematological parameters (mainly leukocytes dropped to 4.6 ± 0.32 and platelets dropped to 799.6 ± 25.46 versus 9.48 ± 0.19 and 1654 ± 273.26 × 10
˄
9/L in the saline group, p less than 0.05) and bone marrow hypocellularity (dropped to ∼30–40% compared to 95%–100% in the saline group). The spleens showed white pulp lymphoid depletion, red pulp mild hypocellularity, greater immunostaining for MYD88, and greater content for TLR4, NF-κB, MYD88, TNF-α and IL-1β proteins. Results of molecular docking showed that hesperetin is an interesting complementarity with the TLR4/MD2 interface which was a good rationale for the experimental validation. The mouse experiment showed that hesperetin prevented the decrease hematological parameters, enhanced the bone marrow cellularity to 80%–90%, and the splenic architecture. Hesperetin further inhibited the increases in the target proteins (TLR4, NF-κB, MYD88, TNF-α and IL-1β) significantly.
The present data documents the novel role of hesperetin in mitigating myelotoxicity of vincristine through modulation of TLR4/MYD88/NF-κB signaling and a direct binding to TLR4 was proposed by molecular docking. This highlights possible usefulness of this combination after adequate clinical studies.
Ghada A. Badawi, Asmaa K. K. AbdelMaogood, Nada H. Ahmed et al.· Frontiers in Pharmacology· 0 citations
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