Exploring Kaempferol's Potential Immunomodulation and Alleviation of Tacrolimus-Induced Hyperglycemia
| Author | Ahmed S Ali | en |
| Author | Abdullah Saddah Almalki | en |
| Author | Mohammed A Bazuhair | en |
| Author | Huda Mohammed Alkreathy | en |
| Orcid | Ahmed S Ali [0000-0002-3341-8177] | en |
| Orcid | Abdullah Saddah Almalki [0000-0002-8996-8880] | en |
| Orcid | Mohammed A Bazuhair [0000-0002-3784-2346] | en |
| Orcid | Huda Mohammed Alkreathy [0000-0002-7824-8802] | en |
| Issued Date | 2025-12-31 | en |
| Abstract | Background: Calcineurin inhibitors (CNIs), such as tacrolimus (TAC), remain central in transplantation and autoimmune disease management; however, adverse effects, particularly hyperglycemia, frequently complicate their use. Kaempferol (KF), a flavonol with hypoglycemic and antioxidant properties, has been proposed as a potential adjunctive modulator of CNI-related toxicities. Objectives: This study investigated the mechanisms of TAC-induced hyperglycemia, focusing on oxidative stress and calcineurin B1 (CnB1) expression, and assessed the protective effects of KF. Methods: Twenty-four male Wistar rats (180 - 230 g) were randomized into three groups (n = 8/group) and treated for 30 days: (1) The TAC 0.6 mg/kg/day intraperitoneally, (2) TAC + KF 10 mg/kg/day orally, and (3) vehicle controls. Blood samples were collected at days 15 and 30 to measure TAC trough levels, glucose, and insulin by enzyme-linked immunosorbent assay (ELISA). Pancreatic tissues were analyzed for oxidative stress markers [malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH)], P-glycoprotein (P-gp), and CnB1 expression. Molecular docking (MD) was also performed to assess KF interactions with calcineurin subunits. Results: The TAC monotherapy markedly increased serum glucose (128% at day 15; 150% at day 30 vs. controls, P < 0.005) and reduced insulin levels (-81% at day 15; -85% at day 30, P < 0.005). The TAC also elevated pancreatic MDA (+1113%) while significantly suppressing CnB1 expression (-98.4%). Co-administration of KF significantly reduced TAC trough levels by 29% at day 30 (P < 0.005), attenuated hyperglycemia (glucose reduction by 35% at day 15 and 50% at day 30 vs. TAC, P < 0.005), and restored insulin levels (+143% and +350% at days 15 and 30 vs. TAC, P < 0.005). In the pancreas, KF lowered MDA (-62%, P < 0.001), enhanced antioxidant defenses (GSH +128%, SOD +68%), and reversed TAC-induced CnB1 suppression (+408%, P < 0.01). The MD supported a moderate binding of KF to both calcineurin A (CnA) and CnB1 chains, providing a mechanistic basis for its effects. Conclusions: The MD analysis revealed that several flavonoids exhibit promising binding affinities toward CnB1, CnA, and cyclophilin. These findings suggest that flavonoids may possess potential immunomodulatory properties through modulation of the calcineurin pathway. Therefore, further comprehensive investigations — combining advanced MD, molecular dynamics simulations, and in vitro as well as in vivo experimental validation — are essential to confirm the mechanistic roles, efficacy, and safety of flavonoids as potential immunomodulatory agents. | en |
| DOI | https://doi.org/10.5812/jrps-165462 | en |
| Keyword | Tacrolimus | en |
| Keyword | Kaempferol | en |
| Keyword | Calcineurin | en |
| Keyword | Oxidative Stress | en |
| Keyword | Hyperglycemia | en |
| Keyword | Immunosuppressant | en |
| Publisher | Brieflands | en |
| Title | Exploring Kaempferol's Potential Immunomodulation and Alleviation of Tacrolimus-Induced Hyperglycemia | en |
| Type | Research Article | en |
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