Flavonoids-mediated TLR4 Inhibition as a Promising Therapy for Renal Diseases

Mahmoud, Ayman M ORCID: https://orcid.org/0000-0003-0279-6500, Sayed, Ahmed M., Ahmeda, Ahmed F., Abd-Alhameed, Esraa K., Salem, Shimaa H., Alruhaimi, Reem S., Shukur, Ali and Hassanein, Emad H.M. (2023) Flavonoids-mediated TLR4 Inhibition as a Promising Therapy for Renal Diseases. Combinatorial Chemistry & High Throughput Screening, 26 (12). pp. 2124-2148. ISSN 1386-2073

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Abstract

Toll-like receptors (TLRs) control both innate and adaptive immunity with a wide expression on renal epithelial cells and leukocytes. Activation of TLRs results in the production of cytokines, chemokines and interferons along with activation of the transcription factor NF-κB, resulting in inflammatory perturbations. TLR4 signaling pathway is the most extensively studied of TLRs. TLR4 is expressed on renal microvascular endothelial and tubular epithelial cells. So, targeting TLR4 modulation could be a therapeutic approach to attenuate kidney diseases that are underlined by inflammatory cascade. Medicinal plants with anti-inflammatory activities display valuable effects and are employed as alternative sources to alleviate renal disease linked with inflammation. Flavonoids and other phytochemicals derived from traditional medicines possess promising pharmacological activities owing to their relatively cheap and high safety profile. Our review focuses on the potent anti-inflammatory activities of twenty phytochemicals to verify if their potential promising renoprotective effects are related to suppression of TLR4 signaling in different renal diseases, including sepsis-induced acute kidney injury, renal fibrosis, chemotherapy-induced nephrotoxicity, diabetic nephropathy and renal ischemia/reperfusion injury. Additionally, molecular docking simulations were employed to explore the potential binding affinity of these phytochemicals to TLR4 as a strategy to attenuate renal diseases associated with activated TLR4 signaling.