TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.

Autor: Badr AM; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia.; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt., Al-Kharashi LA; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia., Attia H; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia.; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt., Alshehri S; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia., Alajami HN; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia., Ali RA; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia., Mahran YF; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
Jazyk: angličtina
Zdroj: Pharmaceuticals (Basel, Switzerland) [Pharmaceuticals (Basel)] 2023 Feb 22; Vol. 16 (3). Date of Electronic Publication: 2023 Feb 22.
DOI: 10.3390/ph16030337
Abstrakt: Background: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA.
Methods: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection.
Results: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-κB and TNF-α) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1β) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes.
Conclusions: This study emphasizes that inhibition of TLR4/NLPR3/IL-1β/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.
Databáze: MEDLINE
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