TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity
first_pagesettingsOrder Article Reprints
Open AccessArticle
TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity
by Amira M. Badr 1,2,*ORCID,Layla A. Al-Kharashi 1ORCID,Hala Attia 1,3ORCID,Samiyah Alshehri 1ORCID,Hanaa N. Alajami 1,Rehab A. Ali 1 andYasmen F. Mahran 2,*ORCID
1
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia
2
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
3
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2023, 16(3), 337; https://doi.org/10.3390/ph16030337
Received: 15 November 2022 / Revised: 6 February 2023 / Accepted: 16 February 2023 / Published: 22 February 2023
(This article belongs to the Section Pharmacology)
Download Browse Figures Versions Notes
Abstract
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.
Conspiracies regarding vaccines are widely prevalent, with negative consequences on health-seeking behaviors.
Autism spectrum disorder (ASD) is a multidimensional disorder in which environmental, immune, and genetic factors act in concert to play a crucial role. ASD is characterized by social interaction…
This study examined the effect of fermented goat milk (oggtt) against non-alcoholic fatty liver disease (NAFLD) in rats induced by chronic high-fat diet (HFD) treatments. Both control-fed and HFD…