Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs.

Autor: Hassan NF; Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: Noha.Fawzy@pharm.mti.edu.eg., El-Ansary MR; Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: mona.el-ansary@pharm.mti.edu.eg., Selim HMRM; Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt. Electronic address: hmustafa@um.edu.sa., Ousman MS; Emergency Medical Services, College of Applied Sciences, AlMaarefa University, P.O. Box 71666, Riyadh, Saudi Arabia. Electronic address: mousman@um.edu.sa., Khattab MS; Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza 1211, Egypt. Electronic address: Marwakhattab@cu.edu.eg., El-Ansary MRM; Medical Microbiology and Immunology Department, Faculty of Medicine, Misr University for Science and Technology (MUST), Giza 12566, Egypt. Electronic address: Mahmoud.roshdy@must.edu.eg., Gad ES; Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology and Toxicology, faculty of Pharmacy, Sinai University-Kantara branch, Ismailia, Egypt., Moursi SMM; Medical Physiology Department, Faculty of Medicine, Zagazig University, 44519, Egypt. Electronic address: SMMorsi@medicine.zu.edu.eg., Gohar A; Microbiology and Immunology Department, Faculty of Pharmacy, Ahram Canadian University, sixth of October city, Giza, Egypt; Microbiology and Immunology Department, Faculty of Pharmacy, Galala University, New Galala City, Suez, 43713, Egypt. Electronic address: Asmaa.Hasseiba@GU.edu.eg., Gowifel AMH; Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt. Electronic address: ayah.gowifel@pharm.mti.edu.eg.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Aug; Vol. 177, pp. 116929. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1016/j.biopha.2024.116929
Abstrakt: Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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