Grape Seed Proanthocyanidin Extract Mitigates Titanium Dioxide Nanoparticle (TiO2-NPs)–Induced Hepatotoxicity Through TLR-4/NF-κB Signaling Pathway

  • Eman T. MohammedEmail author
  • Ghada M. Safwat


With the progress of nanotechnology, the adverse effects of nanoscale materials are receiving much attention. Inhibition of toll-like receptor 4 (TLR-4)/nuclear factor kappa B (NF-κB) signaling is a hallmark for downregulating the expression of many inflammatory genes implicated in oxidative stress. Therefore, the present study aimed to demonstrate the influence of grape seed proanthocyanidin extract (GSE) on the hepatic TLR-4/ NF-κB signaling pathway in TiO2-NP-induced liver damage in rats. Forty male Albino rats were divided into 4 groups (n = 10): G1 was used as a control, G2 received TiO2-NPs (500 mg/kg/day orally) from the 17th to 30th day (acute toxicity), G3 received GSE (75 mg/kg/day orally) for 30 days, and G4 pre- and co-treated with GSE (for 30 days) and TiO2-NPs (from the 17th to 30th day), with the aforementioned doses. TiO2-NPs induced severe hepatic injury that was indicated by biochemical alterations in serum liver markers (acetylcholinesterase, ALT, ALP, total proteins, albumin, and direct bilirubin), oxidative stress indicators (MDA, GSH, and catalase), and histopathological alterations as well. Moreover, TiO2-NPs triggered an inflammatory response via the upregulation of TLR-4, NF-κB, NIK, and TNF-α mRNA expressions. Pre- and co-treatments with GSE alleviated the detrimental effects of TiO2-NPs which were enforced by the histopathological improvements. These results indicated that GSE effectively protected against TiO2-NP-induced hepatotoxicity via the inhibition of TLR-4/NF-κB signaling and hence suppressed the production of pro inflammatory cytokines such as TNF-α and improved the antioxidant status of the rats.


Grape seed proanthocyanidin TiO2 nanoparticles TLR-4/ NF-κB pathway Liver Antioxidants 



Authors thank all the staff members of the Biochemistry and Pathology Departments, Faculty of Veterinary Medicine, Beni-Suef University, Egypt, for their help and advices.

Compliance with ethical standards

All experimental procedures were in accordance with the guidelines of local Animal Care and Use Committee established at the Beni-Suef University (BSU-IACUC). The study was performed after obtaining an approval number (018-8) to conduct the animal experiments.

Conflict of interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of Veterinary MedicineBeni-Suef UniversityBeni SuefEgypt

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