Comprehensive in vivo and in silico approaches to explore the hepatoprotective activity of poncirin against paracetamol toxicity

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 395; no. 2; pp. 195 - 215
• Main Authors: Ullah, Hadayat, Khan, Ashrafullah, Bibi, Tehmina, Ahmad, Sajjad, Shehzad, Omer, Ali, Hussain, Seo, Eun Kyoung, Khan, Salman
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2022; Springer Nature B.V
• Subjects: Acetaminophen - toxicity; Analgesics; Analgesics, Non-Narcotic - toxicity; Animals; Antioxidants; Antioxidants - metabolism; Biomedical and Life Sciences; Biomedicine; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - prevention & control; Computer applications; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Flavonoids - pharmacokinetics; Flavonoids - pharmacology; Hydrophobicity; IL-1β; Immunohistochemistry; Inflammation; Interleukin 6; Liver; Lymphocytes B; Male; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Dynamics Simulation; Neurosciences; NF-κB protein; Original Article; Oxidative stress; Oxidative Stress - drug effects; Paracetamol; Pharmacokinetics; Pharmacology/Toxicology; Toxicity; Tumor necrosis factor-α; Oxidative stress; Poncirin; Hepatoprotection; Cytokines; Antioxidant enzymes
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-021-02192-1

In the present study, poncirin was evaluated against paracetamol-induced liver injury using in vivo and computational approaches. Paracetamol was administered intraperitoneally (i.p,) to establish liver injury in mice and, subsequently, to investigate the hepatoprotective effect of poncirin (administered intraperitoneally) on liver injury. The effect of poncirin was evaluated against the liver injury markers and inflammatory cytokines. Similarly, in the present study, the antioxidants and oxidative stress parameters were also assessed following paracetamol-induced liver injury. The histological studies following liver injury were also assessed using H and E staining, Masson’s trichrome staining, and periodic acid-Schiff staining. Similarly, the computational approach was used to assess the pharmacokinetic parameters of poncirin and its interaction with various protein targets. Poncirin markedly improved the antioxidant enzymes while attenuated the oxidative stress markers and inflammatory cytokines. Poncirin also markedly improved hematological parameters. Furthermore, poncirin treatment significantly improved the histological parameters using H and E staining, Masson’s trichrome, and PAS staining compared to the control. Poncirin treatment also improved the liver function tests and liver synthetic activity compared to paracetamol treated group. The immunohistochemistry analysis revealed significant decrease in the inflammatory signaling protein such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB), Jun N-terminal kinase (JNK), and cyclooxygenase-2 (COX-2) expression level compared to the paracetamol treated group. Computational analysis (molecular docking and molecular dynamic simulation) showed significant binding affinity of poncirin with the NF-κB, JNK, COX-2, IL-1β, IL-6, and TNF-α via multiple hydrophilic and hydrophobic binds. Similarly, the SwissADME software revealed that poncirin follows various drug-likeness rules and exhibited better pharmacokinetic parameters. Poncirin improved the sign and symptoms associated with liver injury using both in vivo and computational approaches.