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

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Abstract

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.

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Funding

The project was supported by the Higher Education Commission (HEC), Pakistan, under the SRGP funding (No. 357 SRGP/HEC/2014).

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Author notes

  1. Hadayat Ullah and Ashrafullah Khan contributed equally to this work.

Authors and Affiliations

  1. Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Hadayat Ullah, Ashrafullah Khan, Tehmina Bibi, Hussain Ali & Salman Khan

  2. Faculty of Pharmacy, Abasyn University, Peshawar, 25000, Pakistan

    Ashrafullah Khan

  3. Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan

    Sajjad Ahmad

  4. Department of Pharmacy, Abdul Wali Khan University, KPK, Mardan, Pakistan

    Omer Shehzad

  5. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea

    Eun Kyoung Seo

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  1. Hadayat Ullah
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Contributions

HU and AUK performed the in vivo activities. SA and AUK performed the computational studies. AUK and SK designed the project. HU, AUK, and TB performed the biochemical assays. EKS, HA, OS, and SK analyzed the results and drafted the manuscript. EKS, HA, OS, and SK revised the manuscript. SK supervised the project. All authors read and approved the final manuscript. The authors declare that all the data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Salman Khan.

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Ethics approval

The study was approved by the animal ethical committee of Quaid-i-Azam University, Islamabad (No. #BEC-FBS-QAU2018-90). All the animal experiments were regulated according to the guidelines of the institutional bioethical committee.

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The authors declare no competing interests.

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Ullah, H., Khan, A., Bibi, T. et al. Comprehensive in vivo and in silico approaches to explore the hepatoprotective activity of poncirin against paracetamol toxicity. Naunyn-Schmiedeberg's Arch Pharmacol 395, 195–215 (2022). https://doi.org/10.1007/s00210-021-02192-1

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