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Therapeutic approaches for cholestatic liver diseases: the role of nitric oxide pathway

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Abstract

Cholestasis describes bile secretion or flow impairment, which is clinically manifested with fatigue, pruritus, and jaundice. Neutrophils play a crucial role in many diseases such as cholestasis liver diseases through mediating several oxidative and inflammatory pathways. Data have been collected from clinical, in vitro, and in vivo studies published between 2000 and December 2021 in English and obtained from the PubMed, Google Scholar, Scopus, and Cochrane libraries. Although nitric oxide plays an important role in the pathogenesis of cholestatic liver diseases, excessive levels of NO in serum and affected tissues, mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme, can exacerbate inflammation. NO induces the inflammatory and oxidative processes, which finally leads to cell damage. We found that natural products such as baicalin, curcumin, resveratrol, and lycopene, as well as chemical likes ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil, are able to markedly attenuate the NO production and iNOS expression, mainly through inducing the nuclear factor κB (NF-κB), Janus kinase and signal transducer and activator of transcription (JAK/STAT), and toll like receptor-4 (TLR4) signaling pathways. This study summarizes the latest scientific data about the bile acid signaling pathway, the neutrophil chemotaxis recruitment process during cholestasis, and the role of NO in cholestasis liver diseases. Literature review directed us to propose that suppression of NO and its related pathways could be a therapeutic option for preventing or treating cholestatic liver diseases.

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Authors and Affiliations

  1. Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., Tehran, Iran, P. O. Box: 19419-33111

    Naser-Aldin Lashgari, Danial Khayatan, Nazanin Momeni Roudsari & Amir Hossein Abdolghaffari

  2. GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Naser-Aldin Lashgari, Danial Khayatan, Nazanin Momeni Roudsari & Amir Hossein Abdolghaffari

  3. Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran

    Saeideh Momtaz

  4. Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Saeideh Momtaz

  5. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad Reza Dehpour

  6. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Ahmad Reza Dehpour

Authors
  1. Naser-Aldin Lashgari
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  2. Danial Khayatan
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  3. Nazanin Momeni Roudsari
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  4. Saeideh Momtaz
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  5. Ahmad Reza Dehpour
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  6. Amir Hossein Abdolghaffari
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Contributions

Naser-Aldin Lashgari: Data curation, Methodology, Writing- Original draft preparation, Danial Khayatan: Data curation, Writing- Original draft preparation, Nazanin Momeni Roudsari: Data curation, Writing- Original draft preparation, Saeideh Momtaz: Conceptualization, Writing, Reviewing and Editing, Ahmad Reza Dehpour: Supervision, Editing, Amir Hossein Abdolghaffari: Conceptualization, Supervision. The authors confirm that no paper mill and artificial intelligence was used.

Corresponding authors

Correspondence to Ahmad Reza Dehpour or Amir Hossein Abdolghaffari.

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Highlights

• The NO signaling pathways play significant roles in the pathogenesis of liver diseases induced by cholestasis.

• Increase of NO in biological fluids and tissues exacerbates the inflammatory responses.

• Natural products may be candidates as therapeutic choices in the prevention and treatment of liver diseases induced by cholestasis.

• Some chemical compounds such as ursodeoxycholic acid, dexamethasone, rosuvastatin, melatonin, and sildenafil can reduce the NO production and iNOS expression via various pathways such as JAK/STAT, NF-κB, and TLR4.

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Lashgari, NA., Khayatan, D., Roudsari, N.M. et al. Therapeutic approaches for cholestatic liver diseases: the role of nitric oxide pathway. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1433–1454 (2024). https://doi.org/10.1007/s00210-023-02684-2

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  • DOI: https://doi.org/10.1007/s00210-023-02684-2

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