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Mechanistic investigation of hepato-protective potential for cucurbitacins

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Abstract

Hepatocellular carcinoma is a major example for inflammatory-associated cancer. cucurbitacins are natural triterpenoids known for their potent anticancer and anti-inflammatory activities. Recent studies showed that cucurbitacins protect the HepG2 cell lines against carbon tetrachloride-induced toxicity, however the mechanism is unknown. A molecular docking study coupled with in vitro biological assays were conducted to test the hepatoprotective effect of cucurbitacin on the inhibition of potential inflammatory factors. The effect of cucurbitacins on the activation of NF-kB pathway was analyzed using in cell-based NF-kB immunoassay. Enzyme-linked immunosorbent assays revealed the potential of Cuc D and dihydro cucurbitacin D to prevent the production of tumor necrosis factor-alpha and interleukin-6 from HSC-T6 cells. Thus, Cuc D and dihydro cucurbitacin D could have hepatoprotective effects on the activated rat HSC-T6 cells due to inhibition of the production of tumor necrosis factor-alpha and interleukin-6 through NF-kB pathway. In-silico molecular modeling data revealed potential cucurbitacin analogs with higher binding affinity to the hydrophobic pocket of NF-kB and IKKβ compared to standard IKK inhibitor (PS-1145).

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Acknowledgements

The authors would like to thank the Libyan ministry of higher education for funding this work, OpenEye® molecular modeling software for supporting an academic license, and Dr. Friedman (Mount. Sinai Hospital, NY) for providing the HSC-T6 cell lines. This work was supported by the Libyan ministry of higher education.

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Authors and Affiliations

  1. Department of Chemistry & Biochemistry, South Dakota State University, Box 2202, Brookings, 57007, SD, USA

    Hajer M. Arjaibi & Fathi T. Halaweish

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Cairo-Suez Desert Road, Al-Sherouk City, 11837, Cairo, Egypt

    Mahmoud S. Ahmed

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  1. Hajer M. Arjaibi
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  2. Mahmoud S. Ahmed
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  3. Fathi T. Halaweish
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Correspondence to Fathi T. Halaweish.

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Arjaibi, H.M., Ahmed, M.S. & Halaweish, F.T. Mechanistic investigation of hepato-protective potential for cucurbitacins. Med Chem Res 26, 1567–1573 (2017). https://doi.org/10.1007/s00044-017-1872-3

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  • DOI: https://doi.org/10.1007/s00044-017-1872-3

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