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Novel Piperazino-Enaminones Decrease Pro-inflammatory Cytokines Following Hemarthrosis in a Hemophilia Mouse Model

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Abstract

Hemarthrosis is the primary cause of hemophiliac arthropathy (HA). Pro-inflammatory cytokines are thought to play an important role in the pathogenesis of HA, and thus, anti-cytokine approaches may be used as an adjuvant therapy. A novel series of enaminone compounds (JODI), that contain the N-aryl piperazino motif, have been shown in vitro to reduce pro-inflammatory cytokines and thus may be efficacious in vivo. In this report, we will assess whether JODI can suppress multiple cytokines which might be potentially responsible for joint inflammation in a mouse model of hemarthrosis. The results showed that JODI significantly improved the survival after LPS treatment, and most pro-inflammatory cytokines/chemokines were decreased significantly after JODI administration. In the hemophilia mouse model, hemarthrosis resulted in local cytokine/chemokine changes, represented by elevated pro-inflammatory (IL-6, MCP-1, MIP-1α, MIP-1β) and pro-angiogenic (VEGF and IL-33) cytokines, and decreased anti-pro-inflammatory cytokines IL-4 and IL-10. The changes were reversed by administration of JODI, which can be used as a novel approach to manage hemophilia arthropathy.

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Acknowledgments

The authors acknowledge the Animal Histopathology and Lab Medicine Core at UNC-CH for multiple cytokine measurements and hematological and liver/kidney tests.

Funding

This work was partly supported by a research grant from Asklepios BioPharmaceutical (to J.S.). It was also supported by “the Fundamental Research Funds for the Central Universities.”

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Author notes

  1. Chen Zhong, Doreen Szollosi, and Junjiang Sun contributed equally to this work.

Authors and Affiliations

  1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China

    Chen Zhong

  2. Department of Pharmaceutical Sciences, University of Saint Joseph, School of Pharmacy and Physician Assistant Studies, Hartford, CT, USA

    Doreen Szollosi, Ola Ghoneim, Ashley Bill & Ivan Edafiogho

  3. Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Junjiang Sun

  4. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Junjiang Sun

  5. Department of Hematology, Clinical Medical College, Yangzhou University, Yangzhou, China

    Baolai Hua

  6. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China

    Yingping Zhuang

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  1. Chen Zhong
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Contributions

All authors reviewed the article and approved its content. JS and DS designed the study. CZ and JS performed the in vivo study and wrote the manuscript. DS, OG, AB, and IE prepared the compound and revised the manuscript. BH and YZ revised the manuscript.

Corresponding authors

Correspondence to Doreen Szollosi or Junjiang Sun.

Ethics declarations

All investigations were approved by the University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee.

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The authors declare that they have no conflicts of interest.

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Zhong, C., Szollosi, D., Sun, J. et al. Novel Piperazino-Enaminones Decrease Pro-inflammatory Cytokines Following Hemarthrosis in a Hemophilia Mouse Model. Inflammation 42, 1719–1729 (2019). https://doi.org/10.1007/s10753-019-01032-y

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