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DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway

Acta Pharmacologica Sinica volume 45, pages 166–179 (2024)Cite this article

Abstract

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 μL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.

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Fig. 1: DZ2002 ameliorates ocular disruption and maintains goblet cells in the BAC-induced DED model.
Fig. 2: DZ2002 decreases angiogenesis and inflammatory signalings in the cornea and conjunctiva of BAC-induced DED rats.
Fig. 3: DZ2002 restrains migration, adhesion, and capillary-like tube formation in TNF-α-elicited HUVECs.
Fig. 4: DZ2002 restrains migration and capillary-like tube formation in TNF-α-elicited HUVECs.
Fig. 5: DZ2002 blocks activation of the STAT3-PI3K-Akt pathway in TNF-α-elicited HUVECs.
Fig. 6: DZ2002 inhibits NF-κB nuclear shift and NF-κB/IκB signaling in TNF-α-elicited HUVECs.
Fig. 7: DZ2002 increases tear production and ameliorates ocular surface barrier damage and inflammation in the SCOP-induced DED model.
Fig. 8: DZ2002 inhibits angiogenesis and inflammation by inhibiting STAT3-PI3K-Akt-NF-κB signaling.

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Acknowledgements

We are thankful for financial support from the National Natural Science Foundation of China (81871240), Shanghai Municipal Science and Technology Major Project and the CAS “Light of West China” Program and CAS Interdisciplinary Innovation Team.

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  1. These authors contributed equally: Chun-mei Wu, Jia-wen Mao

Authors and Affiliations

  1. Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Chun-mei Wu, Can-can Xie, Xiao-qian Yang, Mai Xiang, Yi-fan He, Xiao Tong, Dilinaer Litifu, Xiao-yu Xiong, Meng-nan Cheng, Feng-hua Zhu, Ze-min Lin & Jian-ping Zuo

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Chun-mei Wu, Mai Xiang, Yi-fan He, Xiao Tong, Dilinaer Litifu & Jian-ping Zuo

  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Jia-wen Mao, Xiao-yu Xiong & Jian-ping Zuo

  4. Department of Pharmacy, Shanghai Xuhui Central Hospital, Shanghai, 200031, China

    Jin-zhi Zhu

  5. Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Can-can Xie & Jian-ping Zuo

  6. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China

    Jia-ying Yao

  7. Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Jia-ying Yao & Shi-jun He

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  1. Chun-mei Wu
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Contributions

ZML, SJH, and JPZ contributed to the conception and design of this study; CMW, JWM, XQY, and CCX completed the main part of the experiment; JYY, JWM, JZZ, MX, YFH, XT, DL, FHZ, and XYX participated in the in vivo and in vitro experiment; MNC participated in data statistic analysis; ZML, SJH, and JPZ contributed to drafting the manuscript and revising critically for important intellectual content.

Corresponding authors

Correspondence to Shi-jun He, Ze-min Lin or Jian-ping Zuo.

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Wu, Cm., Mao, Jw., Zhu, Jz. et al. DZ2002 alleviates corneal angiogenesis and inflammation in rodent models of dry eye disease via regulating STAT3-PI3K-Akt-NF-κB pathway. Acta Pharmacol Sin 45, 166–179 (2024). https://doi.org/10.1038/s41401-023-01146-y

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