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  3. Clonorchis sinensis aggravated liver fibrosis by activating PARP-1 signaling to induce parthanatos via DNA damage

Clonorchis sinensis aggravated liver fibrosis by activating PARP-1 signaling to induce parthanatos via DNA damage

  • Vet Parasitol. 2024 Jun 6:330:110217. doi: 10.1016/j.vetpar.2024.110217.
Penglin Bao 1,  Xiaocen Wang 2,  Xu Zhang 3,  Yanhui Yu 4,  Yeting Ma 5,  Haoyang Zhang 6,  Yuru Wang 7,  Xiaolei Liu 8,  Pengtao Gong 9,  Nan Zhang 10,  Soon-Ok Lee 11,  Xin Li 12,  Jianhua Li 13
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: baopl21@mails.jlu.edu.cn.
  • 2 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: wangxiaocen2016@163.com.
  • 3 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: zhangxu1311@163.com.
  • 4 Second Affiliated Hospital, Jilin University, Changchun, China. Electronic address: 1053408972@qq.com.
  • 5 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: 18535444856@163.com.
  • 6 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: 13755227801@163.com.
  • 7 College of Public Health, Jilin Medical University, Jilin 132013, China. Electronic address: yuruwang0109@126.com.
  • 8 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: liuxlei@163.com.
  • 9 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: gongpt@jlu.edu.cn.
  • 10 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: n_zhang@jlu.edu.cn.
  • 11 Department of Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, School of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: amkey68@khu.ac.kr.
  • 12 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: lixin2018@jlu.edu.cn.
  • 13 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: jianhuali7207@163.com.
PMID: 38861911 DOI: 10.1016/j.vetpar.2024.110217
Abstract

Clonorchis sinensis is an important food-borne zoonotic Parasite that is highly associated with liver fibrosis and cholangiocarcinoma. Further understanding of the pathogenesis of C. sinensis, especially liver fibrosis, could help us develop novel strategies for controlling clonorchiasis. Poly (ADP-ribose) polymerase-1 (PARP-1) can induce cellular parthanatos which is reported to be involved in liver fibrosis. Currently, whether C. sinensis could activate PARP-1 signaling to induce parthanatos or whether parthanatos play a role in C. sinensis-induced liver fibrosis is not clear. In the present study, the expression of PARP-1 and parthanatos indicators were detected in C. sinensis-infected mouse liver and in human intrahepatic biliary epithelial cells (HiBEpiCs) incubated with excretory/secretory products (ESPs) of C. sinensis. To explore the role of PARP-1 in C. sinensis Infection, PARP-1 inhibitor NMS-P118 was used to block PARP-1 expression in vivo and vitro. The mortality rate, body weight, worm load, liver and bile duct lesions as well as PARP-1 and parthanatos indicators in C57BL/6 mice infected with C. sinensis, or in HiBEpiCs incubated with C. sinensis ESPs and NMS-P118 were analyzed and compared to the group without NMS-P118. The results showed that C. sinensis Infection induced the activation of PARP-1 signaling as well as the translocation of AIF and MIF into the nucleus in mouse liver. ESPs of C. sinensis could induce PARP-1 up-regulation, ATP depletion and DNA damage in HiBEpiCs, indicating that C. sinensis could induce parthanatos. Inhibiting PARP-1 with NMS-P118 significantly reduced liver fibrosis and the number of larvae, increased the survival rate and body weight gain of the mice infected with C. sinensis. In addition, NMS-P118 decreased the expression of PARP-1 and alleviated ATP depletion as well as DNA damage in HiBEpiCs incubated with ESPs of C. sinensis. Our data indicated that C. sinensis and its ESPs could activate PARP-1 signaling to induce cellular parthanatos. NMS-P118 treatment alleviated liver fibrosis and promoted survival of the mice by inhibiting PARP-1, which suggested that PARP-1 could be used as a potential therapeutic target against clonorchiasis.

Keywords

Clonorchis sinensis; DNA damage; Liver fibrosis; PARP-1; Parthanatos.

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