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Holotoxin A1 from Apostichopus japonicus inhibited oropharyngeal and intra-abdominal candidiasis by inducing oxidative damage in Candida albicans
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  • Min Liao,
  • Xuekui Xia,
  • Qingzhou Meng,
  • chengguang Zhu,
  • Binyou Liao,
  • Jiannan Wang,
  • Lichen Gou,
  • Xuedong Zhou,
  • Wenpeng Yuan,
  • Lei Cheng,
  • Biao Ren
Min Liao
Sichuan University
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Xuekui Xia
Qilu University of Technology
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Qingzhou Meng
Qilu University of Technology
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chengguang Zhu
Sichuan University State Key Laboratory of Oral Diseases
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Binyou Liao
Sichuan University State Key Laboratory of Oral Diseases
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Jiannan Wang
Sichuan University State Key Laboratory of Oral Diseases
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Lichen Gou
Sichuan University State Key Laboratory of Oral Diseases
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Xuedong Zhou
Sichuan University West China Hospital of Stomatology
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Wenpeng Yuan
Sichuan University State Key Laboratory of Oral Diseases
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Lei Cheng
Sichuan University State Key Laboratory of Oral Diseases
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Biao Ren
Sichuan University State Key Laboratory of Oral Diseases

Corresponding Author:[email protected]

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Abstract

Background and Purpose: The holotoxin A1, isolated from Apostichopus japonicus, has shown potent antifungal activities with unclear mechanism and efficacy against candidiasis. This study aimed to reveal the antifungal effects and mechanism of holotoxin A1 against Candida albicans in vitro and in candidiasis murine models for the first time. Experimental Approach: The antifungal effect of holotoxin A1 against C. albicans was tested in vitro. To explore the antifungal mechanism of holotoxin A1, the transcriptome, ROS levels, and mitochondrial function of C. albicans was evaluated. The oropharyngeal and intra-abdominal candidiasis mouse models were used to verify the effectiveness and systematic toxicity in vivo. Key Results: Holotoxin A1 was a potent fungicide against C. albicans SC5314, clinical strains and drug-resistant strains. Holotoxin A1 inhibited the oxidative phosphorylation and induced oxidative damage by increasing intracellular accumulation of ROS in C. albicans. Holotoxin A1 caused the disfunction of mitochondria by depolarizing the mitochondrial membrane potential and reducing the production of ATP. Holotoxin A1 directly inhibited the enzymatic activity of mitochondrial complex I (CI) and antagonized with the rotenone, an inhibitor of CI, against C. albicans. Meanwhile, the CI subunit NDH51 null mutants showed the decreased susceptibility to holotoxin A1. Furthermore, holotoxin A1 significantly reduced fungal burden and infections with no significant systemic toxicity in oropharyngeal and intra-abdominal candidiasis murine models. Conclusions and Implications: Holotoxin A1 was a promising candidate for the development of novel antifungal drug against both oropharyngeal and intra-abdominal candidiasis, especially caused by the drug resistant strains.
21 Jul 2023Submitted to British Journal of Pharmacology
24 Jul 2023Submission Checks Completed
24 Jul 2023Assigned to Editor
24 Jul 2023Review(s) Completed, Editorial Evaluation Pending
08 Aug 2023Reviewer(s) Assigned
29 Aug 2023Editorial Decision: Revise Minor