Irinotecan cause the side effects on development and adult physiology, and induces intestinal damage via innate immune response and oxidative damage in Drosophila

He, Jianzheng; Han, Shuzhen; Wang, Yixuan; Kang, Qian; Wang, Xiaoqian; Su, Yun; Li, Yaling; Liu, Yongqi; Cai, Hui; Xiu, Minghui

doi:10.1016/j.biopha.2023.115906

Cited by 2 publications

(2 citation statements)

References 68 publications

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“…In the midgut of third instar larvae administered with climacostol, we found apoptotic cells and increased generation of ROS, thus demonstrating its gastrointestinal toxicity. ROS is an important factor for gut homeostasis [ 59 ] and excessive ROS may be destructive to the intestine epithelial cells of flies [ 60 , 61 , 62 ]. The Drosophila midgut is a epithelial monolayer with a rapid turnover rate [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although ROS are critical messengers for the differentiation and cell growth of fly intestinal stem cells [ 64 , 65 ], in our system, climacostol did not affect the proliferation of secretory enteroendocrine cells, suggesting moderate damage/ROS increase that did not initiate the repairing program. Apoptosis, impaired ROS production, and decreased antioxidant enzymes have been described in the intestine of Drosophila treated with different toxins [ 60 , 61 , 62 ]. In addition, preliminary observations in flies revealed cytotoxic effects of the climacostol synthetic analog MOMO [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

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Exposure to the Natural Compound Climacostol Induces Cell Damage and Oxidative Stress in the Fruit Fly Drosophila melanogaster

Catalani,

Brunetti,

Del Quondam

et al. 2024

Toxics

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The ciliate Climacostomum virens produces the metabolite climacostol that displays antimicrobial activity and cytotoxicity on human and rodent tumor cells. Given its potential as a backbone in pharmacological studies, we used the fruit fly Drosophila melanogaster to evaluate how the xenobiotic climacostol affects biological systems in vivo at the organismal level. Food administration with climacostol demonstrated its harmful role during larvae developmental stages but not pupation. The midgut of eclosed larvae showed apoptosis and increased generation of reactive oxygen species (ROS), thus demonstrating gastrointestinal toxicity. Climacostol did not affect enteroendocrine cell proliferation, suggesting moderate damage that does not initiate the repairing program. The fact that climacostol increased brain ROS and inhibited the proliferation of neural cells revealed a systemic (neurotoxic) role of this harmful substance. In this line, we found lower expression of relevant antioxidant enzymes in the larvae and impaired mitochondrial activity. Adult offsprings presented no major alterations in survival and mobility, as well the absence of abnormal phenotypes. However, mitochondrial activity and oviposition behavior was somewhat affected, indicating the chronic toxicity of climacostol, which continues moderately until adult stages. These results revealed for the first time the detrimental role of ingested climacostol in a non-target multicellular organism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Exposure to the Natural Compound Climacostol Induces Cell Damage and Oxidative Stress in the Fruit Fly Drosophila melanogaster

Catalani,

Brunetti,

Del Quondam

et al. 2024

Toxics

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Therapeutic potential of Astragalus membranaceus—Pueraria lobata decoction for the treatment of chemotherapy bowel injury

Wang,

Qin,

Kang

et al. 2024

The FASEB Journal

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Intestinal mucositis (IM) is one of the most serious side effects of the chemotherapeutic agent irinotecan (CPT‐11). Astragalus membranaceus‐Pueraria lobata decoction is from the ancient medical book Zhengzhihuibu, has been reported to be used for the treatment of diabetes and hypertension. However, the beneficial effect and mechanism of AP on chemotherapy intestinal mucositis (CIM) remain largely unknown. This study aimed to investigate the efficacy and mechanism of Astragalus membranaceus‐Pueraria lobata decoction (AP) in treating CIM. The beneficial effect and mechanism of AP on chemotherapy intestinal mucositis (CIM) were detected using Drosophila model, and combination with RT qPCR, transcriptomics. AP supplementation could significantly alleviate the CPT‐11‐induced body injury in Drosophila, such as increasing the survival rate, recovering the impaired digestion, improving the movement, and repairing the reproduction and developmental processes. Administration of AP remarkably alleviated the IM caused by CPT‐11, including inhibiting the excretion, repairing the intestinal atrophy, improving the acid–base homeostasis imbalance, and inhibiting the disruption of intestinal structure. Mechanistic studies revealed that the protective role of AP against CPT‐11 induced intestinal injury was regulated mainly by inhibiting immune‐related Toll and Imd pathways, and enhancing the antioxidant capacity. Taken together, these results suggest that AP may be a novel agent to relieve CIM.

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Irinotecan cause the side effects on development and adult physiology, and induces intestinal damage via innate immune response and oxidative damage in Drosophila

Cited by 2 publications

References 68 publications

Exposure to the Natural Compound Climacostol Induces Cell Damage and Oxidative Stress in the Fruit Fly Drosophila melanogaster

Exposure to the Natural Compound Climacostol Induces Cell Damage and Oxidative Stress in the Fruit Fly Drosophila melanogaster

Therapeutic potential of Astragalus membranaceus—Pueraria lobata decoction for the treatment of chemotherapy bowel injury

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