6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology

Li, Wenwen; Zhang, Yun; Wang, Quyi; Wang, Yu; Fan, Yuwen; Shang, Erxin; Jiang, Shu; Duan, Jinao

doi:10.1039/d4fo00952e

Food Funct.

2024

DOI: 10.1039/d4fo00952e

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6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology

Wenwen Li,

Yun Zhang,

Quyi Wang

et al.

Abstract: 6-Gingerol (6-G), an active ingredient of ginger with anti-inflammation and anti-oxidation properties, can treat ulcerative colitis (UC). However, its underlying mechanism is still unclear. In this study, the pharmacodynamic evaluation...

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Cited by 2 publications

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Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Famurewa,

Akhigbe,

George

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient’s quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc–/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

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Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Famurewa,

Akhigbe,

George

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation

Shu,

Xu,

Xiong

et al. 2024

IJMS

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Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K–Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

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6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology

Abstract: 6-Gingerol (6-G), an active ingredient of ginger with anti-inflammation and anti-oxidation properties, can treat ulcerative colitis (UC). However, its underlying mechanism is still unclear. In this study, the pharmacodynamic evaluation...

Cited by 2 publications

References 57 publications

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation

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