Betulinic acid mitigates zearalenone-induced liver injury by ERS/MAPK/Nrf2 signaling pathways in mice

Wu, Jing; Li, Jiayan; Wu, You; Yang, Mengran; Chen, Yunqin; Wang, Naidong; Ji, Wang; Yuan, Zhihang; Yi, Jine; Yang, Chenglin

doi:10.1016/j.fct.2023.113811

Cited by 12 publications

(3 citation statements)

References 51 publications

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“…Research has reported that apoptosis may be induced due to excess ERS 36 . A growing body of evidence has substantiated that in ERS conditions, the accumulation of unfolded or misfolded proteins occurs within the cellular ER, resulting in apoptosis and ultimately contributing to hepatotoxicity 37 . There is evidence that ERS participates in the occurrence and development of various liver disorders, including fatty liver, ischemia–reperfusion injury, liver fibrosis and DILI 38–41 .…”

Section: Discussionmentioning

confidence: 99%

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

Xiong,

Lin,

et al. 2024

Basic Clin Pharma Tox

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Cantharidin (CTD) is a widely used anticancer compound, but its clinical use is mainly limited due to hepatotoxicity. Ginsenoside Rb1 (GRb1) shows potential hepatoprotective effects. Nonetheless, the protective effect and underlying mechanism of GRb1 against CTD‐induced hepatotoxicity in mice have not been investigated. This study aims to elucidate the effect and mechanism of GRb1 on CTD‐induced hepatotoxicity using network pharmacology and in vivo experiments. Network pharmacology studies have shown that 263 targets were the main mechanisms by which GRb1 alleviates CTD‐induced hepatotoxicity. KEGG enrichment analysis revealed that 75 hub genes were mainly enriched in TNF, IL‐17 and apoptosis signalling pathways. Molecular docking analysis showed that GRb1 exhibited high affinity with Akt1, Tnf, Il6, Bcl2 and Caspase3. In addition, results from animal studies demonstrated that GRb1 could ameliorate CTD‐induced hepatotoxicity by inhibiting protein expression of Caspase‐3, Caspase‐8, Bcl‐2/Bax, GRP78, ATF6, ATF4, CHOP, IRE1α and PERK. This research revealed the mechanism of GRb1 against CTD‐induced hepatotoxicity by inhibiting apoptosis and endoplasmic reticulum stress (ERS) and it may provide a scientific rationale for the potential use of GRb1 in the treatment of hepatotoxicity induced by CTD.

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Section: Discussionmentioning

confidence: 99%

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

Xiong,

Lin,

et al. 2024

Basic Clin Pharma Tox

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“…However, ZEN reduces the antioxidant capacity of the liver, leading to inflammation and liver injury of piglets ( Wu et al, 2022a ). In mouse liver, ZEN causes oxidative damage and inflammatory reaction, increasing hepatocyte apoptosis rate and liver injury ( Wu et al, 2023 ). ZEN is also hepatotoxic to rabbits, which significantly increases the alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ -glutamyltransferase and total lactate dehydrogenase activities in rabbits ( Conková et al, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Quercetagetin alleviates zearalenone-induced liver injury in rabbits through Keap1/Nrf2/ARE signaling pathway

Wu,

Wang,

Tang

et al. 2023

Front. Pharmacol.

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Introduction: This study aimed to assess the alleviative effect of quercetagetin (QG) on zearalenone (ZEN)-induced liver injury in rabbits.Methods: Ninety 41-day-old healthy Hyla rabbits were randomly assigned into three groups, including a control (fed with basic diet), ZEN addition group (fed with basic diet + 600 μg/kg ZEN), and ZEN + QG addition group (fed with basic diet + 600 μg/kg ZEN + 100 mg/kg QG), with 30 rabbits per group. The duration of the experiment was 28 days.Results: The results revealed no significant differences in the average daily gain, average daily feed intake, the gain to feed ratio and the liver, kidney and spleen organ indexes (p > 0.05) between the rabbits across the three groups. However, the sacculus rotundus index of the rabbits in the control group was significantly higher than that in the ZEN + QG group (p < 0.05). The intake of ZEN-contaminated diet also significantly increased the activities or levels of alanine transaminase, alkaline phosphatase, total bile acid (TBA), total bilirubin, malondialdehyde, and interleukin-4 (IL-4) and enhanced the abundance of kelch-like ECH-associated protein 1 (Keap1), heat shock protein 70 (HSP70) and cysteine-aspartic acid protease-3 (Caspase-3) mRNA in the blood or liver tissue in ZEN group, compared to the control group (p < 0.05). On the contrary, the activities or levels of immunoglobulin A, complement 3, total antioxidant capacity, glutathione peroxidase (GSH-Px), superoxide dismutase, interleukin-10, and the abundance of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA were significantly decreased (p < 0.05). Supplementing the diet with QG still maintained significantly higher levels of TBA and IL-4, and the abundance of GSH-Px, HSP70, IL-4, and Caspase-3 mRNA in the blood and liver of rabbits in the ZEN + QG group than in the control group (p < 0.05). At the same time, the other indicators were restored to levels in the control group (p > 0.05).Discussion: In conclusion, QG alleviated the ZEN-induced oxidative damage and liver injury caused by inflammatory reaction through the Keap1-Nrf2-antioxidant response element (ARE) signal pathway, which protected the liver. This study revealed the alleviative effect of QG on the hepatotoxicity of ZEN in rabbits for the first time, providing a new perspective for applying QG and developing a ZEN antidote.

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“…Similarly, a mixture of deoxynivalenol and zearalenone has synergistic effects on the levels of pro-in ammatory cytokines in piglets[65]. Endoplasmic reticulum stress has also been observed in numerous studies conducted with fumonisins[12, 46,[66][67][68], deoxynivalenol [69-73], and zearalenone[74][75][76][77][78][79]. This mechanism could play a key role in mitochondrial-induced apoptosis when deoxynivalenol and zearalenone were used in combination[80].…”

mentioning

confidence: 99%

Fumonisins alone or mixed with other fusariotoxins increase the C22–24:C16 sphingolipid ratios in chickens and ducks, while deoxynivalenol and zearalenone have no effect

Guerre,

Lassallette,

Beaujardin-Daurian

et al. 2023

Preprint

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Background The inhibitory effect of fumonisins on ceramide synthases results in several effects on the sphingolipidome, and recent results in chickens suggest that the C22–24:C16 sphingolipid ratios may be complementary biomarkers to Sa:So. Feeding diets containing fumonisins, deoxynivalenol, or zearalenone alone or in combination up to the maximum levels recommended by the European Commission for 35 days in chickens and 12 days in ducks resulted in no effects on performance or toxicity. The aim of this study was to investigate their effects on the liver sphingolipidome. Results Sphingolipids were characterised by UHPLC-MSMS. Numerous significant effects of fusariotoxins on sphingolipids were observed at the class and analyte levels. Fusariotoxins alone decreased sphingolipids in chickens but had weak effects in ducks. Feeding fumonisins in combination with deoxynivalenol and zearalenone increased sphingolipid levels in chickens but not in ducks. These increases were mainly due to an increase in C22–24 sphingolipids, whereas C16 sphingolipids decreased. The Sa:So ratio and the C22–24:C16 ratio for ceramides, sphingomyelins, monohexosylceramides, dihydroceramides, and dihydrosphingomyelins were unaffected in chickens and ducks fed the diets containing deoxynivalenol or zearalenone but increased in animals fed the fumonisin diets. Interestingly, while the effects of feeding fumonisins alone or in combination on the total amount of sphingolipids differed in chickens, the Sa:So and C22-24:C16 ratios were similar. Partial least squares-discriminant analysis of sphingolipids did not allow discrimination of the animals exposed to deoxynivalenol or zearalenone from the unexposed animals. By contrast, good discrimination of the animals fed the diets containing fumonisins was achieved. Sphinganine, d20 sphinganine, a large number of C16 sphingolipids, and dihydrosphingomyelins for which the fatty acid contains more than 18 carbon atoms, were important variables in the models obtained in chickens and ducks. Conclusions The C22–24:C16 ratios of sphingolipids are increased in chickens and ducks by intake of fumonisins but not deoxynivalenol or zearalenone. The increases were similar when fumonisins were fed alone or in combination with deoxynivalenol or zearalenone. The increase in the C22–24:C16 ratio may be an important factor in explaining the interspecies differences in sensitivity to fumonisin toxicity.

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Betulinic acid mitigates zearalenone-induced liver injury by ERS/MAPK/Nrf2 signaling pathways in mice

Cited by 12 publications

References 51 publications

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin‐induced hepatotoxicity in mice

Quercetagetin alleviates zearalenone-induced liver injury in rabbits through Keap1/Nrf2/ARE signaling pathway

Fumonisins alone or mixed with other fusariotoxins increase the C22–24:C16 sphingolipid ratios in chickens and ducks, while deoxynivalenol and zearalenone have no effect

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