Limonin ameliorates acetaminophen-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1

Yang, Runyu; Song, Changqin; Chen, Jiaxi; Zhou, Lvqi; Jiang, Xiubo; Cao, Xiufeng; Sun, Yang; Zhang, Qi

doi:10.1016/j.phymed.2020.153211

Cited by 83 publications

(68 citation statements)

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“…32 Limonin was also reported to inhibit ROS production and cleavage of caspase-3 in L-02 cells. 33 These data suggest that the antioxidant effects of citrus fruits, leaves, stems, and roots on H 2 O 2 -induced RIN-m5F cells are closely related to the main bioactive compositions and content, which need further analysis. Multivariate statistical analysis was therefore performed to provide an insight into their relationships.…”

Section: Antioxidant Effects Of Citrus Extracts On H 2 O 2 -Induced Rmentioning

confidence: 79%

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The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells

et al. 2020

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BACKGROUND Citrus aurantium L. (Aurantii fructus) is a multi‐purpose citrus fruit with high medicinal and nutritional value, but currently there are no data that can be used to investigate the appropriate harvest time to obtain high‐quality citrus bioactive ingredients from it. RESULTS Phytochemicals and the levels of the main bioactive ingredients were investigated by ultra high performance liquid chromatography electrospray ionization quadrupole time‐of‐flight mass spectrometry (UHPLC‐ESI‐Q‐TOF/MS). The flavanone, polymethoxyflavone, coumarin, synephrine, and limonin content in the citrus fruit was analyzed at different harvest periods, and significant differences, ranging from 0.03 ± 0.01 to 116.26 ± 40.20 g kg−1 (DW), were shown. These compounds were present in higher amounts in June and then decreased gradually, while the biomass accumulation of most of them showed an increasing tendency around harvest time. The H2O2‐induced RIN‐m5F cells model was employed to evaluate their antioxidant capacity. Citrus fruit harvested from June 11 to July 7 possessed an excellent antioxidant capacity by inhibiting the intensity of intracellular reactive oxygen species (ROS) (P < 0.01) and improving superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH) activity (P < 0.01). The chemical composition and antioxidant capacity of citrus leaves, stems, and roots were also evaluated, and these showed great variation compared with other citrus fruits. Multivariate statistical analysis indicated that harvesting time was related closely to the phytochemical contents and antioxidant capacity. CONCLUSION Citrus fruit can be appropriately harvested from June to early July when the levels of bioactive ingredients and antioxidant activity reach higher values. This research provides practical information for producing high‐quality citrus products. © 2020 Society of Chemical Industry

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Section: Antioxidant Effects Of Citrus Extracts On H 2 O 2 -Induced Rmentioning

confidence: 79%

“…Synephrine could induce overproduction of intracellular ROS, exert cytostatic effects, and increase the GSH level to prevent intracellular damage in HepG2 cells 32 . Limonin was also reported to inhibit ROS production and cleavage of caspase‐3 in L‐02 cells 33 …”

Section: Resultsmentioning

confidence: 99%

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells

et al. 2020

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“…Oxidative stress increases the expression of proinflammatory genes, and inflammatory cells subsequently similarly trigger the overproduction of ROS, resulting in a vicious circle that triggers the occurrence and development of various diseases. Thus, when exposed to various toxic substances, the liver's detoxification mechanism plays an important role, and the inflammatory response can amplify tissue damage and lead to incorrect tissue repair [35]. Increasing evidence shows that acute paracetamol poisoning can increase the circulating levels of many proinflammatory cytokines [36].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that the CaMKKβ/LKB1/AMPK axis and Ca 2+ levels could provide a quick, adaptable switch to promote the survival of cells [35]. AMPK has extensive roles in numerous pathways, especially those closely related to metabolic diseases [48].…”

Section: Discussionmentioning

confidence: 99%

Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation

et al. 2021

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Liver damage induced by paracetamol overdose is the main cause of acute liver failure worldwide. In order to study the hepatoprotective effect of Sanghuangporus sanghuang mycelium (SS) on paracetamol-induced liver injury, SS was administered orally every day for 6 days in mice before paracetamol treatment. SS decreased serum aminotransferase activities and the lipid profiles, protecting against paracetamol hepatotoxicity in mice. Furthermore, SS inhibited the lipid peroxidation marker malondialdehyde (MDA), hepatic cytochrome P450 2E1 (CYP2E1), and the histopathological changes in the liver and decreased inflammatory activity by inhibiting the production of proinflammatory cytokines in paracetamol-induced acute liver failure. Moreover, SS improved the levels of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase in the liver. Significantly, SS diminished mitogen-activated protein kinase (MAPK), Toll-like receptor 4 (TLR4), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and the nuclear factor-kappa B (NF-κB) axis, as well as upregulated the Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, in paracetamol-induced mice. SS mainly inhibited the phosphorylation of the liver kinase B1 (LKB1), Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ), and AMP-activated protein kinase (AMPK) protein expression. Furthermore, the protective effects of SS on paracetamol-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. In summary, we provide novel molecular evidence that SS protects liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress and inflammation.

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“…As an important bioactive compound in citrus fruit, limonin also shows many bioactivities by interacting with NQO1, such as anti‐inflammation. For example, limonin can up‐regulate the antioxidant pathway of Nrf2 activated by Sirt1 and increase the expression of its downstream target molecules HO‐1, NQO1, and GCLC/GCLM, so as to inhibit NF‐κB inflammation and reduce the hepatotoxicity induced by acetaminophen (APAP; Yang et al., 2020). Chen et al.…”

Section: Discussionmentioning

confidence: 99%

Limonin induces apoptosis of HL‐60 cells by inhibiting NQO1 activity

Chen

Liang

et al. 2021

Food Science & Nutrition

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Limonin is an important bioactive substance in citrus fruits, especially in seeds, which has great potential in cancer prevention and treatment. In order to explore the anticancer activity based on interaction between limonin and NQO1, Human promyelocytic leukemia cells (HL‐60) were studied in vitro. We found that limonin could inhibit proliferation and promote apoptosis of HL‐60 cells, and the effect was positively correlated with its dosage. Western blot results showed that limonin could activate the endogenous apoptosis pathway mediated by mitochondria via up‐regulating pro‐apoptotic proteins (Bax, cytochrome c, Caspase3, and Caspase9) and down‐regulating anti‐apoptotic proteins (Bcl‐2), thus inhibiting the proliferation of HL‐60 cells and promoting apoptosis, which further proved the anticancer activity of limonin from the molecular mechanism. At the same time, limonin down‐regulated the expression of NQO1, indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo, thus exerting its inhibitory effect on tumor cells, which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes.

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Limonin ameliorates acetaminophen-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1

Cited by 83 publications

References 57 publications

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells

Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation

Limonin induces apoptosis of HL‐60 cells by inhibiting NQO1 activity

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Limonin ameliorates acetaminophen-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1

Cited by 83 publications

References 57 publications

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H2O2‐induced RIN‐m5F cells

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H2O2‐induced RIN‐m5F cells

Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation

Limonin induces apoptosis of HL‐60 cells by inhibiting NQO1 activity

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The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells

The levels of bioactive ingredients in Citrus aurantium L. at different harvest periods and antioxidant effects on H₂O₂‐induced RIN‐m5F cells