Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

Huang, Sha; Wang, Yuhua; Xie, Shunwen; Lai, Yuqi; Mo, Chan; Zeng, Ting; Kuang, Shanshan; Deng, Guanghui; Zhou, Chuying; Chen, Yuyao; Huang, Shaohui; Gao, Lei; Lv, Zhen

doi:10.1016/j.jcmgh.2022.02.009

Cited by 54 publications

(23 citation statements)

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“…11 DHODH is an enzyme that operates in parallel with mitochondrial GPX4 and suppresses mitochondrial lipid peroxidation and ferroptosis in a CoQ-dependent manner by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). 12,13 The ferroptosis inhibitor (Fer-1) specifically inhibits ferroptosis but not cell death induced by other oxidative lethal compounds and apoptosis-inducing agents. 8 Ferroptosis is associated with the pathophysiological processes of several diseases, such as cancer, nervous system diseases, cerebral hemorrhage, and kidney and liver ischemia-reperfusion injury.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

et al. 2022

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“…Accumulating evidence has shown that massive hepatocyte apoptosis appeared during the pathogenetic process of acute liver injury [ 37 , 38 ]. Similarly, we also found a large number of apoptotic hepatocytes after LPS/D-Gal stimulation in mice, while Ala-Gln pretreatment significantly alleviated the degree of apoptosis in the liver, as shown by a reduction in the percentage of TUNEL-positive cells and the levels of cleaved caspase-3.…”

Section: Discussionmentioning

confidence: 99%

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Ying

Zheng

et al. 2022

Antioxidants

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Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages.

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“…Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, is the major regulator of the cellular antioxidant response and plays a critical role in regulating lipid peroxidation and iron metabolism in the regulation of ferroptosis [12]. Recently, certain studies have clari ed that Nrf2/Gpx4 activation prevents lipopolysaccharide (LPS)/D-GalN-induced acute liver injury and inhibits ferroptosis [13]. Hence, we explore here the feasibility of targeting Nrf2 to attenuate ferroptosis in SALI.…”

Section: Introductionmentioning

confidence: 99%

Nobiletin attenuates Nrf2-Gpx4-regulated ferroptosis in septic liver injury by modulating the gut microbiota

Huang

Chen

et al. 2023

Preprint

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Background Nobiletin (NOB), a plant-based polymethoxyflavone, has been shown to be a promising protective agent against sepsis; yet the mechanisms were not fully elucidated. The gut microbiota is found to be strongly associated with sepsis-associated acute liver injury (SALI). Here, our study aimed to determine whether these protective effects of NOB against SALI were related to modulations in the gut microbiota. Methods Cecal ligation and puncture (CLP) was used to induce SALI in mice. NOB therapy by gavage (50 mg/kg/day) was administrated for 7 days before CLP treatment. The 16S rRNA gene sequencing and fecal microbiota transplantation (FMT) were performed to explore the function of gut microbiota in SALI mice. Markers of ferroptosis, inflammation, gut microbiota composition, and liver injury were determined. Results NOB administration significantly alleviated hepatic ferroptosis and inflammation in septic mice. Meanwhile, NOB upregulated nuclear factor E2-related factor 2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) expression levels in the liver. Nrf2 inhibitor ML385 significantly eradicated NOB administration decreased hepatic ferroptosis in SALI mice. Additionally, increased abundances of Ligilactobacillus, Akkermansia, and Lactobacillus, and decreased abundances of Dubosiella and Bacteroides in the gut were observed under NOB treatment, suggesting that NOB ameliorated SALI-induced microbial dysbiosis. Furthermore, gut microbiota ablation by antibiotic treatment partly eradicated NOB administration decreased hepatic ferroptosis and activated Nrf2 signaling in SALI mice, suggesting NOB inhibited ferroptosis and activated Nrf2 signaling in SALI mice by modulating gut microbiota. Moreover, transplantation of the NOB-microbiota to microbiota-depleted mice was sufficient to decreased hepatic ferroptosis, inflammation, and activated Nrf2 signaling in the liver. Conclusions We have shown that NOB attenuates Nrf2-Gpx4-regulated ferroptosis in septic liver injury by modulating the gut microbiota. Of note, NOB might be employed as a potential therapeutic agent for sepsis treatment. Our findings also provide novel insights into microbiome-based therapeutic approaches for sepsis.

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Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

Cited by 54 publications

References 59 publications

Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Nobiletin attenuates Nrf2-Gpx4-regulated ferroptosis in septic liver injury by modulating the gut microbiota

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Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

Cited by 54 publications

References 59 publications

Vitamin D3attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Vitamin D3attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Alanyl-Glutamine Protects against Lipopolysaccharide-Induced Liver Injury in Mice via Alleviating Oxidative Stress, Inhibiting Inflammation, and Regulating Autophagy

Nobiletin attenuates Nrf2-Gpx4-regulated ferroptosis in septic liver injury by modulating the gut microbiota

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Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission

Vitamin D₃attenuates cisplatin-induced intestinal injury by inhibiting ferroptosis, oxidative stress, and ROS-mediated excessive mitochondrial fission