Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway

Wen, E; Xin, Guang; Su, Wei; Li, Shiyi; Zhang, Yi; Dong, Yuman; Yang, Xijing; Wan, Chengyu; Chen, Zhe; Yu, Xiuxian; Zhang, Kun; Niu, Hai; Huang, Wen

doi:10.1016/j.molimm.2021.12.012

Cited by 20 publications

(14 citation statements)

References 65 publications

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“…Combined with literature evidence, PI3K-Akt-mTOR pathway may be involved in AP progression by inhibiting autophagy. 20 , 21 Nuclear FoxOs transactivate genes that control the formation of autophagosomes and their fusion with lysosomes. Independently of transactivation, cytosolic FoxO proteins induce autophagy by directly interacting with autophagy proteins.…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Qin

Ali

et al. 2022

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This study aims to explore the molecular mechanism of N6-methyladenosine (m6A) modification-related long noncoding RNA (lncRNA)–microRNA (miRNA)–messenger RNA (mRNA) network in regulating autophagy and affecting the occurrence and development of acute pancreatitis (AP). RNA-seq datasets related to AP were obtained from Gene Expression Omnibus (GEO) database and merged after batch effect removal. lncRNAs significantly related to m6A in AP, namely candidate lncRNA, were screened by correlation analysis and differential expression analysis. In addition, candidate autophagy genes were screened through the multiple databases. Furthermore, the key pathways for autophagy to play a role in AP were determined by functional enrichment analysis. Finally, we predicted the miRNAs binding to genes and lncRNAs through TargetScan, miRDB and DIANA TOOLS databases and constructed two types of lncRNA-miRNA-mRNA regulatory networks mediated by upregulated and downregulated lncRNAs in AP. Nine lncRNAs related to m6A were differentially expressed in AP, and 21 candidate autophagy genes were obtained. Phosphoinositide 3-kinase (PI3K)-Akt signaling pathway and Forkhead box O (FoxO) signaling pathway might be the key pathways for autophagy to play a role in AP. Finally, we constructed a lncRNA-miRNA-mRNA regulatory network. An upregulated lncRNA competitively binds to 13 miRNAs to regulate 6 autophagy genes, and a lncRNA-miRNA-mRNA regulatory network in which 2 downregulated lncRNAs competitively bind to 7 miRNAs to regulate 2 autophagy genes. m6A modification-related lncRNA Pvt1, lncRNA Meg3 and lncRNA AW112010 may mediate the lncRNA-miRNA-mRNA network, thereby regulating autophagy to affect the development of AP.

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Section: Resultsmentioning

confidence: 99%

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Qin

Ali

et al. 2022

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“…Autophagy can be triggered by ROS generation (Signorelli et al, 2019). Our previous research proved ROS impaired autophagy in the spleen stimulated by SAP through PI3K/ AKT/mTOR pathway (Wen et al, 2022). Meanwhile, autophagy can alleviate oxidative damage by degrading or phagocytizing oxidative substances (Li et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with these studies, Xn significantly alleviated SAP-associated oxidative stress. ROS impaired autophagy by activating the classic AKT/mTOR pathway ( Wen et al, 2022 ). A high level of mTOR activation inhibits autophagy initiation and autophagosome nucleation ( Saxton and Sabatini, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR

Huangfu

Wan

et al. 2023

Front. Pharmacol.

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Severe acute pancreatitis (SAP) is a lethal gastrointestinal disorder, yet no specific and effective treatment is available. Its pathogenesis involves inflammatory cascade, oxidative stress, and autophagy dysfunction. Xanthohumol (Xn) displays various medicinal properties,including anti-inflammation, antioxidative, and enhancing autophagic flux. However, it is unclear whether Xn inhibits SAP. This study investigated the efficacy of Xn on sodium taurocholate (NaT)-induced SAP (NaT-SAP) in vitro and in vivo. First, Xn attenuated biochemical and histopathological responses in NaT-SAP mice. And Xn reduced NaT-induced necrosis, inflammation, oxidative stress, and autophagy impairment. The mTOR activator MHY1485 and the AKT activator SC79 partly reversed the treatment effect of Xn. Overall, this is an innovative study to identify that Xn improved pancreatic injury by enhancing autophagic flux via inhibition of AKT/mTOR. Xn is expected to become a novel SAP therapeutic agent.

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“…Major signaling molecules in TLR4‐mediated inflammatory pathway may also affect ROS‐regulated signaling or be regulated by ROS production. The increase of TLR4 activity will aggregate severe acute pancreatitis or related diseases through ROS‐mediated mitophagy pathway (Wen et al, 2022). In contrast, the changes of ROS‐regulated energy metabolism may induce the apoptosis of pancreatic cancer via PI3K/AKT/mTOR signaling (Zhu et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Quercetin improves pancreatic cancer chemo‐sensitivity by regulating oxidative‐inflammatory networks

Jin

et al. 2022

Journal of Food Biochemistry

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Chemotherapy is the main method for controlling pancreatic cancer metastasis but the prevalent chemotherapy resistance limits its utilization. The response of oxidation and inflammation often promotes pancreatic cancer progression and chemo‐resistance. It is critical to explore the potential natural products with few side effects to control inflammatory responses and understand the related mechanisms. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti‐inflammatory properties, which may be associated with improvement of chemotherapy sensitivity during pancreatic cancer treatment. Quercetin may sensitize pancreatic cancer cells to the chemotherapeutic agents, including bromodomain and extraterminal domain inhibitors (BETI), daunorubicin, gemcitabine, sulforaphane, doxorubicin, and tumor necrosis factor‐related signaling apoptosis‐inducing ligand (TRAIL). Meanwhile, during the chemo‐resistance therapy, many signaling molecules are involved with toll‐like receptor 4 (TLR4)‐mediated oxidative and inflammatory pathway. The effects of quercetin on other oxidative and inflammatory pathways were also explored. Quercetin may exert antitumor activity during the prevention of pancreatic cancer progression by regulating oxidative and inflammatory networks, which can promote immune escape of cancer cells by inducing immunosuppressive cytokines. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo‐sensitivity. Practical applications Chemotherapy is the major way for treating pancreatic cancer metastasis but the prevalent chemotherapy resistance caused by oxidative and inflammatory responses limits its utilization. It is necessary to explore the potential natural products with few side effects to prevent the oxidative and inflammatory responses. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti‐inflammatory properties, which may be associated with improvement of chemotherapy sensitivity of pancreatic cancer treatment by sensitizing pancreatic cancer cells to various chemotherapeutic agents via the regulation of oxidative and inflammatory networks. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo‐sensitivity.

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Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway

Cited by 20 publications

References 65 publications

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Molecular mechanism analysis of m6A modification-related lncRNA-miRNA-mRNA network in regulating autophagy in acute pancreatitis

Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR

Quercetin improves pancreatic cancer chemo‐sensitivity by regulating oxidative‐inflammatory networks

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