γ-Oryzanol alleviates acetaminophen-induced liver injury: roles of modulating AMPK/GSK3β/Nrf2 and NF-κB signaling pathways

Gao, Shu; Qiu, Yunhan; Jiang, Hao; Fu, Qian; Deng, Xukun

doi:10.1039/c9fo01808e

Cited by 38 publications

(26 citation statements)

References 55 publications

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“…It is known that PPARα interferes with NF-κB involving direct protein-protein interaction with subunit p65, thus diminishing NF-κB DNA binding. NF-κB is an upstream signal molecule of many inflammatory mediators and is involved in apoptosis, which can promote the production of many inflammatory mediators and directly participate in acute and chronic inflammation of the liver [25,26]. Studies have shown that in the process of establishing a model of alcoholic fatty liver, NF-κB is consistent with the degree of steatosis in liver tissue at the gene transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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“…[ 31 ] Orz was proven to suppress IκB‐α degradation, thereby hampering NF‐κB p65 nuclear translocation, which is essential for maintaining the resting states of DCs. [ 32 ] In addition, extracellular ATP and HMGB1 after treatment induced DC maturation. [ 33 ] Moreover, AOZNs, act as DNMTi and may also increase the expression of genes associated with antigen presentation and costimulatory molecules such as CD80 and CD86.…”

Section: Resultsmentioning

confidence: 99%

Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

Xiong

Wang

et al. 2021

Adv Funct Materials

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Overcoming innate or adaptive resistance to immune checkpoint inhibitor therapy in solid tumors with limited T‐cell responses remains challenging. Increasing evidence has indicated that epigenetic alterations, especially overexpression of DNA methyltransferase and immunosuppressive adenosine, are major obstacles to T cell activation. Here, a tumor microenvironment (TME) inspired prodrug nanomicelle (AOZN) composed of the epigenetic modulator γ‐oryzanol (Orz), the adenosine inhibitor α, β‐methylene adenosine 5′ diphosphate (AMPCP), and GSH‐activable crosslinker, is rationally designed. High glutathione redox triggers Orz and AMPCP release in the TME. The released Orz act as a DNA methyltransferases inhibitor to upregulate gasdermin D (GSDMD) expression and AMPCP converted procaspase‐1 into active caspase‐1 by increasing ATP levels. Active caspase‐1 elicited GSDMD cleavage and induced pyroptosis in tumor cells. Furthermore, it is demonstrated that Orz and AMPCP likely have a synergistic effect in combating the immunosuppressive TME. Moreover, Orz enhances programmed death‐ligand 1 (PD‐L1) expression and sensitize tumors to anti‐PD‐L1 therapy. Thus, the AOZNs nano‐formulation drastically improves the hydrophobic properties of Orz with advantages of safe, affordable, readily available, and efficiency in regressing tumor growth, enhancing PD‐L1 responsive rate and prolonging survival of the B16F10 melanoma‐bearing mouse model. As a result, AOZNs provides a promising strategy for enhancing cancer immunotherapy.

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“…NF-κB is an upstream signal molecule of many in ammatory mediators, which can promote the production of many in ammatory mediators and directly participate in acute and chronic in ammation of the liver [23]. In addition, NF-κB exerts its anti-apoptotic effect by directly activating anti-apoptotic genes [24].…”

Section: Discussionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2020

Preprint

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Abstract Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory response are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigate the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissect the pathogenic role of Fmo5 in AFLD-induced liver pathology. Materials and methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. Weighted gene co-expression network analysis (WGCNA) approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized by Cytoscape software. Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expressions. ELISA assay was used to detect the level of serum inflammatory cytokines. Lipid droplets in cytoplasm were observed using Oil Red O staining. Cell apoptosis was detected using TUNEL assay and flow cytometry analysis. ROS level were detected using flow cytometry analysis. The nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation were used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 was a key DEG and closely associated with gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal model with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusions Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition, alleviated AFLD-induced liver injury, apoptosis and inflammatory response via inhibiting the nuclear translocation of NF-κB p65 to inhibit NF-κB signaling pathway.

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γ-Oryzanol alleviates acetaminophen-induced liver injury: roles of modulating AMPK/GSK3β/Nrf2 and NF-κB signaling pathways

Abstract: γ-Oryzanol alleviates acetaminophen-induced liver injury in mice.

Cited by 38 publications

References 55 publications

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Inspired Epigenetic Modulation Synergy with Adenosine Inhibition Elicits Pyroptosis and Potentiates Cancer Immunotherapy

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

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