Noncanonical NF-κB Signaling Pathway in Liver Diseases

Chen, Qianhui; Lu, Xinyu; Zhang, Xiaoyong

doi:10.14218/jcth.2020.00063

Cited by 12 publications

(14 citation statements)

References 67 publications

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“…To link our findings to protein cascades, we also performed pathway analysis. These results indicated that TWEAK and TNFSF14 belong to the noncanonical NF-κB signaling pathway, which regulates inflammation and host immune response 36 . In an animal model, both FGF-inducible 14 (Fn14) and TWEAK in knockout mice and wild-type mice showed proliferation in hepatocytes and cholangiocytes after partial hepatectomy, indicating that the proteins signal is essential for mouse liver regeneration after hepatectomy 36,37 .…”

Section: Discussionmentioning

confidence: 93%

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

et al. 2023

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Background and Aims: Fatty liver disease (FLD) is caused by excess fat in the liver, and its global prevalence exceeds 33%. The role of protein expression on the pathogenesis of FLD and accompanied fibrosis and its potential as a disease biomarker is currently not clear. Hence, we aimed to identify plasma proteomics associated with FLD and fibrosis using population-based data. Approach and Results: Blood samples were collected from 2578 participants from the population-based Rotterdam Study cohort. The proximity extension assay reliably measured plasma levels of 171 cardiometabolic and inflammatory-related proteins (Olink Proteomics). FLD was assessed by ultrasound, and fibrosis by transient elastography. Logistic regression models quantified the association of plasma proteomics with FLD and fibrosis. In addition, we aimed to validate our results in liver organoids. The cross-sectional analysis identified 27 proteins significantly associated with FLD surpassing the Bonferroni-corrected p<2.92×10−4. The strongest association was observed for FGF-21 (β=0.45, p=1.07×10−18) and carboxylesterase 1 (CES1) protein (β=0.66, p=4.91×10−40). Importantly, 15 of the 27 proteins significantly associated with FLD were also associated with liver fibrosis. Finally, consistent with plasma proteomic profiling, we found the expression levels of IL-18 receptor 1 (IL-18R1) and CES1 to be upregulated in an FLD model of 3-dimensional culture human liver organoids. Conclusions: Among the general population, several inflammatory and cardiometabolic plasma proteins were associated with FLD and fibrosis. Particularly, plasma levels of FGF-21, IL-18R1, and CES1 were largely dependent on the presence of FLD and fibrosis and may therefore be important in their pathogenesis.

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Section: Discussionmentioning

confidence: 93%

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

et al. 2023

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“…However, these changes were significantly alleviated by CoPP ( Figure 5 A–C). Nuclear factor-κB (NF-κB) is an essential transcription factor modulating the expression of various inflammatory genes [ 22 ]. DDC feeding led to an increase in phosphorylated forms of IκBα and NF-κB p65 in the liver ( Figure 5 D–F).…”

Section: Resultsmentioning

confidence: 99%

Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

Kim

Choi

Leem

et al. 2021

IJMS

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Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

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“…36 Similarly, NF-kB signaling pathway is crucial for liver diseases, involving multiple important BPs, such as inflammatory response, and apoptosis. 37,38 All chronic liver diseases lead to the activation of factors such as NF-kB or AP-1, and mediated activation of NF-kB signaling pathway. 39,40 In the current study, it was evident that SGNI may protect liver by attenuating inflammation through inhibition of TNF and NF-kB signaling pathways.…”

Section: Analysis Of Molecular Mechanism Of Sgnimentioning

confidence: 99%

Active Compounds Screening and Hepatoprotective Mechanism of Shuganning Injection Based on Network Pharmacology and Experimental Validation

Wang

Duan

shan

et al. 2022

Natural Product Communications

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Objective: The study aimed to analyze the core active compounds and the potential mechanism of Shuganning injection (SGNI) through network pharmacology with biological experiments. Methods: Active compounds and targets of SGNI were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Targetnet database, whereas the liver disease-related targets were identified through the Genecards and Online Mendelian Inheritance in Man databases. The “compound-target” and “protein-protein interaction” networks construction, core target identification, and pathway enrichment were then performed. Finally, the exploration of the mechanism of action for SGNI against acetaminophen (APAP)-induced liver injury in the HepaRG cells and validation of three identified protein targets was also carried out through western blot assay, including tumor protein p53 (p53, TP53), transcription factor Jun (Jun), and Caspase 3 (CASP3). Results: The result showed that a total of 312 active compounds of SGNI and 408 liver disease-related targets, as well as 131 core targets were revealed through databases, such as prostaglandin G/H synthase 1, prostaglandin G/H synthase 2, and nuclear factor NF-kappa B (NF-kB) p65 subunit (RELA). The core targets of SGNI were involved in regulating hepatitis B signaling pathway, NF-kB signaling pathway, Toll-like receptor signaling pathway, and tumor necrosis factor (TNF) signaling pathway. Moreover, results of molecular docking in this study indicated that chlorogenic acid, geniposide, baicalin, indirubin, and ganoderic acid A could act on RELA, JUN, TP53, TNF, CASP3, Caspase 8 (CASP8) and nuclear factor NF-kB p105 subunit (NFKB1). Similarly, results of western blot revealed that SGNI reduced the expression of p53, Jun, and Caspase 3 proteins in HepaRG cells as compared with the APAP group ( P < 0.01 or P < 0.05). Conclusion: The present study verified the therapeutic effects and mechanism of SGNI on liver diseases and pointed out new directions for further research.

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Noncanonical NF-κB Signaling Pathway in Liver Diseases

Cited by 12 publications

References 67 publications

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

Plasma proteomic signature of fatty liver disease: The Rotterdam Study

Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

Active Compounds Screening and Hepatoprotective Mechanism of Shuganning Injection Based on Network Pharmacology and Experimental Validation

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