Lipopolysaccharide (LPS)-induced
liver injury is the main factor
in acute liver failure. The current study aims to investigate the
protection of limonin, an antioxidant compound from citrus fruit,
against LPS-induced liver toxicity and elucidate the potential mechanisms.
We found that limonin elevated cell viability and reduced LDH release
in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis
by inhibiting membrane rupture, reducing ROS generation, and decreasing
gasdermin D activation. Moreover, limonin inhibited the formation
of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like
protein containing a CARD (ASC) complex by reducing the related protein
expression and the colocalization cytosolic of NLRP3 and caspase-1
and then suppressed IL-1β maturation. Ultimately, we established
LPS-induced hepatotoxicity in vivo by using C57BL/6
mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50
and 100 mg/kg) orally. We found that limonin dereased the serum ALT
and AST activity and LDH release and increased the hepatic GSH amount
in LPS-treated mice. Additionally, the liver histological evaluation
revealed that limonin protects against LPS-induced liver damage. We
further demonstrated that limonin ameliorated LPS-induced hepatotoxicity
by inhibiting pyroptosis via the NLRP3/gasdermin
D signaling pathway. In summary, this study uncovered the mechanism
whereby limonin mitigated LPS-induced hepatotoxicity and documented
that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.
Background
Receptor-interacting protein kinase 2 (RIPK2, also known as RIP2) was reported to be associated with bacterial infections as well as inflammatory responses. However, the role of RIPK2 in prognosis and immunotherapy response is yet to be elucidated in human pan-cancer.
Methods
In this study, we investigated the expression, gene alteration landscape and prognostic value of RIPK2 in 33 cancers through various databases including Ualcan, cBioportal and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, the correlation between RIPK2 and immune infiltration, immune score, stromal score, and ESTIMATE score was investigated in the Cancer Genome Atlas (TCGA) and tumor immune estimation resource (TIMER) databases. Independent cohorts were utilized to explore the role of RIPK2 in tumor immunotherapy response. Furthermore, Gene set enrichment analysis (GSEA) was conducted to explore the mechanisms by which RIPK2 regulates immune therapy resistance. Single-cell RNA-seq datasets were used to analyze the expression level of RIPK2 on different immune cells. Moreover, CellMiner database was used to explore the relationship between RIPK2 expression with drug response.
Result
Compared with normal tissue, tumor tissue had a higher expression level of RIPK2 in various cancers. Survival analysis showed that high expression of RIPK2 associated with poor prognosis in numerous cancers. RIPK2 was found to promote a series of immune cell infiltration and B cells, macrophages, and neutrophils were significantly positively correlated with the expression of RIPK2. Moreover, RIPK2 affected immune score, stromal score and ESTIMATE score for a wide range of cancers. In the vast majority of 33 cancers, gene co-expression analysis showed that RIPK2 was positively correlated with the expression of immune checkpoint markers, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4 and TIGIT. RIPK2 aggravated cytotoxic T lymphocyte (CTL) dysfunction and related to the poor efficacy of immune checkpoint blockade in skin cutaneous melanoma (SKCM) and kidney renal clear cell carcinoma (KIRC). High expression of RIPK2 promoted innate immunotherapy resistance and adaptive immunotherapy resistance through IL-6/JAK/STAT3 signaling, interferon-gamma response, and interferon-alpha response pathway.
Conclusions
These results confirmed that RIPK2 could serve as a prognostic biomarker and promoted immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.
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