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17(R)-RvD1 Ameliorates Liver Injury in Hyperuricemia Through Inhibiting Pyroptosis via NF-κB Signaling Pathway
Lei Zhao1, Yang Zhang2, Yanling Qiao3
1GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, People's Republic of China.
Purpose:
The prevalence of hyperuricemia has been increasing worldwide. Most studies have focused on the influences of hyperuricemia on kidney damage and cardiovascular disease. However, the impacts of hyperuricemia on the liver remain unclear. 17(R)-RvD1 (Resolvin D1) plays a crucial role in various pathological conditions associated with inflammation. This study aims to investigate the effects of 17(R)-RvD1 on hyperuricemia-induced hepatic injury.
Methods:
Potassium oxonate and hypoxanthine were used to establish a hyperuricemic mouse model and investigate the effects of 17(R)-RvD1 on hyperuricemia and concomitant liver injury. Serum uric acid, xanthine oxidase (XOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and inflammatory cytokines levels were assessed. Hematoxylin-eosin (HE), Masson and Sirius Red staining were used to detect histological alterations in the liver. The mRNA and protein expression levels were determined by qRT-PCR and Western blot, respectively. Anti-inflammatory and anti-pyroptosis effects of 17(R)-RvD1 were also observed in LO2 cells exposed to uric acid.
Results:
17(R)-RvD1 administration ameliorated serum uric acid, ALT, AST levels; decreased serum IL-1β, IL-6, TNF-α and IL-18 levels; mitigated hepatic inflammatory responses; reduced hepatic NLRP3, ASC and caspase-1 mRNA expression levels and c-caspase-1, IL-1β and IL-18 levels in hyperuricemic mice. Furthermore, 17(R)-RvD1 administration increased cell viability and reduced LDH release; decreased NLRP3, ASC and caspase-1 mRNA expression levels and Gasdermin D (GSDMD), c-caspase-1, IL-1β and IL-18 levels in LO2 cells exposed to uric acid. Finally, the anti-pyroptosis effects of 17(R)-RvD1 were blocked when the NF-κB signaling pathway was inhibited by BAY 11-7082.
Conclusion:
17(R)-RvD1 possesses anti-hyperuricemic and anti-inflammatory effects, and the underlying mechanism for ameliorating hepatic injury in hyperuricemia is the inhibition of cell pyroptosis via downregulating the NF-κB signaling pathway. 17(R)-RvD1 could serve as an ideal candidate drug and increase options for the treatment of hyperuricemia.
Insights
17(R)-RvD1 reduces uric acid and liver damage in hyperuricemia by inhibiting inflammation and pyroptosis through the NF-κB pathway. This compound shows potential as a novel treatment for hyperuricemia.
Area of Science:
- Biomedical Science
- Pharmacology
- Hepatology
Background:
- Hyperuricemia prevalence is rising globally, with significant focus on kidney and cardiovascular impacts.
- The effects of hyperuricemia on liver health are less understood.
- 17(R)-RvD1 is recognized for its anti-inflammatory properties in various diseases.
Purpose of the Study:
- To investigate the therapeutic potential of 17(R)-RvD1 in mitigating hyperuricemia-induced liver injury.
- To elucidate the mechanisms underlying 17(R)-RvD1's effects on hepatic inflammation and cell death.
Main Methods:
- A hyperuricemic mouse model was established using potassium oxonate and hypoxanthine.
- 17(R)-RvD1's effects were evaluated by measuring serum uric acid, liver enzymes (ALT, AST), inflammatory cytokines, and XOD activity.
- Liver histology was assessed using HE, Masson, and Sirius Red staining; molecular analysis involved qRT-PCR and Western blotting; in vitro studies used LO2 cells.
Main Results:
- 17(R)-RvD1 treatment significantly lowered serum uric acid, ALT, and AST levels in hyperuricemic mice.
- It reduced hepatic inflammation by decreasing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18) and pyroptosis markers (NLRP3, ASC, caspase-1, GSDMD).
- In vitro, 17(R)-RvD1 enhanced LO2 cell viability and inhibited uric acid-induced pyroptosis, effects dependent on the NF-κB pathway.
Conclusions:
- 17(R)-RvD1 demonstrates anti-hyperuricemic and anti-inflammatory properties, effectively ameliorating liver injury.
- The mechanism involves suppressing cell pyroptosis via downregulation of the NF-κB signaling pathway.
- 17(R)-RvD1 presents a promising therapeutic candidate for managing hyperuricemia and its associated liver complications.
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