5-O-methyldihydroquercetin and cilicicone B isolated from Spina Gleditsiae ameliorate lipopolysaccharide-induced acute kidney injury in mice by inhibiting inflammation and oxidative stress via the TLR4/MyD88/TRIF/NLRP3 signaling pathway.

Abstract

OBJECTIVE:

Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)-induced AKI. Spina Gleditsiae is a traditional Chinese anti-inflammatory medicine, from which a large number of flavonoids, such as 5-O-methyldihydroquercetin (GS1) and cilicicone B (GS2), were isolated in the present study. Here, we examined the reno-protective effects and potential underlying mechanisms of GS1 and GS2 in mice with LPS-induced AKI.

METHODS:

We analyzed renal function; the serum metabolic profile, inflammatory cytokine levels, peripheral white blood cell count, renal cell apoptosis, renal oxidant and antioxidant levels, and renal expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), nuclear factor-ĸB (NF-ĸB), interferon regulatory factor 3 (IRF3), NOD-, LRR- and pyrin domain-containing 3 (NLRP3, inflammasome), cleaved caspase-1, and interleukin 1 receptor type I (IL-1R1) in mice with LPS-induced AKI.

RESULTS:

GS1 and GS2 improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. In addition, PCA score scatter plots suggest that the GS1 and GS2 groups were clustered with the control group, indicating that these compounds contributed to the recovery of mice with AKI toward the normal condition. Moreover, GS1 and GS2 inhibited the expression of TLR4, MyD88, TRIF, p-NF-ĸB, p-IRF3, NLRP3, cleaved caspase-1, and IL-1R1.

CONCLUSION:

The reno-protective effects of GS1 and GS2 are mediated via the MyD88/TRIF and NLRP3 pathways to reduce inflammation and oxidative stress through TLR4 signaling.

• Authors: Mengnan Zeng, Man Qi, Yangyang Wang, Ruiqi Xu, Yuanyuan Wu, Meng Li, Xiaoke Zheng, Weisheng Feng
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 80 Pg. 106194 (Mar 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 31986326 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• 5-O-methyldihydroquercetin
• Adaptor Proteins, Vesicular Transport
• Benzopyrans
• Drugs, Chinese Herbal
• Inflammasomes
• Lipopolysaccharides
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• TICAM-1 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Zao-Jiao-Ci
• Quercetin

Topics

• Acute Kidney Injury (drug therapy, immunology)
• Adaptor Proteins, Vesicular Transport (metabolism)
• Animals
• Benzopyrans (chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Drugs, Chinese Herbal (chemistry, pharmacology, therapeutic use)
• Gleditsia (chemistry)
• Humans
• Inflammasomes (drug effects, immunology, metabolism)
• Lipopolysaccharides (immunology)
• Male
• Mice
• Myeloid Differentiation Factor 88 (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oxidative Stress (drug effects, immunology)
• Quercetin (analogs & derivatives, pharmacology, therapeutic use)
• Signal Transduction (drug effects, immunology)
• Toll-Like Receptor 4 (metabolism)