Myricetin-Loaded Nanomicelles Protect against Cisplatin-Induced Acute Kidney Injury by Inhibiting the DNA
Xueju Qi1, Jing Wang2, Fengshu Fei1
1Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
Abstract:
Acute kidney injury (AKI) is the most common side effect of the anti-cancer drug cisplatin, and currently, no effective preventive measures are available in clinical practice. Oxidative stress and DNA damage mechanisms may be involved in cisplatin-induced AKI. In this study, we prepared Kolliphor HS15-based myricetin-loaded (HS15-Myr) nanomicelles and explored the mechanism of protection against cisplatin-induced AKI. In vitro results showed that the HS15-Myr nanomicelles enhanced the antioxidant activity of myricetin (Myr) and inhibited cisplatin-induced proliferation inhibition of HK-2 cells. Moreover, the HS15-Myr nanomicelles inhibited cisplatin-induced reactive oxygen species accumulation, mitochondrial membrane potential reduction, and DNA damage, which might be related to the inhibition of the cyclic GMP-AMP synthase (cGAS)─stimulating interferon gene (STING) signaling pathway. In vivo results in mice showed that the significant reductions in body weight and renal indices and the increased blood urea nitrogen and serum creatinine levels induced by cisplatin could be significantly reversed by pretreating with the HS15-Myr nanomicelles. Furthermore, nanomicelle pretreatment significantly altered the activities of antioxidant enzymes (e.g., GSH, MDA, and SOD) induced by cisplatin. In addition, cisplatin-induced inflammatory responses in mouse kidney tissue were found to be inhibited by pretreatment with HS15-Myr nanomicelles, such as IL-1β and TNF-α expression. The nanomicelles also significantly inhibited cisplatin-induced activation of the DNA damage-cGAS-STING pathway in kidney tissues. Together, our findings suggest that Myr-loaded nanomicelles are potential nephroprotective drugs.
Insights
Myricetin-loaded nanomicelles protect against cisplatin-induced acute kidney injury by reducing oxidative stress and inflammation. This study highlights their potential as a nephroprotective treatment for chemotherapy side effects.
Area of Science:
- Pharmacology
- Nanotechnology
- Nephrology
Background:
- Acute kidney injury (AKI) is a common side effect of cisplatin chemotherapy.
- Current preventive measures for cisplatin-induced AKI are limited.
- Oxidative stress and DNA damage are implicated in AKI pathogenesis.
Purpose of the Study:
- To develop Kolliphor HS15-based myricetin-loaded nanomicelles (HS15-Myr).
- To investigate the protective mechanism of HS15-Myr against cisplatin-induced AKI in vitro and in vivo.
- To explore the role of the cGAS-STING pathway in cisplatin nephrotoxicity.
Main Methods:
- Preparation and characterization of HS15-Myr nanomicelles.
- In vitro assessment of antioxidant activity and cell protection in HK-2 cells.
- In vivo evaluation in mice, measuring renal function markers, body weight, and inflammatory cytokines.
- Analysis of oxidative stress markers and DNA damage-related pathways (cGAS-STING).
Main Results:
- HS15-Myr enhanced myricetin's antioxidant capacity and protected HK-2 cells from cisplatin.
- Nanomicelles reduced reactive oxygen species, preserved mitochondrial potential, and inhibited DNA damage in vitro.
- In vivo, HS15-Myr reversed cisplatin-induced kidney damage, normalized renal indices, and reduced inflammatory markers (IL-1β, TNF-α).
- HS15-Myr inhibited the activation of the DNA damage-cGAS-STING pathway in kidney tissues.
Conclusions:
- Myricetin-loaded nanomicelles demonstrate significant nephroprotective effects against cisplatin-induced AKI.
- The protective mechanism involves mitigating oxidative stress, reducing inflammation, and inhibiting the cGAS-STING pathway.
- HS15-Myr nanomicelles represent a promising therapeutic strategy for preventing chemotherapy-related kidney injury.
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