1. Research Projects
(1) National Natural Science Foundation of China: The anti-atherosclerotic effect of nitazoxanide and the potential mechanisms (2022.01-2025.12)
(2) National Natural Science Foundation of China: The application of poly (glycerol-sebacate) as biodegradable drug carrier. (2008.01-2010.12)
2. Representative Research Achievements
(1) The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. we aim to demonstrate that nitazoxanide would protect against atherosclerosis. The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum- and PDGF-induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF-κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL-1β and IL-6 levels and suppressed atherosclerosis in Western diet-fed ApoE (-/-) mice. In conclusion, nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (-/-) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti-atherosclerotic drug with clinical translational potential.
(2) Activation of NLRP3 inflammasome is implicated in varieties of pathologies, we aim to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1β mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.
Mitochondrial metabolism; Cardiovascular pharmacology.
1. Research Projects
(1) National Natural Science Foundation of China: The anti-atherosclerotic effect of nitazoxanide and the potential mechanisms (2022.01-2025.12)
(2) National Natural Science Foundation of China: The application of poly (glycerol-sebacate) as biodegradable drug carrier. (2008.01-2010.12)
2. Representative Research Achievements
(1) The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. we aim to demonstrate that nitazoxanide would protect against atherosclerosis. The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum- and PDGF-induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF-κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL-1β and IL-6 levels and suppressed atherosclerosis in Western diet-fed ApoE (-/-) mice. In conclusion, nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (-/-) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti-atherosclerotic drug with clinical translational potential.
(2) Activation of NLRP3 inflammasome is implicated in varieties of pathologies, we aim to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1β mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.
1. Jiang M, Zhang YX, Bu WJ, Li P, Chen JH, Cao M, Dong YC, Sun ZJ*, Dong DL*. Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells. Br J Pharmacol. 2023 Feb 5. doi: 10.1111/bph.16050. Epub ahead of print. PMID: 36740831.
2. Ma MH, Li FF, Li WF, Zhao H, Jiang M, Yu YY, Dong YC, Zhang YX, Li P, Bu WJ, Sun ZJ*, Dong DL*. Repurposing nitazoxanide as a novel anti-atherosclerotic drug based on mitochondrial uncoupling mechanisms. Br J Pharmacol. 2023 ;180(1):62-79.
3. Li F, Jiang M, Ma M, Chen X, Zhang Y, Zhang Y, Yu Y, Cui Y, Chen J, Zhao H, Sun Z*, Dong D*. Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice. Acta Pharm Sin B. 2022;12(3):1322-1338.
4. Hu N, Fu Y, Li WF, Yang XR, Cao M, Li FF, Chen JH, Chen XY, Zhao H, Sun ZJ*, Dong DL*. Chemical mitochondrial uncouplers share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation. Toxicol Appl Pharmacol. 2021;414:115426.
5. Ma R, Ma ZG, Gao JL, Tai Y, Li LJ, Zhu HB, Li L, Dong DL, Sun ZJ*. Injectable pegylated niclosamide (polyethylene glycol-modified niclosamide) for cancer therapy. J Biomed Mater Res A. 2020;108(1):30-38.
6. Ma R, Ma ZG, Zhen CL, Shen X, Li SL, Li L, Zheng YF, Dong DL, Sun ZJ*. Design, synthesis and characterization of poly (methacrylic acid-niclosamide) and its effect on arterial function. Mater Sci Eng C Mater Biol Appl. 2017;77:352-9.
7. Ma ZG, Ma R, Xiao XL, Zhang YH, Zhang XZ, Hu N, Gao JL, Zheng YF, Dong DL, Sun ZJ*. Azo polymeric micelles designed for colon-targeted dimethyl fumarate delivery for colon cancer therapy. Acta Biomater. 2016;44:323-31.
8. Guo XL, Lu XL, Dong DL, Sun ZJ*. Characterization and optimization of glycerol/sebacate ratio in poly(glycerol-sebacate) elastomer for cell culture application. J Biomed Mater Res A. 2014;102(11):3903-7.
9. Sun ZJ*, Sun B, Tao RB, Xie X, Lu XL, Dong DL*. A poly (glycerol-sebacate-curcumin) polymer with potential use for brain gliomas. J Biomed Mater Res A. 2013;101(1):253-60.
10. Sun ZJ*, Chen C, Sun MZ, Ai CH, Lu XL, Zheng YF, Yang BF, Dong DL*. The application of poly (glycerol-sebacate) as biodegradable drug carrier. Biomaterials. 2009;30(28):5209-14.
