A self-assembled nanomicelle-based "one stone for two birds" strategy for precision therapy of hepatic ischemia-reperfusion injury
(
), Xiao Xu6,7 ()Graphical Abstract
Abstract
Hepatic ischemia-reperfusion injury (IRI) is an intricate and inevitable physiological event occurred in the liver transplantation (LT) and it is of paramount importance to devise novel and efficient methods to ameliorate IRI. Herein, we report a "one stone for two birds" strategy for IRI therapy. In this study, we engineered carvacrol-artesunate (CAR-ART) nanoparticles (CANPs) utilizing CAR and ART as precursor monomers and simulated IRI in an in vivo mouse model. Our research results indicate that CANPs proficiently surmount the constraints linked with the solitary components utilized in preceding studies such as water solubility, stability, and biocompatibility. Furthermore, they exhibit a distinctive accumulation in the liver. From an immunological standpoint, CANPs have been observed to significantly impede the accumulation and activation of various immune cells such as macrophages, neutrophils, and Kupffer cells. This results in the restoration of the hepatic immune cell distribution to a state akin to that of a normal liver. Furthermore, CANPs markedly inhibit the accumulation of a multitude of pro-inflammatory cytokines. Cellularly, it has been observed that CANPs significantly hinder the onset of ferroptosis in hepatocytes. This is accomplished by inhibiting the accumulation of crucial enzymes such as long-chain-fatty-acid-CoA ligase 4 (ACSL4), as well as associated lipid oxidation intermediates like malondialdehyde (MDA), which are relevant to the process of ferroptosis. Consequently, a solitary intravenous administration of CANPs has the potential to simultaneously inhibit ferroptosis of hepatocytes and normalize proinflammatory immune cells, one stone for two birds. In conclusion, CANPs may serve as a promising multi-bioactive nanotherapeutic agent and a bioresponsive targeting delivery nanocarrier, offering a potentially effective treatment strategy for hepatic IRI.
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References
Lucey, M. R.; Furuya, K. N.; Foley, D. P. Liver transplantation. N. Engl. J. Med. 2023, 389, 1888–900.
Xu, X. State of the art and perspectives in liver transplantation. Hepatobiliary Pancreat. Dis. Int. 2023, 22, 1–3.
Dar, W. A.; Sullivan, E.; Bynon, J. S.; Eltzschig, H.; Ju, C. Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms. Liver Int. 2019, 39, 788–801.
Zhou, J. B.; Chen, J.; Wei, Q.; Saeb-Parsy, K.; Xu, X. The role of ischemia/reperfusion injury in early hepatic allograft dysfunction. Liver Transpl. 2020, 26, 1034–1048.
Cannistrà, M.; Ruggiero, M.; Zullo, A.; Gallelli, G.; Serafini, S.; Maria, M.; Naso, A.; Grande, R.; Serra, R.; Nardo, B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int. J. Surg. 2016, 33 Suppl 1, S57–S70.
Scozzi, D.; Gelman, A. E. Avoid being trapped by your liver: Ischemia-reperfusion injury in liver transplant triggers S1P-mediated netosis. J. Clin. Invest. 2023, 133, e167012.
Gao, F. Q.; Qiu, X.; Wang, K.; Shao, C. X.; Jin, W. J.; Zhang, Z.; Xu, X. Targeting the hepatic microenvironment to improve ischemia/reperfusion injury: New insights into the immune and metabolic compartments. Aging Dis. 2022, 13, 1196–1214.
Liu, H.; Man, K. New insights in mechanisms and therapeutics for short- and long-term impacts of hepatic ischemia reperfusion injury post liver transplantation. Int. J. Mol. Sci. 2021, 22, 8210.
Hirao, H.; Nakamura, K.; Kupiec-Weglinski, J. W. Liver ischaemia-reperfusion injury: A new understanding of the role of innate immunity. Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 239–256.
Liu, Y.; Lu, T. F.; Zhang, C.; Xu, J.; Xue, Z. Z.; Busuttil, R. W.; Xu, N.; Xia, Q.; Kupiec-Weglinski, J. W.; Ji, H. F. Activation of yap attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury. J. Hepatol. 2019, 71, 719–730.
Nakamura, K.; Zhang, M.; Kageyama, S.; Ke, B. B.; Fujii, T.; Sosa, R. A.; Reed, E. F.; Datta, N.; Zarrinpar, A.; Busuttil, R. W, et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J. Hepatol. 2017, 67, 1232–1242.
Junzhe, J.; Meng, L.; Weifan, H.; Min, X.; Jiacheng, L.; Yihan, Q.; Ke, Z.; Fang, W.; Dongwei, X.; Hailong, W, et al. Potential effects of different cell death inhibitors in protecting against ischemia-reperfusion injury in steatotic liver. Int. Immunopharmacol. 2024, 128, 111545.
Chen, X.; Li, J. B.; Kang, R.; Klionsky, D. J.; Tang, D. L. Ferroptosis: Machinery and regulation. Autophagy 2021, 17, 2054–2081.
Doll, S.; Proneth, B.; Tyurina, Y. Y.; Panzilius, E.; Kobayashi, S.; Ingold, I.; Irmler, M.; Beckers, J.; Aichler, M.; Walch, A, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 2017, 13, 91–98.
Li, J.; Cao, F.; Yin, H. L.; Huang, Z. J.; Lin, Z. T.; Mao, N.; Sun, B.; Wang, G. Ferroptosis: Past, present and future. Cell Death Dis. 2020, 11, 88.
Liu, J.; Kang, R.; Tang, D. L. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2022, 289, 7038–7050.
Stockwell, B. R.; Friedmann Angeli, J. P.; Bayir, H.; Bush, A. I.; Conrad, M.; Dixon, S. J.; Fulda, S.; Gascón, S.; Hatzios, S. K.; Kagan, V. E, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017, 171, 273–285.
Tang, D. L.; Chen, X.; Kang, R.; Kroemer, G. Ferroptosis: Molecular mechanisms and health implications. Cell Res. 2021, 31, 107–125.
Friedmann Angeli, J. P.; Schneider, M.; Proneth, B.; Tyurina, Y. Y.; Tyurin, V. A.; Hammond, V. J.; Herbach, N.; Aichler, M.; Walch, A.; Eggenhofer, E, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 2014, 16, 1180–1191.
Yamada, N.; Karasawa, T.; Wakiya, T.; Sadatomo, A.; Ito, H.; Kamata, R.; Watanabe, S.; Komada, T.; Kimura, H.; Sanada, Y, et al. Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis. Am. J. Transplant. 2020, 20, 1606–1618.
Li, X. Y.; Ma, N.; Xu, J. P.; Zhang, Y. C.; Yang, P.; Su, X.; Xing, Y. F.; An, N.; Yang, F.; Zhang, G. X. et al. Targeting ferroptosis: Pathological mechanism and treatment of ischemia-reperfusion injury. Oxid. Med. Cell. Longev. 2021, 2021, 1587922.
Sun, S. M.; Shen, J.; Jiang, J. W.; Wang, F. D.; Min, J. X. Targeting ferroptosis opens new avenues for the development of novel therapeutics. Signal Transduct. Target. Ther. 2023, 8, 372.
Silva, E. R.; de Carvalho, F. O.; Teixeira, L. G. B.; Santos, N. G. L.; Felipe, F. A.; Santana, H. S. R.; Shanmugam, S.; Quintans Júnior, L. J.; de Souza Araújo, A. A.; Nunes, P. S. Pharmacological effects of carvacrol in in vitro studies: A review. Curr. Pharm. Des. 2018, 24, 3454–3465.
Mączka, W.; Twardawska, M.; Grabarczyk, M.; Wińska, K. Carvacrol-a natural phenolic compound with antimicrobial properties. Antibiotics (Basel.) 2023, 12, 824.
Guan, X. Y.; Li, X. L.; Yang, X. J.; Yan, J. W.; Shi, P. L.; Ba, L. N.; Cao, Y. G.; Wang, P. The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Life Sci. 2019, 235, 116795.
Rosenthal, P. J. Artesunate for the treatment of severe falciparum malaria. N. Engl. J. Med. 2008, 358, 1829–1836.
Gao, X.; Lin, X.; Wang, Q. W.; Chen, J. Artemisinins: Promising drug candidates for the treatment of autoimmune diseases. Med. Res. Rev. 2024, 44, 867–891.
Noubiap, J. J. N. Shifting from quinine to artesunate as first-line treatment of severe malaria in children and adults: Saving more lives. J. Infect. Public Health 2014, 7, 407–412.
Ji, T.; Chen, M.; Liu, Y. Y.; Jiang, H. X.; Li, N.; He, X. H. Artesunate alleviates intestinal ischemia/reperfusion induced acute lung injury via up-regulating akt and ho-1 signal pathway in mice. Int. Immunopharmacol. 2023, 122, 110571.
Liu, Z. H.; Zhang, J. J.; Li, S. T.; Jiang, J. H. Artesunate inhibits renal ischemia reperfusion-stimulated lung inflammation in rats by activating ho-1 pathway. Inflammation 2018, 41, 114–121.
Gashe, F.; Wynendaele, E.; De Spiegeleer, B.; Suleman, S. Degradation kinetics of artesunate for the development of an ex-tempore intravenous injection. Malar. J. 2022, 21, 256.
Li, S. K.; Zhang, W. J.; Xing, R. R.; Yuan, C. Q.; Xue, H. D.; Yan, X. H. Supramolecular nanofibrils formed by coassembly of clinically approved drugs for tumor photothermal immunotherapy. Adv. Mater. 2021, 33, 2100595.
Cheetham, A. G.; Chakroun, R. W.; Ma, W.; Cui, H. G. Self-assembling prodrugs. Chem. Soc. Rev. 2017, 46, 6638–6663.
Yang, Z. T.; Xie, H. Y.; Wan, J. Q.; Wang, Y. C.; Zhang, L.; Zhou, K.; Tang, H.; Zhao, W. T.; Wang, H. X.; Song, P, H. et al. A nanotherapeutic strategy that engages cytotoxic and immunosuppressive activities for the treatment of cancer recurrence following organ transplantation. EBioMedicine 2023, 92, 104594.
Zhou, K.; Chen, X. N.; Zhang, L.; Yang, Z. T.; Zhu, H.; Guo, D. J.; Su, R.; Chen, H.; Li, H.; Song, P, H. et al. Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection. Am. J. Transplant. 2021, 21, 3871–3882.
Li, G. T.; Sun, B. J.; Li, Y. Q.; Luo, C.; He, Z. G.; Sun, J. Small-molecule prodrug nanoassemblies: An emerging nanoplatform for anticancer drug delivery. Small 2021, 17, 2101460.
Li, S. K.; Zou, Q. L.; Li, Y. X.; Yuan, C. Q.; Xing, R. R.; Yan, X. H. Smart peptide-based supramolecular photodynamic metallo-nanodrugs designed by multicomponent coordination self-assembly. J. Am. Chem. Soc. 2018, 140, 10794–10802.
Sun, T. M.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M. X.; Xia, Y. N. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem., Int. Ed. 2014, 53, 12320–12364.
Li, M.; Zhao, L. W.; Zhang, T.; Shu, Y.; He, Z. G.; Ma, Y.; Liu, D.; Wang, Y. J. Redox-sensitive prodrug nanoassemblies based on linoleic acid-modified docetaxel to resist breast cancers. Acta Pharm. Sin. B 2019, 9, 421–432.
Xie, S.; Manuguri, S.; Proietti, G.; Romson, J.; Fu, Y.; Inge, A. K.; Wu, B.; Zhang, Y.; Häll, D.; Ramström, O, et al. Design and synthesis of theranostic antibiotic nanodrugs that display enhanced antibacterial activity and luminescence. Proc. Natl. Acad. Sci. USA 2017, 114, 8464–8469.
Ou, Y.; Wang, S. J.; Li, D. W.; Chu, B.; Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl. Acad. Sci. USA 2016, 113, E6806–E6812.
Yang, W. S.; SriRamaratnam, R.; Welsch, M. E.; Shimada, K.; Skouta, R.; Viswanathan, V. S.; Cheah, J. H.; Clemons, P. A.; Shamji, A. F.; Clish, C. B. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014, 156, 317–331.
Chrishtop, V. V.; Mironov, V. A.; Prilepskii, A. Y.; Nikonorova, V. G.; Vinogradov, V. V. Organ-specific toxicity of magnetic iron oxide-based nanoparticles. Nanotoxicology 2021, 15, 167–204.
Yang, W.; Wang, L.; Mettenbrink, E. M.; DeAngelis, P. L.; Wilhelm, S. Nanoparticle toxicology. Annu. Rev. Pharmacol. Toxicol. 2021, 61, 269–289.
Hirao, H.; Dery, K. J.; Kageyama, S.; Nakamura, K.; Kupiec-Weglinski, J. W. Heme oxygenase-1 in liver transplant ischemia-reperfusion injury: From bench-to-bedside. Free Radic. Biol. Med. 2020, 157, 75–82.
Kaltenmeier, C.; Wang, R. H.; Popp, B.; Geller, D.; Tohme, S.; Yazdani, H. O. Role of immuno-inflammatory signals in liver ischemia-reperfusion injury. Cells 2022, 11, 2222.
Mohseni, R.; Karimi, J.; Tavilani, H.; Khodadadi, I.; Hashemnia, M. Carvacrol downregulates lysyl oxidase expression and ameliorates oxidative stress in the liver of rats with carbon tetrachloride-induced liver fibrosis. Indian J. Clin. Biochem. 2020, 35, 458–464.
Aristatile, B.; Al-Assaf, A. H.; Pugalendi, K. V. Carvacrol suppresses the expression of inflammatory marker genes in d-galactosamine-hepatotoxic rats. Asian Pac. J. Trop. Med. 2013, 6, 205–211.
Ismail, M.; Srivastava, V.; Marimani, M.; Ahmad, A. Carvacrol modulates the expression and activity of antioxidant enzymes in Candida auris. Res. Microbiol. 2022, 173, 103916.
Sharifi-Rad, M.; Varoni, E. M.; Iriti, M.; Martorell, M.; Setzer, W. N.; Del Mar Contreras, M.; Salehi, B.; Soltani-Nejad, A.; Rajabi, S.; Tajbakhsh, M, et al. Carvacrol and human health: A comprehensive review. Phytother. Res. 2018, 32, 1675–1687.
Sordi, R.; Nandra, K. K.; Chiazza, F.; Johnson, F. L.; Cabrera, C. P.; Torrance, H. D.; Yamada, N.; Patel, N. S. A.; Barnes, M. R.; Brohi, K, et al. Artesunate protects against the organ injury and dysfunction induced by severe hemorrhage and resuscitation. Ann. Surg. 2017, 265, 408–417.
Chen, Y. Y.; Zheng, S. H.; Wang, Z. W.; Cai, X.; Che, Y. J.; Wu, Q.; Yuan, S.; Zhong, X. H. Artesunate restrains maturation of dendritic cells and ameliorates heart transplantation-induced acute rejection in mice through the PERK/ATF4/CHOP signaling pathway. Mediators Inflamm. 2021, 2021, 2481907.
Cerrah, S.; Ozcicek, F.; Gundogdu, B.; Cicek, B.; Coban, T. A.; Suleyman, B.; Altuner, D.; Bulut, S.; Suleyman, H. Carvacrol prevents acrylamide-induced oxidative and inflammatory liver damage and dysfunction in rats. Front. Pharmacol. 2023, 14, 1161448.
Zhao, W. T.; Tang, H.; Liang, Z.; Wang, N.; Sun, R. Q.; Su, R.; Yang, Z. T.; Zhou, K.; Peng, Y. Y.; Zheng, S. S. et al. Carvacrol ameliorates skin allograft rejection through modulating macrophage polarization by activating the wnt signalling pathway. Phytother. Res. 2024, 38, 4675–4694.
Golatkar, V.; Bhatt, L. K. Artesunate attenuates isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation. Eur. J. Pharmacol. 2024, 977, 176709.
Kumar, V. L.; Verma, S.; Das, P. Artesunate suppresses inflammation and oxidative stress in a rat model of colorectal cancer. Drug Dev. Res. 2019, 80, 1089–1097.
Kim, H.; Kim, Y.; Guk, K.; Yoo, D.; Lim, H.; Kang, G.; Lee, D. Fully biodegradable and cationic poly(amino oxalate) particles for the treatment of acetaminophen-induced acute liver failure. Int. J. Pharm. 2012, 434, 243–250.
Ko, E.; Jeong, D.; Kim, J.; Park, S.; Khang, G.; Lee, D. Antioxidant polymeric prodrug microparticles as a therapeutic system for acute liver failure. Biomaterials 2014, 35, 3895–3902.
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