Zaizhi Du,Xie Huang,Zifei Wu,Mingquan Gao,Rong Li,Shenglin Luo
Radionuclide uranium has both a chemical and radioactive toxicity, leading to severe nephrotoxicity as it predominantly deposits itself in the kidneys after entering into human bodies. It crosses renal cell membranes, accumulates in mitochondria and causes mitochondrial oxidative damage and dysfunction. In this study, a mitochondria-targeted heptamethine indocyanine small molecule chelator modified with gallic acid (IR-82) is synthesized for uranium detoxication. Both gallic acid and sulfonic acid, as two hydrophilic endings, make IR-82, being excreted feasibly through kidneys. Gallic acid with polyphenol groups has a steady metal chelation effect and potent antioxidant ability, which may facilitate IR-82-alleviated uranium nephrotoxicity simultaneously by enhancing uranium decorporation from the kidneys and reducing mitochondrial oxidative damage. Cell viability assays demonstrate that IR-82 can significantly improve the cell viability of uranium-exposed human renal (HK-2) cells. It is also demonstrated to accumulate in mitochondria and reduce mitochondrial ROS and total intracellular ROS, as well as intracellular uranium content. In vivo imaging experiments in mice show that IR-82 could be excreted out through kidneys. ICP-MS tests further reveal that IR-82 can efficiently decrease the uranium deposition in mouse kidneys. IR-82 treatment improves the animal survival rate and renal function of experimental mice after high-dose uranium exposure. Collectively, our study may evidence that the development of uranium decorporation agents with kidney–mitochondrion dual targeting abilities is a promising strategy for attenuating uranium-induced nephrotoxicity.
Spinal cord injury is hard to repair due to the aggregated injury to neighbor cells caused by neuro-inflammation, which always results in severe outcomes. In this work, Tc peptide, which served as the antagonist of CXCR4 and the agonist of CXCR7, was loaded in a self-healing hydrogel. The hydrogel containing Tc was found to possess superior spinal cord injury repair abilities, including motor neuron regeneration, axon bridging repair and motor functions recovery, due to the inflammation inhibition. The mechanism analysis by RNA-sequencing and in vitro experiments found that the elevated ANT1 accelerates OPTN recruitment, which subsequently recognized by LC3 to form phagophore around dysfunctional mitochondria, resulting in a regressive NLRP3 expression. However, this regression was abolished after inhibiting OPTN. Beneficial from the mitophagy process, ROS was reduced and type 1 microglia activation was diminished. This positive feedback loop accelerated spinal cord injury repair. In summary, the hydrogel containing Tc could promote spinal cord injury repair through reducing neuro-inflammation via enhanced ANT1/OPTN axis mediated mitophagy, which may provide a new peptide containing hydrogel for repairing spinal cord injury.
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