ABSTRACT
Although as a mainstay modal for cancer treatment, the clinical effect of radiotherapy (RT) does not yet meet the need of cancer patients. Developing tumour-preferential radiosensitizers or combining RT with other treatments has been acknowledged highly necessary to enhance the efficacy of RT. The present study reported a multifunctional bioactive small-molecule (designated as IR-83) simultaneously exhibiting tumour-preferential accumulation, near-infrared imaging and radio/photodynamic/photothermal therapeutic effects. IR-83 was designed and synthesized by introducing 2-nitroimidazole as a radiosensitizer into the framework of heptamethine cyanine dyes inherently with tumour-targeting and photosensitizing effects. As results, IR-83 preferentially accumulated in tumours, suppressed tumour growth and metastasis by integrating radio/photodynamic/photothermal multimodal therapies. Mechanism studies showed that IR-83 accumulated in cancer cell mitochondria, induced excessive reactive oxygen species (ROS), and generated high heat after laser irradiation. On one hand, these phenomena led to mitochondrial dysfunction and a sharp decline in oxidative phosphorylation to lessen tissue oxygen consumption. On the other hand, excessive ROS in mitochondria destroyed the balance of antioxidants and oxidative stress balance by down-regulating the intracellular antioxidant system, and subsequently sensitized ionizing radiation-generated irreversible DNA double-strand breaks. Therefore, this study presented a promising radiosensitizer and a new alternative strategy to enhance RT efficacy via mitochondria-targeting multimodal synergistic treatment.
ABSTRACT
Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury inducing glomerular filtration barrier and proteinuria. The occurrence and development of DN could be partly attributed to the reactive oxygen species (ROS) generated by mitochondria. However, research on how mitochondrial dysfunction (MtD) ultimately causes DNA damage is poor. Here, we investigated the influence of Klotho deficiency on high glucose (HG)-induced DNA damage in vivo and in vitro. First, we found that the absence of Klotho aggravated diabetic phenotypes indicated by podocyte injury accompanied by elevated urea albumin creatinine ratio (UACR), creatinine and urea nitrogen. Then, we further confirmed that Klotho deficiency could significantly aggravate DNA damage by increasing 8-OHdG and reducing OGG1. Finally, we demonstrated Klotho deficiency may promote MtD to promote 8-OHdG-induced podocyte injury. Therefore, we came to a conclusion that Klotho deficiency may promote diabetes-induced podocytic MtD and aggravate 8-OHdG-induced DNA damage by affecting OOG1.
