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Int J Radiat Oncol Biol Phys ; 104(3): 644-655, 2019 07 01.
Article in English | MEDLINE | ID: mdl-30844421

ABSTRACT

PURPOSE: The impairment of the salivary glands is a permanent side effect of 131I ablation therapy for patients with differentiated thyroid cancer. Effective and safe treatments for protecting the salivary glands against 131I are currently not available. Mitochondria are susceptible to ionizing radiation, but alterations after 131I exposure are unknown. Here, we investigated the mechanisms of 131I damage in submandibular glands (SMGs) and evaluated the cytoprotective effect of phenylephrine (PE) against mitochondrial radiation damage. METHODS AND MATERIALS: Rats were randomly divided into 4 groups: control, PE alone, 131I alone, and 131I with PE pretreatment. The mitochondrial structure of SMGs was observed under transmission electron microscopy. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Cytochrome c, cleaved-caspase 3, SIRT1, NAMPT, and PGC-1α protein levels were determined with Western blot and immunohistochemistry. Levels of mitochondrial membrane potential, nicotinamide adenine dinucleotide (NAD), and adenosine triphosphate (ATP) were measured with relevant kits. RESULTS: After exposing rat SMGs to 131I, the mitochondrial membrane structures were destroyed, the mitochondrial membrane potential decreased, the release of cytochrome c increased, and cleaved-caspase 3 and cell apoptosis were activated. Moreover, the expression of SIRT1, NAMPT, and PGC-1α was downregulated, and the levels of NAD and ATP decreased. In contrast, PE alleviated the 131I-induced mitochondrial damages and upregulated the expression of SIRT1/NAMPT/PGC-1α and the levels of NAD and ATP. CONCLUSIONS: These findings demonstrate that 131I impairs the salivary glands via the downregulation of SIRT1/NAMPT/PGC-1α signal pathways, which disturbs mitochondrial homeostasis. PE alleviated the 131I damage in SMGs at the mitochondrial level, suggesting that PE could be used as a potential radioprotector for patients with differentiated thyroid cancer with radiation sialadenitis.


Subject(s)
Iodine Radioisotopes/adverse effects , Mitochondria/radiation effects , Phenylephrine/therapeutic use , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/therapeutic use , Submandibular Gland/radiation effects , Adenosine Triphosphate/metabolism , Adenosine Triphosphate/radiation effects , Animals , Apoptosis/radiation effects , Caspase 3/metabolism , Caspase 3/radiation effects , Cytochromes c/metabolism , Cytochromes c/radiation effects , Cytokines/metabolism , Cytokines/radiation effects , Down-Regulation , Homeostasis , In Situ Nick-End Labeling , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/radiation effects , Mitochondria/drug effects , NAD/metabolism , NAD/radiation effects , Nicotinamide Phosphoribosyltransferase/metabolism , Nicotinamide Phosphoribosyltransferase/radiation effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/radiation effects , Radiation Injuries, Experimental/metabolism , Random Allocation , Rats , Rats, Wistar , Sirtuin 1/metabolism , Sirtuin 1/radiation effects , Submandibular Gland/ultrastructure , Thyroid Neoplasms/radiotherapy
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