International Journal of Radiation Research

en Role of microRNA-665 in modulating PI3K/AKT/JNK signaling pathways: implications for radiation-induced neurobehavioral disorders Radiation Biology Radiation Biology تحقيق بديع Original Research <div style="text-align: justify;">Background: Radiotherapy is an essential treatment for brain tumors but often causes radiation-induced brain injury (RIBI), leading to neurobehavioral deficits such as depression-like behaviors. MicroRNA-665 (miR-665) may regulate these injury pathways through its interaction with the PI3K/AKT (pro-survival) and JNK/p38 (pro-apoptotic) signaling cascades. Materials and Methods: Ninety-six male C57BL/6 mice received 10 Gy cranial irradiation and were assigned to four groups (n=24): control, radiation + pioglitazone (PIO), radiation + PIO + GW9662, and radiation + PIO + LY294002 or anisomycin. Depression-like behaviors were assessed by sucrose preference, open field, and forced swimming tests. miR-665 expression and signaling markers (p-AKT, p-JNK, p-p38) in the PFC were measured using qPCR and Western blot. Results: Cranial irradiation significantly reduced sucrose preference, exploratory activity, and increased immobility time (all P < 0.01). PIO pretreatment activated PI3K/AKT and suppressed JNK/p38 signaling, producing marked behavioral improvement (P < 0.01). These neuroprotective effects were fully abolished by GW9662 (PPAR-γ antagonist), LY294002 (PI3K inhibitor), and anisomycin (JNK/p38 activator). miR-665 expression increased 2.8-fold in the GW9662 group (P < 0.01), where PPAR-γ and PI3K/AKT protection were blocked, but was reduced (0.4–0.5-fold) when PI3K/AKT was inhibited or JNK/p38 was activated. Conclusion: These findings indicate that PIO protects against radiation-induced depression-like behaviors via PPAR-γ–dependent activation of PI3K/AKT and inhibition of JNK/p38. The bidirectional changes in miR-665 strongly suggest it acts as a negative regulator of the PI3K/AKT pathway or is suppressed by JNK/p38 activation. miR-665 may therefore represent a promising therapeutic target for mitigating neurobehavioral complications of cranial radiotherapy.</div> miR-665, Cranial irradiation, Depression-like behavior, PI3K/AKT pathway, JNK/p38 pathway. 705 711 http://ijrr.com/browse.php?a_code=A-10-1-1567&slc_lang=en&sid=1 J. Yang 7900319475328460034294 7900319475328460034294 No Department of Psychiatry, The Affiliated Xi’an Central Hospital of Xi’an Jiaotong University, Xi’an, 710003, Shaanxi Province, China R. Luan 7900319475328460034295 7900319475328460034295 No Department of Psychiatry, The Affiliated Xi’an Central Hospital of Xi’an Jiaotong University, Xi’an, 710003, Shaanxi Province, China X. Zhao 18791083860@163.com 7900319475328460034296 7900319475328460034296 Yes Department of Psychiatry, The Affiliated Xi’an Central Hospital of Xi’an Jiaotong University, Xi’an, 710003, Shaanxi Province, China