Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects / Efectos Protectores y Mecanismos de la Decocción de Huangqi Contra los Efectos Secundarios Inducidos por la Radiación

SUMMARY: The 12C6+ heavy ion beam irradiation can cause bystander effects. The inflammatory cytokines, endocrine hormones and apoptotic proteins may be involved in 12C6+ irradiation-induced bystander effects. This study characterized the protective effects and mechanisms of Huangqi decoction (HQD) against 12C6+ radiation induced bystander effects. Wistar rats were randomly divided into control, 12C6+ heavy ion irradiation model, and high-dose/medium-dose/low-dose HQD groups. HE staining assessed the pathological changes of brain and kidney. Peripheral blood chemical indicators as well as inflammatory factors and endocrine hormones were detected. Apoptosis was measured with TUNEL. Proliferating cell nuclear antigen (PCNA) expression was determined with real-time PCR and Western blot.Irradiation induced pathological damage to the brain and kidney tissues. After irradiation, the numbers of white blood cells (WBC) and monocyte, and the expression of interleukin (IL)-2, corticotropin-releasing hormone (CRH) and PCNA decreased. The damage was accompanied by increased expression of IL-1β, IL-6, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) as well as increased neuronal apoptosis. These effects were indicative of radiation-induced bystander effects. Administration of HQD attenuated the pathological damage to brain and kidney tissues, and increased the numbers of WBC, neutrophils, lymphocyte and monocytes, as well as the expression of IL-2, CRH and PCNA. It also decreased the expression of IL-1β, IL-6, CORT and ACTH as well as neuronal apoptosis. HQD exhibits protective effects against 12C6+ radiation-induced bystander effects. The underlying mechanism may involve the promotion of the production of peripheral blood cells, inhibition of inflammatory factors and apoptosis, and regulation of endocrine hormones.

La irradiación con haz de iones pesados 12C6+ puede provocar efectos secundarios. Las citoquinas inflamatorias, las hormonas endocrinas y las proteínas apoptóticas pueden estar involucradas en los efectos secundarios inducidos por la irradiación 12C6+. Este estudio caracterizó los efectos y mecanismos protectores de la decocción de Huangqi (HQD) contra los efectos externos inducidos por la radiación 12C6+. Las ratas Wistar se dividieron aleatoriamente en grupos control, modelo de irradiación de iones pesados 12C6+ y grupos de dosis alta/media/baja de HQD. La tinción con HE evaluó los cambios patológicos del cerebro y el riñón. Se detectaron indicadores químicos de sangre periférica, así como factores inflamatorios y hormonas endocrinas. La apoptosis se midió con TUNEL. La expresión del antígeno nuclear de células en proliferación (PCNA) se determinó mediante PCR en tiempo real y transferencia Western blot. La irradiación indujo daños patológicos en los tejidos cerebrales y renales. Después de la irradiación, disminuyó el número de glóbulos blancos (WBC) y monocitos, y la expresión de interleucina (IL)-2, hormona liberadora de corticotropina (CRH) y PCNA. El daño estuvo acompañado por una mayor expresión de IL-1β, IL-6, corticosterona (CORT) y hormona adrenocorticotrópica (ACTH), así como un aumento de la apoptosis neuronal. Estas alteraciones fueron indicativas de efectos inducidos por la radiación. La administración de HQD atenuó el daño patológico a los tejidos cerebrales y renales, y aumentó el número de leucocitos y monocitos, así como la expresión de IL-2, CRH y PCNA. También disminuyó la expresión de IL-1β, IL-6, CORT y ACTH, así como la apoptosis neuronal. HQD exhibe mecanismos protectores contra los efectos externos inducidos por la radiación 12C6+. El mecanismo subyacente puede implicar la promoción de la producción de células sanguíneas periféricas, la inhibición de factores inflamatorios y la apoptosis y la regulación de hormonas endocrinas.

The effects of the Wnt/ß­catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation.

The molecular mechanisms underlying the biological effects of carbon ions are unclear. The aim of this study was to explore the Wnt/ß­catenin pathway in regulating carbon ion (12C6+) radiation­induced cellular toxicity. HLY78 is a Wnt­specific small molecular modulator, whose effects on 12C6+ radiation­induced damage are mostly unknown. HLY78, in combination with 12C6+ radiation was investigated on HeLa cell viability, cell cycle progression, DNA damage, and the expression of apoptotic and Wnt­related proteins. 12C6+ radiation suppressed cell viability in a time­dependent manner, whereas the addition of HLY78 to cells significantly reduced this stress. Moreover, after irradiation with 12C6+, HeLa cells exhibited increased cell apoptosis, G2/M phase arrest, and a number of γ­H2AX foci. However, Wnt signaling activation alleviated these effects. Furthermore, when compared with the radiation alone group, supplementation with HLY78 markedly increased the expression of anti­apoptotic and Wnt­related proteins, and significantly decreased the expression of apoptotic proteins. The present results indicated that activation of the Wnt/ß­catenin signaling pathway by HLY78 reduced 12C6+ radiation­induced HeLa cell dysfunction, suggesting that the Wnt/ß­catenin signaling pathway plays an important role in regulating 12C6+ radiation­induced cellular toxicity in HeLa cells.

Inhibition of Wnt signalling pathway by XAV939 enhances radiosensitivity in human cervical cancer HeLa cells.

Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12C6+ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12C6+ radiation.12C6+ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12C6+ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of γ-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12C6+ radiation alone. Combining XAV939 with 12C6+ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, ß-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/ß-catenin pathway effectively sensitizes HeLa cells to 12C6+ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12C6+ beams.

Curcumin ameliorates cognitive deficits heavy ion irradiation-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways.

Oxidative stress is one of the major mechanisms implicated in carbon ion irradiation. Curcumin is a natural phenolic compound with impressive antioxidant properties. What's more, curcumin is recently proved to exert its effects partly radioprotection. In vivo, we investigated the protective effects of curcumin against (12)C(6+)radiation-induced cerebral injury. Our results showed that 4Gy heavy ion radiation-induced spatial strategy and memory decline and reduction of brain superoxide dismutase (SOD) activity levels were all consistently improved by curcumin, and the augmentation of cerebral malonaldehyde (MDA) was lowered by curcumin. Furthermore, both the cerebral cells nuclear erythroid 2-related factor 2 (Nrf2) protein and three typically recognized Nrf2 downstream genes, NAD(P)H quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and γ-glutamyl cysteine synthetase (γ-GCS) were consistently up-regulated in curcumin-pretreated mice. Our study confirmed the antagonistic roles of curcumin to counteract radiation-induced cerebral injury in vivo and suggested that the potent Nrf2 activation capability might be valuable for the protective effects of curcumin against radiation. This provides a potential useful radioprotection dietary component for human populations.