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Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury.

Li XH, Ha CT, Fu D, Landauer MR, Ghosh SP, Xiao M - PLoS ONE (2015)

Bottom Line: Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression.Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure.Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells.

View Article: PubMed Central - PubMed

Affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.

ABSTRACT
We reported that microRNA-30c (miR-30c) plays a key role in radiation-induced human cell damage through an apoptotic pathway. Herein we further evaluated radiation-induced miR-30 expression and mechanisms of delta-tocotrienol (DT3), a radiation countermeasure candidate, for regulating miR-30 in a mouse model and human hematopoietic CD34+ cells. CD2F1 mice were exposed to 0 (control) or 7-12.5 Gy total-body gamma-radiation, and CD34+ cells were irradiated with 0, 2 or 4 Gy of radiation. Single doses of DT3 (75 mg/kg, subcutaneous injection for mice or 2 μM for CD34+ cell culture) were administrated 24 h before irradiation and animal survival was monitored for 30 days. Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression. Our results showed that radiation-induced IL-1β release and cell damage are pathological states that lead to an early expression and secretion of miR-30b and miR-30c in mouse tissues and serum and in human CD34+ cells. DT3 suppressed IL-1β and miR-30 expression, protected against radiation-induced apoptosis in mouse and human cells, and increased survival of irradiated mice. Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure. Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells. Our data suggest that DT3 protects human and mouse cells from radiation damage may through suppression of IL-1β-induced NFκB/miR-30 signaling.

No MeSH data available.


Related in: MedlinePlus

DT3 repressed radiation-induced proinflammatory factor IL-1β and IL-6 expression in mouse spleens.Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI. Cell homogenates from spleen were generated in PBS after these organs had been collected. One mg of total protein from each sample in indicated groups (N = 6) was applied to determine IL-1β and IL-6 using ELISA. Results were from a total of two experiments (N = 12, 6 mice /point/experiment). Means ± SD. **, p < 0.01, DT3-treated vs. vehicle-treated controls.
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pone.0122258.g003: DT3 repressed radiation-induced proinflammatory factor IL-1β and IL-6 expression in mouse spleens.Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI. Cell homogenates from spleen were generated in PBS after these organs had been collected. One mg of total protein from each sample in indicated groups (N = 6) was applied to determine IL-1β and IL-6 using ELISA. Results were from a total of two experiments (N = 12, 6 mice /point/experiment). Means ± SD. **, p < 0.01, DT3-treated vs. vehicle-treated controls.

Mentions: Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI and cell homogenates from spleens were generated in PBS. An optimized amount of total protein from each sample in indicated groups (N = 6/group) was applied to determine IL-1β and IL-6 using ELISA. These data are reported as cytokine levels detected in 1 mg of total protein/sample. Results in Fig 3 show that 7 and 10 Gy radiation induced more than 5-fold increases of IL-1β and IL-6 in spleen 8 h after irradiation compared to sham-irradiated control, and these increases were exhibited in a radiation dose-dependent manner. DT3 administration significantly inhibited the radiation-induced IL-1β and IL-6 expression in these cells. Levels of IL-1β and IL-6 reverted to baseline as shown in sham-irradiated controls at 24 h post-irradiation.


Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury.

Li XH, Ha CT, Fu D, Landauer MR, Ghosh SP, Xiao M - PLoS ONE (2015)

DT3 repressed radiation-induced proinflammatory factor IL-1β and IL-6 expression in mouse spleens.Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI. Cell homogenates from spleen were generated in PBS after these organs had been collected. One mg of total protein from each sample in indicated groups (N = 6) was applied to determine IL-1β and IL-6 using ELISA. Results were from a total of two experiments (N = 12, 6 mice /point/experiment). Means ± SD. **, p < 0.01, DT3-treated vs. vehicle-treated controls.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4376529&req=5

pone.0122258.g003: DT3 repressed radiation-induced proinflammatory factor IL-1β and IL-6 expression in mouse spleens.Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI. Cell homogenates from spleen were generated in PBS after these organs had been collected. One mg of total protein from each sample in indicated groups (N = 6) was applied to determine IL-1β and IL-6 using ELISA. Results were from a total of two experiments (N = 12, 6 mice /point/experiment). Means ± SD. **, p < 0.01, DT3-treated vs. vehicle-treated controls.
Mentions: Mouse spleens were collected at 8 and 24 h after 0, 7, or 10 Gy TBI and cell homogenates from spleens were generated in PBS. An optimized amount of total protein from each sample in indicated groups (N = 6/group) was applied to determine IL-1β and IL-6 using ELISA. These data are reported as cytokine levels detected in 1 mg of total protein/sample. Results in Fig 3 show that 7 and 10 Gy radiation induced more than 5-fold increases of IL-1β and IL-6 in spleen 8 h after irradiation compared to sham-irradiated control, and these increases were exhibited in a radiation dose-dependent manner. DT3 administration significantly inhibited the radiation-induced IL-1β and IL-6 expression in these cells. Levels of IL-1β and IL-6 reverted to baseline as shown in sham-irradiated controls at 24 h post-irradiation.

Bottom Line: Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression.Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure.Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells.

View Article: PubMed Central - PubMed

Affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, United States of America.

ABSTRACT
We reported that microRNA-30c (miR-30c) plays a key role in radiation-induced human cell damage through an apoptotic pathway. Herein we further evaluated radiation-induced miR-30 expression and mechanisms of delta-tocotrienol (DT3), a radiation countermeasure candidate, for regulating miR-30 in a mouse model and human hematopoietic CD34+ cells. CD2F1 mice were exposed to 0 (control) or 7-12.5 Gy total-body gamma-radiation, and CD34+ cells were irradiated with 0, 2 or 4 Gy of radiation. Single doses of DT3 (75 mg/kg, subcutaneous injection for mice or 2 μM for CD34+ cell culture) were administrated 24 h before irradiation and animal survival was monitored for 30 days. Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1β and IL-6, miR-30, and stress response protein expression. Our results showed that radiation-induced IL-1β release and cell damage are pathological states that lead to an early expression and secretion of miR-30b and miR-30c in mouse tissues and serum and in human CD34+ cells. DT3 suppressed IL-1β and miR-30 expression, protected against radiation-induced apoptosis in mouse and human cells, and increased survival of irradiated mice. Furthermore, an anti-IL-1β antibody downregulated radiation-induced NFκBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure. Knockdown of NFκBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells. Our data suggest that DT3 protects human and mouse cells from radiation damage may through suppression of IL-1β-induced NFκB/miR-30 signaling.

No MeSH data available.


Related in: MedlinePlus