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Preparation for medical responses to major radiation accidents, further driven by increases in the threat of nuclear warfare, has led to a pressing need to understand the underlying mechanisms of radiation injury (RI) alone or in combination with other trauma (combined injury, CI). The identification of these mechanisms suggests molecules and signaling pathways that can be targeted to develop radiation medical countermeasures. Thus far, the United States Food and Drug Administration (U.S. FDA) has approved seven countermeasures to mitigate hematopoietic acute radiation syndrome (H-ARS), but no drugs are available for prophylaxis and no agents have been approved to combat the other sub-syndromes of ARS, let alone delayed effects of acute radiation exposure or the effects of combined injury. From its inception, Radiation Research has significantly contributed to the understanding of the underlying mechanisms of radiation injury and combined injury, and to the development of radiation medical countermeasures for these indications through the publication of peer-reviewed research and review articles. [ABSTRACT FROM AUTHOR]

Radiation-combined injury (RCI) augments the risk of morbidity and mortality when compared to radiation injury (RI) alone. No FDA-approved medical countermeasures (MCMs) are available for treating RCI. Previous studies implied that RI and RCI elicit differential mechanisms leading to their detrimental effects. We hypothesize that accelerating wound healing improves the survival of RCI mice. In the current study, we examined the effects of RCI at different doses on lethality, weight loss, wound closure delay, and proinflammatory status, and assessed the relative contribution of systemic and local elements to their delayed wound closure. Our data demonstrated that RCI increased the lethality and weight loss, delayed skin wound closure, and induced a systemic proinflammatory status in a radiation dose-dependent manner. We also demonstrated that delayed wound closure did not specifically depend on the extent of hematopoietic suppression, but was significantly influenced by the toxicity of the radiation-induced systemic inflammation and local elements, including the altered levels of proinflammatory chemokines and factors, and the dysregulated collagen homeostasis in the wounded area. In conclusion, the results from our study indicate a close association between delayed wound healing and the significantly altered pathways in RCI mice. This insightful information may contribute to the evaluation of the prognosis of RCI and development of MCMs for RCI. [ABSTRACT FROM AUTHOR]

On 26 April 1986, reactor 4 at the Chernobyl power plant underwent a catastrophic failure leading to core explosions and open-air fires. On 11 March 2011, a combination of earthquake and tsunami led to a similar disaster at the Fukushima Daiichi power plant. In both cases, radioactive isotopes were released and contaminated the air, soil and water in a substantial area around the power plants. Humans were evacuated from the immediate regions but the wildlife stayed and continued to be affected by the ongoing high radiation exposure initially and later decayed amounts of fallout dusts with time. In this review, we will examine the significant effects of the increased radiation on vegetation, insects, fish, birds and mammals. The initial intense radiation in these areas has gradually begun to decrease but still remains high. Adaptation to radiation is evident and the ecosystems have dynamically changed from the periods immediately after the accidents to the present day. Understanding the molecular mechanisms that allow the adaptation and recovery of wildlife to chronic radiation challenges would aid in future attempts at ecosystem remediation in the wake of such incidents. [ABSTRACT FROM AUTHOR]

Hemorrhage in mice results in decreased ATP levels in the jejunum, lung, kidney, heart, and brain but not in liver tissue lysates, albeit at variable levels and time kinetics. The decreased protein expression and activity of pyruvate dehydrogenase (PDH) accounted for the hemorrhage-induced ATP loss. Treatment with geldanamycin (GA: 1 [micro]g/g body wt), a known inducer of heat shock protein (HSP)70, inhibited the hemorrhage-induced ATP loss in the jejunum, lung, heart, kidney, and brain. GA was found to increase PDH protein, preserve PDH enzymatic activity, and inhibit mucosal injury in jejunum tissues. GA-induced HSP70i was found to form complexes with PDH protein. HSP70 gene transfer into intestinal epithelial cells promoted PDH and ATP levels, whereas HSP70 short interfering RNA limited them. We conclude that agents able to increase the expression of HSP70 and PDH may be of value in reducing pathology resulting from hemorrhage-associated ATP loss. heat shock protein 70; intestine

The nitric oxide (NO) synthase inhibitor [N.sup.[omega]]-nitro-L-arginine (L-NNA) inhibits heat stress (HS)-induced NO production and the inducible 70-kDa heat shock protein (HSP-70i) in many rodent organs. We used human intestinal epithelial T84 cells to characterize the inhibitory effect of L-NNA on HS-induced HSP-70i expression. Intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) was measured using fura-2, and protein kinase C (PKC), and PKA activities were determined. HS increased HSP-70i mRNA and protein in T84 cells exposed to 45 [degrees] C for 10 min and allowed to recover for 6 h. L-NNA treatment for 1 h before HS inhibited the induction of HSP-70i mRNA and protein, with an I[C.sub.50] of 0.0471 [+ or -] 0.0007 [micro]M. Because the HS-induced increase in HSP-70i mRNA and protein is [Ca.sup.2+] dependent, we measured [[[Ca.sup.2+]].sub.i] after treating cells with L-NNA. L-NNA at 100 [micro]M significantly decreased resting [[[Ca.sup.2+]].sub.i]. Likewise, treatment with 1 [micro]M GF-109203X or H-89 (inhibitors of PKC and PKA, respectively) for 30 min also significantly decreased [[[Ca.sup.2+]].sub.i] and inhibited HS-induced increase in HSP-70i. GF-109203X- or H-89-treated cells failed to respond to L-NNA by further decreasing [[[Ca.sup.2+]].sub.i] and HSP-70i. L-NNA effectively blocked heat shock factor-1 (HSF1) translocation from the cytosol to the nucleus, a process requiring PKC phosphorylation. These results suggest that L-NNA inhibits HSP-70i by reducing [[[Ca.sup.2+]].sub.i] and decreasing PKC and PKA activity, thereby blocking HSF1 translocation from the cytosol to the nucleus. heat; nitric oxide; heat shock protein; protein kinase C; protein kinase A

Rise in intracellular Ca2+ concentration and stimulation of G proteins enhance the synthesis of highly-conserved 70-kDa heat-shock proteins (HSP-70). The increase and stimulation depend on the time of heating and the temperature. HSP-70 synthesis is independent of intracellular pH and adenosine 3',5', -cyclic monophosphate.