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Metformin is a biguanide currently used in the treatment of diabetes mellitus type 2. Besides its anti-glycemic effects, metformin has been reported to induce different cellular pleiotropic effects, depending on concentration and time of treatment. Here we report one administration of metformin (0.5 mM) has radioprotective effects in vitro on BJ human fibroblasts, increasing DNA damage repair and increasing SOD1 expression in the nucleus. Importantly, metformin (200 mg/kg) pre-administration for only 3 days in wild type 129/sv mice, decreases the formation of micronuclei in bone marrow cells and DNA damage in colon and lung tissues compared to control irradiated mice at sub-lethal and lethal doses, increasing the overall survival fraction by 37% after 10Gy total body irradiation. We next pre-treated with metformin and then exposed 129/sv mice, to a galactic cosmic rays simulation (GCRsim), at the NASA Space Radiation Laboratory (NSRL). We found metformin pre-treatment decreases the presence of bone marrow micronuclei and DNA damage in colon and lung tissues and an increase of 8-oxoguanine DNA glycosylase-1 (OGG1) expression. Our data highlight a radioprotective effect of metformin through an indirect modulation of the gene expression involved in the cellular detoxification rather than its effects on mitochondria. [ABSTRACT FROM AUTHOR]

SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis. [ABSTRACT FROM AUTHOR]

In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a 'vehicle' formulation alone or with the antioxidant/anti-inflammatory compound CDDO‐EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures. [ABSTRACT FROM AUTHOR]

Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33‐beam‐GCR (33‐GCR) show short‐term cognitive deficits but reports on female rodents and long‐term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33‐GCR on female mice? Also, can an antioxidant/anti‐inflammatory compound (CDDO‐EA) mitigate the impact of 33‐GCR? Mature (6‐month‐old) C57BL/6J female mice received CDDO‐EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham‐irradiation (IRR) or whole‐body 33‐GCR (0.75Gy) on the 4th day. Three‐months post‐IRR, mice underwent two touchscreen‐platform tests: (1) location discrimination reversal (tests behavior pattern separation and cognitive flexibility, abilities reliant on the dentate gyrus) and (2) stimulus–response learning/extinction. Mice then underwent arena‐based behavior tests (e.g. open field, 3‐chamber social interaction). At the experiment's end (14.25‐month post‐IRR), an index relevant to neurogenesis was quantified (doublecortin‐immunoreactive [DCX+] dentate gyrus immature neurons). Female mice exposed to Veh/Sham vs. Veh/33‐GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO‐EA/Sham and CDDO‐EA/33‐GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33‐GCR), and CDDO‐EA/33‐GCR mice had better cognitive flexibility (reversal number) vs. Veh/33‐GCR mice. One radiation effect/CDDO‐EA countereffect also emerged: Veh/33‐GCR mice had slower stimulus–response learning (days to completion) vs. all other groups, including CDDO‐EA/33‐GCR mice. In general, all mice showed normal anxiety‐like behavior, exploration, and habituation to novel environments. There was also a change relevant to neurogenesis: Veh/33‐GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission‐relevant cognitive processes and CDDO‐EA is a potential dietary countermeasure for space‐radiation CNS risks. [ABSTRACT FROM AUTHOR]