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NASA NTRSDate not supplied

Neurovascular effects of simulated space radiation

A major health risk for human deep space exploration is central nervous system (CNS) damage by ionizing radiation. Simulated galactic cosmic rays or their components, especially high-linear energy transfer particles such as 56Fe ions, have been shown to cause CNS damage, neuroinflammation and cognitive dysfunction in rodent models, but their effects on human CNS remain to be investigated. CNS damage from any insult, including ionizing radiation, is partially mediated by the blood-brain barrier (BBB), which regulates interactions between CNS and the rest of the body. Astrocytes are major cellular regulators of BBB permeability and also modulate neuroinflammation and neurodegeneration. However, BBB and astrocyte functions in regulating CNS responses to space radiation remain little investigated, especially in human organ analogs. Therefore, we developed and utilized a high-throughput 3D human neurovascular organ-on-a-chip model, seeded with induced pluripotent stem cell-derived cells. The effects of time course, ionizing radiation dose and dose rate were mapped by exposing the model to either acute, high dose rate radiation with simulated galactic cosmic rays or 600 MeV/n 56Fe particles, or protracted, low dose rate gamma radiation using a 57Co sealed source setup. We investigated BBB permeability, oxidative stress, cellular damage and secreted factors over the time period between 24 hours – 2 weeks after 0.1 – 0.8 Gy irradiation. We observed that ionizing radiation exposure increased BBB permeability, caused oxidative stress, damaged endothelial cells and altered expression of inflammatory cytokines with a subset of outcomes dependent on ionizing radiation dose rate. Furthermore, our results indicated that astrocyte functions were primarily deleterious at early time points and protective later after irradiation, resembling CNS responses to injury in vivo. Our findings in organ models were complemented by studies on true spaceflight using mouse spatial and single cell multi-omics, which similarly indicated spaceflight-mediated changes in astrocyte functions. In summary, our study evaluates the regulation of neurovascular responses to simulated space radiation, suggesting astrocytes as targets for countermeasures to mitigate CNS damage in deep space exploration.

Radiation↗

DOE OSTI2022

Dietary Strategies to Modulate the Health Condition and Immune Responses in Gilthead Seabream (Sparus aurata) Juveniles Following Intestinal Inflammation

Several feed additives have proved to be beneficial in eliciting fish health. Β-glucans and curcumin are compounds with immunomodulatory capacities known to increase growth performance, stimulate immunity, improve general health, and enhance disease resistance in fish. The present study aimed to evaluate the effects of dietary Phaeodactylum tricornutum extracts rich in β-glucans and curcumin on gilthead seabream health status prior to and following an intestinal inflammatory stimulus. Three experimental diets were formulated: a practical commercial-type diet (CTRL), a CTRL diet supplemented with 1% microalgae-derived β-glucans extract (BG), and a CTRL diet supplemented with 0.2% of curcumin (CUR). After 30 days of the feeding trial, fish were sampled and subjected to an oral administration of 1% dextran sodium sulphate (DSS) to induce intestinal inflammation. Four groups were considered: a group of fish continued to be fed on the CTRL diet while the remaining groups were exposed to DSS, including CTRL-D (CTRL + DSS), BG-D (BG + DSS), and CUR-D (CUR + DSS), for 6 days. Growth, plasma and gut humoral immunity, liver and gut oxidative stress biomarkers, and intestinal gene expression were evaluated. No significant differences were found in growth after 30 days of feeding; however, seabream fed BG had decreased anti-protease activity and nitric oxide concentration in plasma while those fed CUR had increased mRNA levels of the tnfα, csf1r, and hep genes compared to those fed CTRL. After the inflammatory stimulus, hematocrit was enhanced in fish fed BG-D and CUR-D while red blood cell counts increased in those fed CTRL-D. Superoxide dismutase activity decreased in the intestine of all DSS groups while lipid peroxidation increased in the gut of fish fed CTRL-D and BG-D compared to CTRL. Moreover, the mRNA expression levels of csfr1 and sod decreased in fish fed CTRL-D and BG-D compared to CTRL, respectively. Despite the mild intestinal inflammatory condition induced by DSS, CUR was able to partially ameliorate its effects, improving the hematological profile and assisting against the oxidative stress.

Teixeira, Carla↗

NASA NTRS2010

Siderophilic Cyanobacteria for the Development of Extraterrestrial Photoautotrophic Biotechnologies

In-situ production of consumables (mainly oxygen) using local resources (In-Situ Resource Utilization-ISRU) will significantly facilitate current plans for human exploration and settlement of the solar system, starting with the Moon. With few exceptions, nearly all technologies developed to date have employed an approach based on inorganic chemistry. None of these technologies include concepts for integrating the ISRU system with a bioregenerative life support system and a food production system. Therefore, a new concept based on the cultivation of cyanobacteria (CB) in semi-closed biogeoreactor, linking ISRU, a biological life support system, and food production, has been proposed. The key feature of the biogeoreactor is to use lithotrophic CB to extract many needed elements such as Fe directly from the dissolved regolith and direct them to any technological loop at an extraterrestrial outpost. Our studies showed that siderophilic (Fe-loving) CB are capable to corrode lunar regolith stimulants because they secrete chelating agents and can tolerate [Fe] up to 1 mM. However, lunar and Martian environments are very hostile (very high UV and gamma-radiation, extreme temperatures, deficit of water). Thus, the selection of CB species with high potential for extraterrestrial biotechnologies that may be utilized in 15 years must be sponsored by NASA as soon as possible. The study of the genomes of candidate CB species and the metagenomes of the terrestrial environments which they inhabit is critical to make this decision. Here we provide preliminary results about peculiarities of the genomes of siderophilic CB revealed by analyzing the genome of siderophilic cyanobacterium JSC-1 and the metagenome of iron depositing hot spring (IDHS) Chocolate Pots (Yellowstone National Park, Wyoming, USA). It has been found that IDHS are richer with ferrous iron than the majority of hot springs around the world. Fe2+ is known to increase the magnitude of oxidative stress in prokaryotes through so called Fenton reaction. It is not surprising therefore that the CB inhabiting IDHS have larger sets of the proteins involved in the maintenance of Fe homeostasis and oxidative stress protection than non-siderophilic CB. This finding combined with our earlier results about the ability of some siderophilic CB to utilize chemical elements released from analogs of lunar and Martian regolith make them the most advanced candidates to be employed in advanced extraterrestrial biotechnologies.

Brown, I. I.↗

NASA NTRS2010

Iron Homeostasis in Yellowstone National Park Hot Spring Microbial Communities

It has been postulated that life may have originated on Earth, and possibly on Mars, in association with hydrothermal activity and high concentrations of ferrous iron. However, it is not clear how an iron-rich thermal hydrosphere could be hospitable to microbes, since reduced iron appears to stimulate oxidative stress in all domains of life and particularly in oxygenic phototrophs. Therefore, the study of microbial diversity in iron-depositing hot springs (IDHS) and the mechanisms of iron homeostasis and suppression of oxidative stress may help elucidate how Precambrian organisms could withstand the extremely high concentrations of reactive oxygen species (ROS) produced by interaction between environmental Fe(2+) and O2. Proteins and clusters of orthologous groups (COGs) involved in the maintenance of Fe homeostasis found in cyanobacteria (CB) inhabiting environments with high and low [Fe] were main target of this analysis. Preliminary results of the analysis suggest that the Chocolate Pots (CP) microbial community is heavily dominated by phototrophs from the cyanobacteria (CB), Chloroflexi and Chlorobi phyla, while the Mushroom Spring (MS) effluent channel harbors a more diverse community in which Chloroflexi are the dominant phototrophs. It is speculated that CB inhabiting IDHS have an increased tolerance to both high concentrations of Fe(2+) and ROS produced in the Fenton reaction. This hypothesis was explored via a comparative analysis of the diversity of proteins and COGs involved in Fe and redox homeostasis in the CP and MS microbiomes.

Brown, I.↗

DOE OSTI2021

Exhaled breath biomarkers of influenza infection and influenza vaccination

Respiratory viral infections are considered a major public health threat, and breath metabolomics can provide new ways to detect and understand how specific viruses affect the human pulmonary system. In this pilot study, we characterized the metabolic composition of human breath for an early diagnosis and differentiation of influenza viral infection, as well as other types of upper respiratory viral infections. We first studied the non-specific effects of planned seasonal influenza vaccines on breath metabolites in healthy subjects after receiving the immunization. We then investigated changes in breath content from hospitalized patients with flu-like symptoms and confirmed upper respiratory viral infection. The exhaled breath was sampled using a custom-made breath condenser, and exhaled breath condensate (EBC) samples were analysed using liquid chromatography coupled to quadruplole-time-of-flight mass spectrometer (LC-qTOF). All metabolomic data was analysed using both targeted and untargeted approaches to detect specific known biomarkers from inflammatory and oxidative stress biomarkers, as well as new molecules associated with specific infections. We were able to find clear differences between breath samples collected before and after flu vaccine administration, together with potential biomarkers that are related to inflammatory processes and oxidative stress. Moreover, we were also able to discriminate samples from patients with flu-related symptoms that were diagnosed with confirmatory respiratory viral panels (RVPs). RVP positive and negative differences were identified, as well as differences between specific viruses defined. These results provide very promising information for the further study of the effect of influenza A and other viruses in human systems by using a simple and non-invasive specimen like breath.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2003

Exposure to Carbon Nanotube Material: Assessment of Nanotube Cytotoxicity Using Human Keratinocyte Cells

Carbon nanotubes are new members of carbon allotropes similar to fullerenes and graphite. Because of their unique electrical, mechanical, and thermal properties, carbon nanotubes are important for novel applications in the electronics, aerospace, and computer industries. Exposure to graphite and carbon materials has been associated with increased incidence of skin diseases, such as carbon fiber dermatitis, hyperkeratosis, and naevi. We investigated adverse effects of single-wall carbon nanotubes (SWCNT) using a cell culture of immortalized human epidermal keratinocytes (HaCaT). After 18 h of exposure of HaCaT to SWCNT, oxidative stress and cellular toxicity were indicated by formation of free radicals, accumulation of peroxidative products, antioxidant depletion, and loss of cell viability. Exposure to SWCNT also resulted in ultrastructural and morphological changes in cultured skin cells. These data indicate that dermal exposure to unrefined SWCNT may lead to dermal toxicity due to accelerated oxidative stress in the skin of exposed workers.

Keratinocytes/drug effects↗

NASA NTRS2016

Gene Expression and Structural Skeletal Responses to Long-Duration Simulated Microgravity in Rats

Spaceflight has deleterious effects on skeletal structure and function, specifically causingprofound loss in bone mass, density, and strength, as well as changes in expression levels of genes related to oxidative stress [Hyeon et al., Smith et al.]. It is known that bone resorption remains elevated after spaceflight and that bone density and strength fail to recover completely even years following spaceflight [Smith et al., Carpenter et al.]. However, our current understanding of the signaling pathways and molecular mechanisms that control bone loss and that link oxidative stress, bone resorption, and mechanical unloading of skeletal tissue is incomplete. Here, we aim to examine skeletal responses to simulated long-duration spaceflight on bone loss using the ground-based hindlimb unloading (HU) model in adult (9 months old) male rats. We hypothesized that simulated microgravity leads to the temporal regulation of oxidative-defense genes and pro-osteoclastogenic factors, showing progression and eventual plateau during long-term unloading, and that transient changes at early timepoints in these pathways precede skeletal adaptations to long-duration unloading. We will identify oxidativestress and bone resorption-related changes using global gene expression analysis (Affymetrix arrays) for both acute (within 14 days) and long-term timepoints (90 days). We will also use quantitative PCR to examine changes in expression of genes related to oxidative metabolism (e.g. Nrf2, SOD-1), bone turnover (resorption and formation markers, e.g. TRAP, osteocalcin respectively, SOST), and osteoclastogenesis (e.g. RANKL, OPG) at both early and late timepoints. We will then use detailed microarchitectural and structural analysis through microcomputed tomography to relate gene expression changes with structural changes in bone, expecting that plateaus in gene expression correlate with long-term changes in bone microarchitecture.

Rael, Victoria E.↗

NASA NTRS2014

Gene Expression Changes in Mouse Intestinal Tissue Following Whole-Body Proton or Gamma-Irradiation

Crew members face potential consequences following exposure to the space radiation environment including acute radiation syndrome and cancer. The space radiation environment is ample with protons, and numerous studies have been devoted to the understanding of the health consequences of proton exposures. In this project, C57BL/6 mice underwent whole-body exposure to 250 MeV of protons at doses of 0, 0.1, 0.5, 2 and 6 Gy and the gastrointestinal (GI) tract of each animal was dissected four hours post-irradiation. Standard H&E staining methods to screen for morphologic changes in the tissue showed an increase in apoptotic lesions for even the lowest dose of 0.1 Gy, and the percentage of apoptotic cells increased with increasing dose. Results of gene expression changes showed consistent up- or down- regulation, up to 10 fold, of a number of genes across exposure doses that may play a role in proton-induced oxidative stress including Gpx2. A separate study in C57BL/6 mice using the same four hour time point but whole-body gamma-irradiation showed damage to the small intestine with lesions appearing at the smallest dose of 0.05 Gy and increasing with increasing absorbed dose. Expressions of genes associated with oxidative stress processes were analyzed at four hours and twenty-four hours after exposure to gamma rays. We saw a much greater number of genes with significant up- or down-regulation twenty-four hours post-exposure as compared to the four hour time point. At both four hours and twenty-four hours post-exposure, Duox1 and Mpo underwent up-regulation for the highest dose of 6 Gy. Both protons and gamma rays lead to significant variation in gene expressions and these changes may provide insight into the mechanism of injury seen in the GI tract following radiation exposure. We have also completed experiments using a BALB/c mouse model undergoing whole-body exposure to protons. Doses of 0, 0.1, 1 and 2 Gy were used and results will be compared to the work mentioned above. The most striking result preliminarily is that both strains of mice show a greater number of genes changing at the lowest dose of exposure for their respective pathways.

Purgason, Ashley↗

NASA NTRS2010

Inferring Properties of Ancient Cyanobacteria from Biogeochemical Activity and Genomes of Siderophilic Cyanobacteria

Interrelationships between life and the planetary system could have simultaneously left landmarks in genomes of microbes and physicochemical signatures in the lithosphere. Verifying the links between genomic features in living organisms and the mineralized signatures generated by these organisms will help to reveal traces of life on Earth and beyond. Among contemporary environments, iron-depositing hot springs (IDHS) may represent one of the most appropriate natural models [1] for insights into ancient life since organisms may have originated on Earth and probably Mars in association with hydrothermal activity [2,3]. IDHS also seem to be appropriate models for studying certain biogeochemical processes that could have taken place in the late Archean and,-or early Paleoproterozoic eras [4, 5]. It has been suggested that inorganic polyphosphate (PPi), in chains of tens to hundreds of phosphate residues linked by high-energy bonds, is environmentally ubiquitous and abundant [6]. Cyanobacteria (CB) react to increased heavy metal concentrations and UV by enhanced generation of PPi bodies (PPB) [7], which are believed to be signatures of life [8]. However, the role of PPi in oxygenic prokaryotes for the suppression of oxidative stress induced by high Fe is poorly studied. Here we present preliminary results of a new mechanism of Fe mineralization in oxygenic prokaryotes, the effect of Fe on the generation of PPi bodies in CB, as well as preliminary analysis of the diversity and phylogeny of proteins involved in the prevention of oxidative stress in phototrophs inhabiting IDHS.

McKay, David S.↗

NASA NTRSDate not supplied

Individual Variability and Predictive Biomarkers of Human Sensitivity to Ionizing Radiation

High-linear energy transfer (LET) ionizing radiation is a major health hazard for astronauts who will be exposed to galactic cosmic rays during upcoming lunar and Mars missions. Predicting and mitigating personalized health risks from space radiation exposure requires understanding the factors underlying individual radiation sensitivity, which currently remain unknown. We started to address this challenge by identifying the genomic and demographic associations with sensitivity to low and high-LET ionizing radiation in the largest human sample cohort to date and by evaluating baseline DNA damage as a potential predictor of radiation responses. We have collected and irradiated peripheral blood mononuclear cells (PBMCs) from 768 healthy donors of matched ethnicity, 50/50 male/female, 18-70 years old. We have analyzed the responses of 576 donor PBMCs to irradiation with simulated galactic cosmic ray components: 350MeV/n 28Si, 350MeV/n 40Ar and 600MeV/n 56Fe, at 1.1 and 3 particles/100μm2 fluences, as well as 0.1Gy and 1Gy doses of gamma rays, at 4 and 24 hours post irradiation. We quantified post-irradiation DNA repair based on radiation-induced 53BP1+ foci formation, together with oxidative stress and cell death using a flow cytometry-based assay. We also assessed baseline levels of DNA repair in PBMCs at the time of sample collection prior to irradiation experiments. We observed a wide variability of subject- and LET-dependent radiation responses, with radiation-induced DNA repair foci increasing with LET, though oxidative stress being notably reduced by high-LET irradiation, potentially due to a switch between hydrogen peroxide and oxygen radical-based mechanisms. We also identified a relationship between few DNA repair foci at baseline and increased DNA repair after irradiation, accompanied by an alteration in immunoregulatory cytokine secretion, which might be adapted as biomarkers to predict ionizing radiation sensitivity. Among demographic variables, baseline foci levels were positively associated with age and latent cytomegalovirus infection. Finally, we have performed low-throughput whole genome sequencing of all samples and are currently in process of identifying the genes and pathways associated with low and high-LET ionizing radiation sensitivity in humans.

Space radiation, human spaceflight, DNA damage↗

DOE OSTI2020

Green synthesis and characterization of nontoxic L-methionine capped silver and gold nanoparticles

The simple green method for synthesis of stable L-Methionine (L-Met) capped silver (Ag@LM NPs) and gold (Au@LM NPs) nanoparticles (NPs) without adding any additional reduction agent or stabilizer was developed. Colloidal dispersions were characterized by UV–Vis spectrophotometry. The size and spherical shape of NPs were evaluated by transmission electron microscopy. Their surface covering was confirmed by atomic force microscopy, Fourier transform infrared spectroscopy, dynamic light scattering, and zeta potential measurements. Density functional theory calculations pointed that the preferential adsorption mode of L-Met on both Ag and Au surfaces was a vertical binding geometry via –NH2 group, while horizontal binding mode via [sbnd]S[sbnd] and –NH2 groups is also possible. The genotoxicity (evaluated by the micronucleus assay) of NPs, as well as their effects on some oxidative stress parameters (catalase activity, malondialdehyde level), were assessed in vitro using human peripheral blood cells as a model system. The influence of NPs on the morphology of lymphocyte cells studied using atomic force microscopy revealed that the membrane of cells remained unaffected after the treatment with NPs. When considering the effects of NPs on catalase activity and malondialdehyde level, neither particle type promoted oxidative stress. However, the treatment of lymphocytes with Ag@LM NPs induced a concentration-dependent enhancement of the micronuclei incidence and suppression of the cell proliferation while Au@LM NPs promoted cell proliferation, with no significant effects on micronuclei formation. The Ag@LM NPs were more prone to induce DNA damage than Au@LM NPs, which makes the latter type more suitable for further studies in nano-medicine. © 2019.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2011

Induction of a Radio-Adaptive Response by Low-dose Gamma Irradiation in Mouse Cardiomyocytes

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) 137Cs gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value < or = 0.003) 4hr after H, but not after 4hr LH compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration.

Westby, Christian M.↗

NASA NTRS2011

Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulation of cells in response to antineoplastic agents, we cultured LNCaP cells for 96 hr either in a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as a control. 24 hr after the culture started, mitoxantrone was introduced to the cells at a final concentration of 1 M. The mitoxantrone treatment lasted 72 hr and then the cells were collected for various measurements. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not show significant differences in cell viability, growth rate, or cell cycle distribution. However, in response to mitoxantrone (1uM), a significant proportion of bioreactor cultured cells (30%) was arrested at G2 phase and a significant number of these cells were apoptotic in comparison to their static controls. The expressions of 84 oxidative stress related genes were analyzed using Qiagen PCR array to identify the possible mechanism underlying the altered responses of bioreactor culture cells to mitoxantrone. Nine out of 84 genes showed higher expression at four hour post mitoxantrone treatment in cells cultured at rotating condition compared to those at static. Taken together, the results reported here indicate that simulated microgravity may alter the responses of LNCaP cells to mitoxantrone treatment. The alteration of oxidative stress pathways in cells cultured under simulated microgravity conditions may be one of the mechanisms to cause such changes of sensitivity of LNCaP cells to mitoxantrone treatment.

Zhang, Ye↗

NASA NTRS2011

Radio-Adaptive Responses of Mouse Myocardiocytes

One of the most significant occupational hazards to an astronaut is the frequent exposure to radiation. Commonly associated with increased risk for cancer related morbidity and mortality, radiation is also known to increase the risk for cardiovascular related disorders including: pericarditis, hypertension, and heart failure. It is believed that these radiation-induced disorders are a result of abnormal tissue remodeling. It is unknown whether radiation exposure promotes remodeling through fibrotic changes alone or in combination with programmed cell death. Furthermore, it is not known whether it is possible to mitigate the hazardous effects of radiation exposure. As such, we assessed the expression and mechanisms of radiation-induced tissue remodeling and potential radio-adaptive responses of p53-mediated apoptosis and fibrosis pathways along with markers for oxidative stress and inflammation in mice myocardium. 7 week old, male, C57Bl/6 mice were exposed to 6Gy (H) or 5cGy followed 24hr later with 6Gy (LH) Cs-137 gamma radiation. Mice were sacrificed and their hearts extirpated 4, 24, or 72hr after final irradiation. Real Time - Polymerase Chain Reaction was used to evaluate target genes. Pro-apoptotic genes Bad and Bax, pro-cell survival genes Bcl2 and Bcl2l2, fibrosis gene Vegfa, and oxidative stress genes Sod2 and GPx4 showed a reduced fold regulation change (Bad,-6.18; Bax,-6.94; Bcl2,-5.09; Bcl2l2,-4.03; Vegfa, -11.84; Sod2,-5.97; GPx4*,-28.72; * = Bonferroni adjusted p-value . 0.003) 4hr after H, but not after 4hr LH when compared to control. Other p53-mediated apoptosis genes Casp3, Casp9, Trp53, and Myc exhibited down-regulation but did not achieve a notable level of significance 4hr after H. 24hr after H, genetic down-regulation was no longer present compared to 24hr control. These data suggest a general reduction in genetic expression 4hrs after a high dose of gamma radiation. However, pre-exposure to 5cGy gamma radiation appears to facilitate a radio-adaptive response that mitigates the reduction in genetic expression associated with single high-dose gamma radiation exposure. This radio-adaptive response may serve as a potential countermeasure to radiation-induced myocardial remodeling and preserve the cardiovascular health of astronauts; thus, reducing the risks of human space exploration.

Seawright, John W.↗

DOE OSTI2021

Silenced long non-coding RNA activated by DNA damage elevates microRNA-495-3p to suppress atherosclerotic plaque formation via reducing Krüppel-like factor 5

Objective: Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation. Methods: The ApoE{sup −/-} mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed. Results: NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5. Conclusion: Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.

60 APPLIED LIFE SCIENCES↗

NASA NTRSDate not supplied

Neuroimmune Responses to Space Radiation

One of the main health risks in human deep space exploration is central nervous system (CNS) damage by ionizing radiation due to exposure to galactic cosmic rays (GCRs). In animal models, irradiation with simulated GCRs or their components has been shown to cause neurodegeneration and neuroinflammation associated with cognitive and behavioral dysfunction. The extent of CNS damage is partially mediated by the blood-brain barrier (BBB), which regulates the interaction between CNS and systemic responses to stressors in the rest of the body. The main cellular regulators of BBB permeability are astrocytes, which also modulate neuronal death, neuroinflammation and oxidative stress. However, studies on BBB and astrocyte functions in regulating CNS responses to ionizing radiation have been limited, especially in human tissue/organ analogs. Therefore, we developed a high-throughput 3D organ-on-a-chip system to study human CNS and BBB impairments caused by deep space radiation. We investigated both immediate and delayed CNS responses to major GCR components: 600MeV/n 56Fe ions. We observed ionizing radiation-mediated dose-dependent increases in BBB permeability that was exacerbated by astrocyte presence and accompanied by altered cytokine expression including interleukin-1 receptor alpha downregulation, and increased oxidative stress. In particular, 600MeV/n 56Fe particle irradiation selectively increased damage and blood-brain barrier permeability only in models that contained astrocytes in addition to endothelial cells, indicating astrocytes as a particularly radiosensitive component of the CNS that could therefore be a suitable a target for neuroprotection. Future studies will compare human and mouse CNS model responses to simulated GCRs and evaluate the induction of an anti-inflammatory phenotype in astrocytes as a potential countermeasure. Furthermore, in our lab we have been exploring the individual variability, genomic associations and secreted biomarkers of responses to space radiation, which could eventually be combined to address personalized CNS health risk and develop individual countermeasures. Ultimately, we aim to expand upon these results to uncover novel cellular and mechanistic targets for countermeasure development to mitigate human CNS damage in deep space exploration.

space radiation↗

NASA NTRS2011

A Hypothesis on Biological Protection from Space Radiation Through the Use of New Therapeutic Gases as Medical Counter Measures

Exposure to astronauts could be a significant obstacle for long duration manned space exploration because of current uncertainties regarding the extent of biological effects. Furthermore, concepts for protective shielding also pose a technically challenging issue due to the nature of cosmic radiation and current mass and power constraints with modern exploration technology. As biological damage from exposure is associated with increased oxidative stress, it would be enabling to mitigate and/or prevent stress prior to the development of clinical symptoms and disease. This paper hypothesizes a "systems biology" approach in which a combination of chemical and biological mitigation techniques are used conjunctively. It proposes using new, therapeutic, medical gases as both chemical radioprotectors for radical scavenging and biological promoters for management of the body s response to exposure. From reviewing radiochemistry of water, biological effects of CO, H2, NO, and H2S gas, and mechanisms of radiation biology, it is concluded that this approach may have great therapeutic potential for exposure. Furthermore, it also appears to have potential for curtailing the pathogenesis of other diseases in which oxidative stress has been implicated including cardiovascular disease, cancer, chronic inflammatory disease, hypertension, ischemia/reperfusion injury, acute respiratory distress syndrome, Parkinson s and Alzheimer s disease, cataracts, and aging.

Schoenfeld, Michael P.↗

DOE OSTI2021

Lipid accumulation-induced hepatocyte senescence regulates the activation of hepatic stellate cells through the Nrf2-antioxidant response element pathway

Highlights: • Oxidative stress caused by lipid deposition causes hepatocyte senescence. • Free fatty acid-induced senescent hepatocytes promote hepatic stellate cell activation and development of hepatic fibrosis. • Senescent hepatocytes regulate hepatic fibrosis through the Nrf2-antioxidant response element pathway. Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease globally. Elderly individuals are at a higher risk of developing NAFLD with severe clinical outcomes. Although NAFLD is closely related to liver aging, the role of hepatocyte senescence in the progression of NAFLD, especially in the development of fibrosis, is still unclear. The early stage of NAFLD is mainly characterized by lipid accumulation in hepatocytes, which could lead to severe oxidative stress, causing cellular senescence. In the present study, hepatocytes cultured in the presence of free fatty acids to induce lipid deposition were used as a hepatocyte senescence model in vitro. Senescent hepatocytes significantly increased the activation of co-cultured primary hepatic stellate cells (HSCs) and the expression of pro-fibrosis molecules. Moreover, the antioxidant regulator nuclear factor erythroid 2-related factor 2 (Nrf2) that was upregulated in senescent hepatocytes was found to be related to the activation of co-cultured HSCs. The Nrf2 agonist sulforaphane, which upregulated the transcriptional activity of the Nrf2-antioxidant response element (ARE) pathway, remarkably inhibited hepatocyte senescence and its activation effect on HSCs. However, the liver tissue obtained from non-alcoholic steatohepatitis (NASH) mice with Nrf2 knockdown showed decreased antioxidation and significant liver senescence and fibrosis. In conclusion, this study confirmed that lipid accumulation induces hepatocyte senescence, which leads to HSC activation and development of hepatic fibrosis. Increasing the activity of the Nrf2-ARE antioxidant pathway in senescent hepatocytes elicited the opposite effect, suggesting that targeting Nrf2 may prevent or delay the progression of aging-related liver fibrosis in NASH.

60 APPLIED LIFE SCIENCES↗