Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “STEROIDS”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7

Changes in Liver Metabolic Gene Expression from Radiation Exposure

Radiation exposure is one of the unique physiological challenges of human spaceflight that is not encountered on earth. While radiation exposure is known to impart physiological stresses and alter normal function, it is unclear how it specifically affects drug metabolism. A major concern is that the actions of medications used in spaceflight may deviate from the expectations formed from terrestrial use. This concern was investigated at the molecular level by analyzing how gamma radiation exposure affected gene expression in the livers of mice. Three different doses of radiation were administered and after various intervals of recovery time, gene expression was measured with RT-qPCR screening arrays for drug metabolism and DNA repair. After examining the results of 192 genes total from each of 72 mice, 65 genes were found to be significantly affected by at least one of the doses of radiation. In general, the genes affected are involved in the metabolism of drugs with lipid or steroid hormone-like structures, as well as the maintenance of redox homeostasis and repair of DNA damage.

Peters, C. P.↗

Changes in Liver Metabolic Gene Expression from Radiation Exposure

Increased exposure to radiation is one physiological stressor associated with spaceflight. While known to alter normal physiological function, how radiation affects metabolism of administered medications is unclear. Crew health could be affected if the actions of medications used in spaceflight deviated from expectations formed during terrestrial medication use. Three different doses of gamma radiation (50 mGy - 6.05 Gy) and a sham were administered to groups of 6 mice each, and after various intervals of recovery time, liver gene expression was measured with RT-qPCR arrays for drug metabolism and DNA repair enzymes. Results indicated approx.65 genes of the 190 tested were significantly affected by at least one of the radiation doses. Many of the affected genes are involved in the metabolism of drugs with hydrophobic or steroid-like structures, maintenance of redox homeostasis and repair of DNA damage. Most affected genes returned to near control expression levels by 7 days post-treatment. With 6 Gy exposure, metallothionein expression was 132-fold more than control at the 4 hr time point, and fell at each later time point (11-fold at 24 hrs, and 8-fold at 7 days). In contrast, Cyp17a1 showed a 4-fold elevation at 4 hrs after exposure and remained constant for 7 days.

Peters, C. P.↗

Expression of Enzymes that Metabolize Medications

INTRODUCTION: Increased exposure to radiation is one physiological stressor associated with spaceflight and it is feasible to conduct ground experiments using known radiation exposures. The health of the liver, especially the activity rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. While radiation is known to alter normal physiological function, how radiation affects liver metabolism of administered medications is unclear. Crew health could be affected if the actions of medications used in spaceflight deviated from expectations formed during terrestrial medication use. This study is an effort to identify liver metabolic enzymes whose expression is altered by spaceflight or by radiation exposures that mimic features of the spaceflight environment. METHODS: Using procedures approved by the Animal Care and Use Committee, mice were exposed to either 137Cs (controls, 50 mGy, 6Gy, or 50 mGy + 6Gy separated by 24 hours) or 13 days of spaceflight on STS 135. Animals were anesthetized and sacrificed at several time points (4 hours, 24 hours or 7 days) after their last radiation exposure, or within 6 hours of return to Earth for the STS 135 animals. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted, purified and quality-tested. Complementary DNA was prepared from high-quality RNA samples, and used in RT-qPCR experiments to determine relative expression of a wide variety of genes involved in general metabolism and drug metabolism. RESULTS: Results of the ground radiation exposure experiments indicated ~65 genes of the 190 tested were significantly affected by at least one of the radiation doses. Many of the affected genes are involved in the metabolism of drugs with hydrophobic or steroid-like structures, maintenance of redox homeostasis and repair of DNA damage. Most affected genes returned to near control expression levels by 7 days post-treatment. Not all recovered completely by the final time point tested: with 6 Gy exposure, metallothionein expression was 132-fold more than control at the 4 hr time point, and fell at each later time point (11-fold at 24 hrs, and 8-fold at 7 days). In contrast, there were other genes whose expression was altered and remained relatively constant through the 7 day period we tested. One examples is Cyp17a1, which showed a 4-fold elevation at 4 hrs after exposure and remained constant for 7 days after the last treatment. Spaceflight samples evaluated with similar methods and comparisons will be made between the radiation-treated groups and the spaceflight samples. CONCLUSION It seems likely that radiation exposure triggers homeostatic mechanisms, which could include alterations of gene expression. Better understanding of these pathways could aid in optimizing medications doses given to crewmembers who require treatment and eventually, to development of new countermeasures to ameliorate or prevent radiation-induced damage to cells and tissues.

Wotring, V. E.↗

Saliva Preservative for Diagnostic Purposes

Saliva is an important body fluid for diagnostic purposes. Glycoproteins, glucose, steroids, DNA, and other molecules of diagnostic value are found in saliva. It is easier to collect as compared to blood or urine. Unfortunately, saliva also contains large numbers of bacteria that can release enzymes, which can degrade proteins and nucleic acids. These degradative enzymes destroy or reduce saliva s diagnostic value. This innovation describes the formulation of a chemical preservative that prevents microbial growth and inactivates the degradative enzymes. This extends the time that saliva can be stored or transported without losing its diagnostic value. Multiple samples of saliva can be collected if needed without causing discomfort to the subject and it does not require any special facilities to handle after it is collected.

Pierson, Duane L.↗

Are Medications Involved in Vision and Intracrancial Pressure Changes Seen in Spaceflight?

The Food and Drug Association Adverse Event Reports (FDA AER) from 2009-2011 were used to create a database from millions of known and suspected medication-related adverse events among the general public. Vision changes, sometimes associated with intracranial pressure changes (VIIP), have been noted in some long duration crewmembers. Changes in vision and blood pressure (which can subsequently affect intracranial pressure) are fairly common side effects of medications. The purpose of this study was to explore the possibility of medication involvement in crew VIIP symptoms. Reports of suspected medication-related adverse events may be filed with the Food and Drug Administration (FDA) by medical professionals or consumers. Quarterly compilations of these reports are available for public download. Adverse Event Reporting System (AERS) reports from 1/1/2009- 6/30/2012 were downloaded and compiled into a searchable database for this study. Reports involving individuals under the age of 18 and older than 65 were excluded from this analysis. Case reports involving chronic diseases such as cancer, diabetes, multiple sclerosis and other serious conditions were also excluded. A scan of the medical literature for medication-related VIIP-like adverse events was used to create a list of suspect medications. These medications, as well as certain medications used frequently by ISS crew, were used to query the database. Queries for use of suspected medications were run, and the nature of the symptoms reported in those cases were tabulated. Symptoms searched in the FDA AERS were chosen to include the typical symptoms noted in crewmembers with VIIP. Vision symptoms searched were: visual acuity reduced, visual impairment, and vitreous floaters. Pressure changes included: abnormal sensation in eye, intracranial pressure increased, intraocular pressure increased, optic neuritis, optic neuropathy, and papilloedema. Limited demographic information is included with the FDA AERS; relevant data were also sorted by age and sex from each report. RESULTS Steroid-containing oral contraceptives had the highest number of reports associated with vision (n=166) and pressure symptoms (n=54). Corticosteroid-containing medications were also high; prednisone, for example, had 137 reports of vision issues and 79 of pressure issues. Pain relievers were also a medication class with vision and pressure-related adverse events reported. Common over-the-counter medications such as acetaminophen, aspirin and ibuprofen each had multiple reports for both vision and pressure symptoms. Antimicrobial medications ciprofloxacin and diflucan were also associated with a number of vision and pressure-related AERS. Unexpectedly, pseudoephedrine and promethazine were mentioned in fewer than 20 reports each over the 3.5 years of data examined. The FDA AERS represents a wealth of data, but there are several limitations to its use. The data are entered by the public or medical professionals, but are not checked for accuracy or completeness and may even be entered multiple times. The causal relationship between a particular adverse event and a particular medication is not tested. The cases represent a broad spectrum of demographics, occupations, and health histories, and thus do not model the astronaut population well. There is no information on the frequency of use of a medication for comparison purposes; it is not possible to assign a rate for any particular adverse event. Nonetheless, there are compelling trends. Use of corticosteroid-containing medications, pain relievers (even over-the-counter), and oral contraceptives were associated with higher numbers of vision- or intracranial pressure-related adverse events. In general, there were more vision problems than pressure problems reported. Certain medications that were once suspected of playing a role in the crew VIIP syndrome, namely pseudoephedrine and promethazine, were found to have extremely low numbers of VIIP-like AERS in the FDA data. However, crew use of corticosteroid-containing medications and pain relievers may warrant additional investigation

Faust, K. M.↗

Dermatitis during Spaceflight Associated with HSV-1 Reactivation

Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report, for the first time, a case of HSV-1 skin rash (dermatitis) occurring during long-duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3 × 104 copies/ng DNA, respectively. Post-mission saliva samples continued to have a high infectious HSV-1 load (1.67 × 107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.9% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines), and biochemical profile markers, including vitamin/mineral status and bone metabolism, are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis to determine viral etiology and guide treatment.

Satish K. Mehta↗

Dermatitis During Spaceflight Associated With HSV-1 Reactivation- A Case Study

Human alpha herpesviruses herpes simplex virus (HSV-1 or -2) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia, and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr Virus (EBV), VZV, HSV-1 and Cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report for the first time, a case of HSV-1 skin rash (dermatitis) occurring during a long duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3×104 copies/ng DNA, respectively. Post-mission saliva samples continued to have high infectious HSV-1 load (1.67×107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.4% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines) and biochemical profile markers including vitamin/mineral status and bone metabolism are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis, to determine viral etiology and guide treatment.

Herpes, Viral Reactivation, Spaceflight, Dermatiti↗

Murine Host-gut Microbiota Interactions are Modulated During Spaceflight

The rodent habitat on the International Space Station has provided critical insight into the impact of spaceflight on mammalian physiology. These effects include dysfunction of carbohydrate, steroid and lipid metabolism, and immune response, as well as induction of symptoms characteristic of liver disease, insulin resistance, osteopenia and myopathy, which are anticipated to intensify over long-duration spaceflight. Although these physiological responses can involve the microbiome, the host-microorganism interactions during spaceflight are still largely unknown. NASA GeneLab curates a wide range of space research data and the current work harnesses GeneLab multi’omic data from recent Rodent Research studies to explore changes to gut microbiota during spaceflight and their associations with host physiology when compared to ground controls. Using a hybrid analysis of DNA barcoding and whole genome shotgun data, an array of bacteria, fungi and nematodes could be identified at species level, and significant differences in relative abundances associated with spaceflight. Functional prediction based on differential abundance of species and metagenome gene inventories as well as metatranscriptomic gene expression at the host-gut microbiome interface implicate microbiota interactions could contribute to spaceflight pathology. Harnessing carefully curated publicly available data, such as from Genelab, to generate multi‘omic space science discoveries can help decipher the complex host-microbiome interactions that influence both health on Earth and the feasibility of long-duration spaceflight.

Microbiome↗

Lucy Mission Design Strategy in a Dynamic Operations Environment from Launch Through First Asteroid Encounter

Lucy, a 12-yearlong NASA Discovery-class mission which launched on October 16, 2021will fly by several Jupiter-Trojan asteroids a t the L4 and L5 La grange points. Prior to theL4 Trojan encounter in 2027 and 2028, Lucy will utilize two Earth gravity-assist flybys and fly by two main-belt a steroids. After the L4 encounters a third Earth flyby will set up the L5 Troja n encounter in 2033. This pa per summarizes the baseline mission plan with focus on the spacecraft trajectory and the corresponding essential trajectory correction maneuvers as well as how the Lucy team adapted to many unforeseen changes to the spacecraft configuration and added an asteroid target of opportunity that required changes to the baseline mission plan. Refinement of asteroid flyby science requirements after launch also required updates to the baseline Lucy trajectory.

James V. Mcadams↗

Identification of Potent and Selective Inhibitors of Acanthamoeba : Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC 50 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness.

60 APPLIED LIFE SCIENCES↗

Determinants affecting physical activity levels in animal models

Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play an underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multifactorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked, making it difficult to determine whether a single, combination, or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to the ventral medial hypothalamus, and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.

Review↗

Influence of atmospheric oxygen on leaf structure and starch deposition in Arabidopsis thaliana

Plant culture in oxygen concentrations below ambient is known to stimulate vegetative growth, but apart from reports on increased leaf number and weight, little is known about development at subambient oxygen concentrations. Arabidopsis thaliana (L.) Heynh. (cv. Columbia) plants were grown full term in pre-mixed atmospheres with oxygen partial pressures of 2.5, 5.1, 10.1, 16.2, and 21.3 kPa O2, 0.035 kPa CO2 and the balance nitrogen under continuous light. Fully expanded leaves were harvested and processed for light and transmission electron microscopy or for starch quantification. Growth in subambient oxygen concentrations caused changes in leaf anatomy (increased thickness, stomatal density and starch content) that have also been described for plants grown under carbon dioxide enrichment. However, at the lowest oxygen treatment (2.5 kPa), developmental changes occurred that could not be explained by changes in carbon budget caused by suppressed photorespiration, resulting in very thick leaves and a dwarf morphology. This study establishes the leaf parameters that change during growth under low O2, and identifies the lower concentration at which O2 limitation on transport and biosynthetic pathways detrimentally affects leaf development. Grant numbers: NAG5-3756, NAG2-1020, NAG2-1375.

Non-NASA Center↗