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Results for “DEXAMETHASONE”

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.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS1986

Dexamethasone regulates glutamine synthetase expression in rat skeletal muscles

The regulation of glutamine synthetase by glucocorticoids in rat skeletal muscles was studied. Administration of dexamethasone strikingly enhanced glutamine synthetase activity in plantaris and soleus muscles. The dexamethasone-mediated induction of glutamine synthetase activity was blocked to a significant extent by orally administered RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves dramatically increased levels of glutamine synthetase mRNA. The induction of glutamine synthetase was selective in that glutaminase activity of soleus and plantaris muscles was not increased by dexamethasone. Furthermore, dexamethasone treatment resulted in only a small increase in glutamine synthetase activity in the heart. Accordingly, there was only a slight change in glutamine synthetase mRNA level in this tissue. Thus, glucocorticoids regulate glutamine synthetase gene expression in rat muscles at the transcriptional level via interaction with intracellular glutamine production by muscle and to mechanisms underlying glucocorticoid-induced muscle atrophy.

Max, Stephen R.↗
DOE OSTI2021

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model

Highlights: • Dexamethasone attenuated thoracic aortic aneurysm and dissection in a mouse model. • Dexamethasone reduced infiltration of inflammatory cell and apoptosis of vascular smooth muscle cell and fibroblast. • Dexamethasone partly alleviated degradation of collagen and phenotype switch. • DEX might ameliorate thoracic aortic aneurysm and dissection by suppressing NF-κB signaling pathway. Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a β-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1986

Dexamethasone mimicks the antimotion sickness effects of amphetamine and scopolamine

Based on preliminary suggestions that individual differences in susceptibility to stressful motion might be related to physiological differences in responses of the hypothalamic-pituitary-adrenal axis, the efficacy of dexamethasone and metyrapone is tested in subjects exposed to cross-coupled accelerative semicircular canal stimulation on a rotating chair. Subjects given 0.5 mg of dexamethasone every 6 h for 48 h could endure 80 percent more stressful motion (P = 0.03) in a within-subjects design study, whereas, no improvement followed treatment with 750 mg of metryapone every 4 h for 24 h. The efficacy of dexamethasone might be explained in terms of its neurochemical actions on several neurotransmitter systems which are also modulated by such classical antimotion sickness drugs as amphetamine and scopolamine. Because dexamethasone induces adaptive changes within the central nervous system it may prove superior to scopolamine and amphetamine which possess significant side effects, are short acting, and rapidly tolerated.

Kohl, Randall Lee↗
NASA NTRS1989

Dexamethasone effects on creatine kinase activity and insulin-like growth factor receptors in cultured muscle cells

The effect of dexamethasone on the activity of creatine kinase (CK) and the insulin-like growth factor I (IGF-I) binding were investigated using skeletal- and cardiac-muscle-derived cultured cell lines (mouse, C2C12; rat, L6 and H9c2). It was found that, in skeletal muscle cells, dexamethasone treatment during differentiation of skeletal-muscle cells caused dose-dependent increases in CK activity and increases in the degree of myotube formation, whereas cardiac cells (H9c2) exhibited very low CK activity during culture or dexamethasone treatment. Results for IGF-I binding were similar in all three cell lines. The IGF-I binding to dexamethasone-treated cells (50 nM for 24 hr on the day prior to confluence) resulted in an increased number of available binding sites, with no effect on the binding affinities.

Whitson, Peggy A.↗
DOE OSTI2021

Coadministration of a Clinically Relevant Dexamethasone Dosage With Ablative Radiation Therapy Reduces Peripheral Lymphocytes But Does Not Alter In Vivo Intratumoral Lymphocyte Phenotype or Inhibit Efficacy of Radiation Therapy in a Murine Colorectal Tumor Model

Dexamethasone is commonly given during radiation therapy (RT) to manage toxicities. Our study examines if dexamethasone coadministration with RT inhibits the RT-induced antitumor T cell response in mouse.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS1998

Osteoblastic phenotype of rat marrow stromal cells cultured in the presence of dexamethasone, beta-glycerolphosphate, and L-ascorbic acid

We investigated the effects of the time course of addition of osteogenic supplements dexamethasone, beta-glycerolphosphate, and L-ascorbic acid to rat marrow stromal cells, and the exposure time on the proliferation and differentiation of the cells. It was the goal of these experiments to determine the time point for supplement addition to optimize marrow stromal cell proliferation and osteoblastic differentiation. To determine this, two studies were performed; one study was based on the age of the cells from harvest, and the other study was based on the duration of exposure to supplemented medium. Cells were seen to proliferate rapidly at early time points in the presence and absence of osteogenic supplements as determined by 3H-thymidine incorporation into the DNA of replicating cells. These results were supported by cell counts ascertained through total DNA analysis. Alkaline phosphatase (ALP) activity and osteocalcin production at 21 days were highest for both experimental designs when the cells were exposed to supplemented medium immediately upon harvest. The ALP levels at 21 days were six times greater for cells maintained in supplements throughout than for control cells cultured in the absence of supplements for both studies, reaching an absolute value of 75 x 10(-7) micromole/min/cell. Osteocalcin production reached 20 x 10(-6) ng/cell at 21 days in both studies for cells maintained in supplemented medium throughout the study, whereas the control cells produced an insignificant amount of osteocalcin. These results suggest that the addition of osteogenic supplements to marrow-derived cells early in the culture period did not inhibit proliferation and greatly enhanced the osteoblastic phenotype of cells in a rat model.

Non-NASA Center↗
NASA NTRS1992

Catecholaminergic responses to stressful motion stimuli, scopolamine plus amphetamine, and dexamethasone

Peripheral levels of epinephrine (EPI) and neoepinephrine (NE) generally rise following stressful motion stimuli. Effective anti-motion sickness drugs, scopolamine plus, d-amphetamine (S/D) and dexamthasone (DEX) modulate release of EPI and NE. This modulation may be of etiological relevance. Methods: Severe nausea was induced by exposure to coriolis simulation using a rotating chair. Chronic administration of S/D (0.4 and 5 mg/da) DEX (3 mg/day) and placebo preceded coriolis simulation. EPI and NE were measured immediately before and after simulation. A double-blind crossover design was used. Results: Nausea-induced elevations of EPI (2.5 fold, p less than .01) and NE were not diminished upon repeated exposure and adaptation to the stressor. Subjects with more pronounced elevations of EPI following simulation displayed higher resistance to stressful motion (p less .05). Alteration of peripheral catechlomaine levels following drug suggested that motion sickness was not mediated by peripheral catechlolamine receptor simulation. EPI and NE levels were 2.8 and 3.6-fold higher (p less than .03 and .01) after nausea without DEX treatment. DEX loading halved pre-stress levels of EPI and NE (p less than .05). Conclusions: Marked differences were noted in individual responses to drug and systematic responses of EPI and NE. It is possible that the responses of EPI to motion sickness may predict resistance to stressful motion and represent a peripheral manifestation of some as yet unknown central event of etiologic relevance.

Kohl, R. L.↗
DOE OSTI2022

The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats

Ozone-induced lung injury/inflammation dissipates despite continued exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. Since ozone effects are mediated through adrenal-derived stress hormones, which also regulate longevity of centrally-mediated stress response, we hypothesized that ozone-adaptation is linked to diminution of neuroendocrine stress-axes activation and glucocorticoid levels. Male Wistar-Kyoto-rats (12-week-old) were injected with vehicle or a therapeutically-relevant dexamethasone dose (0.01-mg/kg/day; intraperitoneal) for 1-month to determine if suppression of glucocorticoid signaling was linked to adaptation. Vehicle- and dexamethasone-treated rats were exposed to air or 0.8-ppm ozone, 4 h/day × 2 or 4 days to assess the impacts of acute exposure and adaptation, respectively. Dexamethasone reduced thymus and spleen weights, circulating lymphocytes, corticosterone and increased insulin. Ozone increased lavage-fluid protein and neutrophils and decreased circulating lymphocytes at day-2 but not day-4. Ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release occurred at day-1 but not day-3. Ozone depleted circulating prolactin, thyroid-stimulating hormone, and luteinizing-hormone at day-2 but not day-4, suggesting central mediation of adaptation. Adrenal epinephrine biosynthesis gene, Pnmt, was up-regulated after ozone exposure at both timepoints. However, genes involved in glucocorticoid biosynthesis were up-regulated after day-2 but not day-4, suggesting that acute 1- or 2-day ozone-mediated glucocorticoid increase elicits feedback inhibition to dampen hypothalamic stimulation of ACTH release in response to repeated subsequent ozone exposures. Although dexamethasone pretreatment affected circulating insulin, lymphocytes and adrenal genes, it had modest effect on ozone adaptation. In conclusion, ozone adaptation likely involves lack of hypothalamic response due to reduced availability of circulating glucocorticoids.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1987

Glucocorticoid receptor-mediated induction of glutamine synthetase in skeletal muscle cells in vitro

The regulation by glucocorticoids of glutamine synthetase in L6 muscle cells in culture is studied. Glutamine synthetase activity was strikingly enhanced by dexamethasone. The dexamethasone-mediated induction of glutamine synthetase activity was blocked by RU38486, a glucocorticoid antagonist, indicating the involvement of intracellular glucocorticoid receptors in the induction process. RU38486 alone was without effect. Northern blot analysis revealed that dexamethasone-mediated enhancement of glutamine synthetase activity involves increased levels of glutamine synthetase mRNA. Glucocorticoids regulate the expression of glutamine synthetase mRNA in cultured muscle cells via interaction with intracellular receptors. Such regulation may be relevant to control of glutamine production by muscle.

Max, Stephen R.↗
NASA NTRS1993

Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting

Glucocorticoids are essential for the increase in protein breakdown in skeletal muscle normally seen during fasting. To determine which proteolytic pathway(s) are activated upon fasting, leg muscles from fed and fasted normal rats were incubated under conditions that block or activate different proteolytic systems. After food deprivation (1 day), the nonlysosomal ATP-dependent process increased by 250%, as shown in experiments involving depletion of muscle ATP. Also, the maximal capacity of the lysosomal process increased 60-100%, but no changes occurred in the Ca(2+)-dependent or the residual energy-independent proteolytic processes. In muscles from fasted normal and adrenalectomized (ADX) rats, the protein breakdown sensitive to inhibitors of the lysosomal or Ca(2+)-dependent pathways did not differ. However, the ATP-dependent process was 30% slower in muscles from fasted ADX rats. Administering dexamethasone to these animals or incubating their muscles with dexamethasone reversed this defect. During fasting, when the ATP-dependent process rises, muscles show a two- to threefold increase in levels of ubiquitin (Ub) mRNA. However, muscles of ADX animals failed to show this response. Injecting dexamethasone into the fasted ADX animals increased muscle Ub mRNA within 6 h. Thus glucocorticoids activate the ATP-Ub-dependent proteolytic pathway in fasting apparently by enhancing the expression of components of this system such as Ub.

Non-NASA Center↗
NASA NTRS1992

Glucocorticoids promote development of the osteoblast phenotype by selectively modulating expression of cell growth and differentiation associated genes

To understand the mechanisms by which glucocorticoids promote differentiation of fetal rat calvaria derived osteoblasts to produce bone-like mineralized nodules in vitro, a panel of osteoblast growth and differentiation related genes that characterize development of the osteoblast phenotype has been quantitated in glucocorticoid-treated cultures. We compared the mRNA levels of osteoblast expressed genes in control cultures of subcultivated cells where nodule formation is diminished, to cells continuously (35 days) exposed to 10(-7) M dexamethasone, a synthetic glucocorticoid, which promotes nodule formation to levels usually the extent observed in primary cultures. Tritiated thymidine labelling revealed a selective inhibition of internodule cell proliferation and promotion of proliferation and differentiation of cells forming bone nodules. Fibronectin, osteopontin, and c-fos expression were increased in the nodule forming period. Alkaline phosphatase and type I collagen expression were initially inhibited in proliferating cells, then increased after nodule formation to support further growth and mineralization of the nodule. Expression of osteocalcin was 1,000-fold elevated in glucocorticoid-differentiated cultures in relation to nodule formation. Collagenase gene expression was also greater than controls (fivefold) with the highest levels observed in mature cultures (day 35). At this time, a rise in collagen and TGF beta was also observed suggesting turnover of the matrix. Short term (48 h) effects of glucocorticoid on histone H4 (reflecting cell proliferation), alkaline phosphatase, osteopontin, and osteocalcin mRNA levels reveal both up or down regulation as a function of the developmental stage of the osteoblast phenotype. A comparison of transcriptional levels of these genes by nuclear run-on assays to mRNA levels indicates that glucocorticoids exert both transcriptional and post-transcriptional effects. Further, the presence of glucocorticoids enhances the vitamin D3 effect on gene expression. Those genes which are upregulated by 1,25(OH)2D3 are transcribed at an increased rate by dexamethasone, while those genes which are inhibited by vitamin D3 remain inhibited in the presence of dexamethasone and D3. We propose that the glucocorticoids promote changes in gene expression involved in cell-cell and cell-extracellular matrix signaling mechanisms that support the growth and differentiation of cells capable of osteoblast phenotype development and bone tissue-like organization, while inhibiting the growth of cells that cannot progress to the mature osteoblast phenotype in fetal rat calvarial cultures.

NASA Discipline Musculoskeletal↗
DOE OSTI2021

Spatio-temporal control of phenylpropanoid biosynthesis by inducible complementation of a cinnamate 4-hydroxylase mutant

Abstract Cinnamate 4-hydroxylase (C4H) is a cytochrome P450-dependent monooxygenase that catalyzes the second step of the general phenylpropanoid pathway. Arabidopsis reduced epidermal fluorescence 3 (ref3) mutants, which carry hypomorphic mutations in C4H, exhibit global alterations in phenylpropanoid biosynthesis and have developmental abnormalities including dwarfing. Here we report the characterization of a conditional Arabidopsis C4H line (ref3-2pOpC4H), in which wild-type C4H is expressed in the ref3-2 background. Expression of C4H in plants with well-developed primary inflorescence stems resulted in restoration of fertility and the production of substantial amounts of lignin, revealing that the developmental window for lignification is remarkably plastic. Following induction of C4H expression in ref3-2pOpC4H, we observed rapid and significant reductions in the levels of numerous metabolites, including several benzoyl and cinnamoyl esters and amino acid conjugates. These atypical conjugates were quickly replaced with their sinapoylated equivalents, suggesting that phenolic esters are subjected to substantial amounts of turnover in wild-type plants. Furthermore, using localized application of dexamethasone to ref3-2pOpC4H, we show that phenylpropanoids are not transported appreciably from their site of synthesis. Finally, we identified a defective Casparian strip diffusion barrier in the ref3-2 mutant root endodermis, which is restored by induction of C4H expression.

Plant Sciences↗
NASA NTRS1994

A sensitive radioimmunoassay for fludrocortisone in human plasma

Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11-desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS).

Non-NASA Center↗
DOE OSTI2021

Glucocorticoids suppressed osteoblast differentiation by decreasing Sema3A expression via the PIK3/Akt pathway

Highlights: • Dex decreased Sema3A expression by suppressing the PI3K/Akt pathway. • Sema3A reversed Dex-induced suppression of osteoblast differentiation. • Sema3A reversed the Dex-mediated reduced transcriptional activity of β-catenin. Glucocorticoids(GCs) are extensively used to treat inflammatory and autoimmune diseases. Excessive prolonged exposure to glucocorticoids is associated with an increased risk of osteoporosis. The inhibition of osteoblast differentiation by GCs is suggested as a major cause for GCs-induced osteoporosis (GIO). However, the precise mechanism underlying the role of GCs in osteoblasts differentiation is not fully elucidated. Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, enhances bone formation and promotes fracture healing, which is known to increase osteoblastic differentiation and stimulate osteogenesis in bone metabolism. Here, the present study explored the effect of Sema3A in osteoblast differentiation using dexamethasone (Dex) treatment of bone marrow stromal cells (BMSCs). Dex treatment decreased Sema3A expression in BMSCs in a dose-dependent manner. Moreover, Dex stimulation suppressed the differentiation of osteoblasts by reducing alkaline phosphatase (ALP) activity, osteoblastic marker genes expression and mineralization, but all of these effects were ameliorated by exogenous recombinant Sema3A administration. Furthermore, exogenous Sema3A administration reversed the Dex-mediated decrease in nuclear accumulation of β-catenin and β-catenin activity in BMSCs. Meanwhile, Dex was capable of simultaneously suppressing the phosphorylation of protein kinase B(Akt) and the expression level of Sema3A in BMSCs. These changes were significantly abolished by the PI3K/Akt agonist. These results suggest that Dex inhibits osteoblast differentiation by suppressing Sema3A expression via the PI3K/Akt pathway. These data provide new insights into the molecular mechanisms of Dex-induced osteoblast differentiation inhibition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Functional characterization of adult human trabecular meshwork stem cells

We earlier identified native human trabecular meshwork stem cells (TMSCs) based on two-parameters- high ABCG2 expression and high nucleus to cytoplasmic ratio. The TMSCs also expressed p75 and AnkyrinG. Based on the high expression of ABCG2 and p75, the TMSCs were identified to be located in the Schwalbe's line region of the TM. In continuation, the current study aimed at elucidating the functional characteristics of human TMSCs. Upon culturing, only a small proportion of TM cells (0.96 ± 0.21% in <30 years) expressing stem cell markers ABCG2 and p75 adhered to the culture dish. This proportion significantly reduced with ageing (0.32 ± 0.23% in 30–60 years and 0.35 ± 0.04% in >60 years). Characterization of the primary TM cultures identified 7.00 ± 1.80% of stem cells with label retaining property. Further, cultured cells had the ability to form TM spheres (0.82 ± 0.23%) which consisted of high ABCG2 and p75 positive cells. Upon dexamethasone induction, 86.00 ± 14.87% and 64.60 ± 7.24% of the cells derived from the TM spheres expressed myocilin and exhibited cross linked actin networks respectively, indicating differentiation of the TMSCs in the sphere to TM cells. In addition, the sphere derived TM cells also possessed phagocytic potential (13.28 ± 3.30%) equivalent to primary TM cells (16.33 ± 4.04%) which was evident upon internalization of zymosan particles. In conclusion, this study has established that a proportion of cultured TM cells had the label retaining property as well as sphere forming ability of adult stem cells. Thus, these results confirm the presence of adult stem cells in the human TM that might be responsible for the maintenance of tissue homeostasis.

60 APPLIED LIFE SCIENCES↗