Mass-Spectrometric Characterization of Phospholipids and Their Hydroperoxide Derivatives In Vivo: Effects of Total Body Irradiation

Lipidomics ◽  
2009 ◽  
pp. 153-183 ◽  
Author(s):  
Yulia Y. Tyurina ◽  
Vladimir A. Tyurin ◽  
Valentina I. Kapralova ◽  
Andrew A. Amoscato ◽  
Michael W. Epperly ◽  
...  
Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4721-4721 ◽  
Author(s):  
Michael W Epperly ◽  
Joshua G Pierce ◽  
Tracy Dixon ◽  
Darcy Franicola ◽  
Suhua Nie ◽  
...  

Abstract Nitroxides are efficient scavengers of free radicals and have been proposed for use as radioprotective agents. To circumvent the need for high concentrations for in vivo effects, and to target drugs to the mitochondria to prevent ionizing irradiation-induced apoptosis, we tested a family of compounds based on combining a hemi-gramicidin linker to a nitroxide. One small molecule (JP4-039) produced a 32-fold increased mitochondrial nitroxide localization in 32D cl 3 cells in vitro after one hour incubation at 37°C compared to the unlinked nitroxide tempo at 10uM. The cells were lyzed by rapidly freezing then thawing, followed by centrifugation to yield the nuclear, cytoplasmic, and mitochondrial fractions. EPR was used to quantitate nitroxide in each JP4-039 or tempo treated cell fraction. There was a 32-fold increase in the nitroxide signal for JP4-039 accumulation in the mitochondria compared to the nitroxide tempo. Irradiation survival curves were performed by incubating 32D cl 3 murine hematopoietic progenitor cells in JP4-039 or tempo (1 μM) for one hour before irradiation or by addition immediately following irradiation. The cells were irradiated to doses ranging from 0 to 8 Gy, suspended in methylcellulose-containing media, incubated for seven days at 37°C and colonies of greater than 50 cells were scored. The data was analyzed using linear quadratic and single-hit, multi-target models. Incubation of 32D cl 3 cells in JP4-039 for one hour prior to irradiation resulted in a significant increase in Do to 2.25 ± 0.11 Gy compared to 1.19 ± 0.13 Gy for 32D cl 3 cells alone or 1.32 ± 0.09 Gy for 32D cl 3 cells incubated in tempo (p=0.0042 or 0.0073, respectively). Similar results were achieved giving JP4-039 after irradiation with a Do of 1.97 ± 0.01 Gy (p < 0.0001). To test effectiveness in vivo, C57BL/6NHsd female mice were injected intraperitoneally with JP4-039 or tempo (10 mg/kg) 10 minutes before (or four hours after) total body irradiation to the LD 75/30 dose of 9.75 Gy. Mice were monitored and those moribund from the hematopoietic syndrome were sacrificed. Mice injected with 10 mg/kg JP4-039 before irradiation had a significant increase in survival of 60% compared to 28% for control irradiated mice (p = 0.0005) or 44% for tempo treated mice (p = 0.2252). JP4-039 given after irradiation had a survival of 53% at 30 days after irradiation (p = 0.0474). Thus, JP4-039, a mitochondrial targeted nitroxide, is an effective radioprotector, and mitigator.


Toxicon ◽  
2019 ◽  
Vol 168 ◽  
pp. S21
Author(s):  
Eric Junqueira Brito Pereira ◽  
Dilza Trevisan Silva ◽  
Solange Maria De Toledo Serrano

1999 ◽  
Vol 18 (1) ◽  
pp. 12-16 ◽  
Author(s):  
E Tanaka ◽  
A Ishikawa ◽  
T Horie

Trimethadione (TMO) has the properties required of a probe drug for the evaluation of hepatic drug-oxidizing capacity and, in this study, we have summarized the in vivo and in vitro metabolism of TMO in various animal species including mouse, hamster, rat, rabbit, dog, monkey and human. In the in vivo study, the plasma TMO level was measured after intravenous or oral (human) administration of TMO at a dose of 4 mg/kg to various animal species. The rate of TMO metabolic clearance in these animal species in vivo was in the order mouse > hamster >rat>rabbit>dog>monkey>human. In the in vitro study, species differences were observed in the cytochrome P450 (P450) content and drug-oxidizing enzyme activity. The content of P450 was monkey> mouse>dog>rabbit>hamster>rat>human. On the other hand, TMO N-demethylation was in the order mouse >hamster >rat >rabbit>dog>monkey>human. There was a good correlation between the mean total body clearance of TMO ( in vivo)andthemeanTMON-demethylase activity ( in vitro) (y=1.7×+0.11, r=0.965, P<0.001). These results show that TMO is a probe agent with metabolic and pharmacokinetic characteristics making it attractive for the in vivo and in vitro characterization of metabolic activity in various animal species.


2009 ◽  
Vol 36 (6Part12) ◽  
pp. 2580-2580 ◽  
Author(s):  
C Esquivel ◽  
M Smith ◽  
S Stathakis ◽  
A Gutiérrez ◽  
C Shi ◽  
...  

2013 ◽  
Vol 40 (6Part11) ◽  
pp. 223-223 ◽  
Author(s):  
C Holloway ◽  
S Mahendra ◽  
D Kaurin ◽  
L Sweeney

1988 ◽  
Vol 43 (1-2) ◽  
pp. 126-132 ◽  
Author(s):  
Karlheinz Tempel ◽  
Rüdiger Heinzelmann

The sedimentation of nucleoids from thymic and splenic cells of rats was tested following totalbody X-irradiation (TBI) with doses ranging from 24 to 1520 cGy. The principal results may be summarized as follows: 1) The nucleoid sedimentation of the cells was reduced immediately after TBI with doses of ≥ 760 cGy. In the following postirradiation period, an enhancement of sedimentation rate has been observed which could be neutralized by addition of proteinase K to the nucleoid preparation. 2) When nucleoids were prepared 6 h after TBI with doses ≥ 190 cGy, beside the main nucleoid band a smaller nucleoid fraction appeared in the ethidium bromide containing saccharose gradient. This fraction was of less sedimentability than the main nucleoid peak and could not be distinguished from pure, high molecular DNA. - From the present results it is suggested that the reduction of the nucleoid sedimentation immediately following high doses of TBI is the result of primary (non-repaired) DNA lesions whereas the changes detectable some hours later are due to the secondary enzymatic changes connected with the interphase death of the cells. With respect to the detection of in vivo effects of X-irradiation, the nucleoid sedimentation has to be regarded much less sensitive than some biochemical and/or cytomorphological methods


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4565-4565
Author(s):  
Sebastian Giebel ◽  
Leszek Miszczyk ◽  
Krzysztof Slosarek ◽  
Leila Moukhtari ◽  
Fabio Ciceri ◽  
...  

Background Total body irradiation (TBI) is widely used for conditioning prior to both allogeneic and autologous hematopoietic stem cell transplantation. Myeloablatitve doses of TBI are considered highly effective but also associated with relevant toxicity. Both, the efficacy and toxicity may depend on many methodological aspects of TBI. The goal of the survey was to explore current practice across centers collaborating in the European Group for Blood and Marrow Transplantation (EBMT). Methods The questionnaire sent to all EBMT centers included 19 questions regarding the doses used for myeloabaltive TBI, the way of fractionation, the modes of delivering the dose, type of immobilization, methods of dosimetry and organ shielding. 56 centers from 23 countries responded. Results All centers differ with regard at least one of the methodological aspects. The total dose of TBI used for myeloablative transplantation ranges from 8 to 14.4 Gy, the number of fractions ranges from 1 to 8, while the dose per fraction is 1.65 – 8 Gy. Altogether 16 modalities of dosing/fractionation have been identified with 6 x 2 Gy being the most frequent one (n=36, 64%). The dose rate in the axis of the beam ranges from 4.5 – 30 cGy/min (27 modalities; most frequently 18 cGy/min, 5%). The treatment unit is regular linac (n=51, 91%) or cobalt unit (n=5, 9%). Beams used for regular linac are 6 to 23 MV (most frequently 6 MV, n=26, 51%). The most frequent technique used for irradiation is “patient in one field” using two fields per fraction and two patient positions per fraction (n=36, 64%), however, altogether 11 modalities were described with regard to the technique, number of fields and positions per fraction. Source to surface distance is 2 to 5 m (most frequently 4 m; n=10, 18%). In 23 (41%) centers patients are immobilized during TBI, using 9 different types of device. Fifty-two centers (93%) measure acquired dose of irradiation using 5 types of detectors for in vivo dosimetry (most frequently semiconductors; n=37, 66%). Accepted discrepancy between planned and measured dose ranges from 1.5 to 10%. In 47 (84%) centers lungs are shielded during irradiation and lung density is considered for treatment planning. Maximum accepted dose for lungs ranges from 6 to 12 Gy. Additionally, in some centers lenses (14%), thyroid gland (7%), larynx (4%), kidneys (4%) and/or salivary glands (2%) are shielded. Conclusions TBI is an extremely heterogeneous treatment modality. Differences between centers regard all methodological aspects. Our findings should warrant caution in interpretation of clinical studies involving TBI. Further investigation is needed to evaluate whether differences between treatment modalities influence the efficacy and safety of the TBI procedure. Finally, efforts to standardize the method should be considered. Disclosures: No relevant conflicts of interest to declare.


1973 ◽  
Vol 138 (1) ◽  
pp. 130-142 ◽  
Author(s):  
Varda Rotter ◽  
Amiela Globerson ◽  
Ichiro Nakamura ◽  
Nathan Trainin

The immune response to SRBC was measured in the spleens of adult thymectomized, total body irradiated mice injected with various combinations of thymus and bone marrow cells together with thymic humoral factor (THF). It was found that the number of plaque-forming cells was significantly increased when THF was given in vivo immediately after thymus cell administration or when thymus cells were incubated in THF before injection. On the other hand, bone marrow cells equally treated did not manifest any T cell activity, since THF-treated bone marrow cells were not able to substitute thymus cells in the system used. The results accumulated in the present experiments indicate, therefore, that the target cells for THF activity are thymus cells which acquire a higher T helper cell capacity after THF treatment.


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