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31.
Induction of DNA polymerase beta-dependent base excision repair in response to oxidative stress in vivo 总被引:5,自引:0,他引:5
Base excision repair (BER) is the DNA repair pathway primarily responsible for repairing small base modifications and abasic sites caused by normal cellular metabolism or environmental insult. Strong evidence supports the requirement of DNA polymerase beta (beta-pol) in the BER pathway involving single nucleotide gap filling DNA synthesis in mammalian systems. In this study, we examine the relationship between oxidative stress, cellular levels of beta-pol and BER to determine whether oxidizing agents can upregulate BER capacity in vivo. Intraperitoneal injection of 2-nitropropane (2-NP, 100 mg/kg), an oxidative stress-inducing agent, in C57BL/6 mice was found to generate 8-hydroxydeoxyguanosine (8-OHdG) in liver tissue (4-fold increase, P < 0.001). We also observed a 4-5-fold increase in levels of DNA single strand breaks in 2-NP treated animals. The protein level of the tumor suppressor gene, p53 was also induced in liver by 2-NP (2.1-fold, P < 0.01), indicating an induction of DNA damage. In addition, we observed a 2-3-fold increase in mutant frequency in the lacI gene after exposure to 2-NP. Interestingly, an increase in DNA damage upregulated the level of beta-pol as well as BER capacity (42%, P < 0.05). These results suggest that beta-pol and BER can be upregulated in response to oxidative stress in vivo. Furthermore, data show that heterozygous beta-pol knockout (beta-pol(+/-)) mice express higher levels of p53 in response to 2-NP as compared with wild-type littermates. While the knockout and wild-type mice display similar levels of 8-OHdG after 2-NP exposure, the beta-pol(+/-) mice exhibit a significant increase in DNA single strand breaks. These findings suggest that in mice, a reduction in beta-pol expression results in a higher accumulation of DNA damage by 2-NP, thus establishing the importance of the beta-pol-dependent BER pathway in repairing oxidative damage. 相似文献
32.
Loss of tumor-promoting activity of unleaded gasoline in N- nitrosodiethylamine-initiated ovariectomized B6C3F1 mouse liver 总被引:1,自引:0,他引:1
Unleaded gasoline (UG) vapor (2056 ppm) increased the incidence of liver
tumors in a chronic bioassay and exhibited tumor-promoting activity in
N-nitrosodiethylamine (DEN)-initiated female mouse liver. Estrogen
inhibited mouse liver tumor development and the hepatocarcinogenic and
tumor-promoting dose of UG produced uterine changes suggestive of estrogen
antagonism. To directly test the hypothesis that UG-induced tumor-promoting
ability is secondary to its interaction with the mouse liver tumor
inhibitor, estrogen, we compared the tumor-promoting ability of UG in
ovariectomized (Ovex) mice with the hepatic tumor-promoting ability of UG
in intact mice. Ovaries were surgically removed at 4 weeks of age. Exposure
to wholly vaporized UG (2018 ppm) under bioassay and tumor-promoting
conditions began at 8 weeks of age. After 4 months of exposure, UG
increased relative liver weight and hepatic microsomal cytochrome P450
pentoxyresourfin-O- dealkylase and ethoxyresorufin-O-deethylase activity to
a similar extent in intact and Ovex mice. Non-focal hepatocyte
proliferation, as measured by the incorporation of bromo-deoxyuridine, was
not changed by UG exposure and was similar in all treatment groups. After 4
months of exposure to DEN-initiated mice, UG significantly increased the
volume fraction of liver occupied by foci (three-fold) as compared to
control intact mice. As expected, volume of foci was elevated in
DEN/Ovex/control mice as compared to DEN/intact/control mice. In DEN/Ovex
mice UG did not significantly increase the focal volume fraction. Thus, the
tumor promoting activity of UG, as demonstrated by increased volume
fraction of liver occupied by hepatic foci in intact mice, is greatly
attenuated in Ovex mice. The volume fraction data in Ovex mice support the
hypothesis that the tumor promoting activity of UG is dependent upon the
interaction of UG with ovarian hormones. These data also indicate that
hepatic microsomal cytochrome P450 PROD and EROD induction, hepatomegaly
and non-focal hepatic LI are not specific markers of hepatic tumor
promoting activity of UG.
相似文献
33.
Perkins SN; Hursting SD; Haines DC; James SJ; Miller BJ; Phang JM 《Carcinogenesis》1997,18(5):989-994
Transgenic mice with both alleles of the p53 tumor suppressor gene product
'knocked out' by gene targeting are susceptible to early development of
tumors, chiefly lymphomas and sarcomas. Compared with the control group,
administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to male
p53-deficient mice extended their lifespan by delaying death due to
neoplasms (from 105 to 166 days on study, P = 0.002), primarily by
suppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P =
0.010). Treatment with a synthetic DHEA analog,
16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet
also increased lifespan, to 140 days for mice that developed tumors (P =
0.037). The effects of these steroids on lifespan and tumor development did
not appear to be strongly related to inhibition of food consumption and
weight gain, in that a group pair-fed with control diet to the reduced food
consumption of the DHEA-treated group developed and died of the same types
of neoplasms at the same rate as the controls fed ad libitum. The
chemopreventive effect of these steroids has been proposed to be due to
suppression of DNA synthesis by inhibition of glucose 6-phosphate
dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway.
Although DHEA and its analog are strong non- competitive inhibitors of this
enzyme in vitro, treatment with DHEA did not deplete cellular nucleotide
pools in the liver, as would have been predicted. The chemopreventive
effect of DHEA in this model may be due to steroid-induced thymic atrophy
and suppression of T cell lymphoma, permitting these mice to survive long
enough to develop tumors with longer latency.
相似文献
34.
Wu DC; Liu JM; Chen YM; Yang S; Liu SM; Chen LT; Whang-Peng J 《Japanese journal of clinical oncology》1997,27(2):115-118
Hemolytic uremic syndrome spontaneously arises in a few patients with
advanced cancer, but it is more commonly related to the use of certain
chemotherapeutic agents. Mitomycin-C is, etiologically, the most common
causative agent inducing hemolytic uremic syndrome, in a dose dependent
manner. We report this syndrome, attributable to mitomycin-C at a
cumulative dose of 40 mg/m2, in a gastric cancer patient. A 42-year-old
female with stage III gastric cancer underwent radical gastrectomy and was
given mitomycin-C at 10 mg/m2 intravenously every four weeks as adjuvant
therapy. Hemolytic uremic syndrome was diagnosed three months after the
last dose of mitomycin-C administration. The most prominent symptoms
included pallor, hypertension and anasarca, with laboratory evidence of
microangiopathic hemolytic anemia, azotemia and hyperkalemia. Her disease
was progressive, but fortunately stabilized after staphylococcus column A
dialysis. Her disease remained in remission for 24 months from the time of
diagnosis, and then relapsed in the form of peritoneal carcinomatosis with
partial intestinal obstruction.
相似文献
35.
MM Harjai DC Agarwal P Dave SS Jog P Arora SM VSM 《Medical Journal Armed Forces India》2005,61(2):143-147
Background
The sudden increase in incidence and magnitude of mine blast injuries prompted us to highlight the problem and its management.Methods
The cases of mine blast injuries occurring during mining and demining in a particular geographical area were analysed. Total 27 cases of mine blast injuries occurred during mining or demining operations in a period of 13 months.Results
Various body regions were involved in the mine blast injuries but the main brunt was borne by feet and legs followed by multiple body regions due to splinters. 14 patients underwent below knee (BK) amputation while 4 patients required through knee (TK) amputations. The effect of blast was so severe that most of the cases required 2 to 5 times wound debridements. The initial aggressive debridement / open stump amputation saved the limb and life of all patients.Conclusion
A mine blast causes extensive injuries and psychological trauma. Management is needed urgently, surgery is difficult, and amputation is often inevitable. Maximum lives and limbs can be saved with aggressive debridement, repeated inspections and dressings under anaesthesia and definitive closure at optimum time.Key Words: Amputation, Antipersonnel mine, Crush syndrome, Debridements, Mine blast injury, Secondary missiles, Shrapenels 相似文献36.
37.
The use of the Bene-Anthony Family Relations Test is described and illustrated by three examples of child abuse. This test should be considered in the investigation of definite or suspected cases of abuse and as part of the preparation of court evidence. 相似文献
38.
39.
40.
Di Chiro G; Girton ME; Frank JA; Dietz MJ; Gansow OA; Wright DC; Dwyer AJ 《Radiology》1986,160(1):221-222
Canine cerebrospinal fluid rhinorrhea, which occurs frequently in purebred beagles, was demonstrated in two dogs on magnetic resonance images after cisternal introduction of gadolinium-DTPA dimeglumine. 相似文献