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1.
Joost P.M. Melis Raoul V. Kuiper Edwin Zwart Joke Robinson Jeroen L.A. Pennings Conny T.M. van Oostrom Mirjam Luijten Harry van Steeg 《DNA Repair》2013,12(12):1081-1086
XPC is one of the key DNA damage recognition proteins in the global genome repair route of the nucleotide excision repair (NER) pathway. Previously, we demonstrated that NER-deficient mouse models Xpa?/? and Xpc?/? exhibit a divergent spontaneous tumor spectrum and proposed that XPC might be functionally involved in the defense against oxidative DNA damage. Others have mechanistically dissected several functionalities of XPC to oxidative DNA damage sensitivity using in vitro studies. XPC has been linked to regulation of base excision repair (BER) activity, redox homeostasis and recruitment of ATM and ATR to damage sites, thereby possibly regulating cell cycle checkpoints and apoptosis. XPC has additionally been implicated in recognition of bulky (e.g. cyclopurines) and non-bulky DNA damage (8-oxodG). However, the ultimate contribution of the XPC functionality in vivo in the oxidative DNA damage response and subsequent mutagenesis process remains unclear. Our study indicates that Xpc?/? mice, in contrary to Xpa?/? and wild type mice, have an increased mutational load upon induction of oxidative stress and that mutations arise in a slowly accumulative fashion. The effect of non-functional XPC in vivo upon oxidative stress exposure appears to have implications in mutagenesis, which can contribute to the carcinogenesis process. The levels and rate of mutagenesis upon oxidative stress correlate with previous findings that lung tumors in Xpc?/? mice overall arise late in the lifespan and that the incidence of internal tumors in XP-C patients is relatively low in comparison to skin cancer incidence. 相似文献
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Gilian Guerreiro Alexandre U. Amaral Rafael Teixeira Ribeiro Jéssica Faverzani Ana Carolina Groehs Angela Sitta Marion Deon Moacir Wajner Carmen Regla Vargas 《生物化学与生物物理学报:疾病的分子基础》2019,1865(9):2420-2427
The deficiency of the enzyme glutaryl-CoA dehydrogenase leads to predominant accumulation of glutaric acid (GA) in the organism and is known as glutaric acidemia type I (GA1). Despite the mechanisms of brain damage involved in GA1 are not fully understood, oxidative stress may be involved in this process. Treatment is based on protein/lysine (Lys) restriction and l-carnitine (L-car) supplementation. L-car was recently shown to have an important antioxidant role. A knockout mice model (Gcdh?/?) submitted to a dietary overload of Lys was developed to better understand the GA1 pathogenesis. In this study, we evaluated L-car and glutarylcarnitine levels, the lipid and protein damage, reactive oxygen species (ROS) production and antioxidant enzymes activities in striatum of Gcdh?/? and wild-type (WT) mice. We also determined the effect of the L-car treatment on these parameters. Thirty-day-old Gcdh?/? and WT mice were fed a normal chow (0.9% Lys) or submitted to a high Lys diet (4.7%) for 72 h. Additionally, these animals were administered with three intraperitoneal injections of saline or L-car in different times. Gcdh?/? mice were deficient in L-car and presented a higher glutarylcarnitine levels. They also presented lipid and protein damage, an increased ROS production and altered antioxidant enzymes compared to WT mice. Additionally, mice exposed to Lys overload presented higher alterations in these parameters than mice under normal diet, which were significantly decreased or normalized in those receiving L-car. Thus, we demonstrated a new beneficial effect of the L-car treatment attenuating or abolishing the oxidative stress process in Gcdh?/? mice. 相似文献
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Gaurav Agrahari Shyam Kishor Sah Min Jung Lee Chul Hwan Bang Yeong Ho Kim Hey-Young Kim Tae-Yoon Kim 《Biochemistry and Biophysics Reports》2022
Immunoglobulin E (IgE) functions as a first-line defense against parasitic infections. However, aberrant production of IgE is known to be associated with various life-threatening allergic diseases. Superoxide dismutase 3 (SOD3) has been found to suppress IgE in various allergic diseases such as allergic conjunctivitis, ovalbumin-induced allergic asthma, and dust mite-induced atopic dermatitis-like skin inflammation. However, the role of SOD3 in the regulation of IgE production in B cells remains elusive. In this study, we investigated the effect of SOD3 on LPS/IL-4 and anti-CD40/IL-4-mediated secretion of IgE in murine B cells. Our data showed that SOD3 can suppress both LPS/IL-4 and antiCD40/IL-7-induced IgE secretion in B cells isolated from both wild-type (SOD3+/+) and SOD3 knock-out (SOD3?/?) mice. Interestingly, B cells isolated from SOD3?/? mice showed higher secretion of IgE, whereas, the use of DETCA, a known inhibitor of SOD3 activity, reversed the inhibitory effect of SOD3 on IgE production. Similarly, SOD3 was found to reduce the proliferation, IgE isotype switch, ROS level, and CCL17 and CCL22 productions in B cells. Furthermore, SOD3 was found to suppress both LPS/IL-4 and anti-CD40/IL-4-mediated activation of downstream signaling such as JAK1/JAK3, STAT6, NF-κB, p38, and JNK in B cells. Taken together, our data showed that SOD3 can be used as an alternative therapy to restrict IgE-mediated allergic diseases. 相似文献
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Itsaso Garcia-Arcos Sangmi S. Park Michelle Mai Roger Alvarez-Buve Lillian Chow Huchong Cai Nathalie Baumlin-Schmid Christina W. Agudelo Jennifer Martinez Michael D. Kim Abdoulaye J. Dabo Matthias Salathe Ira J. Goldberg Robert F. Foronjy 《Journal of lipid research》2022,63(4):100185
The LDL receptor-related protein 1 (LRP1) partakes in metabolic and signaling events regulated in a tissue-specific manner. The function of LRP1 in airways has not been studied. We aimed to study the function of LRP1 in smoke-induced disease. We found that bronchial epithelium of patients with chronic obstructive pulmonary disease and airway epithelium of mice exposed to smoke had increased LRP1 expression. We then knocked out LRP1 in human bronchial epithelial cells in vitro and in airway epithelial club cells in mice. In vitro, LRP1 knockdown decreased cell migration and increased transforming growth factor β activation. Tamoxifen-inducible airway-specific LRP1 knockout mice (club Lrp1?/?) induced after complete lung development had increased inflammation in the bronchoalveolar space and lung parenchyma at baseline. After 6 months of smoke exposure, club Lrp1?/? mice showed a combined restrictive and obstructive phenotype, with lower compliance, inspiratory capacity, and forced expiratory volume0.05/forced vital capacity than WT smoke-exposed mice. This was associated with increased values of Ashcroft fibrotic index. Proteomic analysis of room air exposed-club Lrp1?/? mice showed significantly decreased levels of proteins involved in cytoskeleton signaling and xenobiotic detoxification as well as decreased levels of glutathione. The proteome fingerprint created by smoke eclipsed many of the original differences, but club Lrp1?/? mice continued to have decreased lung glutathione levels and increased protein oxidative damage and airway cell proliferation. Therefore, LRP1 deficiency leads to greater lung inflammation and damage and exacerbates smoke-induced lung disease. 相似文献
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《Journal of lipid research》2022,63(11):100289
FXR regulates bile acid metabolism, and FXR null (Fxr?/?) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response pathway activated in response to endoplasmic reticulum stress. Here, we sought to determine the role of the inositol-requiring enzyme 1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr?/? mouse model. Western blotting and quantitative PCR analysis demonstrated that hepatic XBP1 and other unfolded protein response pathways were activated in 24-week-old Fxr?/? compared with 10-week-old Fxr?/? mice but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr?/? mice, we generated mice with whole-body FXR and liver-specific XBP1 double KO (DKO, Fxr?/?Xbp1LKO) and Fxr?/?Xbp1fl/fl single KO (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared with SKO mice. RNA sequencing revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein pathway and cell cycle marker cyclin D1 were also activated in DKO mice. Furthermore, we found that total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr?/? mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses. 相似文献
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Ines Marek Maurizio Canu Nada Cordasic Manfred Rauh Gudrun Volkert Fabian B. Fahlbusch Wolfgang Rascher Karl F. Hilgers Andrea Hartner Carlos Menendez-Castro 《Biology of sex differences》2017,8(1):19
Background
Apoe-deficient (Apoe ?/?) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe ?/? mice deficient in the mesenchymal integrin chain Itga8 (Itga8 ?/?). Here, we used this Apoe ?/?, Itga8 ?/? mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model.Methods
Apoe ?/? mice were backcrossed with Itga8 ?/? mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe ?/? Itga8 +/+ mice or Apoe ?/? Itga8 ?/? mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed.Results
When compared to male mice, Apoe ?/? Itga8 +/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe ?/? mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different.Conclusions
In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.11.
Hideo Tsuji Hiroko Ishii-Ohba Yuko Noda Eiko Kubo Takeshi Furuse Kouichi Tatsumi 《Mutation research》2009,660(1-2):22-32
The pathways of thymic lymphomagenesis are classified as Rag-dependent or -independent according to their dependence on recombination-activating gene (Rag1/2) proteins. The role of the two-lymphoma pathways in oncogene rearrangements and the connection between lymphoma pathways and rearrangement mechanisms, however, remain obscure. We compared the incidence and latency of thymic lymphomas, and associated rearrangements of the representative oncogene Notch1 among Rag2?/?, ataxia telangiectasia mutated (Atm)?/?, and severe combined immune deficiency (scid) mice combined with Rag2 deficiency. Contrary to expectations, Rag2?/? mice were prone to thymic lymphoma development, suggesting the existence of a Rag2-independent lymphoma pathway in Rag2?/? mice. The lymphoma incidence in Rag2?/?Atm?/? mice was lower than that in Atm?/? mice, but higher than that in Rag2?/? mice, indicating that Atm?/? mice develop lymphomas through both pathways. Scid mice developed lymphomas with an incidence and latency similar to Rag2?/?scid mice, suggesting that Rag2-mediated V(D)J recombination-driven events are not necessarily required for lymphomagenesis in scid mice. Notch1 rearrangement mechanisms were classified as Rag2-dependent or Rag2-independent based on the presence of recombination signal-like sequences at rearranged sites. In Rag2?/? lymphomas, Notch1 must be rearranged independently of Rag2 function, implying that Rag2?/? mice are susceptible to lymphomagenesis due to the presence of other rearrangement mechanisms. The results in Atm?/? mice suggest that Notch1 was rearranged through both lymphoma pathways. In scid mice, the frequency of Rag2-mediated rearrangements was relatively low compared with that in wild-type mice, suggesting that the Rag2-independent lymphoma pathway prevails in the development of thymic lymphomas in scid mice. Thus, two rearrangement mechanisms underlie the lymphoma pathways and constitute the mechanistic bases for lymphomagenesis, thereby providing the molecular criteria for distinguishing between Rag2-dependent and Rag2-independent lymphoma pathways. 相似文献
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Yoon-Ha Kim Abdul Latif Khan Muhammad Waqas Hee-Jeong Jeong Duk-Hwan Kim Jeong Sheop Shin Jong-Guk Kim Myung-Hun Yeon In-Jung Lee 《Journal of plant research》2014,127(4):525-532
We investigated the effects of silicon (Si) application on rice plants (Oryza sativa L.) and its responses in the regulation of jasmonic acid (JA) during wounding stress. Endogenous JA was significantly higher in wounded rice plants than in non-wounded. In contrast, Si treatment significantly reduced JA synthesis as compared to non-Si applications under wounding stress. mRNA expression of O. sativa genes showed down-regulation of lipoxygenase, allene oxide synthase 1, allene oxide synthase 2, 12-oxophytodienoate reductase 3, and allene oxide cyclase upon Si application and wounding stress as compared to non-Si-treated wounded rice plants. The physical injury-induced-oxidative stress was modulated by Si treatments, which resulted in higher catalase, peroxidase, and polyphenol oxidase activities as compared with non-Si-treated plants under wounding stress. The higher Si accumulation in rice plants also reduced the level of lipid peroxidation, which helped the rice plants to protect it from wounding stress. In conclusion, Si accumulation in rice plants mitigated the adverse effects of wounding through regulation of antioxidants and JA. 相似文献
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KCa3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress
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Shinkyu Choi Ji Aee Kim Hai‐yan Li Kyong‐Oh Shin Goo Taeg Oh Yong‐Moon Lee Seikwan Oh Yael Pewzner‐Jung Anthony H. Futerman Suk Hyo Suh 《Aging cell》2016,15(5):801-810
Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial KCa3.1, which contributes to EDR, is upregulated by H2O2. We investigated whether KCa3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H2O2 levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and KCa3.1 upregulation. Catalase/GPX1 double knockout (catalase?/?/GPX1?/?) upregulated KCa3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase?/?/GPX1?/? MAECs. However, KCa3.1 activation‐induced, NG‐nitro‐l ‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase?/?/GPX1?/? mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated KCa3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H2O2 and thereby upregulate KCa3.1 expression and function via a H2O2/Fyn‐mediated pathway. Altogether, enhanced KCa3.1 activity may compensate for decreased NO signaling during vascular aging. 相似文献
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Joost Willebrords Michaël Maes Isabel Veloso Alves Pereira Tereza Cristina da Silva Veronica Mollica Govoni Valéria Veras Lopes Sara Crespo Yanguas Valery I. Shestopalov Marina Sayuri Nogueira Inar Alves de Castro Anwar Farhood Inge Mannaerts Leo van Grunsven Jephte Akakpo Margitta Lebofsky Hartmut Jaeschke Bruno Cogliati Mathieu Vinken 《生物化学与生物物理学报:疾病的分子基础》2018,1864(3):819-830
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Shuichi Shibuya Yusuke Ozawa Kenji Watanabe Naotaka Izuo Toshihiko Toda Koutaro Yokote Takahiko Shimizu 《PloS one》2014,9(10)
Cu-Zn superoxide dismutase (Sod1) loss causes a redox imbalance as it leads to excess superoxide generation, which results in the appearance of various aging-related phenotypes, including skin atrophy. Noble metal nanoparticles, such as palladium (Pd) and platinum (Pt) nanoparticles, are considered to function as antioxidants due to their strong catalytic activity. In Japan, a mixture of Pd and Pt nanoparticles called PAPLAL has been used to treat chronic diseases over the past 60 years. In the present study, we investigated the protective effects of PAPLAL against aging-related skin pathologies in mice. Transdermal PAPLAL treatment reversed skin thinning associated with increased lipid peroxidation in Sod1
−/− mice. Furthermore, PAPLAL normalized the gene expression levels of Col1a1, Mmp2, Has2, Tnf-α, Il-6, and p53 in the skin of the Sod1
−/− mice. Pt nanoparticles exhibited marked SOD and catalase activity, while Pd nanoparticles only displayed weak SOD and catalase activity in vitro. Although the SOD and catalase activity of the Pt nanoparticles significantly declined after they had been oxidized in air, a mixture of Pd and Pt nanoparticles continued to exhibit SOD and catalase activity after oxidation. Importantly, a mixture of Pd and Pt nanoparticles with a molar ratio of 3 or 4 to 1 continued to exhibit SOD and catalase activity after oxidation, indicating that Pd nanoparticles prevent the oxidative deterioration of Pt nanoparticles. These findings indicate that PAPLAL stably suppresses intrinsic superoxide generation both in vivo and in vitro via SOD and catalase activity. PAPLAL is a potentially powerful tool for the treatment of aging-related skin diseases caused by oxidative damage. 相似文献
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Michael K. Chan Maria T. Ocampo-Hafalla Vladimir Vartanian Pawel Jaruga Güldal Kirkali Karen L. Koenig Stuart Brown R. Stephen Lloyd Miral Dizdaroglu George W. Teebor 《DNA Repair》2009,8(7):786-794
We have generated a strain of mice lacking two DNA N-glycosylases of base excision repair (BER), NTH1 and NEIL1, homologs of bacterial Nth (endonuclease three) and Nei (endonuclease eight). Although these enzymes remove several oxidized bases from DNA, they do not remove the well-known carcinogenic oxidation product of guanine: 7,8-dihydro-8-oxoguanine (8-OH-Gua), which is removed by another DNA N-glycosylase, OGG1. The Nth1?/?Neil1?/? mice developed pulmonary and hepatocellular tumors in much higher incidence than either of the single knockouts, Nth1?/? and Neil1?/?. The pulmonary tumors contained, exclusively, activating GGT → GAT transitions in codon 12 of K-ras of their DNA. Such transitions contrast sharply with the activating GGT → GTT transversions in codon 12 of K-ras of the pathologically similar pulmonary tumors, which arose in mice lacking OGG1 and a second DNA N-glycosylase, MUTY. To characterize the biochemical phenotype of the knockout mice, the content of oxidative DNA base damage was analyzed from three tissues isolated from control, single and double knockout mice. The content of 8-OH-Gua was indistinguishable among all genotypes. In contrast, the content of 4,6-diamino-5-formamidopyrimidine (FapyAde) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) derived from adenine and guanine, respectively, were increased in some but not all tissues of Neil1?/? and Neil1?/?Nth1?/? mice. The high incidence of tumors in our Nth1?/?Neil1?/? mice together with the nature of the activating mutation in the K-ras gene of their pulmonary tumors, reveal for the first time, the existence of mutagenic and carcinogenic oxidative damage to DNA which is not 8-OH-Gua. 相似文献
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Muhsin Muhsin Jesuthas Ajendra Katrin Gentil Afiat Berbudi Anna-Lena Neumann Lil Klaas Kim E. Schmidt Achim Hoerauf Marc P. Hübner 《International journal for parasitology》2018,48(12):925-935
IL-6 has a wide range of biological activities that includes anti- and pro-inflammatory aspects. In this study, we investigated the role of IL-6 in immune responses to the rodent filarial nematode Litomosoides sigmodontis, a model for human filarial infections. IL-6?/? mice had a significantly increased worm burden after natural infection compared with wild type controls at early time points p.i. Given that the worm burden in IL-6?/? mice was already increased at the time point the infective larvae reached the pleural cavity, immune responses that may facilitate the migration from the site of infection (skin) via the lymphatics to the pleural cavity were analysed. Increased vascular permeability may facilitate larval migration, but blocking of histamine receptors had no effect on worm burden and vascular permeability was similar between IL-6?/? mice and wild type controls. In contrast, blocking mast cell degranulation reduced the worm burden in IL-6?/? mice partially, suggesting that release of mast cell-derived mediators improves larval migration to some degree. Protective immune responses within the skin were involved, as bypassing the skin barrier by inoculating infective L3s subcutaneously resulted in a comparable worm recovery in both mouse strains. Analysis of the cellular composition by flow cytometry and PCR array in the skin after exposure to filarial extract or L3s, respectively, indicate that the absence of IL-6 results in a delayed recruitment of neutrophils and macrophages to the site of initial infection. These results demonstrate that IL-6 is essentially involved in protective immune responses within the skin that impair migration of infective L3s. 相似文献
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《Luminescence》2003,18(1):37-41
Ultra‐weak bio‐chemiluminescence (UBC) from germinating soybean (Glycine max L. Merr) cotyledon under mechanical wounding was observed using a high‐sensitivity imaging system based on an ICCD detector and a highly sensitive single photon counter (SPC) device. The UBC imaging showed that the intensity at the injury location on a wounded cotyledon was obviously enhanced as compared with that at the non‐injured point. The UBC intensity of wounded cotyledons was initially very high and reached a stationary state after about 5 min. Wounding‐induced emission could be suppressed by wounding in the presence of sodium azide. Deuterium oxide amplified the emission intensity. It was concluded that singlet oxygen (1O2) was the main cause of the emission during the wounding phase. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献