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Confers Resistance (confer + resistance)
Kinds of Confers Resistance Selected AbstractsMethylenedisalicylic Acid Derivatives: New PTP1B Inhibitors that Confer Resistance to Diet-Induced Obesity.CHEMINFORM, Issue 36 2007Suja Shrestha Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Glutamate Fermentation By-product Activates Plant Defence Responses and Confers Resistance Against Pathogen InfectionJOURNAL OF PHYTOPATHOLOGY, Issue 10 2010Daisuke Igarashi Abstract In the food industry, glutamate fermentation by-product (GFB) is generated by purifying glutamate products from microbial fermentation. The potential applications of GFB for upgrading agricultural soil, for foliar fertility, and as plant plankton for shrimp have been studied. We examined the efficacy of GFB foliar application and determined that GFB treatment increased the resistance of Arabidopsis leaves to infection by bacterial pathogens. Microarray gene expression analysis of Arabidopsis leaves after treatment with GFB indicated that the expression of plant defence-related genes increased. In Corynebacterium fermentation, the active substances for induction of the defence response were extracted or solubilized after treatment with heating under acidic conditions. This extract was also effective in strawberry and grape leaves for the induction of hydrogen peroxide production. These findings suggest that foliar application of GFB that contains elicitor molecules derived from fermentation bacteria is useful for plant protection in agricultural fields. [source] Characterization of cecal gene expression in a differentially susceptible mouse model of bacterial-induced inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 7 2007Matthew H. Myles DVM Abstract Background: A/JCr mice develop typhlitis in response to Helicobacter hepaticus infection, whereas C57BL/6 mice coexist with this bacterium in a "commensal" relationship and do not develop disease even during prolonged colonization. Methods: To determine mechanisms that control this balance between responsiveness and nonresponsiveness, the mucosal response of A/JCr and C57BL/6 mice to acute H. hepaticus colonization was evaluated using genome-wide profiling. Transcription levels for a subset of gene discoveries were then evaluated longitudinally by semiquantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) to identify changes in gene expression that occur during progression from the acute to chronic phase of colonization. To determine whether chronic mucosal inflammation in A/JCr mice was mediated through a Th1 mechanism, as was inferred from the gene expression data, mice with typhlitis were treated with neutralizing antibody targeting IL-12/23p40 or IFN-gamma and the response to treatment was determined by cecal lesion severity and transcription of disease-related genes. Results: A/JCr mice had a biphasic expression of proinflammatory genes that corresponded with the acute and chronic phases of disease. In contrast, C57BL/6 mice exhibited a less robust acute transcriptional response that waned by day 30 postinoculation. Sustained upregulation of proinflammatory signals and responsiveness to anti-IL-12/23p40 and anti-IFN-, antibody suggests that inflammation in A/JCr mice was mediated through a Th1 mechanism. Prolonged upregulation of SOCS3 during the acute response to colonization suggests that C57BL/6 mice maintain mucosal homeostasis, at least in part by attenuating responsiveness to cytokine signaling. Conclusions: Collectively, these findings provide a foundation for understanding the immunological mechanisms that confer resistance or susceptibility to H. hepaticus -induced typhlitis. (Inflamm Bowel Dis 2007) [source] Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell linesINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Piyali Dasgupta Abstract Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer (NSCLC). Nicotine, an active component of cigarettes, has been found to induce proliferation of lung cancer cell lines. In addition, nicotine can induce angiogenesis and confer resistance to apoptosis. All these events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells. In this study, we demonstrate that nicotine can promote anchorage-independent growth in NSCLCs. In addition, nicotine also induces morphological changes characteristic of a migratory, invasive phenotype in NSCLCs on collagen gel. These morphological changes were similar to those induced by the promigratory growth factor VEGF. The proinvasive effects of nicotine were mediated by ,7-nAChRs on NSCLCs. RT-PCR analysis showed that the ,7-nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines. Nicotine was found to promote proliferation and invasion in human breast cancer. The proinvasive effects of nicotine were mediated via a nAChR, Src and calcium-dependent signaling pathway in breast cancer cells. In a similar fashion, nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells. Most importantly, nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition (EMT), characterized by reduction of epithelial markers like E-cadherin expression, ZO-1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells. Therefore, it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers. © 2008 Wiley-Liss, Inc. [source] ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastasesINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Laurent Candeil Abstract Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo. © 2004 Wiley-Liss, Inc. [source] RNA interference-mediated knockdown of ,-synuclein protects human dopaminergic neuroblastoma cells from MPP+ toxicity and reduces dopamine transportJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2007Timothy M. Fountaine Abstract The critical observation in the pathology of Parkinson's disease (PD) is that neurodegeneration is largely restricted to dopaminergic neurons that develop cytoplasmic inclusions called Lewy bodies. These aggregations contain the protein ,-synuclein. Furthermore, it is becoming apparent that ,-synuclein expression levels are a major factor in PD pathogenesis. Patients with additional copies of the ,-synuclein gene develop PD with a severity proportional to levels of ,-synuclein overexpression. Similarly, overexpression of ,-synuclein in in vitro and in vivo models has been shown to be toxic. However, little is known about the effects of reducing ,-synuclein expression in human neurons. To investigate this, we have developed a system in which levels of ,-synuclein can be acutely suppressed by using RNA interference (RNAi) in a physiologically relevant human dopaminergic cellular model. By using small interfering RNA (siRNA) molecules targeted to endogenous ,-synuclein, we achieved 80% protein knockdown. We show that ,-synuclein knockdown has no effect on cellular survival either under normal growth conditions over 5 days or in the presence of the mitochondrial inhibitor rotenone. Knockdown does, however, confer resistance to the dopamine transporter (DAT)-dependent neurotoxin N-methyl-4-phenylpyridinium (MPP+). We then demonstrate for the first time that ,-synuclein suppression decreases dopamine transport in human cells, reducing the maximal uptake velocity (Vmax) of dopamine and the surface density of its transporter by up to 50%. These results show that RNAi-mediated ,-synuclein knockdown alters cellular dopamine homeostasis in human cells and may suggest a mechanism for the increased survival in the presence of MPP+, a toxin used extensively to model Parkinson's disease. © 2006 Wiley-Liss, Inc. [source] Alcohol Inhibits the Progression as Well as the Initiation of Atherosclerotic Lesions in C57Bl/6 Hyperlipidemic MiceALCOHOLISM, Issue 9 2000Eugene E. Emeson Background: Evidence that a moderate consumption of alcohol is associated with a reduced incidence of and mortality due to coronary artery disease continues to accumulate. Despite recent evidence that substances in red wine confer resistance to coronary artery disease, it is clear that at least a substantial proportion of the protective effect is due to the alcohol content of the beverage. We have previously shown that the chronic ingestion of alcohol incorporated into a total liquid diet during a 24-week period inhibits the development of fatty streak lesions in hyperlipidemic C57Bl/6 mice. We have now repeated this study and demonstrated that alcohol continues to markedly inhibit atherogenesis during a 48-week period. Methods: Mice were fed a high fat atherogenic liquid diet with 0% or 6% alcohol or a high fat atherogenic pelleted diet with 0% or 15% alcohol in their drinking water. After 24 and 48 weeks on these diets, subgroups of mice were euthanized and the aortas were studied for extent of atherosclerosis. Plasma lipid levels were also measured and flow cytometry studies performed to characterize their T and B lymphocyte populations. Additional groups of mice were given the high fat atherogenic diets for 24 weeks to allow lesions to develop and were then treated with alcohol diets to determine whether they inhibit the progression of the lesions. Results: The alcohol diets suppressed the development of atherosclerotic lesions at both 24 and 48 weeks in both the liquid and pelleted diet models. The addition of the alcohol diets after allowing lesions to form for 24 weeks halted the further progression of the lesions. The alcohol treatments also decreased the plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol at almost all time intervals. Conclusions: We conclude that alcohol not only inhibits the initial development of atherosclerotic lesions but also inhibits the progression of existing atherosclerotic lesions. The alcohol-mediated decrease in HDL cholesterol in these experiments suggests that HDL plays little or no role in amelioration of atherogenesis in this model. [source] Differences in immune parameters are associated with resistance to Haemonchus contortus in Caribbean hair sheepPARASITE IMMUNOLOGY, Issue 7 2010K. M. MacKINNON Summary Caribbean hair sheep are more resistant to gastrointestinal nematodes than conventional wool breeds, but mechanisms that confer resistance are not fully understood. This study compared immune effector cell populations and antibody concentrations in 12 hair and 12 wool lambs infected with the abomasal parasite Haemonchus contortus and sacrificed at 3 or 27 days post-infection (p.i.) and 14 uninfected animals of each breed. Faecal egg counts were over 2·5-fold higher (P = 0·12) and packed cell volumes approximately 8% lower (P < 0·10) in infected wool lambs. Abomasal lymph nodes were heavier in infected animals (P < 0·05) and infected hair sheep had larger lymph nodes than infected wool sheep (P < 0·05). Tissue eosinophil concentrations were likewise larger (P = 0·07) in hair compared with wool sheep at 3 days p.i. Circulating levels of IgE and IgA in uninfected lambs were higher in hair sheep (P < 0·05) and during infection, hair sheep had higher serum IgA than wool sheep at 3, 5, and 21 days p.i. (P < 0·05). Serum IgE in infected lambs did not differ between breeds, but concentrations of IgE in lymph nodes were higher (P < 0·01) at 27 days p.i. in infected hair sheep. [source] The Arabidopsis her1 mutant implicates GABA in E -2-hexenal responsivenessTHE PLANT JOURNAL, Issue 2 2008Rossana Mirabella Summary When wounded or attacked by herbivores or pathogens, plants produce a blend of six-carbon alcohols, aldehydes and esters, known as C6-volatiles. Undamaged plants, when exposed to C6-volatiles, respond by inducing defense-related genes and secondary metabolites, suggesting that C6-volatiles can act as signaling molecules regulating plant defense responses. However, to date, the molecular mechanisms by which plants perceive and respond to these volatiles are unknown. To elucidate such mechanisms, we decided to isolate Arabidopsis thaliana mutants in which responses to C6-volatiles were altered. We observed that treatment of Arabidopsis seedlings with the C6-volatile E -2-hexenal inhibits root elongation. Among C6-volatiles this response is specific to E -2-hexenal, and is not dependent on ethylene, jasmonic and salicylic acid. Using this bioassay, we isolated 18 E -2-hexenal-response (her) mutants that showed sustained root growth after E -2-hexenal treatment. Here, we focused on the molecular characterization of one of these mutants, her1. Microarray and map-based cloning revealed that her1 encodes a ,-amino butyric acid transaminase (GABA-TP), an enzyme that degrades GABA. As a consequence of the mutation, her1 plants accumulate high GABA levels in all their organs. Based on the observation that E -2-hexenal treatment induces GABA accumulation, and that high GABA levels confer resistance to E -2-hexenal, we propose a role for GABA in mediating E -2-hexenal responses. [source] Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugsCANCER SCIENCE, Issue 9 2009Satoshi Mizutani The majority of cancer cells harbor homoplasmic somatic mutations in the mitochondrial genome. We show here that mutations in mitochondrial DNA (mtDNA) are responsible for anticancer drug tolerance. We constructed several trans -mitochondrial hybrids (cybrids) with mtDNA derived from human pancreas cancer cell lines CFPAC-1 and CAPAN-2 as well as from healthy individuals. These cybrids contained the different mitochondrial genomes with the common nuclear background. We compared the mutant and wild-type cybrids for resistance against an apoptosis-inducing reagent and anticancer drugs by exposing the cybrids to staurosporine, 5-fluorouracil, and cisplatin in vitro, and found that all mutant cybrids were more resistant to the apoptosis-inducing and anticancer drugs than wild-type cybrids. Next, we transplanted mutant and wild-type cybrids into nude mice to generate tumors. Tumors derived from mutant cybrids were more resistant than those from wild-type cybrids in suppressing tumor growth and inducing massive apoptosis when 5-fluorouracil and cisplatin were administered. To confirm the tolerance of mutant cybrids to anticancer drugs, we transplanted a mixture of mutant and wild-type cybrids at a 1:1 ratio into nude mice and examined the effect by the drugs on the drift of the ratio of mutant and wild-type mtDNA. The mutant mtDNA showed better survival, indicating that mutant cybrids were more resistant to the anticancer drugs. Thus, we propose that mutations in the mitochondrial genome are potential targets for prognosis in the administration of anticancer drugs to cancer patients. (Cancer Sci 2009; 100: 1680,1687) [source] Multidrug resistance-associated proteins and implications in drug developmentCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2010Ya-He Liu Summary 1.,The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood,brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2.,Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C4. Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3.,Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4.,Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5.,A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug,drug interactions, as well as help overcome drug resistance. [source] Interleukin-10 is associated with resistance to febrile seizures: Genetic association and experimental animal studiesEPILEPSIA, Issue 4 2009Yoshito Ishizaki Summary Purpose:, Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) ,, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls. Methods:, The promoter SNPs of four inflammatory cytokine genes (IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs (IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models. Results:, The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10,administered rats was significantly higher than that in the saline-treated control ones (p = 0.027). Conclusions:, The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1,, confers resistance to FS. [source] Inhibitory effects of gallic acid ester derivatives on Saccharomyces cerevisiae multidrug resistance protein Pdr5pFEMS YEAST RESEARCH, Issue 3 2010Luciana Pereira Rangel Abstract Overexpression of the Saccharomyces cerevisiae ABC transporter Pdr5p confers resistance to a range of structurally unrelated xenobiotics. This property allows Pdr5p to be used as a target for novel multidrug resistance reversal reagents or chemosensitizers. Herein, we report the effects of gallic acid derivatives with substitutions either on the ester moiety or in the benzene ring on the activity of Pdr5p. Compounds with a longer side chain (8,16 carbons) resulted in greater inhibition of Pdr5p ATPase. Derivatives with side chains of 8,12 carbons that retained hydroxyl groups on the benzene ring extensively inhibited Pdr5p ATPase activity. These compounds almost completely inhibited the efflux of the Pdr5p fluorescent substrate Rhodamine 6G and at 25 ,M chemosensitized the Pdr5p-overexpressing strain AD124567 to fluconazole (0.4 mg mL,1). Gallic acid derivatives may be a new class of Pdr5p inhibitors. [source] Upregulated claudin-1 expression confers resistance to cell death of nasopharyngeal carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2010Jeng-Woei Lee Abstract Accumulating evidence reveals that aberrant expression of claudins manifests in various tumors; however, their biological functions are poorly understood. Here, we report on the elevated expression of claudin-1 in nasopharyngeal carcinoma (NPC) cell lines under serum deprivation or fluorouracil (5-FU) treatment. Interestingly, an increase in expression of claudin-1 considerably reduced apoptosis rather than enhancing cell proliferation. However, claudin-1 expression and activity were unaffected by external stimuli or Akt and NF-,B activation. Notably, predominant cytoplasmic and nuclear localization of claudin-1 in NPC cells reflected the aforementioned feature. On the other hand, loss of epithelial morphology and E-cadherin expression was associated with serum withdrawal in NPC cells. Interestingly, restoration of E-cadherin inhibited the protein elevation and antiapoptotic activity of claudin-1. In conclusion, our data demonstrate the regulation and novel biological function of claudin-1 and indicate the important role of claudin-1 in NPC tumorigenesis. [source] Antisense oligodeoxynucleotide therapy targeting clusterin gene for prostate cancer: Vancouver experience from discovery to clinicINTERNATIONAL JOURNAL OF UROLOGY, Issue 9 2005HIDEAKI MIYAKE Abstract Background The objective of this study was to review our experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy for prostate cancer targeting antiapoptotic gene, clusterin. Methods We initially summarized our data demonstrating that clusterin could be an optimal therapeutic target for prostate cancer, then presented the process of developing AS ODN therapy using several preclinical animal models. Finally, the preliminary data of the recently completed phase I clinical trial using AS clusterin ODN as well as the future prospects of this therapy are discussed. Results Expression of clusterin was highly up-regulated after androgen withdrawal and during progression to androgen-independence, but low or absent in untreated tissues in both prostate cancer animal model systems and human clinical specimens. Introduction of the clusterin gene into human prostate cancer cells confers resistance to several therapeutic stimuli, including androgen ablation, chemotherapy and radiation. AS ODN targeting the translation initiation site of the clusterin gene markedly inhibited clusterin expression in prostate cancer cells in a dose-dependent and sequence-specific manner. Systemic treatment with AS clusterin ODN enhanced the effects of several conventional therapies through the effective induction of apoptosis in prostate cancer xenograft models. Based on these findings, a phase I clinical trial was completed using AS clusterin ODN incorporating 2,-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), showing up to 90% suppression of clusterin in prostate cancer. Conclusions The data described above identified clusterin as an antiapoptotic gene up-regulated in an adaptive cell survival manner following various cell death triggers that helps confer a phenotype resistant to therapeutic stimuli. Inhibition of clusterin expression using AS ODN technology enhances apoptosis induced by several conventional treatments, resulting in the delay of AI progression and improved survival. Clinical trials using AS ODN confirm potent suppression of clusterin expression and phase II studies will begin in early 2005. [source] The pentose-phosphate pathway in neuronal survival against nitrosative stressIUBMB LIFE, Issue 1 2010Juan P. Bolaños Abstract Neurons are thought to be particularly vulnerable cells against reactive oxygen and nitrogen species (RONS) damage (nitrosative stress), due in part to their weak antioxidant defense and low ability to compensate energy homeostasis. Intriguingly, nitrosative stress efficiently stimulates the rate of the antioxidant pentose-phosphate pathway (PPP), which generates NADPH a necessary cofactor for the reduction of glutathione disulfide. In fact, inhibition of PPP sensitizes cultured neurons to glutathione oxidation and apoptotic death, whereas its stimulation confers resistance to nitrosative stress. Furthermore, we recently described that neurons can preferentially use glucose through the PPP by inhibiting glycolysis, which is achieved by continuously degrading the glycolytic positive-effector protein, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3) by the action of the E3 ubiquitine ligase anaphase-promoting complex/cyclosome (APC/C)Cdh1. These results suggest that the antioxidant fragility of neurons may be compensated by the PPP at the expense of inhibiting bioenergetic glycolysis. © 2009 IUBMB IUBMB Life, 62(1):14,18, 2010 [source] Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Tilman D. Rachner Abstract Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-,B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-231 cells. In both cells, OPG mRNA levels and protein secretion were dose- and time-dependently enhanced by interleukin (IL)-1, and suppressed by dexamethasone. In contrast to MCF-7 cells, MDA-MB-231 abundantly expressed TRAIL mRNA, which was enhanced by IL-1, and inhibited by dexamethasone. TRAIL activated pro-apoptotic caspase-3, -7, and poly-ADP-ribose polymerase and decreased cell numbers of MDA-MB-231, but had no effect on MCF-7 cells. Gene silencing siRNA directed against OPG resulted in a 31% higher apoptotic rate compared to non-target siRNA-treated MDA-MB-231 cells. Furthermore, TRAIL induced significantly less apoptosis in cells cultured in conditioned media (containing OPG) compared to cells exposed to TRAIL in fresh medium lacking OPG (P,<,0.01) and these protective effects were reversed by blocking OPG with its specific ligand RANKL (P,<,0.05). The association between cancer cell survival and OPG production by MDA-MB-231 cells was further supported by the finding, that modulation of OPG secretion using IL-1, or dexamethasone prior to TRAIL exposure resulted in decreased and increased rate of apoptosis, respectively (P,<,0.05). Thus, OPG secretion by breast cancer cells is modulated by cytokines and dexamethasone, and may represent a critical resistance mechanism that protects against TRAIL-induced apoptosis. J. Cell. Biochem. 108: 106,116, 2009. © 2009 Wiley-Liss, Inc. [source] Inhibition of constitutive activity of nuclear transcription factor kappaB sensitizes doxorubicin-resistant cells to apoptosisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2009Charitha Gangadharan Abstract Doxorubicin is one of the most effective agents used in the treatment of various tumors. Its use is restricted by the development of resistance to apoptosis, the mechanism of which is not fully understood. Nuclear transcription factor kappaB (NF-,B) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered as an important target for anticancer drug development. We found that in wild type and Dox-revertant MCF-7 cells, Doxorubicin induced NF-,B was transient and Dox-resistant cells showed high basal activity of NF-,B and expression of genes dependent on it. Moreover, in resistant cells Doxorubicin was unable to induce apoptosis as detected by assays for reactive oxygen intermediates generation, lipid peroxidation, cytotoxicity, PARP degradation and Bcl-2 expression. High basal expressions of multi-drug resistant protein and transglutaminase were found in Dox-resistant cells and inhibition of NF-,B decreased those amounts and also sensitized these cells by Doxorubicin. These observations collectively suggest that high NF-,B activity confers resistance to Doxorubicin and its inhibition potentiates apoptosis. This study indicates that NF-,B plays an important role in chemoresistance and establishes the fact that inhibition of NF-,B will be a novel approach in chemotherapy. J. Cell. Biochem. 107: 203,213, 2009. © 2009 Wiley-Liss, Inc. [source] Elevated expression of TMEM205, a hypothetical membrane protein, is associated with cisplatin resistanceJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Ding-Wu Shen Development of cisplatin resistance in cancer cells appears to be a consequence of multiple epigenetic alterations in genes involved in DNA damage repair, proto-oncogenes, apoptosis, transporters, transcription factors, etc. In this study, we found that expression of the hypothetical transmembrane protein TMEM205 (previously known as MBC3205) is associated with cisplatin resistance. TMEM205 was first detected by functional cloning from a retroviral cDNA library made from human cisplatin-resistant (CP-r) cells. TMEM205 is predicted to be a transmembrane protein, but its expression, localization, and function have not previously been investigated. A polyclonal antibody directed to the TMEM205 protein was raised in our laboratory. Using this antibody, it was demonstrated that this protein is located at the cell surface. Its expression is increased in our cisplatin-selected CP-r cell lines, as demonstrated by immunoblotting, confocal examination, and immuno-electron microscopy. Stable transfection of the TMEM205 gene confers resistance to cisplatin by approximately 2.5-fold. Uptake assays with Alexa Fluor-cisplatin showed reduced accumulation in CP-r KB-CP.3 and KB-CP.5 cells, and in TMEM205-transfected cells. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver, pancreas, and adrenal glands. These results indicate that a novel mechanism for cisplatin resistance is mediated by TMEM205, and also suggest that overexpression of TMEM205 in CP-r cells may be valuable as a biomarker or target in cancer chemotherapy. J. Cell. Physiol. 225: 822,828, 2010. © 2010 Wiley-Liss, Inc. [source] Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environmentAGING CELL, Issue 2 2009Nica M. Borradaile Summary Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease. [source] Escherichia coli outer membrane protease OmpT confers resistance to urinary cationic peptidesMICROBIOLOGY AND IMMUNOLOGY, Issue 8 2010Chang-Ye Hui ABSTRACT Escherichia coli OmpT, located in the outer membrane, has been characterized as a plasminogen activator, with the ability to hydrolyze protamine and block its entry. In this investigation, a complex of low molecular weight cationic peptides purified from human urine by a combination of membrane ultrafiltration and weak cation exchange chromatography was characterized. The impact of OmpT on E. coli resistance to urinary cationic peptides was investigated by testing ompT knockout strains. The ompT mutants were more susceptible to urinary cationic peptides than ompT+ strains, and this difference was abolished by complementation of the mutants with pUC19 carrying the ompT gene. The urinary protease inhibitor ulinastatin greatly decreased the resistance of the ompT+ strains. Overall, the data indicate that OmpT may help E. coli persist longer in the urinary tract by enabling it to resist the antimicrobial activity of urinary cationic peptides. [source] The MprF protein is required for lysinylation of phospholipids in listerial membranes and confers resistance to cationic antimicrobial peptides (CAMPs) on Listeria monocytogenesMOLECULAR MICROBIOLOGY, Issue 5 2006Kathrin Thedieck Summary Pathogenic bacteria have to cope with defence mechanisms mediated by adaptive and innate immunity of the host cells. Cationic antimicrobial peptides (CAMPs) represent one of the most effective components of the host innate immune response. Here we establish the function of Lmo1695, a member of the VirR-dependent virulence regulon, recently identified in Listeria monocytogenes. Lmo1695 encodes a membrane protein of 98 kDa with strong homology to the multiple peptide resistance factor (MprF) of Staphylococcus aureus. Like staphylococcal MprF, we found that Lmo1695 is involved in the synthesis of the membrane phospholipid lysylphosphatidylglycerol (L-PG). In addition, Lmo1695 is also essential for lysinylation of diphosphatidylglycerol (DPG), another phospholipid widely distributed in bacterial membranes. A ,lmo1695 mutant lacking the lysinylated phospholipids was particularly susceptible to CAMPs of human and bacterial origin. The mutant strain infected both epithelial cells and macrophages only poorly and was attenuated for virulence when tested in a mouse model of infection. Lmo1695 is a member of a growing list of survival factors which enable growth of L. monocytogenes in different environments. [source] Characterization of TetD as a transcriptional activator of a subset of genes of the Escherichia coli SoxS/MarA/Rob regulonMOLECULAR MICROBIOLOGY, Issue 4 2005Kevin L. Griffith Summary In Escherichia coli, SoxS, MarA and Rob form a closely related subset of the AraC/XylS family of positive regulators, sharing ,42% amino acid sequence identity over the length of SoxS and the ability to activate transcription of a common set of target genes that provide resistance to redox-cycling compounds and antibiotics. On the basis of its ,43% amino acid sequence identity with SoxS, MarA and Rob, TetD, encoded by transposon Tn10, appears to be a fourth member of the subset. However, although its expression has been shown to be negatively regulated by TetC and not inducible by tetracycline, the physiological function of TetD is unknown. Accordingly, in the work presented here, we initiate a molecular characterization of TetD. We show that expression of TetD activates transcription of a subset of the SoxS/MarA/Rob regulon genes and confers resistance to redox-cycling compounds and antibiotics. We show that mutations in the putative TetD binding site of a TetD-activatable promoter and a mutation in the protein's N-terminal DNA recognition helix interfere with transcription activation, thereby indicating that TetD directly activates target gene transcription. Finally, we show that TetD, like SoxS and MarA, is intrinsically unstable; however, unlike SoxS and MarA, TetD is not degraded by Lon or any of the cell's known cytoplasmic ATP-dependent proteases. Thus, we conclude that TetD is a bona fide member of the SoxS/MarA/Rob subfamily of positive regulators. [source] Possible role of the adhesin ace and collagen adherence in conveying resistance to disinfectants on Enterococcus faecalisMOLECULAR ORAL MICROBIOLOGY, Issue 6 2008G. Kayaoglu Introduction:, This study aimed to evaluate whether the presence of the ace gene and Ace-mediated binding to collagen confers on Enterococcus faecalis resistance against common endodontic disinfectants. Methods:, Isogenic strains of E. faecalis: OG1RF (wild-type) and TX5256 (ace insertion mutant of OG1RF) were grown in brain,heart infusion broth at 46°C overnight. Standardized bacterial suspensions were pretreated for 1 h either with acid-soluble collagen or acidified phosphate-buffered saline (ac-PBS). Bacteria were challenged with chlorhexidine digluconate (CHX), iodine potassium-iodide (IKI), sodium hypochlorite (NaOCl), and calcium hydroxide [Ca(OH)2]. Samples were removed at 1, 3, and 6 h, and cultured on Todd,Hewitt agar plates. Colonies were counted, the absolute values were log transformed, and the data were statistically analyzed using Fisher's least significant differences test and t -test. Results:, OG1RF was more resistant than TX5256 to IKI, NaOCl, and Ca(OH)2 (P < 0.05). Collagen-exposed OG1RF was more resistant than the ac-PBS-pretreated OG1RF against CHX at 3 h and against IKI at 1 h (P < 0.05); no significant difference was found against NaOCl. As expected, the ace mutant strain, TX5256, pretreated with collagen or ac-PBS did not differ significantly in viability when challenged with CHX, IKI, and NaOCl. An unexpected result was found for Ca(OH)2: collagen-pretreated OG1RF and TX5256 were both more susceptible than ac-PBS-pretreated OG1RF and TX5256, respectively (P < 0.05). Conclusion:, The presence of the ace gene confers resistance against IKI, NaOCl, and Ca(OH)2 on E. faecalis. Exposure to collagen makes the wild-type bacterium more resistant against CHX and IKI; however, exposure to collagen apparently decreases resistance to Ca(OH)2. [source] Salicylic acid confers resistance to a biotrophic rust pathogen, Puccinia substriata, in pearl millet (Pennisetum glaucum)MOLECULAR PLANT PATHOLOGY, Issue 2 2009BRIDGET G. CRAMPTON SUMMARY Studies were undertaken to assess the induction of defence response pathways in pearl millet (Pennisetum glaucum) in response to infection with the leaf rust fungus Puccinia substriata. Pretreatment of pearl millet with salicylic acid (SA) conferred resistance to a virulent isolate of the rust fungus, whereas methyl jasmonate (MeJA) did not significantly reduce infection levels. These results suggest that the SA defence pathway is involved in rust resistance. In order to identify pearl millet genes that are specifically regulated in response to SA and not MeJA, and thus could play a role in resistance to P. substriata, gene expression profiling was performed. Substantial overlap in gene expression responses between the treatments was observed, with MeJA and SA treatments exhibiting 17% co-regulated transcripts. However, 34% of transcripts were differentially expressed in response to SA treatment, but not in response to MeJA treatment. SA-responsive transcripts represented genes involved in SA metabolism, defence response, signal transduction, protection from oxidative stress and photosynthesis. The expression profiles of pearl millet plants after treatment with SA or MeJA were more similar to one another than to the response during a compatible infection with P. substriata. However, some SA-responsive genes were repressed during P. substriata infection, indicating possible manipulation of host responses by the pathogen. [source] Negative native,exotic diversity relationship in oak savannas explained by human influence and climateOIKOS, Issue 9 2009Patrick L. Lilley Recent research has proposed a scale-dependence to relationships between native diversity and exotic invasions. At fine spatial scales, native,exotic richness relationships should be negative as higher native richness confers resistance to invasion. At broad scales, relationships should be positive if natives and exotics respond similarly to extrinsic factors. Yet few studies have examined both native and exotic richness patterns across gradients of human influence, where impacts could affect native and exotic species differently. We examined native,exotic richness relationships and extrinsic drivers of plant species richness and distributions across an urban development gradient in remnant oak savanna patches. In sharp contrast to most reported results, we found a negative relationship at the regional scale, and no relationship at the local scale. The negative regional-scale relationship was best explained by extrinsic factors, surrounding road density and climate, affecting natives and exotics in opposite ways, rather than a direct effect of native on exotic richness, or vice versa. Models of individual species distributions also support the result that road density and climate have largely opposite effects on native and exotic species, although simple life history traits (life form, dispersal mode) do not predict which habitat characteristics are important for particular species. Roads likely influence distributions and species richness by increasing both exotic propagule pressure and disturbance to native species. Climate may partially explain the negative relationship due to differing climatic preferences within the native and exotic species pools. As gradients of human influence are increasingly common, negative broad-scale native,exotic richness relationships may be frequent in such landscapes. [source] Validation of a real-time PCR for the quantitative estimation of a G143A mutation in the cytochrome bc1 gene of Pyrenophora teresPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 3 2007Arash Kianianmomeni Abstract A single nucleotide polymorphism (SNP) in the cytochrome b gene confers resistance to strobilurin fungicides for several fungal pathogens. Therefore, on the basis of a change at amino acid position 143 from glycine to alanine, a real-time PCR assay was established for the quantitative detection of the analogous SNP in the cytochrome b sequence of Pyrenophora teres Drechsler, which causes barley net blotch. Allelic discrimination was achieved by using allele specific primers with artificially mismatched nucleic acid bases and minor groove binding probes. Validation parameters for the lower limits of the working range, namely limits of detection (LOD) and limits of quantification (LOQ), were statistically determined by the variance of calibration data, as well as by the variance of the 100% non-strobilurin-resistant allele DNA sample (blank values). It was found that the detection was limited by the variance of blank values (five in 801 458 copies; 0.0006%), whereas the quantification was limited by the variance of calibration data (37 in 801 458 copies; 0.0046%). The real-time PCR assay was finally used to monitor strobilurin-resistant cytochrome b alleles in barley net blotch field samples, which were already classified in in vivo biotests to be fully sensitive to strobilurins. All signals for strobilurin-resistant cytochrome b alleles were below the LOD, and therefore the results are in total agreement with the phenotypes revealed by biotests. Copyright © 2006 Society of Chemical Industry [source] psbA mutation (Asn266 to Thr) in Senecio vulgaris L. confers resistance to several PS II-inhibiting herbicidesPEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 9 2006Kee Woong Park Abstract DNA sequence analysis of the psbA gene encoding the D1 protein of photosystem II (PS II), the target site of PS II-inhibiting herbicides, identified a point mutation (Asn266 to Thr) in a bromoxynil-resistant Senecio vulgaris L. population collected from peppermint fields in Oregon. Although this mutation has been previously reported in Synechocystis, this is the first report of this particular point mutation in a higher plant exhibiting resistance to PS II-inhibiting herbicides. The resistant population displayed high-level resistance to bromoxynil and terbacil (R/S ratio 10.1 and 9.3, respectively) and low-level resistance to metribuzin and hexazinone (R/S ratio 4.2 and 2.6, respectively) when compared with the susceptible population. However, the population was not resistant to the triazine herbicides atrazine and simazine or to the urea herbicide diuron. A chlorophyll fluorescence assay confirmed the resistance levels and patterns of cross-resistance of the whole-plant studies. The resistant S. vulgaris plants produced fewer seeds. Differences in cross-resistance patterns to PS II-inhibiting herbicides and the difference in fitness cost could be exploited in a weed management program. Copyright © 2006 Society of Chemical Industry [source] Preferential expression of a plant cystatin at nematode feeding sites confers resistance to Meloidogyne incognita and Globodera pallidaPLANT BIOTECHNOLOGY JOURNAL, Issue 1 2004Catherine J. Lilley Summary The expression patterns of three promoters preferentially active in the roots of Arabidopsis thaliana have been investigated in transgenic potato plants in response to plant parasitic nematode infection. Promoter regions from the three genes, TUB-1, ARSK1 and RPL16A were linked to the GUS reporter gene and histochemical staining was used to localize expression in potato roots in response to infection with both the potato cyst nematode, Globodera pallida and the root-knot nematode, Meloidogyne incognita. All three promoters directed GUS expression chiefly in root tissue and were strongly up-regulated in the galls induced by feeding M. incognita. Less activity was associated with the syncytial feeding cells of the cyst nematode, although the ARSK1 promoter was highly active in the syncytia of G. pallida infecting soil grown plants. Transgenic potato lines that expressed the cystatin OcI,D86 under the control of the three promoters were evaluated for resistance against Globodera sp. in a field trial and against M. incognita in containment. Resistance to Globodera of 70 ± 4% was achieved with the best line using the ARSK1 promoter with no associated yield penalty. The highest level of partial resistance achieved against M. incognita was 67 ± 9% using the TUB-1 promoter. In both cases this was comparable to the level of resistance achieved using the constitutive cauliflower mosaic virus 35S (CaMV35S) promoter. The results establish the potential for limiting transgene expression in crop plants whilst maintaining efficacy of the nematode defence. [source] Inheritance of resistance to wheat midge, Sitodiplosis mosellana, in spring wheatPLANT BREEDING, Issue 5 2002R. I. H. McKenzie Abstract Inheritance of resistance to a wheat midge, Sitodiplosis mosellana (Géhin), was investigated in spring wheats derived from nine resistant winter wheat cultivars. F1 hybrids were obtained from crosses between resistant winter wheats and susceptible spring wheats, and used to generate doubled haploid populations. These populations segregated in a ratio of 1:1 resistant to susceptible, indicating that a single gene confers the resistance. The F2 progeny from an intercross among spring wheats derived from the nine resistance sources did not segregate for resistance. Therefore, the same gene confers resistance in all nine sources of resistance, although other genes probably affect expression because the level of resistance varied among lines. Heterozygous plants from five crosses between diverse susceptible and resistant spring wheat parents all showed intermediate levels of response, indicating that resistance is partly dominant. Susceptible plants were reliably discriminated from heterozygous or homozygous resistant ones in laboratory tests, based on the survival and development of wheat midge larvae on one or two spikes. This powerful resistance gene, designated Sm1, is simply inherited and can be incorporated readily into breeding programmes for spring or winter wheat. However, the use of this gene by itself may lead to the evolution of a virulent population, once a resistant cultivar is widely grown. [source] | |||||||||||||||||||||||||||||||