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181.
Scanlan PD Shanahan F Clune Y Collins JK O'Sullivan GC O'Riordan M Holmes E Wang Y Marchesi JR 《Environmental microbiology》2008,10(3):789-798
A role for the intestinal microbiota is routinely cited as a potential aetiological factor in colorectal cancer initiation and progression. As the majority of bacteria in the gut are refractory to culture we investigated this ecosystem in subjects with colorectal cancer and with adenomatous polyposis who are at high risk of developing colorectal cancer, using culture-independent methods. Twenty colorectal cancer and 20 polypectomized volunteers were chosen for this analysis. An exploration of the diversity and temporal stability of the dominant bacteria and several bacterial subgroups was undertaken using 16S rRNA gene denaturing gradient gel electrophoresis and ribosomal intergenic spacer analysis (RISA). Metabonomic analysis of the distal gut microbiota's environment was also undertaken. A significantly reduced temporal stability and increased diversity for the microbiota of subjects with colorectal cancer and polyposis was evident. A significantly increased diversity of the Clostridium leptum and C. coccoides subgroups was also noted for both disease groups. A clear division in the metabonome was observed for the colorectal cancer and polypectomized subjects compared with control volunteers. The intestinal microbiota and their metabolites are significantly altered in both colorectal cancer and polypectomized subjects compared with controls. 相似文献
182.
Sandeep S. Hothi Stephen W. Booth Ian N. Sabir Matthew J. Killeen Fergus Simpson Yanmin Zhang Andrew A. Grace Christopher L.-H. Huang 《Progress in biophysics and molecular biology》2008,98(2-3):267
The gain-of-function Scn5a+/ΔKPQ mutation in the cardiac Na+ channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The KATP channel-opener nicorandil (20 μM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Δ hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD90) that (2) restored transmural repolarization gradients, ΔAPD90. Scn5a+/Δ hearts showed longer epicardial but not endocardial APD90s, giving shorter ΔAPD90s than WT hearts. Nicorandil reduced epicardial APD90 in both Scn5a+/Δ and WT hearts thereby increasing ΔAPD90. (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Δ hearts showed greater differences between APD90 and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD90 alternans. Scn5a+/Δ hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Δ hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Δ hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Δ and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Δ and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil. 相似文献
183.
Jerzy A. Woznicki Nisha Saini Peter Flood Subhasree Rajaram Ciaran M. Lee Panagiota Stamou Agnieszka Skowyra Milan Bustamante-Garrido Karine Regazzoni Nyree Crawford Simon S. McDade Daniel B. Longley Pedro Aza-Blanc Fergus Shanahan Syed A. Zulquernain Jane McCarthy Silvia Melgar Bradford L. McRae Ken Nally 《Cell death & disease》2021,12(10)
Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). Th1-type cytokines—IFN-γ and TNF-α—occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs.Subject terms: Necroptosis, Cell death and immune response, Interferons, Tumour-necrosis factors, Crohn''s disease 相似文献
184.
McKenzie RC Beckett GJ McLean S Arthur JR Macve JC Nicol F Howie AF Norval M 《Biological trace element research》2008,125(3):255-267
The effect of three different doses of dietary l-selenomethionine (SM) and sodium selenite (SS) on skin selenium (Se) content, glutathione peroxidase (GPx) activity, Langerhans
cell (LC) and mast cell numbers in ultraviolet radiation-B (UVB)-irradiated and unirradiated C3H/HeN mice was determined.
After weaning, groups of mice were given Se-deficient, Se-adequate, or Se-high diets. Six weeks later, some animals in each
group were exposed to a single UVB dose (acute), while others were exposed three times weekly for the following 40 weeks (chronic).
The skin Se content and GPx activity increased in all the Se-supplemented groups, and the latter was not altered by UVB exposure.
Generally, the Se-containing diets caused an increase in LC numbers at 6 weeks and a further rise at 40 weeks, but did not
prevent the loss induced by acute or chronic UVB radiation. Skin mast cell numbers were highest in animals fed the Se-deficient
diet after 6 and 40 weeks. Acute and chronic UVB radiation decreased the mast cell number and dietary Se did not prevent the
reduction. While the present study shows that Se plays an important role in governing the number of LCs and mast cells in
the skin, no protective effect against the immunomodulating properties of UVB radiation on these cell types was observed.
However, this conclusion may only apply to the experimental conditions chosen, and additional studies at different Se dosages
and reduced intensities of chronic UVB exposure are required to confirm the results. 相似文献
185.
The molecular action of the novel insecticide, Pyridalyl 总被引:1,自引:0,他引:1
Powell GF Ward DA Prescott MC Spiller DG White MR Turner PC Earley FG Phillips J Rees HH 《Insect biochemistry and molecular biology》2011,41(7):459-469
Pyridalyl is a recently discovered insecticide that exhibits high insecticidal activity against Lepidoptera and Thysanoptera. Pyridalyl action requires cytochrome P450 activity, possibly for production of a bioactive derivative, Pyridalyl metabolism being prevented by general P450 inhibitors. Apoptosis is apparently not involved in the cytotoxicity. Continuous culture of Spodoptera frugiperda Sf21 cells in sub-lethal doses of Pyridalyl, results in a Pyridalyl-resistant cell line. Probing the molecular action of Pyridalyl by comparison of the proteomes of Pyridalyl-resistant and -susceptible cell lines, revealed differential expression of a number of proteins, including the up-regulation of thiol peroxiredoxin (TPx), in the resistant cells. Treatment of Bombyx mori larvae with Pyridalyl, followed by comparison of the midgut microsomal sub-proteome, revealed the up-regulation of three proteasome subunits. Such subunits, together with Hsp70 stress proteins, glyceraldehyde 3-phosphate dehydrogenases (GAPDHs) and thiol peroxiredoxin (TPx) were also up-regulated in the whole proteome of B. mori BM36 cells following treatment with the insecticide. The foregoing results lead to the hypothesis that cytochrome P450 action leads to an active Pyridalyl metabolite, which results in production of reactive oxygen species (ROS), that leads to damage to cellular macromolecules (e.g., proteins) and enhanced proteasome activity leads to increased protein degradation and necrotic cell death. 相似文献
186.
187.
188.
Seventy strains of Bacillus thuringiensis representing 21 serovars were allocated to 38 genomic groups using pulsed field gel electrophoresis (PFGE) of restriction enzyme-digested DNA. There was a broad correlation between PFGE type and serotype for serovars darmstadiensis, israelensis, kenyae, kumamotoensis, kurstaki, sotto, thuringiensis, and tolworthi, although some serovars included atypical strains. Serovars canadensis and entomocidus were heterogeneous. Detection of crystal protein genes by polymerase chain reaction indicated an approximate correlation between PFGE type and cry gene complement. For example, cry1 products were amplified from DNA from PFGE type 17 strains of serovar aizawai and from PFGE type 23 strains of serovar tolworthi but not from a PFGE 18 strain of aizawai nor from a PFGE type 24 strain of tolworthi. These data suggest a clonal population structure to B. thuringiensis with some consistency of Cry-plasmid composition within PFGE types. 相似文献
189.
Ohashi A Zdzienicka MZ Chen J Couch FJ 《The Journal of biological chemistry》2005,280(15):14877-14883
The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2.FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination. 相似文献
190.
The role of substance P in inflammatory disease 总被引:26,自引:0,他引:26
O'Connor TM O'Connell J O'Brien DI Goode T Bredin CP Shanahan F 《Journal of cellular physiology》2004,201(2):167-180
The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin-1 receptor (NK-1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK-1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus-associated respiratory infection, non-productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK-1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK-1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK-1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease. 相似文献