Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs) generated by ionizing radiation (IR) and anti-cancer drugs. Therefore, inhibiting the activity of ...proteins involved in this pathway is a promising way of sensitizing cancer cells to both radiotherapy and chemotherapy. In this study, we developed an assay for evaluating NHEJ activity against DSBs in chromosomal DNA in human cells to identify the chromatin modification/remodeling proteins involved in NHEJ. We showed that ablating the activity of the homologous histone acetyltransferases, CBP and p300, using inhibitors or small interfering RNAs-suppressed NHEJ. Ablation of CBP or p300 impaired IR-induced DSB repair and sensitized lung cancer cells to IR and the anti-cancer drug, etoposide, which induces DSBs that are repaired by NHEJ. The CBP/p300 proteins were recruited to sites of DSBs and their ablation suppressed acetylation of lysine 18 within histone H3, and lysines 5, 8, 12, and 16 within histone H4, at the DSB sites. This then suppressed the recruitment of KU70 and KU80, both key proteins for NHEJ, to the DSB sites. Ablation of CBP/p300 also impaired the recruitment of BRM, a catalytic subunit of the SWI/SNF complex involved in chromatin remodeling at DSB sites. These results indicate that CBP and p300 function as histone H3 and H4 acetyltransferases at DSB sites in NHEJ and facilitate chromatin relaxation. Therefore, inhibition CBP and p300 activity may sensitize cancer cells to radiotherapy and chemotherapy.
Recent advances in endoscopic techniques such as capsule endoscopy have revealed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) often cause mucosal lesions not only in the upper ...gastrointestinal tract, but also in the small intestine in humans. Gastric and duodenal lesions caused by NSAIDs can be treated with anti-secretory agents such as proton pump inhibitors or histamine H2-receptor antagonists; however, these drugs are ineffective in treating NSAID-induced lesions in the small intestine. Furthermore, there are few effective agents for the treatment of small intestinal lesions. Therefore, identification of effective therapies for the treatment of NSAID/aspirin-induced small intestinal lesions remains an urgent priority. In the present review, we focus on novel pharmacological treatments to prevent or reduce NSAID-induced intestinal lesions, i.e., 1) GI-sparing NSAIDs (NO- or H2S-NSAIDs, NSAIDs mixed with phosphatidylcholine); 2) anti-ulcer drugs such as mucosal protective agents (misoprostol, rebamipide, teprenone, etc.) and anti-secretory agents (lansoprazole, etc.); 3) antibiotics (metronidazole) and probiotics (Lactobacillus sp.); and 4) food constituents (lactoferrin and soluble dietary fibers). We surveyed data from clinical trials evaluating these novel treatments. Also reviewed herein were the pros and cons of the novel protective methods from the standpoint of safety, efficacy, convenience, and cost.
Aims/hypothesis Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical ...studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. Methods Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor κB (NF-κB) activation was assessed by reporter gene assay. Results Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokine-induced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-κB activation. We therefore examined the effect of liraglutide on TNFα-induced NF-κB activation and NF-κB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-κB activation and TNFα-induced IκB degradation. It also reduced TNFα-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-κB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. Conclusions/interpretation Liraglutide exerts an anti-inflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-κB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.
This paper describes ramp rate control of a photovoltaic (PV) generator with an electric double-layer capacitor. The capacitor absorbs rapid fluctuations of PV generation, and allows the generator to ...change its output at a limited ramp rate. The output is mainly determined by a moving average of the PV generation, but the capacitor voltage is also counted to keep the voltage at a specified value, and accordingly, to make the capacitor small. An expression for the capacitor size is derived. The feedback gain of the capacitor voltage is also examined to maintain enough energy storage in the capacitor. Some experiments are executed to demonstrate and validate the proposed method.
Emission of nitrous oxide (N2O) during biological wastewater treatment is of growing concern since N2O is a major stratospheric ozone-depleting substance and an important greenhouse gas. The emission ...of N2O from a lab-scale granular sequencing batch reactor (SBR) for partial nitrification (PN) treating synthetic wastewater without organic carbon was therefore determined in this study, because PN process is known to produce more N2O than conventional nitrification processes. The average N2O emission rate from the SBR was 0.32 ± 0.17 mg-N L−1 h−1, corresponding to the average emission of N2O of 0.8 ± 0.4% of the incoming nitrogen load (1.5 ± 0.8% of the converted NH4+). Analysis of dynamic concentration profiles during one cycle of the SBR operation demonstrated that N2O concentration in off-gas was the highest just after starting aeration whereas N2O concentration in effluent was gradually increased in the initial 40 min of the aeration period and was decreased thereafter. Isotopomer analysis was conducted to identify the main N2O production pathway in the reactor during one cycle. The hydroxylamine (NH2OH) oxidation pathway accounted for 65% of the total N2O production in the initial phase during one cycle, whereas contribution of the NO2− reduction pathway to N2O production was comparable with that of the NH2OH oxidation pathway in the latter phase. In addition, spatial distributions of bacteria and their activities in single microbial granules taken from the reactor were determined with microsensors and by in situ hybridization. Partial nitrification occurred mainly in the oxic surface layer of the granules and ammonia-oxidizing bacteria were abundant in this layer. N2O production was also found mainly in the oxic surface layer. Based on these results, although N2O was produced mainly via NH2OH oxidation pathway in the autotrophic partial nitrification reactor, N2O production mechanisms were complex and could involve multiple N2O production pathways.
•A lab-scale autotrophic SBR for partial nitrification was operated.•Average N2O emission factor was 0.8%.•NH2OH oxidation was the main N2O production pathway in initial 60 min.•AOB were abundant in the oxic surface layer of the granules.•Partial nitrification and N2O production occurred mainly in the outer 300 μm.
•Nonadherence among pediatric transplant recipients reduces graft survival.•Transient hyperuricemia is a risk factor for nonadherence after kidney transplant.•Monitoring for transient hyperuricemia ...may allow early detection of nonadherence.
Nonadherence among pediatric transplant recipients is a significant problem that reduces graft survival and leads to poor kidney graft outcomes. It is, however, extremely difficult to detect during a regular follow-up. This study, therefore, aimed to investigate the risk factors involved in nonadherence, focusing on unexplained transient hyperuricemia in pediatric kidney transplant (KTx) recipients at a single pediatric center.
This retrospective study included 167 patients who underwent KTx at our pediatric center. A Cox proportional hazards analysis was performed to evaluate the risk of nonadherence using the following factors: age, sex, body mass index SD score, transient hyperuricemia, hypertension, and follow-up period.
Nonadherence was identified in 19 patients (11%), with the average (SD) age and post-KTx duration at diagnosis being 17.21 (4.73) years and 79.21 (38.77) months, respectively. Thirty-four patients (20%) were diagnosed with transient hyperuricemia at a median of 14 months after KTx. On multivariate Cox regression analysis, transient hyperuricemia was the only independent risk factor for nonadherence after KTx.
Transient hyperuricemia was identified as one of the risk factors for nonadherence after KTx; therefore, careful monitoring for transient hyperuricemia may allow early detection of nonadherence.
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