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81.
C-reactive protein (CRP) is the prototypic marker of inflammation and a strong predictor of cardiovascular events in humans. There are questions regarding the validity of the biological effects reported for CRP, in spite of adherence to rigorous control measures minimizing endotoxin [lipopolysaccharide (LPS)] contamination in these in vitro studies. In this study, we addressed the key question of endotoxin contamination in CRP preparations using Toll-like receptor 4 (TLR4) knockdown endothelial cells. Human aortic endothelial cells (HAECs) transfected with prevalidated TLR4 small interfering RNA (siRNA) and scrambled siRNA controls were challenged with pleural fluid-derived CRP or LPS for 12-16 h. Secreted interleukin-6 (IL-6), IL-1beta, IL-8, and plasminogen activator inhibitor-1 (PAI-1) levels and endothelial Nitric oxide synthase (eNOS) activity were determined. TLR4 knockdown in HAECs significantly decreased LPS-induced IL-1beta, IL-6, and IL-8, whereas the stimulatory effects of CRP were similar in both scrambled control and TLR4 knockdown cells. Furthermore, CRP significantly stimulated PAI-1 levels in both control and TLR4-transfected cells and inhibited eNOS activity, whereas LPS effects were negated in TLR4-transfected cells. The data presented cogently demonstrate and further confirm that the biological effects of CRP on HAECs are independent of LPS and thus are attributable to native protein per se. This is the first study to positively authenticate the significance of earlier in vitro reports on CRP biological effects. 相似文献
82.
Human ribosomal protein S3 (hS3) has a high apparent binding affinity for the oxidative lesion 7,8-dihydro-8-oxoguanine (8-oxoG). The hS3 ribosomal protein has also been found to inhibit the base excision repair (BER) enzyme hOGG1 from liberating 8-oxoG residing in a 5'-end-labeled oligonucleotide. To understand the in vivo involvement of hS3 in BER, we have turned to RNA interference to generate knockdown of hS3 in cells exposed to DNA damaging agents. Here we show that a 40% knockdown of hS3 resulted in as much as a seven-fold increase in the 24h survival-rate of HEK293 cells exposed to hydrogen peroxide. Significant protection to the alkylating agent methyl methanesulfonate (MMS) was also observed. Protection to the chemotherapeutic alkylating agent Thio-TEPA was only revealed at longer exposure times where the agent became more toxic to untransfected human cells. Overall, these results raise the possibility that hS3 interferes with the repair of the DNA lesions produced by genotoxic agents that potentially could play a role in the onset of cancer and other pathological states such as aging. 相似文献
83.
Dasu MR Devaraj S Jialal I 《American journal of physiology. Endocrinology and metabolism》2007,293(1):E337-E346
Previously, IL-1beta secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1beta induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of d-glucose (10-25 mM) for 6-72 h. IL-1beta and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RT-PCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-kappaB, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1beta-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P < 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1beta expression pattern; however, the molar ratio of IL-1beta to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1beta release under HG is mediated by PKC-alpha, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-kappaB activation, resulting in increased mRNA and protein for IL-1beta. At the same time, it appears that NADPH oxidase via p47phox activates NF-kappaB, resulting in increased IL-1beta secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1beta through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1beta release could result in the amelioration of inflammation and possibly diabetic vasculopathies. 相似文献
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85.
Type 1 diabetes (T1DM) is associated with increased vascular complications and is a pro-inflammatory state. Recent findings have shown increased TLR2 and 4 expression, signaling, ligands, and functional activation in T1DM subjects compared to controls and further accentuated in T1DM with microvascular complications. Thus, the aim of this study was to examine if genetic deficiency of TLR4 attenuates the increased inflammation associated with T1DM using the streptozotocin-induced diabetic mouse model. C57BL/6 and TLR4(-/-) mice were obtained and studied in the native state and following induction of diabetes using streptozotocin. Diabetic (WT+STZ) mice had increased expression of both TLR2 and TLR4, while TLR4(-/-) STZ mice had increased expression only of TLR2, but not TLR4 compared to the non-diabetic mice TLR2 expression was significantly increased with STZ-induced diabetes and was unaffected by knockout of TLR4. Also, levels of MyD88, IRAK-1 protein phosphorylation, Trif, IRF3, and NF-κB activity were significantly reduced in TLR4(-/-) +STZ mice compared to the WT+STZ mice. WT+STZ mice exhibited significantly increased levels of serum and macrophage IL-1β, IL-6, KC/IL-8, IP-10, MCP-1, IFN beta and TNF-α compared to WT mice and this was significantly attenuated in TLR4(-/-) +STZ mice (P<0.01). Thus, TLR4 contributes to the pro-inflammatory state and TLR4KO attenuates inflammation in diabetes. 相似文献
86.
Thalamic neurons receive inputs from cortex and their responses are modulated by the basal ganglia (BG). This modulation is necessary to properly relay cortical inputs back to cortex and downstream to the brain stem when movements are planned. In Parkinson's disease (PD), the BG input to thalamus becomes pathological and relay of motor-related cortical inputs is compromised, thereby impairing movements. However, high frequency (HF) deep brain stimulation (DBS) may be used to restore relay reliability, thereby restoring movements in PD patients. Although therapeutic, HF stimulation consumes significant power forcing surgical battery replacements, and may cause adverse side effects. Here, we used a biophysical-based model of the BG-Thalamus motor loop in both healthy and PD conditions to assess whether low frequency stimulation can suppress pathological activity in PD and enable the thalamus to reliably relay movement-related cortical inputs. We administered periodic pulse train DBS waveforms to the sub-thalamic nucleus (STN) with frequencies ranging from 0-140 Hz, and computed statistics that quantified pathological bursting, oscillations, and synchronization in the BG as well as thalamic relay of cortical inputs. We found that none of the frequencies suppressed all pathological activity in BG, though the HF waveforms recovered thalamic reliability. Our rigorous study, however, led us to a novel DBS strategy involving low frequency multi-input phase-shifted DBS, which successfully suppressed pathological symptoms in all BG nuclei and enabled reliable thalamic relay. The neural restoration remained robust to changes in the model parameters characterizing early to late PD stages. 相似文献
87.
Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning
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88.
Sridevi Nagarajan Willem Rens James Stalker Tony Cox Malcolm A Ferguson-Smith 《BMC bioinformatics》2008,9(1):168
Background
Comparative genomics has become a significant research area in recent years, following the availability of a number of sequenced genomes. The comparison of genomes is of great importance in the analysis of functionally important genome regions. It can also be used to understand the phylogenetic relationships of species and the mechanisms leading to rearrangement of karyotypes during evolution. Many species have been studied at the cytogenetic level by cross species chromosome painting. With the large amount of such information, it has become vital to computerize the data and make them accessible worldwide. Chromhome is a comprehensive web application that is designed to provide cytogenetic comparisons among species and to fulfil this need. 相似文献89.
90.
V. Sridevi P. Giridhar P. S. Simmi G. A. Ravishankar 《Plant Cell, Tissue and Organ Culture》2010,101(3):339-347
Direct differentiation of shoot buds from the collar region of hypocotyl segments of Coffea canephora was obtained on Murashige and Skoog (MS) medium supplemented with 40 μM silver nitrate (AgNO3) and growth regulators indole-3-acetic acid (IAA) and N6 benzyladenine (BA). The highest response to shoot differentiation
of 60% frequency and the maximum number of multiple shoots (2–3) per explant were obtained on MS medium containing 8.87 μM
BA and 2.85 μM IAA. Apart from this, 70% of hypocotyl explants produced yellow friable embryogenic callus and also globular
primary somatic embryos. Subsequent transfer onto the same medium induced secondary somatic embryogenesis. The micro-shoots,
upon transfer to the same medium, in the following 6 weeks developed into 4-cm-long shoots with a single root. Further subculturing
onto the same medium induced 4–5 roots in a 4-week period. The resulting plantlets were hardened and transferred to micro-pots
containing sand:compost mixture (1:2), where 65% of them survived and resumed growth. By using optimal levels of AgNO3, it was possible to obtain effective direct organogenesis and embryogenesis. This system was used for genetic transformation
using Agrobacterium tumefaciens. A stable transformation frequency of 2–5% was obtained when both types of explants, i.e., hypocotyl explants with collar
region or hypocotyl explants without collar region, were co-cultivated with A. tumefaciens GV 3101 harboring pCAMBIA 1305.2 binary vector. This is the first report of a hypocotyl collar region-based Agrobacterium-mediated transformation protocol for the economically important tropical plant C. canephora. 相似文献