Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work ...constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation-quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2-MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2-MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate-cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2-MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
DC-SIGN and L-SIGN: the SIGNs for infection Khoo, Ui-Soon; Chan, Kelvin Y. K.; Chan, Vera S. F. ...
Journal of molecular medicine,
08/2008, Letnik:
86, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Two closely related
trans
-membrane C-type lectins dendritic cell-specific intracellular adhesion molecules (ICAM)-3 grabbing non-integrin (DC-SIGN or
CD209
) and liver/lymph node-specific ICAM-3 ...grabbing non-integrin (L-SIGN also known as
DC-SIGNR
,
CD209L
or
CLEC4M
) directly recognize a wide range of micro-organisms of major impact on public health. Both genes have long been considered to share similar overall structure and ligand-binding characteristics. This review presents more recent biochemical and structural studies, which show that they have distinct ligand-binding properties and different physiological functions. Of importance in both these genes is the presence of an extra-cellular domain consisting of an extended neck region encoded by tandem repeats that support the carbohydrate-recognition domain, which plays a crucial role in influencing the pathogen-binding properties of these receptors. The notable difference between these two genes is in this extra-cellular domain. Whilst the tandem-neck-repeat region remains relatively constant size for DC-SIGN, there is considerable polymorphism for L-SIGN. Homo-oligomerization of the neck region of L-SIGN has been shown to be important for high-affinity ligand binding, and heterozygous expression of the polymorphic variants of L-SIGN in which neck lengths differ could thus affect ligand-binding affinity. Functional studies on the effect of this tandem-neck-repeat region on pathogen-binding, as well as genetic association studies for various infectious diseases and among different populations, are discussed. Worldwide demographic data of the tandem-neck-repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups are presented. These findings support the neck region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens.
The high-temperature (Tg > 650°) wholly aromatic polybenzoxazoles (PBO) polymer chains in thin films underwent elastic energy release via local deformation of crazing when stretched beyond a critical ...strain around 0.5%. The strain localization in the ultra-rigid polymer was quickly superseded by craze fibril breakdown, triggering catastrophic fracture at low extensions below ∼3%. Although the drawing stress of craze fibrillation, determined to be ∼3 GPa, was insufficient to separate chains in PBO crystallites, it forced the chains in the amorphous regions to flow into large molecular deformations (∼300% strain) at room temperature. The poor craze fibril stability of the rigid-rod chains was enhanced dramatically when surface-functionalized single-walled carbon nanotubes (SWCNTs) were dispersed into the polymer. No toughening effects were observed, however, for multi-walled carbon nanotubes (MWCNTs) although the elastic enhancement leading to increase of strain delocalization was still operative. The toughening selectivity was attributed to the PBO/CNT load transfer coupling during nanoplastic flows in which only the CNTs of compatible bending moments permitting fibril drawing were allowed to participate.
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Human CMV (HCMV) is an important pathogen that causes widespread diseases in immunocompromised individuals. Among the opportunistic HCMV infections, HCMV retinitis is most common in transplant ...recipients and AIDS patients. It often leads to blindness if left untreated. The question as to how HCMV infection causes retinal pathogenesis remains unresolved. Here, we report that viral immediate-early gene product 2 (IE2), but not IE1, up-regulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithelium cells. Increased secretion of FasL from virally infected cells into cultured medium was observed upon HCMV infection. The capability of such cell-free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells further implies that Fas-FasL interaction might mediate cell death in the lesion of HCMV retinitis. To support this idea, we observed augmented soluble FasL levels in vitreous from AIDS patients with HCMV retinitis as compared with that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of FasL, the existence of viral IE Ags and apoptotic cells at the same sites in the lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event that takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.
Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an ...immune response gene, both located on chromosome 19p13.3 were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS-CoV infection was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P=.0067; odds ratio OR, 4.31 95% confidence interval CI, 1.37–13.56) and lower total white blood cell counts (P=.022; OR, 0.30 95% CI, 0.10–0.89) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS.
Premature neonates with short bowel syndrome often have diverting enterostomies and distal mucous fistulae. The authors reviewed their experience in 12 premature neonates in whom proximal bowel ...contents were re-fed into the mucous fistula.
We reviewed the records of 12 premature neonates who presented with acute abdomen and who underwent intestinal resection with formation of diverting enterostomy and mucous fistula between July 1999 and December 2002. All received parenteral nutrition. Refeeding of enterostomy contents into the distal mucous fistula was commenced after patency of the distal intestine was confirmed by radiologic examination. Demographic data, body weight and clinical outcomes were recorded.
Median gestational age was 31 weeks and mean birth weight was 1.59 kg. Diagnoses included necrotizing enterocolitis (n = 6), meconium ileus-like conditions (n = 2), ileal atresia (n = 2), malrotation with volvulus (n = 1) and focal intestinal perforation (n = 1). Refeeding was successfully established in all patients with no complications. The mean duration of refeeding was 63.5 days. All patients achieved good weight gain after refeeding (18.9 +/- 2.9 g/d) with a reduction of parenteral nutrition requirements. All enterostomies were subsequently closed. Four patients died of unrelated causes after reanastomosis and the remaining eight were discharged.
Mucous fistula refeeding is safe in premature neonates with enterostomies. It can prevent disuse atrophy in the distal loop and facilitate subsequent reanastomosis. Furthermore, the increased absorptive function provided by the small bowel incorporated in the mucous fistula can reduce the requirement for total parenteral nutrition.
Peritoneal dialysis is one of the standard methods for blood purification. It is particularly well suited for treating children with acute renal failure. Here we report a rare case of small bowel ...herniation at the peritoneal catheter exit site following removal, leading to gangrenous infarction.
Calcium-iron phosphate glasses with an iron oxide content ranging from 5 wt.% to 22 wt.% were prepared to investigate the effect of iron oxide on the properties of the glass. It was found that the ...dissolution rate, the fibre strength and the glass transition temperature were strongly affected by iron oxide. The glass dissolution rate exhibited a 50-fold reduction while the fibre strength doubled when the iron oxide content was increased from 5 wt.% to 22 wt.%. The phosphate glass containing 22 wt.% of iron oxide had a dissolution rate of about 5 micrograms/(cm2 day). The fibres drawn from this glass also exhibited the highest tensile strength over 1000 MPa. A cortical bone plug method was used to assess the biocompatibility of the glasses with the hard and soft tissues. The tissues surrounding the samples showed no inflammation at 9 wk.
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