Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

The pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments

Characterization of Kaposi's sarcoma-associated herpesvirus (KSHV) K1 promoter activation by Rta

The K1 gene of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 46-kDa transmembrane glycoprotein that possesses transforming properties, initiates signaling pathways in B cells, and prevents apoptosis. Here, we demonstrate a mechanism for activation of the K1 promoter by the Rta transactivator. Electrophoretic mobility shift assay (EMSA) analysis of the K1 promoter demonstrated that purified Rta protein bound to the K1 promoter at three locations, independent of other DNA-binding factors. Transcriptional assays revealed that only two of these Rta DNA-binding sites are functionally significant, and that they could impart Rta responsiveness to a heterologous E4 TATA box promoter. In addition, TATA-binding protein (TBP) bound to a TATA box element located 25 bp upstream of the K1 transcription start site and was also shown to associate with Rta by coimmunoprecipitation analysis. Rta transactivation may therefore be mediated in part through recruitment of TBP to target promoters

Actin Cytoskeleton and Golgi Involvement in Barley stripe mosaic virus Movement and Cell Wall Localization of Triple Gene Block Proteins.

Barley stripe mosaic virus (BSMV) induces massive actin filament thickening at the infection front of infected Nicotiana benthamiana leaves. To determine the mechanisms leading to actin remodeling, fluorescent protein fusions of the BSMV triple gene block (TGB) proteins were coexpressed in cells with the actin marker DsRed: Talin. TGB ectopic expression experiments revealed that TGB3 is a major elicitor of filament thickening, that TGB2 resulted in formation of intermediate DsRed:Talin filaments, and that TGB1 alone had no obvious effects on actin filament structure. Latrunculin B (LatB) treatments retarded BSMV cell-to-cell movement, disrupted actin filament organization, and dramatically decreased the proportion of paired TGB3 foci appearing at the cell wall (CW). BSMV infection of transgenic plants tagged with GFP-KDEL exhibited membrane proliferation and vesicle formation that were especially evident around the nucleus. Similar membrane proliferation occurred in plants expressing TGB2 and/or TGB3, and DsRed: Talin fluorescence in these plants colocalized with the ER vesicles. TGB3 also associated with the Golgi apparatus and overlapped with cortical vesicles appearing at the cell periphery. Brefeldin A treatments disrupted Golgi and also altered vesicles at the CW, but failed to interfere with TGB CW localization. Our results indicate that actin cytoskeleton interactions are important in BSMV cell-to-cell movement and for CW localization of TGB3

EFFECT OF SPORTS TAPING APPLIED FUNCTIONAL CORRECTION GARMENT FOR ADOLESCENT IDIOPATHIC SCOLIOSIS IMPROVEMENT

The purpose of this research was to analyze the effect of wearing underwear type functional garment for the correction scoliosis by conducting a case study. Two patients wore the garment for 8–week. Cobb’s angle and EMG activities during a gait were measured before and after the treatment for the analysis. Both subjects showed that the activities of the right psoas, biceps femoris and gluteus medius were increased. The Cobb’s angle was decreased after 8-week period of wearing. These results matched with the purpose of developed functional correction wear that induce the right psoas muscle contraction and the left psoas muscle relaxation. It seems to be useful wear for adolescent scoliosis patients who avoid using orthosis, and to use special functional underwear to improve their posture

Onion peel extracts ameliorate hyperglycemia and insulin resistance in high fat diet/streptozotocin-induced diabetic rats

<p>Abstract</p> <p>Background</p> <p>Quercetin derivatives in onions have been regarded as the most important flavonoids to improve diabetic status in cells and animal models. The present study was aimed to examine the hypoglycemic and insulin-sensitizing capacity of onion peel extract (OPE) containing high quercetin in high fat diet/streptozotocin-induced diabetic rats and to elucidate the mechanism of its insulin-sensitizing effect.</p> <p>Methods</p> <p>Male Sprague-Dawley rats were fed the AIN-93G diet modified to contain 41.2% fat and intraperitoneally injected with a single dose of streptozotocin (40 mg/kg body weight). One week after injection, the rats with fasting blood glucose levels above 126 mg/dL were randomly divided into 4 groups to treat with high fat diet containing 0 (diabetic control), 0.5, or 1% of OPE or 0.1% quercetin (quercetin equivalent to 1% of OPE) for 8 weeks. To investigate the mechanism for the effects of OPE, we examined biochemical parameters (insulin sensitivity and oxidative stresses) and protein and gene expressions (pro-inflammatory cytokines and receptors).</p> <p>Results</p> <p>Compared to the diabetic control, hypoglycemic and insulin-sensitizing capability of 1% OPE were demonstrated by significant improvement of glucose tolerance as expressed in incremental area under the curve (<it>P </it>= 0.0148). The insulin-sensitizing effect of OPE was further supported by increased glycogen levels in liver and skeletal muscle (<it>P </it>< 0.0001 and <it>P </it>= 0.0089, respectively). Quantitative RT-PCR analysis showed increased expression of insulin receptor (<it>P </it>= 0.0408) and GLUT4 (<it>P </it>= 0.0346) in muscle tissues. The oxidative stress, as assessed by superoxide dismutase activity and malondialdehyde formation, plasma free fatty acids, and hepatic protein expressions of IL-6 were significantly reduced by 1% OPE administration (<it>P </it>= 0.0393, 0.0237, 0.0148 and 0.0025, respectively).</p> <p>Conclusion</p> <p>OPE might improve glucose response and insulin resistance associated with type 2 diabetes by alleviating metabolic dysregulation of free fatty acids, suppressing oxidative stress, up-regulating glucose uptake at peripheral tissues, and/or down-regulating inflammatory gene expression in liver. Moreover, in most cases, OPE showed greater potency than pure quercetin equivalent. These findings provide a basis for the use of onion peel to improve insulin insensitivity in type 2 diabetes.</p

Platelet-derived growth factor induces p21/WAF1 promoter in vascular smooth muscle cells via activation of an Sp1 site

AbstractMany studies suggested that cyclin-dependent kinase inhibitor (CDKI) p21 acts as a universal inhibitor of cyclin/CDK catalytic activity. This protein has also been shown to be a component of active cyclin/CDK complexes. In addition, it has recently been suggested that p21 serves as an assembly factor in platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMC). However, little is known concerning the molecular mechanisms by which PDGF induces p21 gene expression in VSMC. In this report we demonstrate that PDGF induces the p21 expression at both the mRNA and protein levels. This increase in p21 gene expression was due to activation of the p21 promoter by PDGF. Through both deletion and mutation analysis of the p21 promoter, we defined a 10-bp sequence that is required for the activation of the p21 promoter by PDGF. In addition, gel shift and supershift assays demonstrated that this PDGF-responsive element binds specifically to the transcription factor Sp1. These results demonstrate that Sp1 mediates PDGF-induced p21 gene expression in VSMC. Moreover, immunoblot and immonoprecipitation analysis showed that the level of hyperphosphorylated retinoblastoma protein (Rb) is increased and the protein is physically associated with Sp1 in PDGF-treated cells, indicating that phosphorylated Rb may play a role in regulating Sp1 to activate p21 expression

Simple method of measuring ocular rotation in supine position during small incision lenticule extraction

AIM: To introduce a novel measurement method of static cyclotorsion in small incision lenticule extraction (SMILE) and to investigate the effect of preoperative parameters on cyclotorsion and the effect of cyclotorsion on postoperative outcomes. METHODS: The medical records of 242 patients and 484 eyes who underwent SMILE surgery were retrospectively reviewed. Preoperative intraocular pressure, refractive error, and corneal thickness were investigated. Refractive values and visual acuity were measured at 1d, 1, 3, and 6mo. Ocular cyclotorsion in the supine position was measured by calculating the location and angle of the incision site of the cornea in the anterior slit photograph taken after surgery. RESULTS: Of the total 484 eyes in 242 patients, preoperative mean spherical equivalent (SE) was -4.10±1.64 D, and the mean astigmatism was -0.82±0.74 D. Uncorrected distance visual acuity (UCVA) and SE improved significantly after the surgery. Moreover, 219 (45.2%) eyes had excyclotorsion, 235 (48.6%) eyes had incyclotorsion, and 30 (6.2%) eyes had no torsion. The right eyes tended to be excyclotorted, and the left eyes tended to be incyclotorted (P<0.01). The mean cyclotorsion was 1.18°±3.69°, and the mean absolute value of cyclotorsion was 3.14°±2.26°. The range of cyclotorsion was 0.5°–11.4°. It was found that the smaller the preoperative sphere, the higher the amount of cyclotorsion (r=0.11, P=0.016). There was no significant association between the amount of cyclotorsion and preoperative astigmatism. There was no correlation between sex, preoperative corneal thickness, preoperative intraocular pressure, amount of cyclotorsion, and direction of cyclotorsion. The ratio of right eye excyclotorsion and left eye incyclotorsion on 1d was higher than that at 1, 3, and 6mo (all P<0.01). There was no difference between the 1, 3, and 6mo results in the right and left eyes (P=0.15, P=0.16, respectively). CONCLUSION: The newly devised ocular cyclotorsion measurement method can be used to evaluate ocular cyclotorsion after SMILE. Preoperative SE is associated with the amount of cyclotorsion, however, cyclotorsion doesn't have a significant effect on the results of SMILE surgery

MR Imaging Findings of Ovarian Cystadenofibroma and Cystadenocarcinofibroma: Clues for the Differential Diagnosis

OBJECTIVE: We wanted to assess the MR imaging findings of ovarian cystadenofibroma and cystadenocarcinofibroma, and we wanted to find clues for making the differential diagnosis between them. MATERIALS AND METHODS: The MR images of 12 pathologically proven cystadenofibromas and two cystadenocarcinofibromas were reviewed, with a focus on the internal architecture, signal intensity and enhancement. RESULTS: All the tumors appeared as multilocular cysts, except for a single unilocular cystic mass and a single solid mass. The previously reported characteristic MR findings of cystadenofibroma (a multilocular cystic mass with a T2-dark-signal-intensity solid component containing small cystic locules) were found in only 43% of the tumors (6/14). Diffuse or partial thickening of the cyst wall with T2-dark signal intensity without a definite solid component was as common as the previous reported findings (6/14). Two cystadenocarcinofibromas showed more prominent solid portions with higher T2-signal intensities and stronger enhancement than did the cystadenofibromas. CONCLUSION: Diffuse or partial thickening of the cyst wall with dark-signal-intensity in multilocular cystic masses may suggest ovarian cystadenofibroma, and this type of appearance may be as common as the previously reported characteristic appearance. A prominent solid component with a higher T2-signal intensity and strong enhancement are the typical findings of cystadenocarcinofibroma