PubMed Health⌕ Search

Biomedical subjects

L Shen

Publications and source records attributed to L Shen.

At least 19 recordsLinked to original sources
PubMed2007

Effects of ertiprotafib on hepatic cytochrome P450 and peroxisomal enzymes in rats and dogs, and in rat and human primary hepatocytes.

Ertiprotafib (ERTI) significantly increased liver weights in male and female rats, and moderately increased liver weights in male dogs after treatment for 28 days. The present study tested the hypotheses that the organ weight increases were associated with peroxisome proliferation in rats and induction of hepatic enzymes in rats and dogs, and would have limited impacts on humans. At a dosage of 200 mg kg-1 day-1, CYP4A was induced by tenfold in male rats and 2.4-fold in female rats. In male rats, CYP2B was induced by 1.2-fold and CYP3A was induced by 1.7-fold. Palmitoyl CoA oxidase was induced by 5.1-fold in male rats and 2.9-fold in female rats; carnitine acetyltransferase was induced by 10.4-fold in male rats and 5.2-fold in female rats. CYP3A, CYP4A and peroxisomal enzymes were not induced in dogs at 150/200 mg kg-1 day-1. ERTI at 50 microM markedly induced the mRNA level of CYP4A by up to fivefold in rat hepatocytes, but not in human primary hepatocytes. In conclusion, the liver weight increases observed in rats treated with ERTI appears to be due to rodent-specific peroxisome proliferation and the substantial induction of CYP4A1. ERTI is not a potent P450 inducer in dogs or in human hepatocytes. Therefore, ERTI is not expected to exert any significant effects on hepatic drug-metabolizing enzymes in humans.

Animals↗
PubMed2006

An apparatus for studying the response of cultured endothelial cells to stresses.

In order to simulate the hemodynamic environment of human arteries in vivo, we designed a laminar flow apparatus which can precisely simulate the normal stress and shear stress to which cultured endothelial cells are exposed. Under both normal and abnormal physiological conditions, this apparatus can accurately control and adjust the values of normal stress and shear stress and the frequency of pulse waves, as well as the amplitude of pulsatile flow. This in vitro apparatus provides an experimental platform for studying the response of the biological characteristics of cultured endothelial cells in a hemodynamic environment.

Blood Flow Velocity↗
PubMed2006

Di-2-ethylhexyl phthalate in the fruits of Benincasa hispida.

Di-2-ethylhexyl phthalate (DEHP) is a commonly used plasticizer that is harmful to human health. magnetic resonance spectroscopy from the edible fruit flesh of Benincasa hispida (wax gourd) of the plant family Curcurbitaceae. The DEHP content of seven wax gourd samples collected from southern and northern provinces in China was determined as (mean +/- SD): 18.3 +/- 0.43, 2.64 +/- 0.44, 44.0 +/- 0.34, 62.5 +/- 0.48, 52.0 +/- 0.42, 58.3 +/- 0.55 and 75.5 +/- 0.63 mg kg-1 fresh weight, respectively, indicating that most wax gourds were severely contaminated with DEHP.

China↗
PubMed2005

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours.

Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2'-deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5' region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5' CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

Base Sequence↗
PubMed2005

Use of CD34+ autologous stem cell transplantation in the treatment of children with refractory systemic lupus erythematosus.

We report on the unique effects and benefits of autologous stem cell transplantation in childhood systemic lupus erythematosus (SLE) and describe this procedure in two young girls with severe and refractory disease. The patients' stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected by CS-3000 Blood Cell Separator (Baxter Healthcare, Round Lake, Ill., USA), and the CliniMACS CD34+ cell selection device (Miltenyi Biotech, Bergisch Gladbach, Germany) was used to obtain CD34+ cells. A total of 1.7x10(6) and 1.0x10(6)/kg CD34+ cells were obtained, with 2.0x10(5) and 1.0x10(4)/kg of CD3+ cells remaining, respectively. The conditioning regimen consisted of cyclophosphamide (50 mg/kg per day for 4 days) plus antithymocyte globulin (ATG-Fresenius, 5 mg/kg per day for 3 days). Neutrophil counts recovered within 9 days in both cases. Within 15 days, the platelet counts recovered and were sustained over 100x10(9)/l. Cushingoid features disappeared completely 3 months after transplantation because of the removal of corticosteroid medication. One 13-year-old child increased her height by 5 cm in 6 months after stopping steroids. She had not increased her height in her previous 7 years of disease. As of the time of this report, the first patient remains in clinical and laboratory remission for nearly 4 years, while the second suffered a relapse of thrombocytopenia 9 months post-transplantation. One residual effect of their treatment is that their CD4+ cell counts remained in the lower range after one year of transplant. The effect of this conditioning regimen plus CD34+ autologous stem cell transplantation on these two children with refractory SLE was beneficial, but long-term follow-up data and additional experience with this procedure are required. Autologous stem cell transplantation may limit the long-term toxicity of therapy in childhood SLE.

Adolescent↗
PubMed2005

Determination of gene organization in the human IGHV region on single chromosomes.

Organization of the IGHV genes (n=108) on single human chromosomes has been determined by detecting these sequences in single sperm using multiplex PCR amplification followed by microarray detection. A total of 374 single sperm samples from five Caucasian males were studied. Three deletion/insertion polymorphisms (Del I-Del III) with deletion allele frequencies ranging from 0.1 to 0.3 were identified. Del I is a previously reported polymorphism affecting three IGHV genes (IGHV1-8, IGHV3-9, and IGHV2-10). Del II affects a region 2-18 kb containing two pseudogenes IGHV(II)-28.1 and IGHV3-29, and Del III spans approximately 21-53 kb involving genes IGHV4-39, IGHV7-40, IGHV(II)-40-1, and IGHV3-41. Deletion alleles of both Dels II and III were found in a heterozygous state, and therefore, could not be easily detected if haploid samples were not used in the study. Results of the present study indicate that deletions/insertions together with other possible chromosomal rearrangements may play an important role in forming the genetic structure of the IGHV region, and may significantly contribute to antibody diversity. Since these three polymorphisms are located within or next to the 3' half of the IGHV region, they may have an important role in the expressed IGHV gene repertoire during immune response.

Chromosomes, Human, Pair 14↗
PubMed2005

A hypoxia-inducible vigilant vector system for activating therapeutic genes in ischemia.

Hypoxia represents an endogenous pathophysiological signal underlying cell growth, adaptation and death in a variety of diseases, including ischemic heart diseases, stroke and solid tumors. A vigilant vector system depends on a gene switch which can sense the hypoxia signal occurring in ischemic events and turn on/off protective gene expressions when necessary. This system uses the oxygen-dependent degradation domain derived from hypoxia-inducible factor 1alpha as the hypoxia sensor and a double-vector system as signal amplifier. For treating ischemic heart diseases, a cardiac-specific MLC-2v promoter is used to deliver transgenes specifically to the heart. When tested in cardiomyocyte cultures, it produced a rapid and robust gene induction upon exposure to low oxygen. In a mouse model for myocardial infarction, the vigilant vectors turned on therapeutic genes such as heme oxygenase-1 in response to ischemia, significantly reduced apoptosis in the infarct area and improved cardiac functions. The hypoxia-regulated gene transfer afforded by the vigilant vectors may provide a powerful tool for delivering therapeutic proteins specifically to ischemic tissues with optimal physiological control.

Animals↗
PubMed2005

Genetic variation of Ginkgo biloba L. (Ginkgoaceae) based on cpDNA PCR-RFLPs: inference of glacial refugia.

Ginkgo biloba, a famous living fossil, is the sole survivor of the genus Ginkgo. To make inferences about the glacial refugia that harbored G. biloba, we examined the genetic structure of eight potential refugial populations and plantations using chloroplast DNA (cpDNA) with eight size variants in the trnK1-trnK2 fragment. The data consist of haplotypes from 158 trees collected from eight localities. The majority of the cpDNA haplotypes are restricted to minor portions of the geographical range. Our results suggest that refugia of G. biloba were located in southwestern China. This area is a current biodiversity hotspot of global importance, and may have been protected from the extremes of climatic fluctuations during the Pleistocene. The Ginkgos on West Tianmu Mountain, which were previously considered to be wild by many researchers, may, instead, have been introduced by Buddhist monks.

China↗
PubMed2005

Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets.

AIMS: In long-term clinical trials in patients with type 1 diabetes spanning a wide range of HbA1c, addition of pramlintide to existing insulin regimens led to reductions in HbA1c that were accompanied by weight loss and no increase in overall severe hypoglycemia event rates. Given that weight gain and increased hypoglycemia risk contribute to the difficulty of attaining HbA1c targets (<7 %), the question arose whether pramlintide could benefit patients approaching, but not reaching glycemic targets with insulin alone. To address this question, we conducted a pooled analysis from 3 long-term clinical trials, including all patients with an entry HbA1c between 7.0 % and 8.5 %. METHODS: Within the subset of patients with an entry HbA1c between 7.0 % and 8.5 % (approximately 28 % of all patients enrolled in the 3 studies), 196 were treated with placebo + insulin (baseline HbA1c 7.9+/-0.4 %, body weight 76.0+/-14.3 kg [mean+/-SD]) and 281 with pramlintide+insulin (baseline HbA1c 7.9+/-0.4 %, body weight 75.4+/-13.1 kg). Endpoints included placebo-corrected changes from baseline to week 26 in HbA1c, body weight, and the event rate of severe hypoglycemia. RESULTS: Adjunctive therapy with pramlintide resulted in significant reductions in HbA1c and body weight from baseline to week 26 (0.3 % and 1.8 kg, placebo-corrected treatment differences, respectively, both p<or=0.0009). These changes occurred without an increase in the overall risk of severe hypoglycemia (1.40 pramlintide vs. 1.86 placebo, events/patient-year of exposure). CONCLUSIONS: Addition of pramlintide to insulin therapy may help patients with type 1 diabetes who are approaching, but not yet reaching, glycemic targets with insulin alone to achieve further reductions in HbA1c without concomitant weight gain and increased risk of severe hypoglycemia.

Adult↗
PubMed2005

Seasonal changes in the structure of RBC heterotrophic biofilms.

Heterotrophic Biofilms, growing in the successive three treatment stages of the RBC reactor in a full-scale wastewater treatment plant in the summer of 2002, were investigated and compared to those growing in the fall of 2001. The seasonal changes in biofilm structure were studied in terms of biofilm thickness, dry solid density, internal pore distribution and patterns, and surface roughness. The comparison results indicated that due to the higher wastewater flow rate in the summer of 2002, these biofilms had thinner, denser and less rugged surface structure than the biofilms sampled in the fall of 2001; furthermore, they showed less heterogeneous intemal pore distribution. However, biofilms from both seasons showed some similarities: biofilms in the treatment stages 2 and 3 had similar structure; and their internal pore distribution and pore surface roughness didn't show any correlation with the biofilm depth.

Biofilms↗
PubMed2004

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines.

DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8+ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumor-associated antigens to DCs to enhance antigen-specific immune responses.

Animals↗
PubMed2004

Identification of novel direct transcriptional targets of glucocorticoid receptor.

Transcription of the genes Granzyme A (GZMA), FK506 binding protein 51 (FKBP5), and Down syndrome critical region gene 1 (DSCR1) is upregulated in leukemic cells upon treatment with glucocorticoids (GCs). Several lines of evidence suggest that these genes are implicated in GC-induced apoptosis upstream of the Bcl-2 family of proteins. These genes were upregulated by GC even in the presence of an inhibitor of protein synthesis, cycloheximide, indicating that they are direct target genes of glucocorticoid receptors. DSCR1 is reported to have four isoforms, each of which has a distinct first exon, E1-E4. Among these isoforms, the one with E1 was selectively upregulated by GC. GZMA and FKBP5 have a cluster of putative glucocorticoid response elements (GREs) in introns 1 and 2, respectively, that was identified to be responsible for the response to GC. They were composed of one complete (A/T)G(A/T)(A/T)C(A/T) sequence surrounded by two incomplete (A/T)G(A/T)(A/T)C(A/T) sequences separated by one to four nucleotides. DSCR1, however, did not have a functional GRE upstream or downstream of exon 1. These studies may lead to improved therapeutic uses of GCs in leukemia and lymphoma based upon the expression of these GC target genes.

Cycloheximide↗
PubMed2004

Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial.

AIMS: The autoimmune-mediated destruction of pancreatic beta-cells in Type 1 diabetes mellitus renders patients deficient in two glucoregulatory peptide hormones, insulin and amylin. With insulin replacement alone, most patients do not achieve glycaemic goals. We aimed to determine the long-term efficacy and safety of adjunctive therapy with pramlintide, a synthetic human amylin analogue, in patients with Type 1 diabetes. METHODS: In a double-blind, placebo-controlled, parallel-group, multicentre study, 651 patients with Type 1 diabetes (age 41 +/- 13 years, HbA(1c) 8.9 +/- 1.0%, mean +/- sd) were randomized to mealtime injections of placebo or varying doses of pramlintide, in addition to their insulin therapy, for 52 weeks. RESULTS: Addition of pramlintide [60 microg three times daily (TID) or four times daily (QID)] to insulin led to significant reductions in HbA(1c) from baseline to Week 52 of 0.29% (P < 0.011) and 0.34% (P < 0.001), respectively, compared with a 0.04% reduction in placebo group. Three times the proportion of pramlintide- than placebo-treated patients achieved an HbA(1c) of < 7%. The greater reduction in HbA(1c) with pramlintide was achieved without an increase in concomitant insulin use and was accompanied by a significant reduction in body weight from baseline to Week 52 of 0.4 kg in the 60 microg TID (P < 0.027) or QID (P < 0.040) pramlintide treatment groups, compared with a 0.8-kg gain in body weight in the placebo group. The most common adverse event in pramlintide-treated patients was transient, mild-to-moderate nausea. CONCLUSIONS: These results show that mealtime amylin replacement with pramlintide, as an adjunct to insulin therapy, improves long-term glycaemic and weight control in patients with Type 1 diabetes.

Adult↗
PubMed2003

Calcium-independent contraction and sensitization of airway smooth muscle by p21-activated protein kinase.

In Triton-skinned phasic ileal smooth muscle, constitutively active recombinant p21-activated kinase (PAK3) has been shown to induce Ca(2+)-independent contraction, which is accompanied by phosphorylation of caldesmon and desmin (Van Eyk JE, Arrell DK, Foster DB, Strauss JD, Heinonen TY, Furmaniak-Kazmierczak E, Cote GP, and Mak AS. J Biol Chem 273: 23433-23439, 1998). In the present study, we investigated whether PAK has a broad impact on smooth muscle in general by testing the hypothesis that PAK induces Ca(2+)-independent contractions and/or Ca(2+) sensitization in tonic airway smooth muscle and that the process is mediated via phosphorylation of caldesmon. In the absence of Ca(2+) (pCa > 9), constitutively active glutathione-S-transferase-murine PAK3 (GST-mPAK3) caused force generation of Triton-skinned canine tracheal smooth muscle (TSM) fibers to approximately 40% of the maximal force generated by Ca(2+) at pCa 4.4. In addition, GST-mPAK3 enhanced Ca(2+) sensitivity of contraction by increasing force generation by 80% at intermediate Ca(2+) concentrations (pCa 6.2), whereas it had no effect at pCa 4.4. Catalytically inactive GST-mPAK3(K297R) had no effect on force production. Using antibody against one of the PAK-phosphorylated sites (Ser(657)) on caldesmon, we showed that a basal level of phosphorylation of caldesmon occurs at this site in skinned TSM and that PAK-induced contraction was accompanied by a significant increase in the level of phosphorylation. Western blot analyses show that PAK1 is the predominant PAK isoform expressed in murine, rat, canine, and porcine TSM. We conclude that PAK causes Ca(2+)-independent contractions and produces Ca(2+) sensitization of skinned phasic and tonic smooth muscle, which involves an incremental increase in caldesmon phosphorylation.

Animals↗
PubMed2003

Effect of pramlintide on A1C and body weight in insulin-treated African Americans and Hispanics with type 2 diabetes: a pooled post hoc analysis.

An unresolved problem in the management of type 2 diabetes is that improvement of glycemic control with insulin, insulin secretagogues, and insulin sensitizers is often accompanied by undesired weight gain. This problem is of particular concern in ethnic groups with a high propensity for diabetes and obesity, such as African Americans and Hispanics. Two 1-year, randomized, double-blind, placebo-controlled clinical trials in insulin-treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide, an analog of the human beta-cell hormone amylin, reduces A(1C) with concomitant weight loss, rather than weight gain. To assess the effect of pramlintide in various ethnic groups with type 2 diabetes using insulin, we conducted a pooled post hoc analysis of the 2 trials, which included all Caucasian (n = 315), African American (n = 47), and Hispanic (n = 48) patients (age 57 years, A(1C) 9.1%, body mass index [BMI] 33 kg/m(2), mean values) who completed 52 weeks of treatment with either pramlintide (120 microg twice daily or 150 microg 3 times a day) or placebo. Primary endpoints included changes from baseline to week 52 in A(1C) and body weight. Collectively, pramlintide-treated patients achieved significant reductions from baseline in both A(1C) and body weight (placebo-corrected treatment effects at week 52: -0.5% and -2.6 kg, respectively, both P <.0001). The simultaneous reduction in A(1C) and body weight at week 52 was evident across all 3 ethnic groups and appeared to be most pronounced in African Americans (-0.7%, -4.1 kg), followed by Caucasians (-0.5%, -2.4 kg) and Hispanics (-0.3%, -2.3 kg). The glycemic improvement with pramlintide was not associated with an increased incidence of hypoglycemia over the entire study period (43% pramlintide v 40% placebo). Nausea, the most common adverse event associated with pramlintide treatment, was mostly mild and confined to the first 4 weeks of therapy (25% pramlintide v 16% placebo) with comparable patterns in the 3 ethnic groups. Thus, pending further experience, the combined improvement in glycemic and weight control with pramlintide treatment appears to be generalizable to a broad population of mixed ethnicity.

Black or African American↗