Biomedical subjects

Lin Zhang

Publications and source records attributed to Lin Zhang.

At least 73 records · Page 4Linked to original sources

PubMed2006

Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells.

It has been proposed that occult, disseminated metastatic cells are refractory to chemotherapy due to lack of proliferation. We have shown that p38 activation induces dormancy of squamous carcinoma cells. We now show that p38 signaling in these cells activates a prosurvival mechanism via the up-regulation of the endoplasmic reticulum (ER) chaperone BiP and increased activation of the ER stress-activated eukaryotic translation initiator factor 2alpha kinase RNA-dependent protein kinase-like ER kinase (PERK) allowing dormant tumor cells to resist drug toxicity. RNA interference and dominant-negative expression studies revealed that both BiP and PERK signaling promote survival and drug resistance of dormant cells, and that BiP up-regulation prevents Bax activation. We propose that stress-dependent activation of p38 via BiP up-regulation and PERK activation protects dormant tumor cells from stress insults, such as chemotherapy.

Apoptosis↗

PubMed2006

Orally active purine-based inhibitors of the heat shock protein 90.

Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC(50) = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H(3)PO(4) salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.

Adenine↗

PubMed2006

Interaction of Pin1 with Nek6 and characterization of their expression correlation in Chinese hepatocellular carcinoma patients.

The peptidyl-prolyl isomerase Pin1 is prevalently overexpressed in human cancers and is regarded as a new diagnostic and therapeutic target. Pin1 interacts with several proteins involved in cell cycle events in a phosphorylation-dependent manner. Among them, NIMA (never in mitosis, gene A) was first identified to interact with Pin1. In this report, we found that Pin1 could interact with Nek6, one of the human NIMA-related kinases (Neks). This interaction was confirmed by GST pull-down assay, which was further confirmed by immunoprecipitation experiments, as well as immunofluorescence colocalization. We further studied Pin1 and Nek6 mRNA level in 40 pairs of hepatocellular carcinoma cases, finding significant correlations between Nek6 and Pin1 mRNA expression levels in these samples.

Adult↗

PubMed2006

Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells.

The key feature of metabolic syndrome, a cluster of metabolic and cardiovascular disorders, is systemic insulin resistance, which is associated with dysregulated endothelial nitric-oxide synthase (eNOS). Stress signaling induced by inflammation can inhibit insulin signaling. However, molecular mechanisms for the cross-talk between stress signaling and insulin resistance are only partially understood. Resistin, an adipokine/cytokine, is involved in inflammatory processes that could lead to insulin resistance status and vascular diseases. In the current study, we observed that resistin inhibited insulin signaling and eNOS activation in endothelial cells. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) expression by resistin may mediate the inhibitory effects. Activated stress signaling p38 MAPK, but not JNK, is involved in PTEN up-regulation. We further found that p38 target transcriptional factor activating transcription factor-2 (ATF-2) bound to ATF sites in the PTEN promoter. The phosphorylation/activation of ATF-2 and its binding to PTEN promoter were increased by resistin treatment. In summary, up-regulation of PTEN is involved in the inhibitory effects of resistin on insulin signaling and eNOS activation in endothelial cells. Resistin induces PTEN expression by activating stress signaling p38 pathway, which may activate target transcription factor ATF-2, which in turn induces PTEN expression. Our findings suggest that resistin-mediated inhibition of insulin signaling and eNOS activation may contribute to cardiovascular diseases.

Activating Transcription Factor 2↗

PubMed2006

A rapid and sensitive LC-MS/MS method for determination of coenzyme Q10 in tobacco (Nicotiana tabacum L.) leaves.

A rapid and sensitive liquid chromatography-tandem mass spectrometry method with multiple reaction monitoring has been proposed for the analysis of coenzyme Q10 in (CoQ10) tobacco leaves. The method used electrospray ionization with detection in positive ion mode. Sample pretreatment involved ultrasonic extraction of fresh tobacco leaves with anhydrous ethanol for 15 min and followed by extraction of the supernatant with hexane. The separation of CoQ10 was performed on a Symmetry Shield RP18 column with a mixture of acetonitrile and isopropanol (8:7, v/v) containing 0.5% formic acid as mobile phase. Quantification of CoQ10 was performed by the standard addition method. The limit of detection and limit of quantitation of CoQ10 were, respectively, 1.2 ng/mL (S/N = 3) and 4.0 ng/mL (S/N = 10). The relative standard deviations of peak area were 0.91% and 1.21% for intra-day and inter-day, respectively. The recoveries of CoQ10 ranged from 98.2 to 99.3% and the corresponding RSDs were less than 2.4%. Analysis took 5 min, making the method suitable for rapid determination of CoQ10 in tobacco leaves. The proposed method has been successfully applied to the analysis of CoQ10 in the leaves from eight varieties of tobacco.

Chromatography, High Pressure Liquid↗

PubMed2006

Construction of fingerprinting and genetic diversity of mulberry cultivars in China by ISSR markers.

The ISSR fingerprintings of 24 mulberry cultivars were constructed. Totally 80 bands were produced using 17 primers selected from 20 primers. Of them, 40 bands showed polymorphism. From the bands amplified, there were three independent ways to identify the mulberry varieties, such as unique ISSR markers, unique band patterns and a combination of the band patterns provided by different primers. ISSRs were very effective in differentiating the mulberry varieties. The mean genetic similarity coefficient, the mean Nei's gene diversity (h), and the mean Shannon's Information index (I) of mulberry cultivars were 0.8731, 0.1210, and 0.1942, respectively. This suggests that the genetic diversity of mulberry cultivars was low and the genetic base was narrow. Both UPGMA cluster and PCA (Principal Coordinates Analysis) analysis showed clear genetic relationships among the 24 mulberry cultivars. The major clusters were related to known pedigree relationships.

China↗

PubMed2006

cis-Terpenones as an effective chemopreventive agent against aflatoxin B1-induced cytotoxicity and TCDD-induced P450 1A/B activity in HepG2 cells.

Aflatoxin B1 (AFB1) is a potent carcinogen, which can significantly increase the risk of hepatocellular carcinoma development through food contamination. In past decades, chemopreventive agents, such as oltipraz and chlorophyllins, have demonstrated that chemo-intervention is an effective approach to reduce hepatotoxicity by AFB1. However, because of the potential adverse effects of these agents, alternative novel mechanism-based chemopreventive agents are needed. We report here that novel cis-terpenones 1-3, which were synthesized as the precursors of natural product analogues in our laboratory, showed promising protective effects against AFB1-induced cytotoxicity in HepG2 cells. Chemo-protection was observed with increasing concentrations of cis-terpenones in the co-treatment of AFB1, and no cytotoxicity was observed with cis-terpenones alone. In addition, cis-terpenones 1-3 at 10 and microM effectively inhibited induced cytochrome P450 1A/1B activity by 50% in HepG2 cells, as indicated by an EROD assay. P450 1A/B is involved in the activation of many pre-carcinogens and is highly inducible in liver cells. These results suggested that novel terpenones 1-3 are candidates for the development of novel mechanism-based chemopreventive agents against AFB1 and other carcinogenic stimuli.

Aflatoxin B1↗

PubMed2006

Incidence of atherosclerotic cardiovascular disease among HIV patients receiving dialysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is increasing in incidence in persons with human immunodeficiency virus (HIV). It is not known whether the morbidity and mortality rate of ASCVD is similarly increasing among patients with HIV end-stage renal disease (ESRD), who are living longer since the initiation of newer therapeutic regimens in 1997. METHODS: We conducted a population-based study of 8,312 HIV ESRD patients enrolled in the US Renal Data System from 1987 to 2001. We determined the incidence of fatal and nonfatal ASCVD events stratified by date of dialysis therapy initiation. RESULTS: There were 3,112 HIV ESRD patients (77.9% men; mean age, 39.6 +/- 9.6 years) who initiated dialysis therapy before 1997 and 2,371 patients (71.5% men; mean age, 41.3 +/- 9.7 years) who initiated dialysis therapy after 1997. Cumulative incidences of ASCVD for those initiating dialysis therapy before 1997 compared with after 1997 were 10.6% versus 13.5% at 12 months, 18.8% versus 27.6% at 24 months, 26.2% versus 42.4% at 36 months, and 33.7% versus 65.9% at 48 months (P < 0.0001 by log rank). Those who initiated dialysis therapy after 1997 had a greater risk for developing ASCVD (adjusted hazard ratio, 1.57; 95% confidence interval, 1.29 to 1.92) than those who initiated dialysis therapy before 1997 after adjusting for demographics and ASCVD risk factors. CONCLUSION: There is an increased risk for ASCVD in patients with HIV who initiated dialysis therapy after 1997. This may reflect the long-term complications of multidrug regimens, as well as improved survival from these regimens leading to prolonged exposure to ASCVD risk factors.

Adult↗

PubMed2006

Concentrations and source characteristics of airborne carbonyl compounds measured outside urban residences.

This paper presents the analysis of ambient air concentrations of 10 carbonyl compounds (aldehydes and ketones) measured in the yards of 87 residences in the city of Elizabeth, NJ, throughout 1999-2001. Most of these residences were measured twice in different seasons; the sampling duration was 48 hr each time. The authors observed higher concentrations for most of the measured carbonyl compounds on warmer days, reflecting larger contributions of photochemical reactions on warmer days. The estimated contributions of photochemical production varied substantially across the measured carbonyl compounds and could be as high as 60%. Photochemical activity, however, resulted in a net loss for formaldehyde. The authors used stepwise multiple linear regression models to evaluate the impact of traffic sources and meteorological conditions on carbonyl concentrations using the data collected on colder days (with lower photochemical activities). They found that the concentrations of formaldehyde, acetaldehyde, acrolein, propionaldehyde, crotonaldehyde, benzaldehyde, glyoxal, and methylglyoxal significantly decreased with increasing distance between a measured residence and one or more major roadways. They also found significant negative associations between concentrations for most of the measured carbonyl compounds and each of the following meteorological parameters: mixing height, wind speed, and precipitation.

Air Pollutants, Occupational↗

PubMed2006

Isolated antiplasmin deficiency presenting as a spontaneous bleeding disorder in a 63-year-old man.

Spontaneous bleeding in adults is a major problem, and in a significant number of these patients no cause is found. A 63-year-old Caucasian man presented to our hematology clinic with a large hematoma of his left thigh. Initial investigations did not show any conclusive abnormalities of primary or secondary hemostasis. Subsequent tests demonstrated a type 1 deficiency of antiplasmin. Treatment with low doses of epsilon-aminocaproic acid resulted in resolution of the hematoma and control of bleeding. We sought to determine the cause of the patient's isolated antiplasmin deficiency but no explanation was found. Three heterozygous polymorphisms were identified in his antiplasmin gene, ruling out major gene deletions. Each of these three polymorphisms has been previously reported in healthy blood donors. Finally, since response to antifibrinolytics can be dramatic, deficiencies of antiplasmin must be considered in patients presenting at any age with a spontaneous bleeding disorder.

Aminocaproates↗

PubMed2006