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Biomedical subjects

H Zheng

Publications and source records attributed to H Zheng.

At least 55 records · Page 3Linked to original sources
PubMed2001

Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway.

Vascular diseases such as atherosclerosis are characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs) within the intimal lining. The intimal VSMCs exhibit an increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), and the administration of pharmacological PPARgamma agonists attenuates vascular lesion formation. The factors that regulate PPARgamma expression in the vasculature are poorly defined. Here we report that platelet-derived growth factor (PDGF) upregulates PPARgamma by the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. Using Northern-blotting and Western-blotting analyses, we observed that the levels of PPARgamma mRNA and protein were increased by 2- to 3.5-fold in human aortic smooth muscle cells (HASMCs) treated with PDGF (20 ng/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhibitor (LY294002, 50 micromol/L), and partially inhibited by a MEK1 inhibitor (U0126, 10 micromol/L), but not affected by a p38 kinase inhibitor (SB202190, 10 micromol/L). In addition, overexpression of the dominant-negative p85 subunit of PI3-kinase or Akt proteins blocked the PDGF-induced PPARgamma expression. Taken together, our results suggest that PDGF induces PPARgamma expression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterization of factors and signaling pathways that modulate PPARgamma expression in VSMCs may have important implications for understanding the pathogenesis of vascular diseases.

Aorta↗
PubMed2001

Food-related gastrointestinal signals activate caudal brainstem neurons expressing both NMDA and AMPA receptors.

Vagal mechano- and chemosensors in the gastrointestinal tract and the portal-hepatic axis signaling the arrival of nutrients are major determinants of the satiation process. Although glutamate and its various receptor subtypes have been shown to transmit gustatory and cardiovascular sensory information at the level of the solitary nucleus (nucleus tractus solitarius; NTS), their involvement in the transmission of gastrointestinal satiety signals is not clear. Gastrointestinal sensors were stimulated by gastric balloon distension or by intraduodenal infusion of either linoleic acid or glucose in chronically catheterized, non-anesthetized rats, leading to activation of second order neurons in the NTS as detected by c-Fos immunohistochemistry. Subsequent (double)-immunohistochemistry for either NMDA or AMPA glutamate receptors was used to determine the percentage of activated neurons expressing a particular receptor subtype. Gastric distension and duodenal nutrient stimuli produced slightly, but significantly different patterns of c-Fos induction in the dorsal vagal complex. Expression of NMDA receptors, as detected by a NR2ab subunit-specific antibody, was abundant throughout the dorsal medulla. The percentage of neurons in the NTS activated by gastric distension (63.9+/-2.9%), linoleic acid (62.8+/-1.4%), and glucose (64.1+/-1.4%), expressing NMDA receptor was similar. Expression of AMPA receptors, as detected by a GLUR2/3 subunit-specific antibody, was equally abundant throughout the dorsal medulla. Again, the percentage of activated neurons expressing GLUR2/3 was similar for the gastric distension (59.8-65.6%) and duodenal linoleic acid (60.6-67.0%) stimuli, and for the various subnuclei of the NTS. Finally, GLUR1-specific immunoreactivity was much less abundant, with only a small percentage of distension-activated (4.4+/-0.4%) and linoleic acid-activated (5.1+/-0.4%) neurons expressing this receptor subunit. The results suggest a widespread, general involvement of both NMDA and AMPA receptors in primary afferent signal transmission at the level of the NTS, with no differential recruitment of the examined receptor subtypes by the different gastrointestinal sensory stimuli. This may indicate a high degree of convergence among sensory signals, or alternatively, the presence of other transmission systems such as peptides referring sensory specificity to second order neurons.

Animals↗
PubMed2001

A recombinant glycine receptor fragment forms homo-oligomers distinct from its GABA(A) counterpart.

The ligand-gated ion channel receptor superfamily includes receptors for glycine, GABA, acetylcholine and serotonin. Whereas the acetylcholine and serotonin receptors mediate excitory neurotransmissions, both glycine and GABA(A) receptors are inhibitory. In this study, a fragment of the human glycine receptor alpha1 subunit, consisting of residues Ala165-Met291 (numbering based on the precursor protein), was hyperexpressed for the first time in Escherichia coli. This fragment is highly homologous in sequence to the corresponding fragment of the GABA(A) receptor. The recombinant fragment was found to have stable beta-rich secondary structure, similar to that found for the homologous GABA(A) receptor fragment, and ordered tertiary packing, suggesting a stable structural domain. Results from laser scattering studies suggest that the fragment forms trimers in solution. In addition, SDS-induced changes in secondary structure were found to occur prior to changes in oligomerization status, suggesting that oligomerization was secondary structure dependent. A study of quaternary structure using single particle analysis electron microscopy (EM) also suggested that the fragment formed homo-trimers. One trimer measures approximately 7.5 nm in diameter with a central cavity approximately 1.5 nm across. This is the first EM study on a single domain of the glycine receptor and the result is in contrast to the pentameric assembly of the equivalent GABA(A) receptor fragment reported by us earlier. The fact that this fragment alone could form oligomers in vitro suggests that amino acid residues within this segment may be involved in the oligomerization of the glycine receptor in vivo. Furthermore, the finding that two cousin receptor fragments form distinct quaternary structures indicates that sequence similarity does not necessarily imply quaternary structure similarity and, hence, care must be taken when applying a structure model derived from studies of individual receptors to the whole ligand-gated ion channel superfamily.

Amino Acid Sequence↗
PubMed2001

Net-targeted mutant mice develop a vascular phenotype and up-regulate egr-1.

The ternary complex factors (TCFs) Net, Elk-1 and Sap-1 regulate immediate early genes through serum response elements (SREs) in vitro, but, surprisingly, their in vivo roles are unknown. Net is a repressor that is expressed in sites of vasculogenesis during mouse development. We have made gene-targeted mice that express a hypomorphic mutant of Net, Net delta, which lacks the Ets DNA-binding domain. Strikingly, homozygous mutant mice develop a vascular defect and up-regulate an immediate early gene implicated in vascular disease, egr-1. They die after birth due to respiratory failure, resulting from the accumulation of chyle in the thoracic cage (chylothorax). The mice have dilated lymphatic vessels (lymphangiectasis) as early as E16.5. Interestingly, they express more egr-1 in heart and pulmonary arteries at E18.5. Net negatively regulates the egr-1 promoter and binds specifically to SRE-5. Egr-1 has been associated with pathologies involving vascular stenosis (e.g. atherosclerosis), and here egr-1 dysfunction could possibly be associated with obstructions that ultimately affect the lymphatics. These results show that Net is involved in vascular biology and egr-1 regulation in vivo.

Animals↗
PubMed2001

Evidence against GRB10 as the gene responsible for Silver-Russell syndrome.

Recent evidence shows that Silver-Russell syndrome (SRS), the major functional deficit of which is limited growth, both intrauterine and postnatal, is due to a double dose of a gene within 7p11.2-p13 that is normally expressed exclusively from the maternal copy. Of the several growth-related genes in this chromosomal region, only GRB10 has been demonstrated to be imprinted; however, imprinting was limited to brain and muscle and was incomplete. Using reverse-transcript PCR, we now confirm GRB10 imprinting in these two tissues is isoform-specific and, more importantly, demonstrate absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth. Thus, it is unlikely that GRB10 is the gene responsible for SRS.

Aged↗
PubMed2001

Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis.

Presenilin 1 (PS1) is required for the proteolytic processing of Notch and the beta-amyloid precursor protein (APP), molecules that play pivotal roles in cell-fate determination during development and Alzheimer's disease pathogenesis, respectively. In addition, PS1 interacts with beta-catenin and promotes its turnover through independent mechanisms. Consistent with this activity, we report here that PS1 is important in controlling epidermal cell proliferation in vivo. PS1 knockout mice that are rescued through neuronal expression of human PS1 transgene develop spontaneous skin cancers. PS1-null keratinocytes exhibit higher cytosolic beta-catenin and beta-catenin/lymphoid enhancer factor-1/T cell factor (beta-catenin/LEF)-mediated signaling. This effect can be reversed by reintroducing wild-type PS1, but not a PS1 mutant active in Notch processing but defective in beta-catenin binding. Nuclear beta-catenin protein can be detected in tumors. Elevated beta-catenin/LEF signaling is correlated with activation of its downstream target cyclin D1 and accelerated entry from G(1) into S phase of the cell cycle. This report demonstrates a function of PS1 in adult tissues, and our analysis suggests that deregulation of beta-catenin pathway contributes to the skin tumor phenotype.

Animals↗
PubMed2001

Scaling of the magnetoconductivity of silicon MOSFETs: evidence for a quantum phase transition in two dimensions.

For a broad range of electron densities n and temperatures T, the in-plane magnetoconductivity of the two-dimensional system of electrons in silicon MOSFETs can be scaled onto a universal curve with a single parameter H(sigma)(n,T), where H(sigma) obeys the empirical relation H(sigma) = A(n) [Delta(n)(2)+T2](1/2). The characteristic energy k(B)Delta associated with the magnetic field dependence of the conductivity decreases with decreasing density, and extrapolates to 0 at a critical density n(0), signaling the approach to a zero-temperature quantum phase transition. We show that H(sigma) = AT for densities near n(0).

Journal Article↗
PubMed2001

[Effect of hepatitis C virus NS3 protein on expression of iNOS mRNA in hepatocarcinogenesis].

OBJECTIVE: To investigate hepatocarcinogenesis by detecting the effect of HCV NS3 protein on expression of inducible nitric oxide synthase (iNOS) mRNA in hepatocellular carcinoma (HCC) and pericarcinomatous liver tissues(PCLT). METHODS: The expression of HCV NS3 protein and iNOSmRNA was detected by immunohistochemical technique (SP method) and in situ hybridization in specimens of HCC and PCLT from 52 patients with HBV(-). The relationship between the positive rate and the signal strength was tested statistically. RESULTS: The positive rate of HCV NS3 protein in HCC was lower (46.2% vs. 67.3%), and signal strength was weaker than those in PCLT. The signal strength of HCV NS3 protein was correlated with the degree of carcinomatous cells differentiation in HCC (P < 0.01). The positive rates (80.8% and 90.4%) of iNOSmRNA in HCC and PCLT had no statistical difference. Signal intensity of iNOSmRNA in HCC was weaker than that in PCLT. The higher HCVNS3 protein expression level was, the stronger iNOSmRNA signals in PCLT (P < 0.01). In particular, the localization and patterns of HCV NS3 protein were much similar to those of iNOSmRNA in the PCLT of some patients. CONCLUSIONS: HCV NS3 protein may exert its hepatocarcinogenic effect in the early stage on host cells by increasing product of nitric oxide, which may bring about transformation of hepatocytes.

Adult↗
PubMed2001

Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow transplantation.

Late-onset hemorrhagic cystitis (HC) is a well-known complication of bone marrow transplantation (BMT) that is mainly attributed to infection with BK virus (BKV) and adenovirus (AdV). From 1986 through 1998, 282 patients underwent BMT, and 45 of them developed HC. Urine samples tested positive for AdV in 26 patients, of which 22 showed virus type 11. Among patients who underwent allogeneic BMT, logistic regression analysis revealed acute graft-versus-host disease (grade, > or = 2) to be the most significant predictive factor for HC (P < .0001). In addition, a total of 193 urine samples regularly obtained from 26 consecutive patients who underwent allogeneic BMT were examined for BKV, JC virus (JCV), and AdV by means of polymerase chain reaction. Of patients without HC, approximately 30% of the specimens tested positive for BKV (58 samples) and JCV (55 samples), whereas 5 (3%) tested positive for AdV. Of the 3 samples obtained from patients with HC, the numbers of positive results for BKV, JCV, and AdV were 3, 1, and 1, respectively; the numbers of positive results increased to 14 of 17, 9 of 17, and 10 of 17, respectively, when we added another 14 samples obtained from 14 patients with HC (P < .0001, P = .026, and P < .0001, respectively). In conclusion, there was significant correlation between AdV and HC in the patients we studied.

Adenovirus Infections, Human↗
PubMed2001

Fourth ventricular injection of CART peptide inhibits short-term sucrose intake in rats.

Expression of CART (cocaine-amphetamine-regulated transcript) in the rat hypothalamus is modulated by nutritional status, and injection of synthetic CART peptide into the forebrain ventricular system suppresses food intake, indicating a possible role in hypothalamic control of energy homeostasis. Its recent identification in cell bodies and central terminals of vagal afferent neurons additionally suggests a role in brainstem mechanisms of meal termination and satiety. We demonstrate here that CART[55-102] (0.2 nmol) suppresses short-term sucrose intake and overnight chow intake in non-food-deprived rats even more when delivered into the fourth ventricle as compared to the lateral ventricle. At the threshold dose (0.02-0.08 nmol) no readily noticeable motor impairments were observed. The results are consistent, but do not prove a site of action within the brainstem, possibly in mediating vagal satiety signals at the level of the NTS.

Afferent Pathways↗
PubMed2001

[Effect of activation of p-MAPK on activating c-fos and c-jun proteins in breast cancer].

OBJECTIVE: This paper was to investigate the relationship between expression of p-MAPK and oncogenesis of breast cancer. METHODS: Immunohistochemical technique was used to detect the expression of p-MAPK and c-fos and c-jun proteins in 68 cases of breast cancers, 42 cases of pericarcinomatous tissues and 7 cases of normal breast tissues. RESULTS: Positive stainings of p-MAPK, c-fos, and c-jun were localized in cancer cell nuclei. The positive rates of p-MAPK, c-fos, and c-jun were 86.8% (59/68), 82.4% (56/68), and 77.9% (53/68), respectively, which were much higher than that in pericarcinomatous tissues (P < 0.01). Of some cases, p-MAPK positive staining was also found in the nuclei of the fibroblastic and angioendothelial cells of cancer stroma. CONCLUSION: Activated or overexpressive MAPK activates the immediately-early oncogenes(c-fos, c-jun), which might play an important role in carcinogenesis of breast cancer and be an early event of oncogenesis of breast cancer.

Adult↗
PubMed2001

[Effects of Stat3 phosphorylation and expression of c-fos and c-jun proteins on hepatocarcinogenesis].

Expression of phosphorylated Stat3 (p-Stat3), c-fos and c-jun proteins was detected by immunohistochemical technique in 55 hepatocellular carcinomas (HCC) and their surrounding liver tissues. The results showed that the positive rates and signal intensity of p-Stat3, c-fos and c-jun protein in HCCs were significantly higher than those in pericarcinomatous tissues. The expressive intensity of c-fos and c-jun proteins was positively related to p-Stat3 expression in HCCs, whereas the positive correlation of expressive intensity was only observed between c-jun protein and p-Stat3 in pericarcinomatous tissues. The data suggest that the phosphorylation of Stat3 may be an early event in hepatocarcinogenesis; the overexpression of p-Stat3 protein, which activates c-fos and c-jun genes, may contribute to malignant transformation of hepatocytes; hepatocytes which expressed p-Stat3, c-fos or c-jun proteins may be potentially malignant pre-cancer cells in pericarcinomatous liver tissues.

Acute-Phase Proteins↗
PubMed2001

Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes.

The influenza A virus pandemic of 1918-1919 resulted in an estimated 20-40 million deaths worldwide. The hemagglutinin and neuraminidase sequences of the 1918 virus were previously determined. We here report the sequence of the A/Brevig Mission/1/18 (H1N1) virus nonstructural (NS) segment encoding two proteins, NS1 and nuclear export protein. Phylogenetically, these genes appear to be close to the common ancestor of subsequent human and classical swine strain NS genes. Recently, the influenza A virus NS1 protein was shown to be a type I IFN antagonist that plays an important role in viral pathogenesis. By using the recently developed technique of generating influenza A viruses entirely from cloned cDNAs, the hypothesis that the 1918 virus NS1 gene played a role in virulence was tested in a mouse model. In a BSL3+ laboratory, viruses were generated that possessed either the 1918 NS1 gene alone or the entire 1918 NS segment in a background of influenza A/WSN/33 (H1N1), a mouse-adapted virus derived from a human influenza strain first isolated in 1933. These 1918 NS viruses replicated well in tissue culture but were attenuated in mice as compared with the isogenic control viruses. This attenuation in mice may be related to the human origin of the 1918 NS1 gene. These results suggest that interaction of the NS1 protein with host-cell factors plays a significant role in viral pathogenesis.

Amino Acid Sequence↗
PubMed2001

Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing.

In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin 1 (PS1) associates with beta-catenin. In this study, we show that this interaction plays a critical role in regulating beta-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic beta-catenin, leading to a beta-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind beta-catenin (PS1Deltacat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Deltacat restores Notch-1 proteolytic cleavage and Abeta generation in PS1-deficient cells, indicating that PS1 function in modulating beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of beta-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of beta-catenin.

Alzheimer Disease↗
PubMed2001

Vagal-enteric interface: vagal activation-induced expression of c-Fos and p-CREB in neurons of the upper gastrointestinal tract and pancreas.

Many gastrointestinal and pancreatic functions are under strong modulatory control by the brain via the vagus nerve. To start identifying location and neurochemical phenotype of the enteric neurons receiving functional vagal efferent input, we activated vagal preganglionic neurons either by electrical or chemical stimulation and examined the expression of phosphorylated CREB (c-AMP response element binding protein) and the immediate early gene c-Fos. There was no spontaneous expression of both markers in the pancreas and considerable spontaneous expression of p-CREB but not Fos in the upper GI-tract. Unilateral electrical vagal stimulation-induced p-CREB was found in 40% of neurons in the head of the pancreas. Fos expression was found in 70-90% of neurons in the esophagus and stomach, in 20-30% of myenteric plexus neurons and 5-15% in submucosal neurons of the proximal duodenum. Double-labeling experiments showed that a majority of pancreatic neurons and about 25-35% of neurons in the stomach and duodenum contain NADPH-diaphorase and that many of these receive functional vagal input. Other neurons that can be vagally activated contain gastrin-releasing peptide or calretinin. Chemical stimulation of the dorsal surface of the caudal brainstem with the stable TRH analog RX77368 resulted in selective activation of vagal efferents with expression of Fos in a small number of gastric myenteric plexus neurons. The results demonstrate the suitability of this method to investigate magnitude and local distribution of vagal input to the enteric nervous system as well as specificity of its neurochemically coded pathways. They represent the first step in the identification of function-specific units of parasympathetic vagal outflow.

Activating Transcription Factor 1↗
PubMed2001

GT repeat polymorphism in the 5' flanking region of the human growth hormone receptor gene.

A polymorphic GT dinucleotide repeat sequence has been identified in the 5' flanking region of the human growth hormone receptor (hGHR) gene on chromosome 5p13.1-p12, within the promoter region of the V9 5'UTR exon. Thirteen alleles have been identified in 50 non-related individuals, with an observed heterozygosity of 52%. The major allele contains 24 repeats, although a range of 19-32 repeats has been observed. Codominant segregation was demonstrated in five two-generation and two three-generation families. This marker may be useful in analysing the role of the hGHR gene in pre- and postnatal growth disorders.

5' Untranslated Regions↗
PubMed2001

Cytoplasmic illuminations: in planta targeting of fluorescent proteins to cellular organelles.

Use of the jellyfish green-fluorescent protein as an in vivo reporter is in the process of revolutionising plant cell biology. By fusing the protein to specific targeting peptides or to sequences of complete proteins, it is now possible to observe the location, structure, and dynamics of a number of intracellular organelles over extended periods of time. In this review we discuss the most recent developments and unexpected results originating from the targeting of this unique protein and its derivatives to elements of the cytoskeleton and to membrane-bounded organelles in a range of plant cell types.

Arabidopsis↗