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Biomedical subjects

J M Wang

Publications and source records attributed to J M Wang.

At least 19 recordsLinked to original sources
PubMed2006

Obesity, fitness and health in Taiwanese children and adolescents.

OBJECTIVE: To examine the prevalence of childhood and adolescent obesity in Taiwan and investigate the association between excess weight and physical fitness and blood pressure. DESIGN: Cross-sectional study. SUBJECTS: A total of 13 935 children and adolescents aged 6-18 years (boys: 7031, girls: 6904) were involved in the 1999 survey and 24 586 (boys: 12 367, girls: 12 219) were available in the 2001 survey. MEASUREMENTS: Weight, height, systolic and diastolic blood pressures, and health-related fitness tests (bent-leg curl-ups, sit-and-reach test and step test) were measured. RESULTS: The overall prevalence of obesity (including overweight) in boys was 19.8% in 1999 and 26.8% in 2001. It was lower in girls with 15.2% in 1999 and 16.5% in 2001. The normal weight group performed better (P<0.05) than the overweight/obese group in all fitness tests except in the 2001 sit-and-reach test where there were no differences between the two groups. The risk of hypertension increased nearly two times for the overweight/obese-fit group and nearly three times for the overweight/obese-unfit group compared to the normal weight-fit group (adjusted odds ratio (AOR)=1.93, 95%CI=1.514-2.451 and AOR=2.93, 95%CI=2.493-3.454, respectively). CONCLUSION: Overall, the findings demonstrated that there is an increasing trend in overweight/obesity prevalence for Taiwanese youth even in a 2-year period. The overweight/obese youngsters tend to have poorer muscular strength and cardiovascular endurance than the normal weight group. The overweight/obese and unfit group had a greater risk of hypertension than other groups. However, this risk was significantly lower if obese/overweight children had a higher than average level of cardiovascular fitness.

Adolescent↗
PubMed2005

17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection.

Our group and others have demonstrated that 17beta-estradiol (E2) induces neurotrophic and neuroprotective responses in hippocampal and cortical neurons which are dependent upon the Src/extracellular signal-regulated kinase (ERK) signaling pathways. The purpose of this study was to determine the upstream mechanism(s) that initiates the signaling cascade leading to E2-inducible neuroprotection. We tested the hypothesis that E2 activates rapid Ca(2+) influx in hippocampal neurons, which would lead to activation of the Src/ERK signaling cascade and up-regulation of Bcl-2 protein expression. Using fura-2 ratiometric Ca(2+) imaging, we demonstrated that E2 induced a rapid rise of intracellular Ca(2+) concentration ([Ca(2+)](i)) within minutes of exposure which was blocked by an L-type Ca(2+) channel antagonist. Inhibition of L-type Ca(2+) channels resulted in a loss of E2 activation of the Src/ERK cascade, activation of cyclic-AMP response element binding protein (CREB) and subsequent increase in Bcl-2. Real-time intracellular Ca(2+) imaging combined with pERK immunofluorescence, demonstrated that E2 induced [Ca(2+)](i) was coincident with ERK activation in the same neuron. Small interfering RNA knockdown of CREB resulted in a loss of E2 activation of CREB and subsequent E2-induced increase of Bcl-2 expression. We further demonstrated the presence of specific membrane E2 binding sites in hippocampal neurons. Together, these data indicate that E2-induced Ca(2+) influx via the L-type Ca(2+) channel is required for E2 activation of the Src/ERK/CREB/Bcl-2 signaling. Implications of these data for understanding estrogen action in brain and use of estrogen therapy for prevention of neurodegenerative disease are discussed.

Animals↗
PubMed2004

Additive effects of combined valsartan and spironolactone on cardiac aldosterone escape in spontaneously hypertensive rats.

The additive effects of combined valsartan and spironolactone on plasma and cardiac aldosterone escape were evaluated in spontaneously hypertensive rats (SHRs). Twenty-four SHRs were treated with valsartan (30 mg/kg body weight per day), spironolactone (20 mg/kg body weight per day) and a combination of both for 4 months. Blood was collected and plasma aldosterone (PA) was estimated with radioimmunoassay (RIA). Ex vivo heart perfusion was performed, the ex vivo cardiac aldosterone (EXCA) was assessed by RIA after high-performance liquid chromatography separation. PA and EXCA were significantly decreased after one month but increased after 4 months in valsartan administration group. The combined valsartan and spironolactone therapy normalized cardiac aldosterone levels. This study provides the first evidence that the long-term treatment with Angiotensin II type 1 receptor antagonist (AT1A) induces local aldosterone escape in cardiovascular tissue, whereas the combined AT1A and spironolactone therapy inhibits the escape in hypertensive rats.

Aldosterone↗
PubMed2003

Glutamate enhances caspase-3 immunoreactivity in cultured spinal cord neurons of newborn rats.

The role of glutamate in the mechanism of spinal neuron death is not fully understood. With addition of glutamate to primary culture of 11-day-old rat spinal cord, the number of caspase-3 positive small neurons of the dorsal horn greatly increased at 6-24 h in contrast to the case with vehicle. The addition of glutamate made caspase-3 immunoreactivity stronger in the cytoplasm of large motor neurons in the ventral horn. The present results show that excessive amount of glutamate enhances apoptotic pathway through caspase-3 in cultured spinal neurons of newborn rat.

Animals↗
PubMed2002

The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R.

The function of urokinase and its receptor is essential for cell migration in pathological conditions, as shown by the analysis of knockout mice phenotypes. How a protease of a fibrinolytic pathway can induce migration is not understood and no link between this protease and migration-promoting G protein-coupled receptors has been described. We now show that FPRL1/LXA4R, a G protein-coupled receptor for a number of polypeptides and for the endogenous lipoxin A4 (LXA4), is the link between urokinase-type plasminogen activator (uPA) and migration as it directly interacts with an activated, soluble, cleaved form of uPA receptor (uPAR) (D2D3(88-274)) to induce chemotaxis. In this article we show that (i) both uPAR and FPRL1/LXA4R are necessary for the chemotactic activity of uPA whereas FPRL1/LXA4R is sufficient to mediate D2D3(88-274)-induced cell migration. (ii) Inhibition or desensitization of FPRL1/LXA4R by antibodies or specific ligands specifically prevents chemotaxis induced by D2D3(88-274) in THP-1 cells and human peripheral blood monocytes. (iii) Desensitization of FPRL1/LXA4R prevents the activation of tyrosine kinase Hck induced by D2D3(88-274). (iv) D2D3(88-274) directly binds to FPRL1/LXA4R and is competed by two specific FPRL1/LXA4R agonists, the synthetic MMK-1 peptide and a stable analog of LXA4. Thus, a naturally produced cleaved form of uPAR is a unique endogenous chemotactic agonist for FPRL1/LXA4R receptor and its activity can be antagonized by specific ligands. These results provide the first direct link, to our knowledge, between the fibrinolytic machinery and the inflammatory response, demonstrating that uPA-derived peptide fragments can activate a specific chemotactic receptor.

Animals↗
PubMed2002

Up-regulation of FPR2, a chemotactic receptor for amyloid beta 1-42 (A beta 42), in murine microglial cells by TNF alpha.

Human FPRL1 and its mouse homologue FPR2 are functional receptors for several exogenous and host-derived chemotactic peptides, including amyloid beta(42) (A beta(42)), a critical pathogenic factor in Alzheimer's disease. We investigated the effect of TNF alpha on the expression and function of FPR2 in mouse microglial cells, a crucial inflammatory cell type in the CNS. Primary murine microglia and a cell line N9 in resting state expressed low levels of FPR2 gene and lacked the response to chemotactic agonists for this receptor. Incubation with TNF alpha, however, increased microglial expression of FPR2 gene, in association with potent chemotactic responses to FPR2-specific agonists including A beta(42). The effect of TNF alpha was dependent on the p55 TNF alpha receptor and activation of MAP kinase p38. TNF alpha concomitantly down-regulated microglial response to the chemokine SDF-1 alpha. Thus, by selectively up-regulating FPR2 in microglia, TNF alpha has the capacity to amplify host response in inflammatory diseases in the CNS.

Amyloid beta-Peptides↗
PubMed2001

Expressions of nitrotyrosine and TUNEL immunoreactivities in cultured rat spinal cord neurons after exposure to glutamate, nitric oxide, or peroxynitrite.

Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanism is not fully understood. We examined cell damage of primary culture of 11-day-old rat spinal cord by addition of glutamate, nitric oxide (NO) or peroxynitrite (PN) with detection of nitrotyrosine (NT) or terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL). With addition of glutamate, NOC18 (a slow NO releaser) or PN, immunoreactivity for NT became stronger in the cytoplasm of large motor neurons in the ventral horn at 6 to 48 hr and positive in the axons of the ventral horn at 24 to 48 hr. TUNEL positive nuclei were found in spinal large motor neurons from 24 hr, and the positive cell number greatly increased at 48 hr in contrast to the vehicle. Pretreatment of cultures with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor antagonist, NO-suppressing agent, and antioxidant protected the immunoreactivity for NT or TUNEL. The present results suggest that both excitotoxic and oxidative stress play an important role in the upregulation of NT nitration and the apoptotic pathway in cultured rat spinal neurons.

Animals↗
PubMed2001

Differential regulation of chemokine gene expression by 15-deoxy-delta 12,14 prostaglandin J2.

Ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), such as 15-deoxy-Delta(12,14)PGJ2 (15d-PGJ2) have been proposed as a new class of antiinflammatory compounds with possible clinical applications. As there is some controversy over the inhibitory effects of 15d-PGJ2 on chemokine gene expression, we investigated whether 15d-PGJ2 itself affected chemokine gene expression in human monocytes/macrophages and two monocytic cell lines. Here we demonstrate that the 15d-PGJ2 can induce IL-8 gene expression. In contrast, monocyte chemoattractant protein-1 gene expression was suppressed by 15d-PGJ2, while the expression of RANTES was unaltered. Furthermore, concomitant treatment of monocytes/macrophages with 15d-PGJ2 (2.5 x 10(-6) M) potentiated LPS-induced gene expression of IL-8 mRNA, but suppressed PMA-induction of IL-8 mRNA. In addition, treatment of U937 and THP-1 cells with 15d-PGJ2 also resulted in induction of IL-8 gene expression. Further studies demonstrated that 15d-PGJ2 regulated IL-8 gene expression via a ligand-specific and PPARgamma-dependent pathway. Our observations revealed a previous unappreciated function and mechanism of 15d-PGJ2-mediated regulation of cytokine gene expression in monocytes/macrophages.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2001

Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes.

It has been proposed that in the early stages of human immunodeficiency (HIV) infection, before the loss of CD4(+) T cells, inhibition of IL-12 production from host antigen-presenting cells plays a critical role in the suppression of T-helper cell type 1 responses. Activation of the G(i)-protein-coupled high-affinity N-formyl peptide receptor by f-met-leu-phe and HIV-derived peptide T-20-suppressed IL-12 p70 production from human monocytes in response to both T-cell-dependent and T-cell-independent stimulation are reported. Activation of the low-affinity N-formyl peptide receptor by the HIV-derived F-peptide suppressed IL-12 production more modestly. This suppression was pertussis toxin sensitive and was selective for IL-12; the production of IL-10, transforming growth factor-beta, and tumor necrosis factor-alpha was unaltered. The production of IL-12 p70 by dendritic cells was unaffected by these peptides despite functional expression of the high-affinity fMLP receptor. These findings provide a potential direct mechanism for HIV-mediated suppression of IL-12 production and suggest a broader role for G-protein-coupled receptors in the regulation of innate immune responses. (Blood. 2001;97:3531-3536)

Amino Acid Sequence↗
PubMed2001

The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1.

The G protein-coupled 7 transmembrane (STM) chemoattractant receptors can be inactivated by heterologous desensitization. Earlier work showed that formly peptide receptor-like 1 (FPRL1), an STM receptor with low affinity for the bacterial chemotactic peptide formyl-methionyl-leucyl-phenylalamine (fMLF), is activated by peptide domains derived from the human immunodeficiency virus (HIV)-1 envelope glycoprotein gp120 and its activation results in desensitization and down-regulation of the chemokine receptors CCR5 and CXCR4 from monocyte surfaces. This study investigated the possibility of interfering with the function of CCR5 or CXCR4 as HIV-1 coreceptors by activating FPRL1. Cell lines were established expressing FPRL1 in combination with CD4/CXCR4 or CD4/CCR5 and the effect of a synthetic peptide, WKYMVm, a potent activator of formyl peptide receptors with preference for FPRL1 was determined. Both CXCR4 and CCR5 were desensitized by activation of the cells with WKYMVm via a staurosporine-sensitive pathway. This desensitization of CXCR4 and CCR5 also attenuated their capacity as the fusion cofactors for HIV-1 envelope glycoprotein and resulted in a significant inhibition of p24 production by cell lines infected with HIV-1 that use CCR5 or CXCR4 as coreceptors. Furthermore, WKYMVm inhibited the infection of human peripheral monocyte-derived macrophages and CD4(+) T lymphocytes by R5 or X4 strains of HIV-1, respectively. These results indicate that heterologous desensitization of CCR5 and CXCR4 by an FPRL1 agonist attenuates their major biologic functions and suggest an approach to the development of additional anti-HIV-1 agents. (Blood. 2001;97:2941-2947)

Antiviral Agents↗
PubMed2001

Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain.

Amyloid-beta, the pathologic protein in Alzheimer's disease, induces chemotaxis and production of reactive oxygen species in phagocytic cells, but mechanisms have not been fully defined. Here we provide three lines of evidence that the phagocyte G protein-coupled receptor (N-formylpeptide receptor 2 (FPR2)) mediates these amyloid-beta-dependent functions in phagocytic cells. First, transfection of FPR2, but not related receptors, including the other known N-formylpeptide receptor FPR, reconstituted amyloid-beta-dependent chemotaxis and calcium flux in HEK 293 cells. Second, amyloid-beta induced both calcium flux and chemotaxis in mouse neutrophils (which express endogenous FPR2) with similar potency as in FPR2-transfected HEK 293 cells. This activity could be specifically desensitized in both cell types by preincubation with a specific FPR2 agonist, which desensitizes the receptor, or with pertussis toxin, which uncouples it from G(i)-dependent signaling. Third, specific and reciprocal desensitization of superoxide production was observed when N-formylpeptides and amyloid-beta were used to sequentially stimulate neutrophils from FPR -/- mice, which express FPR2 normally. Potential biological relevance of these results to the neuroinflammation associated with Alzheimer's disease was suggested by two additional findings: first, FPR2 mRNA could be detected by PCR in mouse brain; second, induction of FPR2 expression correlated with induction of calcium flux and chemotaxis by amyloid-beta in the mouse microglial cell line N9. Further, in sequential stimulation experiments with N9 cells, N-formylpeptides and amyloid-beta were able to reciprocally cross-desensitize each other. Amyloid-beta was also a specific agonist at the human counterpart of FPR2, the FPR-like 1 receptor. These results suggest a unified signaling mechanism for linking amyloid-beta to phagocyte chemotaxis and oxidant stress in the brain.

Amyloid beta-Peptides↗
PubMed2001

The neutrophil granule protein cathepsin G activates murine T lymphocytes and upregulates antigen-specific IG production in mice.

Cathepsin G is a neutrophil granule derived antimicrobial chymotrypsin-like enzyme. Our previous study showed that cathepsin G induces chemotactic migration of human phagocytic leukocytes and increases random migration of T lymphocytes. In this study, we investigated the capacity of cathepsin G to activate T lymphocytes and to modulate antigen-specific humoral responses in mice. We found that cathepsin G is mitogenic for and induces production of IFN-gamma by murine T cells in vitro. Injection of cathepsin G in BALB/c mice immunized with keyhole limpet hemocyanin (KLH) adsorbed to aluminum hydroxide resulted in a significantly increased production of KLH-specific IgG1 and IgG2a antibodies. There was a dose-dependent increase in KLH-specific proliferation of lymphocytes from draining lymph nodes from mice treated with KLH and cathepsin G when compared with those treated with KLH alone. Subsequent analysis of IFN-gamma and IL-4 release following in vitro re-stimulation of draining lymph node lymphocytes obtained from KLH-immunized mice suggested that cathepsin G augments KLH-specific Ig antibody production via activation of T cells, presumably involving both Th1 and Th2 pathways. Thus, neutrophil granule cathepsin G, in addition to its capacity to kill microbes and to enhance leukocyte motility, activates T lymphocytes and modulates humoral immunity.

Adjuvants, Immunologic↗
PubMed2001

Primary hepatocytes from mice treated with IL-2/IL-12 produce T cell chemoattractant activity that is dependent on monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2).

The IFN-gamma-inducible proteins monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2) can contribute to IL-12-induced antiangiogenic and leukocyte-recruiting activities, but the extent to which leukocytes vs parenchymal cells in different organs contribute to the production of these molecules remains unclear. The results presented herein show that IFN-gamma-dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 plus IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-gamma. In addition to depending on IFN-gamma, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate up-regulation of the IFN-gamma R alpha and beta-chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-gamma contain increased chemotactic activity for enriched human and mouse CD3(+) T cells, as well as mouse DX5(+) NK cells. The hepatocyte-derived chemotactic activity for mouse T cells but not NK cells was ablated by Abs specific for Mig and Crg-2. These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses.

Animals↗
PubMed2001

Differential regulation of formyl peptide receptor-like 1 expression during the differentiation of monocytes to dendritic cells and macrophages.

Monocytes are the common precursors for myeloid dendritic cells (DC) and macrophages. Identification of chemotactic receptors expressed by myeloid DC, macrophages, and their precursors in the course of differentiation and maturation is important not only for elucidation of their in vivo trafficking, but also for understanding of the functional distinction between DC and macrophages. We chose to study formyl peptide receptor like-1 (FPRL1), a chemotactic receptor known to interact with several endogenous agonists that are involved in inflammatory and host defense responses. Here we show that FPRL1 is down-regulated as monocytes differentiate into DC. This down-regulation occurs at both mRNA and functional levels. Therefore, the interaction of FPRL1 with its agonists is more likely to regulate the in vivo trafficking of DC precursors than DC. In contrast, FPRL1 expression is maintained at both mRNA and functional levels as monocytes differentiate into macrophages. Thus, our results demonstrate further distinctions between myeloid DC and macrophages, albeit they share a common precursor. The fact that macrophages rather than myeloid DC express functional FPRL1 suggests that this chemotactic receptor may be more involved in inflammatory reactions and innate host defense than in adaptive immune responses.

Animals↗
PubMed2001

The neurotoxic prion peptide fragment PrP(106-126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1.

Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP(106-126), was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes. The cell surface receptor(s) mediating the activity of PrP(106-126) is unknown. In this study, we show that PrP(106-126) is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP(106-126), FPRL1 underwent a rapid internalization and, furthermore, PrP(106-126) enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin. Thus, FPRL1 may act as a "pattern recognition" receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases.

Animals↗
PubMed2001

Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1.

Amyloid beta (Abeta) is a major contributor to the pathogenesis of Alzheimer's disease (AD). Although Abeta has been reported to be directly neurotoxic, it also causes indirect neuronal damage by activating mononuclear phagocytes (microglia) that accumulate in and around senile plaques. In this study, we show that the 42 amino acid form of beta amyloid peptide, Abeta(42), is a chemotactic agonist for a seven-transmembrane, G-protein-coupled receptor named FPR-Like-1 (FPRL1), which is expressed on human mononuclear phagocytes. Moreover, FPRL1 is expressed at high levels by inflammatory cells infiltrating senile plaques in brain tissues from AD patients. Thus, FPRL1 may mediate inflammation seen in AD and is a potential target for developing therapeutic agents.

Alzheimer Disease↗
PubMed2001

Desensitization of chemokine receptor CCR5 in dendritic cells at the early stage of differentiation by activation of formyl peptide receptors.

Chemokine receptors are subjected to heterologous desensitization by activation of formyl peptide receptors. We investigated the cross-talk between formyl peptide receptors and the chemokine receptor CCR5 in human monocyte-differentiated immature dendritic cells (iDC). Monocytes cultured with GM-CSF and IL-4 for 4 days exhibit markers characteristic of iDC and maintain the expression of both formyl peptide receptors FPR and FPRL1, as well as CCR5. Pretreatment of iDC with W peptide (WKYMVm), a potent agonist for FPR and FPRL1 but with preference for FPRL1, resulted in down-regulation of CCR5 from the cell surface and reduced cell response to the CCR5 ligands through a PKC-dependent pathway. Furthermore, W peptide induced a PKC-dependent phosphorylation of CCR5 and inhibited infection of iDC by R5 HIV-1. Our results indicate that the expression and functions of CCR5 in iDC can be attenuated by W peptide, which activates formyl peptide receptors, and suggest an approach to the design of novel anti-HIV-1 agents.

Cell Differentiation↗