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Biomedical subjects

L Yao

Publications and source records attributed to L Yao.

At least 19 recordsLinked to original sources
PubMed1999

Terreic acid, a quinone epoxide inhibitor of Bruton's tyrosine kinase.

Bruton's tyrosine kinase (Btk) plays pivotal roles in mast cell activation as well as in B cell development. Btk mutations lead to severe impairments in proinflammatory cytokine production induced by cross-linking of high-affinity IgE receptor on mast cells. By using an in vitro assay to measure the activity that blocks the interaction between protein kinase C and the pleckstrin homology domain of Btk, terreic acid (TA) was identified and characterized in this study. This quinone epoxide specifically inhibited the enzymatic activity of Btk in mast cells and cell-free assays. TA faithfully recapitulated the phenotypic defects of btk mutant mast cells in high-affinity IgE receptor-stimulated wild-type mast cells without affecting the enzymatic activities and expressions of many other signaling molecules, including those of protein kinase C. Therefore, this study confirmed the important roles of Btk in mast cell functions and showed the usefulness of TA in probing into the functions of Btk in mast cells and other immune cell systems. Another insight obtained from this study is that the screening method used to identify TA is a useful approach to finding more efficacious Btk inhibitors.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12.

Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-gamma (IFN-gamma) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10-positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-gamma. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

Animals↗
PubMed1999

Functions of Bruton's tyrosine kinase in mast and B cells.

Bruton's tyrosine kinase (Btk) plays crucial roles in B cell differentiation as well as mast cell activation through the high-affinity IgE receptor (FcepsilonRI). Defects in the btk gene lead to agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Mast cells from xid and btk null mice exhibit mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FcepsilonRI cross-linking. Recent studies demonstrated the role of Btk in a sustained increase in intracellular calcium concentrations in response to antigen receptor stimulation. Btk is also involved in the activation of stress-activated protein kinases, JNK/SAPK1/2, and thereby regulates c-Jun and other transcription factors that are important in cytokine gene activation. Regulation of the JNK/SAPK activation pathway by Btk may be related to the proapoptotic function of Btk in the programmed cell death in these hematopoietic cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Correlations of bcl-2 and p53 expression with the clinicopathological features in tongue squamous cell carcinomas.

bcl-2 oncogene prolongs cell survival by inhibition of apoptosis. p53 tumor suppressor gene participates not only in cell proliferation control but also in induction of apoptosis. The expression of both bcl-2 and p53 proteins in 52 primary tongue squamous cell carcinomas (SCCs) was immunohistochemically explored in correlations with clinico-pathological features, patient's prognosis and apoptosis index (AI) of this tumor type. bcl-2 and p53 expression were identified in 26/52 (50%) cases and 31/52 (60%) cases, respectively. The frequency of bcl-2 expression was associated with tumor histologic grade (P = 0.0128) and marginally with mode of tumor invasion (P = 0.0671) but not with lymph nodal involvement. The frequency of p53 expression was associated with mode of tumor invasion (P = 0.0458) and pN status (P = 0.0224) but not with tumor histologic grade. Moreover, the three combined bcl-2/p53 staining patterns of bcl-2-/p53-, bcl-2+/p53- and bcl-2-/p53+, and bcl-2+/p53+ were significantly correlated with tumor histologic grade (P = 0.0299), mode of tumor invasion (P = 0.0022) and pN status (P = 0.0024). In addition, the frequent appearance of bcl-2 protein expression was associated with a decrease in AI (P = 0.0290). Our results suggest that the combined investigation on the two biological markers may have value in assessment of tumor aggressiveness, and that the suppressing mechanism of bcl-2 oncogene in regulation of apoptosis preserves in tongue SCC.

Apoptosis↗
PubMed1999

Combining qualitative with quantitative approaches to study contraceptive pill use.

According to large-scale studies, oral contraceptive users become pregnant at rates that exceed ideal use failure rates. It is thought that a major cause is missed pills, but current research on consistent contraceptive pill taking is characterized by inadequate measures and a failure to investigate women's thinking about their own patterns of use. The purpose of this study was to gain some understanding about women's interpretations of consistency in their own pill taking through combining qualitative with quantitative data. The study was conducted in China, where contraception is free and widely available. Five urban and five rural oral contraceptive users were followed for up to three pill-taking cycles during 1996 for a total of 759 person-days. Consistency of pill taking was measured with electronic data obtained from a new blister package made by Anderson Clinical Technologies (Elmhurst, IL). Data from these devices were reviewed and interpreted by the study participants during in-depth private interviews. The users' reasons for missing pills included disruptions in their daily routines, their husband's absence, spotting, and trouble implementing the family planning program's instructions to take one pill per day for 22 days and start the next cycle on the fifth day of menses. One user gave these reasons for two cycles but denied missing numerous pills in her third cycle. Data from a series of four questionnaires showed that most demographic, psychosocial, and service system characteristics were not related to missed pills. However, results suggested that the daily routines of rural living may make consistent use more likely and that instructions for taking the pill may be associated with prolonged pill-free intervals and skipping pills during episodes of spotting. Three of the 10 women were at increased risk of pregnancy during the study period because of their pill-taking pattern. We concluded that the combination of qualitative with quantitative data enhances understanding of contraceptive use. Women themselves offer plausible reasons for their use behaviors. Listening to women could be useful in improving programs.

Adolescent↗
PubMed1998

Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth.

An endothelial cell inhibitor was purified from supernatant of an Epstein-Barr virus-immortalized cell line and identified as fragments of calreticulin. The purified recombinant NH2-terminal domain of calreticulin (amino acids 1-180) inhibited the proliferation of endothelial cells, but not cells of other lineages, and suppressed angiogenesis in vivo. We have named this NH2-terminal domain of calreticulin vasostatin. When inoculated into athymic mice, vasostatin significantly reduced growth of human Burkitt lymphoma and human colon carcinoma. Compared with other inhibitors of angiogenesis, vasostatin is a small, soluble, and stable molecule that is easy to produce and deliver. As an angiogenesis inhibitor that specifically targets proliferating endothelial cells, vasostatin has a unique potential for cancer treatment.

Animals↗
PubMed1998

Small structural ensembles for a 17-nucleotide mimic of the tRNA T psi C-loop via fitting dipolar relaxation rates with the quadratic programming algorithm.

Solution structures are typically average structures determined with the help of nmr-derived distance and torsion angle information. However, when a biomolecule populates significantly different conformations, the average structure might be prone to artifacts, and other refinement strategies are necessary. For example, when experimental restraints are used in molecular dynamics simulations in a time-averaged fashion (MDtar), the experimental structural information does no longer need to be satisfied at each step of the simulation; instead, the whole trajectory must agree with the restraints. However, the resulting structural ensembles are large and not unique and it is not trivial to extract the essential dynamic features for a system. Here we demonstrate that large MDtar ensembles can be simplified substantially by reducing the number of members to just a few on the basis of adjusting the individual probabilities of the members with the PDQPRO program [N. B. Ulyanov et al. Biophysical Journal (1995), Vol. 68, p. 13]. This algorithm finds the global minimum for a search function that represents the best match of a given ensemble with the experimental dipolar interproton relaxation rates. We have applied this strategy to a 17-residue RNA hairpin, whose loop exhibited considerable flexibility evident from nmr data. This 17mer is a mimic of the T psi C-loop of tRNA, where nucleotide 54 is usually a ribosylthymidine. The methylation of U54, which is completely buried in transfer ribonucleic acid, is administered by tRNA (m5 U54)-methyltransferase (RUMT). Since the 17mer is a good substrate for RUMT, we previously concluded that the flexibility of the 17mer's loop is a key to how RUMT gains access to the methylation site [L. J. Yao et al. Journal of Biomolecular NMR (1996) Vol. 9. p. 229]. Application of the PDQPRO algorithm to the previously acquired MDtar trajectories allowed us to reduce the number of conformations from several hundred to one major and five or six minor conformations with individual populations from approximately 5% to approximately 50% without any deterioration in the match with the experimental data. The major conformation exhibits a continuation of A-form helicity through part of the loop, involving C60 and U59. In this and most other conformations the methylation site in U54 is no longer buried.

Algorithms↗
PubMed1998

OFQ reverses the kappa-opioid receptor-mediated depression of calcium current in rat dorsal root ganglion neurons.

Since the characterization of orphanin FQ (OFQ), the endogenous ligand of ORL1 receptor, much work has focused on its physiological functions. OFQ was reported to antagonize the effect of opioid-induced antinociception, although its mechanism remains obscure. In the present study, whole-cell patch clamp recording technique was used to observe if OFQ can reverse the inhibition of calcium current produced by the kappa-opioid agonist U50,488H (U50) in acutely dissociated rat DRG neurons. The concentrations of OFQ and U50 were 50 nM and 10 microM, respectively. Among 49 cells recorded, the calcium channel currents of 37 (75.5%) cells were inhibited by U50, of which 30 (81.1%) cells could be reversed by OFQ. It was interesting to note the similarity between OFQ and the well characterized anti-opioid peptide CCK-8 in that it reversed kappa-opioid receptor agonist induced suppression on calcium channel current, while by itself showed a calcium channel suppressive effect. Thus OFQ may be regarded as another anti-opioid peptide.

Animals↗
PubMed1998

Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.

We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Tumor necrosis factor-alpha- or lipopolysaccharide-induced expression of the murine P-selectin gene in endothelial cells involves novel kappaB sites and a variant activating transcription factor/cAMP response element.

Tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) increases expression of the P-selectin gene in murine, but not in human, endothelial cells. These mediators augment expression of a reporter gene driven by the murine, but not the human, P-selectin promoter in transfected endothelial cells. The regions from -593 to -474 and from -229 to -13 in the murine P-selectin promoter are required for TNF-alpha or LPS to stimulate reporter gene expression. Within these regions, we identified two tandem kappaB elements, a reverse-oriented kappaB site and a variant activating transcription factor/cAMP response element (ATF/CRE), that participate in TNF-alpha- or LPS-induced expression. The tandem kappaB elements bound to NF-kappaB heterodimers and p65 homodimers, the reverse-oriented kappaB site bound to p65 homodimers, and the variant ATF/CRE bound to nuclear proteins that included activating transcription factor-2. Mutations in each individual element eliminated binding to nuclear proteins and decreased by 20-60% the TNF-alpha- or LPS-induced expression of a reporter gene driven by the murine P-selectin promoter in transfected endothelial cells. Simultaneous mutations of all elements further decreased, but did not abolish, induced expression. Co-overexpression of p50 and p65 enhanced murine P-selectin promoter activity in a kappaB site-dependent manner. These data indicate that the kappaB sites and the variant ATF/CRE are required for TNF-alpha or LPS to optimally induce expression of the murine P-selectin gene. The presence of these elements in the murine, but not the human, P-selectin gene may explain in part why TNF-alpha or LPS stimulates transcription of P-selectin in a species-specific manner.

Animals↗
PubMed1998

Use of high-precision gas isotope ratio mass spectrometry to determine natural abundance 13C in lutein isolated from C3 and C4 plant sources.

A method was developed for high-precision stable carbon isotope ratio analysis of lutein isolated from a C3 (marigold flower) and a C4 (corn gluten meal) plant source using gas chromatography-combustion interfaced isotope ratio mass spectrometry. The natural abundance of 13C (expressed as delta 13C versus the international standard, Pee Dee Belemnite, in per mil units, denoted /1000) in lutein isolated from marigold flower and corn gluten meal was determined to be -29.90 +/- 0.20/1000 and -19.77 +/- 0.27/1000 (mean +/- S.D.), respectively. The high precision of gas isotope ratio mass spectrometry is potentially applicable to detect differences of isotopic composition of lutein in the blood, tissues, or excreta of animal models or humans that result from differences in the natural abundance of 13C in C3 and C4 plant foods.

Carbon Isotopes↗
PubMed1998

A proteasome inhibitor, an antioxidant, or a salicylate, but not a glucocorticoid, blocks constitutive and cytokine-inducible expression of P-selectin in human endothelial cells.

Proteasome inhibitors, antioxidants, salicylates, or glucocorticoids block the cytokine-induced expression of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. These pharmacological agents have been assumed to inhibit the expression of adhesion molecules primarily by blocking activation of the transcription factor NF-kappaB. We found that the proteasome inhibitor ALLN, the antioxidant PDTC, or sodium salicylate, but not the glucocorticoid dexamethasone, inhibited both the constitutive and the interleukin-4- or oncostatin M-induced expression of the adhesion molecule P-selectin in human endothelial cells. ALLN, PDTC, or sodium salicylate decreased P-selectin expression without a detectable requirement for inhibition of NF-kappaB activation or for an intact kappaB element in the P-selectin gene. These results extend the potential anti-inflammatory utility of such drugs to inhibition of P-selectin expression and suggest that they have important actions that do not involve the NF-kappaB system.

Animals↗
PubMed1998

Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12.

The mechanisms by which interleukin-12 (IL-12) exerts antitumor effects have been difficult to dissect. In this study, we examined the potential contribution of the chemokines interferon-gamma-inducible protein-10 (IP-10) and Mig to the antitumor effects of IL-12. Using an athymic mouse model, local inoculations with IL-12 consistently produced tumor size reductions associated with characteristic tumor necrosis and vascular damage. These effects were indistinguishable from those produced by IP-10 or Mig injected locally in the same tumor model. Local and systemic treatment with IL-12 was associated with expression of the interferon-gamma (IFN-gamma), IP-10, and Mig genes and proteins in the tumor. Levels of IP-10 and Mig expression in the tumor, the liver, and the kidney were inversely correlated with tumor size. Administration in vivo of neutralizing antibodies to IP-10 and Mig reduced substantially the antitumor effects of IL-12 inoculated locally into the tumors. These results support the notion that IP-10 and Mig contribute to the antitumor effects of IL-12 through their inhibitory effects on tumor vasculature.

Animals↗
PubMed1998

A comparison of lycopene and canthaxanthin absorption: using the rat to study the absorption of non-provitamin A carotenoids.

The purpose of this study was to validate the use of the mesenteric lymph duct cannulated rat to study the absorption of carotenoids which do not have provitamin A activity. The absorption of two carotenoids, a hydrocarbon carotenoid (lycopene) and a xanthophyll carotenoid (canthaxanthin), were investigated. In the first experiment, lipid emulsions containing lycopene (LYC) or canthaxanthin (CTX) were continuously infused into the duodenum, and lymph was collected for analysis at 2-h intervals. The time course for absorption of carotenoids and triacylglycerol (TAG) was similar. Carotenoids and TAG reached steady-state concentrations in the lymph by 6 h. There was no evidence for a delayed release of either carotenoid from the intestine relative to TAG. During a second experiment, emulsions containing increasing concentrations of LYC or CTX (5, 10, 15, 20 mumol/L) were infused. The LYC and CTX in the lymph increased in a dose-dependent manner. The average efficiency of CTX absorption was 16% while the efficiency of LYC absorption averaged only 6%. Efficiency of carotenoid absorption was not related to concentration infused. Finally, to test whether LYC and CTX interact during absorption both were added to a lipid emulsion at equal concentrations (20 mumol/L) and infused. The carotenoids did not significantly affect each other's absorption. These results demonstrate the usefulness of the rat as an animal model to study the absorption of non-provitamin A carotenoids.

Animals↗
PubMed1998

Insulin-induced vasodilation is dependent on tetrahydrobiopterin synthesis.

Insulin has been shown to elicit vasodilation through increases in nitric oxide (NO) production. To examine whether insulin may modulate the availability of tetrahydrobiopterin (BH4) (an absolute cofactor requirement for NO synthase activation), we studied the effects of insulin (150 nmol/L) on femoral arterial reactivity (to norepinephrine [NE]) in the presence and absence of 2,4-diamino-6-hydroxypyrimidine (DAHP), a specific inhibitor of BH4 production. Our data indicate that inhibition of BH4 synthesis results in an attenuation in the vasodepressor effect of insulin. One possibility is that insulin may regulate NO production by increasing cofactor (BH4) availability for activation of NO synthase.

Animals↗
PubMed1998

Stress injuries of bone: analysis of MR imaging staging criteria.

RATIONALE AND OBJECTIVES: The authors examined the prognostic value of magnetic resonance (MR) imaging in stress injuries of bone. MATERIALS AND METHODS: Clinical follow-up data were collected in 35 patients who underwent MR imaging because of suspected stress fractures. MR findings were correlated with total duration of symptoms, the time to return to sports activity, and findings at follow-up radiography. RESULTS: The MR imaging finding of a "fracture" or "fatigue" line or a cortical signal intensity abnormality was predictive of a longer symptomatic period, whereas muscle edema was predictive of a shorter symptomatic period. A published grading system could be used in only 24 patients; the MR imaging grade of injury did not show correlation with clinical outcome. CONCLUSION: The MR imaging finding of either a medullary line or a cortical abnormality appears to indicate a more severe stress injury of bone. A previously published MR imaging grading system for stress injuries of the tibia was not prognostic in this more heterogeneous patient group.

Adolescent↗
PubMed1998

Surface lesions of bone.

A surface lesion of bone may arise within the cortex, between the cortex and the periosteum, within the periosteum, or in the tissues immediately adjacent to the periosteum including tendinous and ligamentous attachments. While these lesions generally reflect the spectrum of more common intramedullary lesions and have an appearance similar to that of their intramedullary counterparts, their unusual surface origin often renders diagnosis difficult. Surface sarcomas are usually of a lower grade than that of the intramedullary tumor, and often they have a more favorable prognosis. Traumatic lesions of the bone surface are common and should be considered in the differential diagnosis of a surface lesion, especially in the young or athletic individual. An elevated peripheral white blood cell count and erythrocyte sedimentation rate may herald an infection of the bone surface.

Bone Diseases↗