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Biomedical subjects

A Huang

Publications and source records attributed to A Huang.

At least 127 records · Page 7Linked to original sources
PubMed1998

Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling.

Vertebrates and invertebrates initiate a series of defence mechanisms following infection by Gram-negative bacteria by sensing the presence of lipopolysaccharide (LPS), a major component of the cell wall of the invading pathogen. In humans, monocytes and macrophages respond to LPS by inducing the expression of cytokines, cell-adhesion proteins, and enzymes involved in the production of small proinflammatory mediators. Under pathophysiological conditions, LPS exposure can lead to an often fatal syndrome known as septic shock. Sensitive responses of myeloid cells to LPS require a plasma protein called LPS-binding protein and the glycosylphosphatidylinositol-anchored membrane protein CD14. However, the mechanism by which the LPS signal is transduced across the plasma membrane remains unknown. Here we show that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14. A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1-receptor-associated kinase is required for this response. Our results indicate that TLR2 is a direct mediator of signalling by LPS.

Binding Sites↗
PubMed1998

The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation.

Ribonucleotide reductase, which is composed of the two protein components R1 and R2, is a highly regulated enzyme activity that is essential for DNA synthesis and repair. Recent studies have shown that elevated expression of the rate-limiting R2 component increases Raf-1 protein activation and mitogen-activated protein kinase activity and acts as a novel malignancy determinant in cooperation with H-ras and rac-1. We show that R2 cooperation in cellular transformation extends to a variety of oncogenes with different functions and cellular locations. Anchorage-independent growth of cells transformed with v-fms, v-src, A-raf, v-fes, c-myc, and ornithine decarboxylase was markedly enhanced when the R2 component of ribonucleotide reductase was overexpressed. In addition, we observed that elevated R2 expression conferred on c-myc-transformed NIH 3T3 cells an increased tumorigenic potential in immunoincompetent mice. Taken together, these observations demonstrate that the R2 protein is not only a rate-limiting component for ribonucleotide reduction but that it is also capable of acting in cooperation with a variety of oncogenes to determine transformation and tumorigenic potential.

3T3 Cells↗
PubMed1998

Adaptation of flow-induced dilation of arterioles to daily exercise.

We aimed to test the hypothesis that daily exercise elicits an adaptation of blood flow/shear stress-induced dilation of arterioles. To this end we investigated the responses of isolated, pressurized arterioles of mesentery (MES) and plantaris (PL) skeletal muscle of sedentary (SED) and exercised (EX) rats to increases in perfusate flow (PF, range 0-30 microl/min). Rats were run on a treadmill, once daily for 3 to 4 weeks (with gradually increasing intensity up to 40 min at 28 m/min; a total of 15-19 sessions on the treadmill). The passive diameters of arterioles (obtained in Ca2+-free solution) were similar ( approximately 140 microm) but the pressure-induced active diameter (at 80 mmHg) of skeletal muscle arterioles was significantly smaller than that of mesenteric arterioles. The basal diameter of MES arterioles of SED and EX rats was: 83.5 +/- 3.6 and 83.9 +/- 2.9 microm, respectively; increases in PF increased the diameter of SED and EX arterioles to a similar degree by 33.2 +/- 4. 7 and 31.9 +/- 6.1 microm, respectively). The diameters of PL muscle arterioles of SED and EX rats were 62.1 +/- 6.2 and 68.0 +/- 5.5 microm. In contrast to arterioles of MES, the highest PF increased the diameters of arterioles of PL muscle from EX rats to a significantly greater extent than those from SED rats (52.4 +/- 7.8 vs 30.3 +/- 3.9 microm). Thus, there is a functional adaptation to exercise activity in arterioles of skeletal muscle but not in those of arterioles of mesentery. We speculate that the intermittent increase in blood flow/shear stress in arterioles of skeletal muscle during the periods of exercise activity may be the underlying mechanism responsible for this adaptation.

Adaptation, Physiological↗
PubMed1998

Pre- and postnatal exposure to 3,3',4,4'-tetrachlorobiphenyl: I. Effects on breeding ability and sperm fertilizing ability in male mice.

This study investigated the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on the reproductive performance and in vitro sperm fertilizing ability of male mice. C57BL/6J female mice (F-0) were fed diets containing 0, 3, or 30 ppm TCB for 2 weeks before pairing with nontreated males for a 10-day breeding period. Females were continued on their treatment diet throughout mating, gestation, and lactation. Male offspring (F-1) were given the same diet as their dams throughout this study. F-1 males at 7 and 17 weeks of age were mated to nontreated B6D2-F1 female mice. Body weight, litter size, and survival indices of offspring sired by F-1 males were recorded. Sperm fertilizing ability of F-1 males at 9 and 19 weeks of age was examined in vitro using eggs collected from nontreated B6D2-F1 females. Sperm motion analysis was performed at the same time. When 7- and 17-week-old F-1 males were mated to nontreated females, no differences in fecundity, litter size, sex ratio, or survival indices among any of the treatments were observed. However, sperm fertilizing ability of 30 ppm-treated F-1 males at 19 weeks of age was less than that of the control mice. Testes weights were greater in 3-week-old, 30 ppm-treated mice.

Animals↗
PubMed1998

Pre- and postnatal exposure to 3,3',4,4'-tetrachlorobiphenyl: II. Effects on the reproductive capacity and fertilizing ability of eggs in female mice.

This study investigated the effects of 3,3',4,4'-tetrachlorobiphenyl (TCB) on the reproductive capacity of female mice. Female C57BL/6J mice (F-0) were fed diets containing 0, 3, or 30 ppm TCB for 2 weeks before pairing with nontreated C57BL/6J males for a 10-day breeding period. Females were continued on their treatment diet throughout mating, gestation, and lactation. Female offspring (F-1) were fed the same diet as their dams throughout the study. The reproductive capacity of F-1 females was examined by mating with non-treated B6D2-F1 males. In addition, the fertilizing ability of eggs from F-1 females was examined in vitro by insemination with sperm from nontreated B6D2-F1 males. Fecundity in F-0 females after mating was 80%, 71%, and 47% in the 0, 3, and 30 ppm treatment groups, respectively. Four-day and 21-day survival indices were lower for offspring of 30 ppm TCB-treated F-0 females than for offspring of the control females. Fecundity in F-1 females was the same among all treatment groups, however, all offspring born to 3- and 30-ppm TCB-treated F-1 females died before 4 days of age. Although the litter size at birth was not affected, the in vitro fertilizing ability of eggs in the 3- and 30-ppm treatment groups was lower than in the control group. This decrease in fertilizing ability was associated with an increase in degenerated eggs. F-0 females treated with 30 ppm TCB had enlarged livers during pregnancy and lactation. At 5 and 6 weeks, liver enlargement and thymus atrophy were apparent in F-1 females exposed to 30 ppm TCB. This study demonstrated impaired reproductive capacity and decreased egg fertilizing ability in TCB-treated female mice.

Animals↗
PubMed1998

Fluoride profiles of perikymata in enamel surfaces of human premolars.

Twenty-five premolars (from Nagoya, Japan < 0.1 parts/10(-6)F in drinking water) were sampled to determine the fluoride content in imbrication lines of Retzius between the grooves and ridges of perikymata on the enamel surface. Eight small windows were formed on each surface in groove and ridge regions using an etched microsampling technique. By using a regression curve, y = ax(-b), fluoride concentrations were compared at depths of 1, 3, 5, 10, 20, 30 and 50 microm in the perikymata regions. Fluoride concentrations increased gradually from the age of 10 to 12 years on the premolar surfaces, but were significantly higher in 12-year-olds or older (erupted teeth) than in 10-year-olds or younger (unerupted teeth). No obvious difference in fluoride concentrations was found between males and females. In the outermost enamel ( < 5 microm depth), fluoride concentrations were significantly higher in the grooves than the ridges of the perikymata. Comparison of the exponential regression coefficients (-b) of the fluoride profiles showed a significant difference between the grooves and ridges. It was concluded that fluoride concentrations and profiles were higher in grooves than in ridges of perikymata, probably because they are naturally porous and are stagnation areas attracting dental plaque.

Acid Etching, Dental↗
PubMed1998

p53 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy.

OBJECTIVES: Radiation therapy is definitive treatment for localized prostate cancer. It causes cellular deoxyribonucleic acid (DNA) damage, which, if irreparable, results in apoptosis or programmed cell death. Overexpression of mutant p53 and/or bcl-2 proteins prolongs cell survival despite exposure to damaging agents. We examined whether abnormal expression of either gene could help to explain radiation therapy failures in prostate cancer. METHODS: Archival tissue from patients who had failed radiation therapy as treatment for prostate cancer was obtained before and after treatment. These cancer samples were examined immunohistochemically for accumulation of p53 and bcl-2 proteins. Comparison was made with specimens from patients who had no evidence of recurrent or persistent disease at least 3 years following radiation therapy. RESULTS: High rates of p53 immunopositivity were found in the prostate tissue from all groups studied. More patients who had failed radiation therapy were found to have bcl-2 immunopositive specimens than were those without evidence for recurrent disease (41% preradiation and 61% postradiation versus 8%, P <0.05). More patients who failed radiation therapy had both p53 and bcl-2 immunopositive prostate tissue than did those who were treated successfully (32% preradiation and 48% postradiation versus 8%). CONCLUSIONS: bcl-2 immunopositivity, with or without concomitant detection of p53, was found in significantly more cancers of patients who failed radiation therapy. Positive staining for bcl-2 may serve as a marker for determining the radiation sensitivity of a tumor and thus may help to guide treatment options. It is also notable that a high proportion of the prostate cancers examined were immunopositive for p53.

Humans↗
PubMed1998

Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide.

Previous studies show that agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are greater in female than in male rats. Thus we hypothesized that flow-dependent arteriolar dilation, which is in part mediated by NO, is also greater in females than in males. Gracilis muscle arterioles from 12-wk-old female and male Wistar rats were isolated, cannulated, and pressurized. At 80 mmHg of perfusion pressure, the active diameter and passive diameter (PD) of arterioles of female and male rats were 58.3 +/- 3.4 and 53.2 +/- 2.6 micrometer as well as 103.6 +/- 4.0 and 115.3 +/- 4.8 micrometer, respectively. Dilations to step increases in perfusate flow from 0 to 25 microliter/min were significantly greater in arterioles of female rats and ovariectomized rats with estrogen replacement (OVE) than in male and ovariectomized female (OV) rats (98.6 +/- 0.6 and 97.4 +/- 1.1% vs. 72.6 +/- 3.3 and 72.5 +/- 3.6% of PD at 25 microliter/min). Calculation of wall shear stress (WSS) revealed that the maintained WSS was significantly lower in arterioles of female than in those of male rats (approximately 20 vs. approximately 35 dyn/cm2). After indomethacin pretreatment, Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) eliminated flow-dependent dilation in arterioles of male and OV rats but only attenuated (by approximately 50%) the responses in arterioles of female and OVE rats. In vessels of these latter two groups of rats, the remaining flow-induced dilation was completely eliminated by administration of 10(-5) M Hb or 10(-3) M L-NAME. The greater flow/shear stress-induced dilation of arterioles of female rats indicates a gender difference in the regulation of WSS, which is likely to be due to the greater release of NO in female vessels requiring the chronic presence of estrogen. These findings suggest an important role for estrogen in the regulation of peripheral resistance in females.

Animals↗
PubMed1998

Estrogen preserves regulation of shear stress by nitric oxide in arterioles of female hypertensive rats.

Previously we found that flow-induced arteriolar dilation in male spontaneously hypertensive rats (SHR) is significantly impaired, due to the absence of the nitric oxide (NO)-mediated portion of the response, resulting in an elevation of maintained wall shear stress. Since estrogen has been shown to affect NO-mediated responses, we hypothesized that in female SHR (fSHR) the NO-mediated portion of flow-induced responses is preserved. Gracilis muscle arterioles (approximately 45 to 55 microm) from 12-week-old fSHR, ovariectomized fSHR (OV fSHR), or ovariectomized and supplemented with estrogen fSHR (OVE fSHR) were isolated, cannulated, and pressurized at 80 mm Hg of perfusion pressure. Arteriolar dilations elicited by step increases in perfusate flow from 0 to 25 microL/min were significantly less (by approximately 30%) in OV fSHR compared with fSHR and OVE fSHR (delta19.4+/-1.5 versus 26.0+/-0.9 and 26.8+/-2.0 microm, respectively at maximum flow rate). Inhibition of prostaglandin synthesis with indomethacin elicited a approximately 50% reduction in flow-dependent dilation in all three groups of rats. N(omega)-nitro-L-arginine (L-NNA) significantly inhibited flow-induced responses in arterioles of fSHR and OVE fSHR (by approximately 50%) but not in those of OV fSHR. Constrictions to norepinephrine (10(-7)-3 x 10(-7) mol/L) were significantly greater (up to approximately 40%) in arterioles of OV fSHR compared with those of fSHR and OVE fSHR; these differences, however, were abolished in the presence of L-NNA. In conclusion, estrogen seems to preserve the NO-mediated portion of flow/shear stress-induced dilation in female hypertensive rats resulting in a lower maintained wall shear stress in female than in male SHR. The lower wall shear stress may contribute to the mechanisms by which estrogen lowers systemic blood pressure and the incidence of cardiovascular diseases in women.

Animals↗
PubMed1997

A novel receptor for Apo2L/TRAIL contains a truncated death domain.

Apo2 ligand (Apo2L [1], also called TRAIL for tumor necrosis factor (TNF)-related apoptosis-inducing ligand [2]) belongs to the TNF family and activates apoptosis in tumor cells. Three closely related receptors bind Apo2L: DR4 and DR5, which contain cytoplasmic death domains and signal apoptosis, and DcR1, a decoy receptor that lacks a cytoplasmic tail and inhibits Apo2L function [3-5]. By cross-hybridization with DcR1, we have identified a fourth Apo2L receptor, which contains a cytoplasmic region with a truncated death domain. We subsequently named this protein decoy receptor 2 (DcR2). The DcR2 gene mapped to human chromosome 8p21, as did the genes encoding DR4, DR5 and DcR1. A single DcR2 mRNA transcript showed a unique expression pattern in human tissues and was particularly abundant in fetal liver and adult testis. Upon overexpression, DcR2 did not activate apoptosis or nuclear factor-kappaB; however, it substantially reduced cellular sensitivity to Apo2L-induced apoptosis. These results suggest that DcR2 functions as an inhibitory Apo2L receptor.

Adult↗
PubMed1997

The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments.

Our recent studies have shown that deregulated expression of R2, the rate-limiting component of ribonucleotide reductase, enhances transformation and malignant potential by cooperating with activated oncogenes. We now demonstrate that the R1 component of ribonucleotide reductase has tumor-suppressing activity. Stable expression of a biologically active ectopic R1 in ras-transformed mouse fibroblast 10T(1/2) cell lines, with or without R2 overexpression, led to significantly reduced colony-forming efficiency in soft agar. The decreased anchorage independence was accompanied by markedly suppressed malignant potential in vivo. In three ras-transformed cell lines, R1 overexpression resulted in abrogation or marked suppression of tumorigenicity. In addition, the ability to form lung metastases by cells overexpressing R1 was reduced by >85%. Metastasis suppressing activity also was observed in the highly malignant mouse 10T(1/2) derived RMP-6 cell line, which was transformed by a combination of oncogenic ras, myc, and mutant p53. Furthermore, in support of the above observations with the R1 overexpressing cells, NIH 3T3 cells cotransfected with an R1 antisense sequence and oncogenic ras showed significantly increased anchorage independence as compared with control ras-transfected cells. Finally, characteristics of reduced malignant potential also were demonstrated with R1 overexpressing human colon carcinoma cells. Taken together, these results indicate that the two components of ribonucleotide reductase both are unique malignancy determinants playing opposing roles in its regulation, that there is a novel control point important in mechanisms of malignancy, which involves a balance in the levels of R1 and R2 expression, and that alterations in this balance can significantly modify transformation, tumorigenicity, and metastatic potential.

Animals↗
PubMed1997

Ribonucleotide reductase R2 gene expression and changes in drug sensitivity and genome stability.

Ribonucleotide reductase is a highly regulated, cell cycle-controlled activity that plays an important role in DNA synthesis and repair. Recent studies have shown that elevated expression of the rate-limiting R2 component of ribonucleotide reductase increases Raf-1 protein activation and mitogen-activated protein kinase activity and acts as a novel malignancy determinant in cooperation with activated oncogenes like H-ras. We show that hydroxyurea-resistant mouse L cells with elevated R2 gene expression and increased ribonucleotide reductase activity exhibit significantly decreased sensitivities to the chemotherapeutic compounds N-(phosphonacetyl)-L-aspartate (PALA) and methotrexate (MTX). Furthermore, BALB/c 3T3 cells containing a retroviral expression vector encoding the R2 sequence also showed decreased sensitivity to PALA and MTX when compared to cells containing the same vector but without the R2 coding region. Colonies that developed in the presence of PALA or MTX contained amplifications of the CAD or dihydrofolate reductase genes and exhibited wild-type p53 function as determined in sequence-specific p53 binding activity assays. NIH-3T3 cells containing the R2 retroviral expression vector also showed significantly decreased sensitivity to hydroxyurea and MTX but not to PALA. Furthermore, NIH-3T3 cells transfected with a vector containing the R2 sequence in antisense orientation exhibited increased sensitivity to hydroxyurea, PALA, and MTX. Similarly, mouse 10T1/2 cells that are highly transformed and drug resistant due to alterations in H-ras and a mutant oncogenic form of p53 exhibited significant increases in sensitivity to hydroxyurea, PALA, and MTX when transfected with a vector containing the R2 sequence in antisense orientation and compared to cells containing the same vector without the antisense sequence. These results indicate that altered expression of the R2 component is capable of significantly modifying drug sensitivity properties of tumor cells. We hypothesize that this occurs, at least in part, through a mechanism of increased genetic instability that is independent of direct p53 mutation or loss and involves R2 stimulation of the mitogen-activated protein kinase signal pathway.

3T3 Cells↗
PubMed1997

Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice.

BACKGROUND: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for hospitalization and death from gastrointestinal bleeding and perforation. OBJECTIVES: To 1) estimate the extent to which NSAIDs are prescribed unnecessarily and NSAID-related side effects are inaccurately diagnosed and inappropriately managed and 2) identify the physician and visit characteristics associated with suboptimal use of NSAIDs. DESIGN: Prospective cohort study. SETTING: Montreal, Canada. PARTICIPANTS: 112 physicians representing academically affilliated general practitioners, community-based general practitioners, and residents in family medicine and internal medicine. INTERVENTIONS: Blinded, office-based assessment of the management of two clinical cases (chronic hip pain due to early osteoarthritis and NSAID-related gastropathy) using elderly standardized patients. MEASUREMENTS: Quality of drug management and potential predictors of suboptimal drug management. RESULTS: Unnecessary prescriptions for NSAIDs or other drugs were written during 41.7% of visits. Gastropathy related to NSAID use was correctly diagnosed in 93.4% of visits and was acceptably managed in 77.4% of visits. The risk for an unnecessary NSAID prescription was greater when the contraindications to NSAID therapy were incompletely assessed (odds ratio, 2.3 [95% CI, 1.0 to 5.2]) and when the case was managed by residents in internal medicine (odds ratio, 4.1 [CI, 1.2 to 14.7]). The risk for suboptimal management of NSAID-related side effects was increased by incorrect diagnosis (odds ratio, 16.6 [CI, 3.6 to 76.5]) and shorter visits. CONCLUSIONS: Unnecessary NSAID prescribing and suboptimal management of NSAID-related side effects were sufficiently common to raise questions about the appropriateness of NSAID use in the general population. If these results reflect current practice, prescribing patterns may contribute to avoidable gastrointestinal morbidity in elderly persons.

Aged↗
PubMed1997

Benzodiazepine use and the risk of motor vehicle crash in the elderly.

CONTEXT: Benzodiazepines, used by a sizable number of the elderly population, may affect the ability to drive and thus increase the risk of a motor vehicle crash. Epidemiologic studies of this question have produced inconsistent results that may be due to the different effects of long- and short-half-life benzodiazepines and variations in their duration of use. OBJECTIVE: To determine whether the use of benzodiazepines of either long- or short-elimination half-life is associated with the risk of injurious motor vehicle crash in the elderly. DESIGN AND SETTING: Nested case-control design within a cohort of 224,734 drivers from the Canadian province of Quebec, aged 67 to 84 years, followed up from 1990 to 1993. Computerized data for the study were obtained from provincial driver's license files, police reports of injurious crashes, and health insurance records. PATIENTS: We identified all 5579 drivers involved in an injurious crash (cases) and a random sample of 10 controls per case selected from a subcohort of 13,256 subjects. MAIN OUTCOME: Involvement of a cohort member as a driver in a motor vehicle crash in which at least 1 person (not necessarily the driver) sustained bodily injury. RESULTS: The adjusted rate ratio of crash involvement within the first week of long-half-life benzodiazepine use was 1.45 (95% confidence interval [CI], 1.04-2.03). The rate ratio for continuous use of longer duration up to 1 year was slightly lower but remained significant (rate ratio, 1.26; 95% CI, 1.09-1.45). In contrast, there was no increased risk after the initiation of treatment with short-half-life benzodiazepines (rate ratio, 1.04; 95% CI, 0.81-1.34) or with their continued use (rate ratio, 0.91; 95% CI, 0.82-1.01). CONCLUSIONS: Brief or extended periods of exposure to long-half-life benzodiazepines are associated with an increased risk of motor vehicle crash involvement in the elderly population. There is no such elevated risk for short-half-life benzodiazepines.

Accidents, Traffic↗