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Biomedical subjects

K Yang

Publications and source records attributed to K Yang.

351 records · Page 20Linked to original sources
PubMedDate not supplied

Glucocorticoid actions and metabolism in pregnancy: implications for placental function and fetal cardiovascular activity.

The isoforms of the enzyme 11beta hydroxysteroid dehydrogenase (11betaHSD) are expressed in placental tissue and fetal membranes. The two major isoforms, 11betaHSD-1 and 11betaHSD-2, are compartmentalized discretely, and regulated differentially by steroids (oestrogen, progesterone), activators of cAMP pathway, and nitric oxide. 11BetaHSD-2 appears important in human pregnancy in regulating the amount of maternal cortisol that crosses the placenta to reach the fetal compartment. On the other hand, 11betaHSD-1 may allow the local conversion of biologically inactive cortisone to biologically active cortisol, particularly within chorion trophoblasts. The localization, regulation, and importance of these isozymes are examined.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Regulation of 11beta-hydroxysteroid dehydrogenase type 2 by steroid hormones and epidermal growth factor in the Ishikawa human endometrial cell line.

The biological actions of glucocorticoids in target organs are determined at least in part by the local expression of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which is responsible for the inactivation of glucocorticoids. The human endometrium is a glucocorticoid target tissue, and is known to express 11beta-HSD2. However, little is known about the function and regulation of 11beta-HSD2 in the endometrium, probably owing to the lack of in vitro model systems (i.e., cell lines) that express 11beta-HSD2. Here, we describe the characterization of 11beta-HSD expression in Ishikawa cells, a well-differentiated human endometrial adenocarcinoma cell line. The 11beta-HSD activity in intact Ishikawa cells was characteristic of 11beta-HSD2 in that it only possessed dehydrogenase activity (cortisol to cortisone) and had a high affinity for cortisol (apparent Km of 34 nM). The exclusive expression of 11beta-HSD2 in Ishikawa cells was confirmed by RT-PCR which demonstrated the presence of the mRNA for 11beta-HSD2 but not that for 11beta-HSD1. To investigate the regulation of 11beta-HSD2 in Ishikawa cells, we treated these cells with sex steroid hormones, glucocorticoids and epidermal growth factor (EGF), and determined the effects of these treatments on 11beta-HSD2 activity by an established intact cell radiometric conversion assay. Treatment with estradiol-17beta (E2, 10 nM) and medroxyprogesterone acetate (MPA, 100 nM) produced a classic sex steroid effect; the greatest increase (330% of the control) in the level of 11beta-HSD2 activity was caused by the combined treatment, followed by MPA (240% of the control) with E2 being the least effective (156% of the control). The stimulatory effect of E2 was blocked by the pure antiestrogen ICI 182,780. The synthetic glucocorticoid dexamethasone (Dex) increased 11beta-HSD2 activity in a time- and dose-dependent manner (200% of the control; 100 nM for 48 h), and the endogenous glucocorticoid cortisol was equally effective in this regard. The antiprogesterone-antiglucocorticoid RU486 did not counteract with MPA or Dex but rather acted as an agonist; increased 11beta-HSD2 activity (160% of the control; 100 nM for 72 h). By contrast, treatment with EGF caused a dose- and time-dependent decrease in 11beta-HSD2 activity (60% of the control; 10 ng/ml for 72 h). In addition, semi-quantitative RT-PCR analysis revealed that there were corresponding changes in the level of 11beta-HSD2 mRNA following the treatment of Ishikawa cells with these steroid hormones and EGF, indicating that the effects of these hormones and EGF are mediated, at least in part, at the level of 11beta-HSD2 gene transcription. In conclusion, we have demonstrated for the first time that the human Ishikawa endometrial cell line expresses exclusively the 11beta-HSD2 isozyme. Moreover, we have presented the first direct evidence that sex steroid hormones and glucocorticoids stimulate while EGF inhibit the expression of 11beta-HSD2 in Ishikawa cells, suggesting that endometrial 11beta-HSD2 is under the control of steroid hormones and EGF. Thus, the Ishikawa cell line represents an excellent model in which the function and regulation of endometrial 11beta-HSD2 may be studied.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMedDate not supplied

Drug delivery systems employing 1,6-elimination: releasable poly(ethylene glycol) conjugates of proteins.

Using lysozyme as a representative protein substrate that loses its activity when PEGylation takes place on the epsilon-amino group of lysine residues, various amounts of a novel releasable PEG linker (rPEG) were conjugated to the protein. rPEG-lysozyme conjugates were relatively stable in pH 7.4 buffer for over 24 h. However, regeneration of native protein from the rPEG conjugates occurred in a predictable manner during incubation in high pH buffer or rat plasma, as demonstrated by enzymatic activity and structural characterization. The rates of regeneration were also correlated with PEG number: native lysozyme was released more rapidly from the monosubstituted conjugate than from the disubstituted conjugate, suggesting possible steric hindrance to the approach of cleaving enzymes. Recovery of normal activity and structure for the regenerated native lysozyme was shown by a variety of assays.

Animals↗
PubMedDate not supplied

Anterior intervertebral disc excision and bone grafting in cervical spondylotic myelopathy.

An analysis of 121 cases of cervical spondylotic myelopathy treated by anterior excision of the disc and fusion was undertaken. All patients were followed at least six months, and follow-up averaged 22 months. Results showed that 97.5% of patients had no aggravation of symptoms, 90.9% were improved, and 72.6% were able to resume normal activity. Surgical intervention can greatly improve the prospects of patients with severe cervical spondylotic myelopathy, and its use should not be lightly ruled out. Autografts yield higher fusion rates and better overall results than homografts. Selection of the number and level of discs to be excised depends upon clinical and roentgenographic indications, as well as the myelogram and the amount of fluid injected into the discs.

Adult↗
PubMedDate not supplied

Ovine 11 beta-hydroxysteroid dehydrogenase: from gene to function.

Two distinct isoforms of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) with respect to enzymatic activity were identified in the ovine liver and kidney. 11 beta-HSD1 (the hepatic isoform) was reversible and NADP(H)-dependent. By contrast, 11 beta-HSD2 (the renal isoform) was unidirectional and NAD-dependent. Ovine placenta contained both forms of 11 beta-HSD activities. The cDNA encoding ovine 11 beta-HSD1 was cloned, and used as a probe to study 11 beta-HSD1 gene expression in fetal sheep during development. It was found that fetal and adult liver was the major site of 11 beta-HSD1 biosynthesis, and that 11 beta-HSD1 gene expression was regulated in a tissue-specific and developmentally programmed manner. Two non-functional variants of 11 beta-HSD1 were also identified. In addition, sheep kidney was unique in that both 11 beta-HSD1 mRNA and activity were absent. Although the physiological significance of 11 beta-HSD in individual fetal organs during development remains largely speculative, 11 beta-HSD in the fetal pituitary may contribute, at least in part, to the proposed resetting of cortisol negative feedback on pituitary ACTH during the last few days of gestation. In the fetal liver, the action of 11 beta-HSD may lead to the formation of cortisol which could act locally as well as systematically to modulate developmental processes. Placental 11 beta-HSD may protect fetus from exposure to the growth-inhibiting effects of maternal glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMedDate not supplied

Cell proliferation in rat colon measured with bromodeoxyuridine, proliferating cell nuclear antigen, and [3H]thymidine.

Epithelial cell proliferation was studied in the normal colonic mucosa of 5-week-old Sprague-Dawley rats, comparing [3H]thymidine incorporation (group 1) with two newer proliferation markers, bromodeoxyuridine (group 2) and proliferating cell nuclear antigen (group 3). Microautoradiography (group 1) or immunoperoxidase assays (groups 2 and 3) were carried out. Cells were counted for positive reaction and position along 50 colonic crypt columns/animal. No significant differences were found in number or distribution of labeled epithelial cells in proliferative compartments in crypt columns of normal colonic mucosa; labeled cells were mainly in the lower 60% of colonic crypts. Thus, in this model, bromodeoxyuridine and proliferating cell nuclear antigens were comparable to [3H]thymidine as reliable markers of proliferating epithelial cells in rat colon.

Animals↗
PubMedDate not supplied

Effects of vitamin/mineral supplementation on the proliferation of esophageal squamous epithelium in Linxian, China.

Abnormalities of epithelial proliferation have been proposed as an early step in gastrointestinal carcinogenesis. To determine whether micronutrient supplementation may reduce squamous epithelial proliferation in the esophagus, we evaluated proliferation in subjects participating in a randomized nutrition intervention trial in Linxian, China, where esophageal cancer rates are among the highest in the world. After 30 months of intervention involving daily supplementation with multiple vitamins and minerals, an endoscopic survey was performed and squamous biopsies from 512 subjects were labeled with tritiated thymidine and autoradiographed. Analysis showed no treatment effect on the overall amount of squamous epithelial proliferation measured by the total labeling index. However, a measure of the vertical distribution of labeled cells showed lower values with supplementation: a 14% reduction in all subjects (P = 0.29), and a 29% reduction in nonsmokers (P = 0.03). These results suggest a potential modest benefit for short-term intervention with multiple vitamins and minerals on squamous epithelial cell proliferation of the esophagus in this high-risk population.

Adult↗
PubMedDate not supplied

Effects of hypoxemia on 11 beta-hydroxysteroid dehydrogenase types 1 and 2 gene expression in preterm fetal sheep.

OBJECTIVE: To examine the effect of sustained hypoxia on the expression of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1 and 2 genes in preterm fetal sheep. METHODS: Fetal liver and kidney as well as placental tissues were collected at days 111-113 of gestation (term = 145 days) after 8 hours of sustained hypoxemia induced by lowering the maternal inspired oxygen (n = 7) or after 8 hours of normoxia to serve as controls (n = 5). Changes in the levels of 11 beta-HSD1 and 11 beta-HSD2 mRNA were determined by Northern blot analysis using ovine 11 beta-HSD types 1 and 2 cDNAs as probes. Levels of 11 beta-HSD2 activity were determined by a standard radiometric conversion assay. RESULTS: In hypoxic fetuses, there was a tendency for a decrease (P = .08) in levels of 11 beta-HSD2 mRNA in the kidney. This decrease was correlated significantly with the degree of associated fetal acidemia (P < .01). However, there were no corresponding changes in the level of renal 11 beta-HSD2 enzyme activity, indicating that changes in 11 beta-HSD2 mRNA were unlikely carried through to 11 beta-HSD2 protein. In contrast levels of 11 beta-HSD1 mRNA in the placenta and fetal liver were unchanged after sustained hypoxia. CONCLUSION: These results demonstrate that fetal hypoxemia-induced acidosis selectively down-regulates 11 beta-HSD2 mRNA expression in the preterm fetal sheep kidney. This may provide a further mechanism whereby fetal acidosis alters developmental processes by regulating the bioavailability of glucocorticoids in specific fetal organs through altered local expression of 11 beta-HSD enzymes.

11-beta-Hydroxysteroid Dehydrogenases↗