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Biomedical subjects

S C Ng

Publications and source records attributed to S C Ng.

At least 91 records · Page 5Linked to original sources
PubMed1999

Roles of cyclin D1 and related genes in growth inhibition, senescence and apoptosis.

It is now apparent that apoptosis is closely linked to the control of cell cycle progression. During the G1 to S progression, cyclin D1, p53, and the cyclin dependent kinase inhibitors p21WAF1 and p27kip1 can play roles in induction of apoptosis. During the G2 and M phases, premature activation of Cdk1 can cause cells to enter mitotic catastrophe, which results in apoptosis. In this review we focus on factors acting during G1 and S, particularly cyclin D1, and their effects on cell growth, senescence and apoptosis. We emphasize that cyclin D1 can have diverse effects on cells depending on its level of expression, the specific cell type, the cell context and other factors. Possible mechanisms by which cyclin D1 exerts these diverse effects, via cyclin dependent kinase-dependent and -independent pathways, are discussed.

Journal Article↗
PubMed1999

Destruction of protamine in human sperm inhibits sperm binding and penetration in the zona-free hamster penetration test but increases sperm head decondensation and male pronuclear formation in the hamster-ICSI assay.

PURPOSE: Our purpose was to investigate the fertilizing ability of human protamine-damaged sperm in a heterologous system using hamster oocytes. METHODS: The protamine of the sperm were damaged by exposure to dithiothreitol, a disulfide-reducing agent. Their ability to penetrate and form male pronuclei were investigated using the zona-free hamster penetration test and the hamster-intracytoplasmic sperm injection assay, respectively. RESULTS: The zona-free hamster penetration test revealed that protamine-damaged sperm are unable to bind and penetrate the hamster oocyte. On the other hand, hamster-intracytoplasmic sperm injection assay results showed that 56.9% and 39.2% of the injected oocytes developed male pronuclei in protamine-damaged and live-intact sperm groups, respectively, with a significant difference in these rates (P < 0.01). CONCLUSIONS: This study shows that protamine-damaged sperm are able to undergo sperm head decondensation and male pronuclear formation only when injected into the ooplasm, although they cannot bind and penetrate through the zona and enter the ooplasm.

Acridine Orange↗
PubMed1999

Sexual dysfunction related to antihypertensive agents: results from the animal model.

The present investigation elucidates the deleterious effects of three prototypical antihypertensive drugs namely, propranolol, clonidine and captopril on the erectile physiology. In order to delineate the direct drug effects from vascular insufficiency inherent in hypertensive states, the study was conducted on a normotensive animal model. The adverse effects of these drugs were estimated as changes in sexual behaviour and intracavernous pressure response of electrical stimulation in the treated rats compared to normal age-matched controls (n = 10, each group). Copulation studies indicated significant impairment of sexual function in the groups on propranolol and clonidine. The cavernous pressure response to nerve stimulation at the end of sixteen weeks further reinforced the gross compromise on sexual function in these two treated groups. In contrast, the captopril administration produced only marginal alterations to the responses recorded. The results from this study clearly indicate that propranolol and clonidine interfere with sexual behaviour and nerve mediated response to erection whereas captopril which is devoid of significant effects on these parameters, may be a better therapeutic option.

Animals↗
PubMed1999

Elevated low-density lipoprotein cholesterol (LDL-C) enhances pro-erectile neurotransmission in the corpus cavernosum.

Hypercholesterolaemia is thought to foster atherosclerosis and impotence through its effects on vascular endothelium. In this study, we investigated the pharmacological changes in rabbit corpus cavernosum (CC) secondary to incubation with lysolecithin and hypercholesterolaemia. A daily egg yolk dietary supplement induced gross hypercholesterolaemia in our rabbits. Group A of test animals (n-12) was fed with the yolk content of single egg and group B (n-6), that from two eggs for eight weeks. Serum level estimation revealed a progressive elevation of cholesterol to 15 and 30 times respectively, in the two treated groups as compared to values in the control group (n-6). Early histological manifestations of atherosclerosis were perceived as fat cell lesions in the cavernosum of treated animals. In vitro pharmacological studies on CC strips from both groups of test animals demonstrated a profound accentuation of the contractile responses to noradrenaline and histamine and attenuation of relaxant response to acetylcholine. However, in contrast to single-egg treated group, which demonstrated a reduction in the relaxant response to electrical field stimulation (EFS), there was a marked and statistically significant potentiation of this nitrergic transmission, in the two-eggs group. Prior incubation of CC strips of normolipidaemic rabbits (n-7) with lysolecithin, reproduced similar exaggerated response to EFS. Therefore, from the results of our study, it is concluded that oxidised LDL or its major amphiphile lysolecithin, at some critical level or beyond, may be capable of reverting at least some of the adverse effects of hypercholesterolaemia on erectile function, through its mediating effect on nitrergic transmission.

Acetylcholine↗
PubMed1999

5-HT4 receptors in isolated human corpus cavernosum?

The novel serotonin subtype-4 (5-HT4) receptor agonist, SC53116 (SC), produced a limited relaxation of noradrenaline (NA) pre-contracted human corpus cavernosum (CC) smooth muscle in vitro. This effect was not significantly attenuated by the 5-HT4 antagonist SDZ250557 (SDZ). In the presence of (+/-) pindolol (1 microM) and methysergide (1 microM), employed to mask 5-HT1 and beta-adrenergic, and 5-HT2 receptors respectively, SC failed to relax NA pre-contracted CC strips to a greater extent than saline. Functional cAMP dependent relaxation pathways were demonstrated by a significant reduction in NA induced tone by prostaglandin E1 (PGE1) and isopropylnoradrenaline (IPNA), the action of the latter compound was effectively eliminated in the presence of (+/-) pindolol. Relaxation of NA induced tone caused by the nitric oxide donor nitro-glycerine (NTG) was significant and similar in the absence and presence of the 5-HT and beta-adrenergic antagonists. The results of this present study indicate that human corporal smooth muscle does not contain 5-HT4 receptors and that, although compounds like SC act to relax non-vascular smooth muscle via cAMP dependent mechanisms, 5-HT4 receptor agonists may be expected to be of limited utility in triggering cAMP dependent relaxation responses in human CC.

4-Aminobenzoic Acid↗
PubMed1999

Association of molecular variants of luteinizing hormone with menstrual disorders.

OBJECTIVE: Luteinizing hormone (LH) promotes ovulation and luteinization of the ovarian follicle, and stimulates steroidogenesis in the ovaries. It is known to be present in different molecular forms, and secretion of abnormal LH has been implicated in menstrual disorders and infertility. The purpose of this study was to determine any association of two recently described LH variants with menstrual disorders in Singapore Chinese women. One of these variants had Trp8 to Arg8 and Ile15 to Thr15 replacements in the LH beta-subunit, while the second variant possessed Ser102 substitution for Gly102. PATIENTS: One hundred and seventy six patients with menstrual disorders and two hundred normal ovulatory women were recruited and screened for the presence of these two LH variants. METHODS: The polymerase chain reaction (PCR) products of patients were analysed by restriction fragment length polymorphism (RFLP) and the results were compared with those of normal ovulatory women and confirmed by DNA sequencing. RESULTS: Twenty one (11.9%) patients with menstrual disorders and twenty (10%) normal ovulatory women were found to carry the first variant, but its occurrence did not show any significant statistical difference between the patient and control groups (P = 0.679). However, the second variant was only detected in seven (4%) patients with menstrual disorders, and none of the normal ovulatory subjects (P = 0.005). CONCLUSIONS: the study showed that the first variant was not associated with menstrual disorders, whereas the second variant might be implicated in menstrual disorders in some Singapore Chinese women.

Adenoma↗
PubMed1999

Expression of C-20, 22 desmolase activity by the human fallopian tube in vitro: evidence for steroidogenesis.

With a view to establishing whether cells of the human Fallopian tubes possess the cholesterol side-chain cleavage activity, homogenates of the tubes, obtained from 6 women (39-45 years) following abdominal hysterectomy for benign conditions, were incubated with (7n-3H)-cholesterol as substrate. Controls (n=6, age 40-44 years) were homogenates heated in a boiling water bath for 10 min. Using the reverse-isotope dilution technique, (3H)-pregnenolone was isolated and characterized. No such metabolite was evident in control incubations of heat-denatured enzymes. The extent of enzymic conversion varied from 1.9 x 10(-3) to 1.3 x 10(-2)%. The results reveal for the first time the existence of an active cholesterol-specific C-20, 22 desmolase system in the viable tissues. It is suggested that there exists a potential for substantial pregnenolone synthesis in vivo. This rate-limiting steroid biosynthetic conversion provides a new dimension to the functional capacity of the Fallopian tubes in the synthesis of steroids, which may be necessary for modulating ciliary beat frequency and in maintenance of hormonal milieu essential for embryogenesis.

Adult↗
PubMed1999

Developmental capacity of damaged spermatozoa.

We report the first detailed and systematic study in a mammalian system to unravel the mystery of the beginnings of life. The fertilizing ability of damaged spermatozoa at various levels of disintegration (cellular and molecular) has been investigated in homologous (mouse) and heterologous (human spermatozoon, hamster oocyte) models. Live pups were produced after destruction of spermatozoa at various cellular and molecular levels followed by injection into oocytes. We demonstrate that with damaged spermatozoa, the key point in the fertilization process is the activation of the oocyte by injection of cytosolic sperm factor. A similar fertilization rate as that using live intact spermatozoa can be achieved following activation. However, the integrity of the genetic material influenced in-vitro development of the embryos and live fetuses. This study contributes to a better understanding of the fertilizing ability of damaged spermatozoa. These findings can be applied clinically to patients with necrozoospermia or very severe oligozoospermia and in wildlife research where damaged spermatozoa from rare species can be used to regenerate young, and hence propagate the species. Also implied is the possible contribution of sperm DNA strand breakage to early pregnancy loss.

Animals↗
PubMed1999

Association of oestrogen receptor gene polymorphisms with outcome of ovarian stimulation in patients undergoing IVF.

Oestrogen plays an important role in follicular formation and oocyte maturation via its receptor (ER). Many studies have shown association of the ER gene polymorphisms with a variety of pathological conditions. In this study we have examined the relationship of a common PvuII and a rare BstUI polymorphism in the ER gene to the mean numbers of follicles and oocytes, their mean ratios, mean number of embryos, mean oestrogen concentrations, mean size of the follicles and pregnancy rates. Analyses were carried out in 200 local Chinese patients undergoing in-vitro fertilization (IVF) and embryo transfer in three consecutive cycles. The mean follicular number, oocyte number, embryo number, follicular size and pregnancy rate were significantly smaller in patients homozygous for PvuII polymorphism (P < 0.001). These results indicate that PvuII polymorphism may be associated with ovarian follicular development and subsequently with the pregnancy rate. This study supports the view that genetic variability in the ER gene may have a role in the quality of the ovarian follicles in stimulation, which may affect implantation. However BstUI polymorphism was not found in either the IVF or control groups, suggesting that it has no role in the local Chinese population.

Adult↗
PubMed1999

Synergistic effect of paclitaxel and 4-hydroxytamoxifen on estrogen receptor-negative colon cancer and lung cancer cell lines.

Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long-term clinical trials with encouraging preliminary results as a chemopreventive agent for breast cancer. The effect of Tam on ER-negative cancers, however, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4-HT) have a synergistic cytotoxic effect on the ER-negative colon cancer cell line HCT15, which is refractory to paclitaxel alone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiproliferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel concentrations used for HCT15, 4-HT and paclitaxel also showed synergistic effect on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the single treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G2/M population and resulted in the increase of apoptosis in both cell lines. Enhanced early release of cytochrome c from mitochondria may be the apoptotic pathway activated in the combination treatment in HCT15 cells.

Adenocarcinoma↗
PubMed1999

New AccI polymorphism in the follicle-stimulating hormone beta-subunit gene and its prevalence in three Southeast Asian populations.

A thymine-cytosine substitution was identified in exon 3 (codon 76, TAT to TAC) of the human follicle-stimulating hormone (FSH) beta-subunit gene. The nucleotide change led to creation of an AccI digestion site. The frequencies of the A allele (with AccI site) in Chinese (n = 201), Malays (n = 168) and Indians (n = 132) were 0.358, 0.333 and 0.402, respectively. The new FSH beta-subunit marker may be useful in gene tracking and association studies.

Alleles↗
PubMed1999

The clinical management of male infertility.

Male infertility is a common cause of subfertility for which sperm disorders are the single most common cause. Genetic abnormalities, for example, microdeletions associated with the Y chromosome, defects in the androgen receptor gene and cystic fibrosis have gained recent prominence and it is envisaged that many of the 60% of men for which no cause is found may have a genetic basis for their subfertility. Although an abnormal semen analysis is commonly the first indicator of a male factor problem, further tests are usually required. Empirical treatment with hormones, varicocelectomy and immunological treatment have been proven to be disappointing whilst the treatment of infection and obstruction do not always translate into significantly higher fertility rates. Ejaculatory disorders and impotence can be effectively treated today whilst donor insemination can be offered to men with untreatable infertility. The advent of assisted reproduction and micromanipulation has greatly improved prospects for fertility of men with very poor semen quality. However, the genetic implications of these procedures have to be quickly addressed so that fertility is maximised without risk to the progeny.

Diagnosis, Differential↗
PubMed1999

Assisted reproductive techniques--promises and problems.

Assisted reproductive techniques (ART) are procedures in which the oocyte is handled before replacement, either as an oocyte or embryo. The current success rates and pregnancy outcomes of in-vitro fertilisation (IVF), gamete intra-fallopian transfer (GIFT), zygote intra-fallopian transfer (ZIFT), intra-cytoplasmic sperm injection (ICSI), donor oocyte and frozen embryo programmes are reviewed. Some problems associated with assisted reproductive procedures are also discussed.

Female↗
PubMed1999

Diagnosis and management of 34 Hürthle cell tumors.

BACKGROUND: Controversies still exist around the diagnosis and management of Hürthle cell tumors. The aim of this study is to reexamine our experience to improve our methods in the future. METHODS: We treated 34 patients with verified Hürthle cell carcinoma and adenoma at Chang Gung Memorial Hospital, Linkou from 1990 through 1996. Clinical characteristics, thyroid ultrasonogram, 131I, 201Tl, 99mTc-methoxy-isobutyl-isonitrile (MIBI) and 99mTc-thyroid scan, fine needle aspiration cytology (FNAC) and histology results were analyzed. RESULTS: Female predominance (82.4%) was noticed among our Hürthle cell tumors. Nine (26.5%) patients had carcinoma. The median size of carcinoma was 4.0 cm, which was significantly larger than the median 3.0 cm for adenoma. No significant differences were found between gender, age, multiplicity or echogenicity between two groups. All 12 adenoma and 3 carcinoma patients who received pre-operative 99mTc and/or 131I thyroid scan showed cold nodules. The sensitivity and specificity of detection Hürthle cell carcinoma as indeterminate and malignant using FNAC was 78% and 18% respectively. These improved to 100% and 86% using frozen sections. One carcinoma patient developed neck lymph node metastasis, with normal serum thyroglobulin, negative 131I but positive 201Tl and 99mTc-MIBI whole body scans. Another one showed mediastinum metastasis with elevated serum thyroglobulin, detected using 131I scan, revealed successful regression after 131I therapeutic scan. CONCLUSION: Tumor size of carcinoma is significantly larger than adenoma. All patients with FNAC suggestive of Hürthle cell tumors should receive surgery for histological diagnosis to differentiate carcinoma from adenoma. Therapeutic radioiodine ablation is indicated whenever there is 131I uptake by tumor cells.

Adenocarcinoma↗
PubMed1998

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

3T3 Cells↗
PubMed1998

NMR structure and mutagenesis of the FADD (Mort1) death-effector domain.

When activated, membrane-bound receptors for Fas and tumour-necrosis factor initiate programmed cell death by recruiting the death domain of the adaptor protein FADD to the membrane. FADD then activates caspase 8 (also known as FLICE or MACH) through an interaction between the death-effector domains of FADD and caspase 8. This ultimately leads to the apoptotic response. Death-effector domains and homologous protein modules known as caspase-recruitment domains have been found in several proteins and are important regulators of caspase (FLICE) activity and of apoptosis. Here we describe the solution structure of a soluble, biologically active mutant of the FADD death-effector domain. The structure consists of six antiparallel, amphipathic alpha-helices and resembles the overall fold of the death domains of Fas and p75. Despite this structural similarity, mutations that inhibit protein-protein interactions involving the Fas death domain have no effect when introduced into the FADD death-effector domain. Instead, a hydrophobic region of the FADD death-effector domain that is not present in the death domains is vital for binding to FLICE and for apoptotic activity.

Adaptor Proteins, Signal Transducing↗