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Biomedical subjects

Y K Fung

Publications and source records attributed to Y K Fung.

At least 55 records · Page 3Linked to original sources
PubMed1991

Depletion of striatal dopamine by the N-oxide of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The N-oxide of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the major metabolite found in vivo and excreted in urine after the parenteral administration of the neurotoxicant, MPTP. In mice (C57BL/6), stereotaxic injection of MPTP N-oxide (15 micrograms) into the neostriatum produced dopamine (DA) depletion similar to that caused by MPTP. The DA depleting effect of MPTP N-oxide was a direct action, whereas the action of MPTP was mediated by the generation of oxidative metabolites. In the mouse striatal synaptosomal preparation, MPTP, MPP+ and MPTP N-oxide all competed with [3H]DA at its uptake site. In addition, MPP+ and MPTP N-oxide promoted [3H]DA release. In contrast to MPTP and MPDP+, MPTP N-oxide did not alter the electrophysiologically recorded field potential in nigro-striatal slices. These observations suggest that MPTP N-oxide can directly cause the chemical depletion of striatal DA without modifying the characteristics of cortico-striate synaptic transmission.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

The importance of nucleus accumbens in nicotine-induced locomotor activity.

Bilateral injections of either nicotine (200 micrograms) or cytisine (30 or 60 micrograms) into the nucleus accumbens elicited locomotor hyperactivity in rats. Pretreatment with mecamylamine (2 mg kg-1, s.c.) was effective in attenuating the stimulatory effect of either nicotine or cytisine. This study suggests that nicotinic agonists such as nicotine and cytisine produce their locomotor excitatory effects through stimulation of the mesolimbic dopaminergic pathway.

Alkaloids↗
PubMed1989

Cell cycle-dependent regulation of phosphorylation of the human retinoblastoma gene product.

The human retinoblastoma gene (RB1) encodes a protein (Rb) of 105 kilodaltons that can be phosphorylated. Analysis of Rb metabolism has shown that the protein has a half-life of more than 10 hours and is synthesized at all phases of the cell cycle. Newly synthesized Rb is not extensively phosphorylated (it is "underphosphorylated") in cells in the G0 and G1 phases but is phosphorylated at multiple sites at the G1/S boundary and in S phase. HL-60 cells that were induced to terminally differentiate by various chemicals lost their ability to phosphorylate newly synthesized Rb at multiple sites when cell growth was arrested. These findings suggest that underphosphorylated Rb may restrict cell proliferation.

Cell Cycle↗
PubMed1989

Effect of nicotine pretreatment on striatal dopaminergic system in rats.

Rats were pretreated with saline or nicotine (1.5 mg/kg/day) by subcutaneously implanting each animal with an Alzet osmotic minipump for 1 or 14 days. Short-term (1-day) administration of nicotine to rats reduced the stimulatory effect of (+)-amphetamine on locomotor activity. This was correlated with an attenuation in the ability of (+)-amphetamine to stimulate [3H]dopamine formation from [3H]tyrosine in rat striatal slices of these nicotine-treated animals. In long-term (14-day) nicotine-pretreated animals, both the apomorphine- and (+)-amphetamine-induced locomotor activity were potentiated. This behavioral potentiation was associated with an increase in the total number of postsynaptic dopaminergic receptor binding sites in the striatum. The development of striatal dopamine receptor supersensitivity may be caused by a decrease in the rate of dopamine turnover in the striatum.

Amphetamine↗
PubMed1989

Effects of prenatal nicotine exposure on rat striatal dopaminergic and nicotinic systems.

Previously we observed that chronic nicotine-treated adult rats developed locomotor hyperactivity which was mediated by changes in nicotinic and dopaminergic receptors in the striatum. In this study, we further examined if such changes would also occur in pups that were prenatally exposed to nicotine. Fourteen-day-old offspring from dams which were implanted with osmotic minipumps containing nicotine (1.5 mg/kg/day) throughout the entire gestational period were employed in this investigation. Prenatal nicotine treatment lowered the number of male pups born and reduced the postnatal gain in body weight and length of both male and female offspring. Prenatal exposure to nicotine did not alter the motor coordination of the pups. A decrease in the number of striatal dopaminergic receptor binding sites (Bmax) was detected in the male pups, however an increase in the ligand affinity to the receptors (1/KD) had been simultaneously detected. No change in the characteristics of nicotinic receptor binding sites and the levels of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid was found in the striatal region. The present study indicates that prenatal exposure to nicotine may cause changes in growth and development of the animals. However, in comparison to chronic nicotine-treated adult rats, prenatal exposure to nicotine had only modified the dopaminergic receptor system in the striatal region of male offspring.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Prenatal cocaine exposure fails to modify neurobehavioral responses and the striatal dopaminergic system in newborn rats.

1. The effects of cocaine on locomotor activity and striatal dopaminergic receptors and dopamine turnover were studied in rat pups exposed to cocaine (30 mg/kg/day) throughout the entire gestational period. 2. Prenatal exposure to cocaine did not alter the motor coordination or spontaneous locomotor activity in the offspring. 3. No change in the characteristics of dopaminergic receptors and the rate of dopamine turnover was detected in the striatum.

Animals↗
PubMed1989

Structural alterations of the RB1 gene in human soft tissue tumours.

Sixty-nine primary soft tissue tumours were examined for alterations of the RB1 gene which has previously been implicated in the genesis of retinoblastoma. In three tumours loss of both alleles of this gene (homozygous deletion) was detected. Two of these, both leiomyosarcomas, contained a chromosomal breakpoint within the RB1 gene, while in the third tumour, a radiation induced sarcoma, complete deletion was observed. Using a probe that detects a polymorphic locus within the RB1 gene we found loss of only one allele (heterozygous deletion) in 33% of soft tissue sarcomas examined, including two leiomyosarcomas, a malignant peripheral nerve sheath tumour, a rhabdomyosarcoma and a chondrosarcoma. When taken together our results suggest that alterations of the RB1 locus may play an important part in the pathogenesis of soft tissue tumours and particularly in leiomyosarcomas which accounted for four of the eight RB1 alterations observed in this study.

Alleles↗
PubMed1989

Effects of systemic administration of nicotine on capillaries in rat oral mucosa.

This study examined the reaction of the local vasculature of the oral mucosa in 16 Sprague Dawley rats receiving systemic nicotine delivered (1.5 mg/kg/day) via subcutaneous minipumps for 24 h or 2wk. Control animals received saline. After treatment animals were killed and biopsies taken from palate, maxillary gingiva and buccal mucosa, frozen and cryostat sections incubated to demonstrate alkaline phosphatase, which is a capillary marker. The total length of the capillary fragments in the nicotine treated groups was significantly less than of the control group. There was also a decrease in capillary height in both of the nicotine groups when compared to the control animals. This study indicates that morphologic alterations occur in the microvasculature of the oral mucosa following systemic nicotine administration. This may have implications for the role of chronic tobacco use in the etiology of oral mucosal disease, including periodontal disease.

Animals↗
PubMed1989

Effects of chronic nicotine pretreatment on (+)-amphetamine and nicotine-induced synthesis and release of [3H]dopamine from [3H]tyrosine in rat nucleus accumbens.

The effects of chronic (14 day) administration of nicotine (1.5 mg kg-1 day-1) on the rat nucleus accumbens have been examined. Pretreatment of animals with nicotine increased the endogenous level of dopamine. The ability of (+)-amphetamine to stimulate formation and release of [3H]dopamine from [3H]tyrosine was greatly potentiated in tissue slices from the nucleus accumbens of rats pretreated with nicotine. Furthermore, nicotine was effective in stimulating the formation and release of from [3H]dopamine from [3H]tyrosine in tissue slices from chronic nicotine-treated animals.

Animals↗
PubMed1989

Postnatal effects of maternal nicotine exposure on the striatal dopaminergic system in rats.

The biochemical effects of continuous prenatal exposure to nicotine (1.5 mg kg-1 day-1) have been examined in 14 day old male and female rat pups. The ability of striatal tissue slices from the nicotine-exposed pups to synthesize [3H]dopamine from [3H]tyrosine was enhanced. However, the ability of (+)-amphetamine to stimulate formation and release of [3H]dopamine from [3H]tyrosine was not affected. Furthermore, prenatal exposure to nicotine increased the rate of striatal dopamine turnover in the male, but not the female nicotine-exposed pups.

Animals↗
PubMed1989

The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours.

We have analysed the organisation of the retinoblastoma (RB1) gene in 77 primary breast carcinomas, in metastatic tissue derived from 16 of those primary tumours, and in a variety of benign breast lesions. Expression of RB1 was also assessed in most samples by immunohistochemical detection of the RB1 protein in tissue sections. Structural abnormalities to RB1 were detected in DNA from 15/77 (19%) of primary breast carcinomas examined. Where DNA was available from metastatic tissue derived from such primary tumours, the same aberration could be detected. No alterations were seen in benign breast lesions. 16/56 (29%) of tumours examined for expression by immunohistochemical methods showed a proportion of tumour cells to be completely negative for the RB1 protein. All tumours in which a structural alteration to RB1 was detected had a proportion of negative cells, except for one case where all cells were positive. Several primary tumour samples were identified where there was no detectable structural change to the gene, but there was loss of expression in some tumour cells. The data presented here demonstrate that changes to the RB1 gene leading to loss of expression of both alleles are frequent in primary human breast tumours.

Amino Acid Sequence↗
PubMed1988

The gene responsible for the development of retinoblastoma and osteosarcoma.

The gene responsible for the formation of both retinoblastoma and osteosarcoma recently has been isolated. This represents the first human recessive cancer gene ever cloned. Structural deletions within one or both retinoblastoma gene alleles were commonly noted in the retinoblastomas and an osteosarcoma. Whether or not changes were observed at the DNA level there was either no expression or an abnormal expression of the gene in the tumor. The fact that we could detect changes in the fibroblasts of some patients with the hereditary form of retinoblastoma also indicates that the gene can be used for diagnostic purposes.

DNA, Neoplasm↗
PubMed1988

Structural rearrangement of the retinoblastoma gene in human breast carcinoma.

Structural changes of the human retinoblastoma gene have been demonstrated previously in retinoblastoma and some clinically related tumors including osteosarcoma. Structural aberrations of the retinoblastoma locus (RB1) were observed in 25% of breast tumor cell lines studied and 7% of the primary tumors. These changes include homozygous internal deletions and total deletion of RB1; a duplication of an exon was observed in one of the cell lines. In all cases, structural changes either resulted in the absence or truncation of the RB1 transcript. No obvious defect in RB1 was detected by DNA blot analysis in primary tumors or cell lines from Wilms' tumor, cervical carcinoma, or hepatoma. These results further support the concept that the human RB1 gene has pleiotropic effects on specific types of cancer.

Breast Neoplasms↗
PubMed1988

Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats.

Rats were pretreated with saline or nicotine (1.5 mg/kg per day) by subcutaneously implanting each animal with an Alzet osmotic mini-pump which continuously released saline or nicotine for 1, 5 and 14 days. At the end of each pretreatment period, animals were used for (i) determining their locomotor response to acutely injected nicotine (0.2 mg/kg, s.c.) and (ii) measuring the density of L-[3H]nicotine and [3H]spiperone binding sites in the striatum. We observed no changes in nicotine-induced locomotor response, striatal L-[3H]nicotine and [3H]spiperone binding in the animals pretreated with nicotine for 1 day. In rats which were pretreated with nicotine for 5 days, there was a significant increase in the nicotine-stimulated locomotor response which was associated with an increase in the number of L-[3H]nicotine binding sites and also with an elevated dopamine (DA) level in the striatum. The number of striatal [3H]spiperone binding sites was not affected. In animals pretreated with nicotine for 14 days, the nicotine-induced locomotor response remained to be potentiated. However, this response was correlated with an elevated number of striatal [3H]spiperone binding sites, whereas the number of striatal L-[3H]nicotine binding sites and the striatal DA level were normal. These results suggest that chronic nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of nicotinic receptors and DA concentration, followed by inducing DA receptor supersensitivity in the striatum.

Animals↗
PubMed1988

Effect of nicotine on central GABAergic system.

1. The acute and chronic effects of nicotine (1.5 mg/kg/day) on the striatal and mesolimbic GABAergic systems were examined in the rat. 2. Despite altering the striatal DAergic activity, neither acute nor chronic administration of nicotine significantly affected the GABAergic system. 3. The nicotine treatment did not alter the ability of muscimol to inhibit the hyperactivity elicited by apomorphine. 4. Similarly, the levels of GABA in striata and nucleus accumbens remained unchanged.

Animals↗
PubMed1988

Postnatal behavioural effects of maternal nicotine exposure in rats.

The effects of nicotine on locomotor activity have been studied in neonate rats exposed to nicotine (1.5 mg kg-1 day-1) throughout the gestational period. Both 14 day old male and female offspring demonstrated an increase in spontaneous locomotor activity when compared with saline-exposed controls. However, systemic administration of (+)-amphetamine was effective in attenuating the hyperactivity of these nicotine-exposed pups.

Animals↗
PubMed1988

Altered expression of the retinoblastoma (RB) gene in small-cell carcinoma of the lung.

Nine lung small-cell carcinoma (SCC) cell lines and 9 lung non-SCC cell lines were examined for structural changes of the retinoblastoma (RB) gene as well as its expression using a complementary DNA probe. The RB protein product was investigated using an anti-RB antibody which we produced. Although homozygosity or hemizygosity of the RB gene was suggested in 8 of 9 SCCs and one of 2 large cell carcinomas (LCCs) by Southern blot analysis using an RB cDNA probe and polymorphic DNA markers for chromosome 13, no obvious structural changes of the RB gene were detected in these 18 cell lines. However, RB transcripts were either markedly reduced in quantity or abnormal in length in 3 of 9 SCCs. The specific 115 kD protein was not immunoprecipitated by the anti-RB antibody in all 9 SCCs with either normal or abnormal size RB mRNA. Three of 4 adenocarcinomas (AdCs), all 3 squamous cell carcinomas, and one of 2 LCCs expressed normal size RB mRNA, and the 115 kD protein was immunoprecipitated by the anti-RB antibody. The 115 kD protein was also absent in one of 2 LCCs with shortened RB mRNA and in one of 4 AdCs with low level of RB mRNA expression. These results strongly suggest that inactivation of the RB gene might be involved in the development of lung cancers, especially of SCCs.

Adenocarcinoma↗