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PubMed2004

Microarray analysis of differentially expressed genes associated with human ovarian cancer.

To define the molecular changes associated with ovarian cancer, DNA microarray analysis has been adapted to detect differentially expressed genes in human normal ovary tissue, borderline, and invasive epithelial ovarian tumors. The differential expression of genes in the tumor tissues and normal tissues was confirmed by Northern and/or semi-quantitative RT-PCR analysis. Analysis of the differential gene-expression profiles of the normal and neoplastic ovary allowed us to detect previously unidentified genes in ovarian tissues. We observed up-regulation of the following genes in ovarian cancer: catechol-O-methyltransferase (COMT), the autocrine motility factor neuroleukin (NLK), the transcription regulator high mobility group I proteins (HMGI), the tyrosine kinase receptor ErbB-3, S100-alpha protein and Acyl-CoA-binding protein (ACBP). The transcription factor, chicken ovalbumin up-stream promoter transcription factor II (COUP-TFII), was the only gene down-regulated in ovarian cancer. Comparable gene-expression profiles were previously reported in breast cancer, suggesting that similar molecular events also exist in ovarian cancer. Our microarray analysis showed that most differentially expressed genes in ovarian cancer are linked to glucose/insulin metabolism, providing a possible molecular link between the glucose/insulin signaling pathway and the neoplasms of ovarian cancer.

Biomarkers, Tumor↗
PubMed2004

[Genetic polymorphism of steroidogenic enzymes and steroid receptor level in tumors of the reproductive system].

The strategy of therapy and prognosis of reproductive system neoplasia generally depend on the steroid receptor status of tumor. The causes of formation of steroid receptor-free tumors are to be investigated. The genetic polymorphism of CYP19 (aromatase), CYP17 (17-hydroxylase; 17,20-lyase), CYP1B1 (4-estrogen hydroxylase) and COMT (catechol-O-methyl transferase) was studied in a total of 254 patients with breast and endometrial cancer, with particular reference to the association of certain polymorphisms and receptor status of tumor. It was found that the lack of estrogen receptor (ER) in breast tumor was due to a deficit in the A3A6 allele (p(0.01), while the absence of progesterone receptors was associated with a lower incidence of the A1A1 and A1A2 variants (p = 0.022) of tetranucleotide repeats in the CYP19 gene. In the same patients, receptor-negative tumors occurred more often (p = 0.032) than in combinations of higher level of 4-hydroxylase estradiol of S-allele in position 48 (Gly/Arg) of the CYP1B1 gene. Moreover, endometrial carcinoma patients tended to reveal (p = 0.058) an increased ratio of A6A7-CYP19 to allele A1-containing variant. No other distinctions between R(+) and R(-) tumors were identified. It is suggested that peculiar polymorphisms of steroidogenic enzymes may moderately influence the genesis of R(-) neoplasms which may be associated with either the rate of estrogen biosynthesis or, as in the case of CYP1B1, with formation of genotoxic derivatives of estrogens. The latter point is to be investigated further.

Adult↗
PubMed2004

[The therapy of wearing-off].

Wearing-off, predictable end of dose deterioration, is one of the major problems of long-term levodopa treatment for Parkinson's disease. The mechanisms of wearing-off are (1) loss of striatal dopamine storage, (2) change in the peripheral pharmacokinetics of levodopa and (3) modification of dopamine receptors. The main therapeutic strategy for wearing-off is continuous stimulation of dopamine system. For this purpose, we increase frequency of levodopa doses and use long half-life dopamine agonist(continuous stimulation of dopamine receptors), COMT inhibitor and MAOB inhibitor (prolongation of the half-life of levodopa and dopamine), and zonisamide (long-term increase of dopamine synthesis).

Age Factors↗
PubMed2004

[Molecular pharmacogenetic studies of drug responses to obsessive-compulsive disorder and six functional genes].

OBJECTIVE: To investigate the associations between the drug responses to obsessive -pulsive disorder (OCD) and six functional genes related with serotonin and dopamine. METHODS: One hundred and thirteen OCD nuclear families were collected. The OCD patients were treated with serotonin reuptake inhibitors (SRIs) for 8 weeks and the drug responses were assessed using the Yale-Brown obsessive-compulsive scale (Y-BOCS). The patients were divided into drug responders group and non-responders group according to the reducing rate of Y-BOCS score. The genotypes of six genes were determined with the Amp-FLP and Amp-RFLP techniques and analyzed by transmission disequilibrium test (TDT). The six genes are serotonin 2A receptor (5-HT2A), serotonin transporter (5-HTT), dopamine D2 receptor ( DRD2), dopamine D4 receptor (DRD4), catechol-O- methyltransferase (COMT) and monoamine oxidase A (MAOA). RESULTS: No association was found between the six genes and different drug responses groups. However, there was significant difference between the drug responders and non-responders in homozygosity at the 5-HT2A -1438G/A locus (chi(2)=4.69, P=0.03). CONCLUSION: The results suggested that the 5-HT2A may play some roles in the effects of drug treatment on OCD.

Adolescent↗
PubMed2004

[Advances in research on lignin biosynthesis and its genetic engineering].

Lignin, one of the main components in vascular plants, is important for the adaptation of terrestrial plants to environment during evolution. However, its presence in plants has negative effects on wood processing during pulping and stock breeding. Therefore much attention has been focused on the regulation of lignin biosynthesis. The pathways leading to the synthesis of lignin polymers have been studied for decades. Much understanding of lignin biosynthesis has been advanced. This paper reviewed the recent progress made in the various steps associated with monolignol biosynthesis. It includes the catalysis by three enzymes, i.e. p-coumarate-3-hydroxylase (C3H), ferulate-5-hydroxylase (F5H) and caffeic acid 3-O-methyltransferase (COMT); the multiform biosynthetic pathway of syringyl (S) lignin in angiosperms; the biosynthesis route of guaiacyl (G) and syringyl (S) lignin specifically regulated by cinnamyl alcohol dehydrogenase (CAD) and sinapyl alcohol dehydrogenase (SAD) and the formation of the lignin macromolecule. Based on the elucidation of lignin biosynthesis pathway, it has also been given the achievements in lignin gene engineering. Many studies were concentrated on the modification of lignin content and composition. In some cases, the potential value of transgenic plants with modified lignin beneficial for pulping has been demonstrated. To better understand the mechanism of lignin biosynthesis and improve the properties of plants, new biotechnological strategies can be developed, which include combinatorial modification of multiple lignin traits in plants through multigene cotransformation, transcriptional control of lignin biosynthesis and the application of RNA interference. The identification of novel genes by molecular and genetic approaches will be useful in opening up new avenues of lignin modification in the future.

Genetic Engineering↗
PubMed2003

[Association study of five pedigree with high incidence of schizophrenia].

This study is to explore the relationship between polymorphism of Catechol O-methyltransferase gene and schizophrenia. Search for a gene predisposing to schizophrenia in the Han nationality in China. Five pedigrees with high incidence of schizophrenia were studied by polymerize chain reaction(PCR) and restriction fragment length polymorphism(RFLP) technique. Statistics analysis of the transmission/disequilibrium test (TDT) showed that the COMT gene is associated with schizophrenia in the five pedigree with high incidence schizophrenia(P=0.0455). The results suggest that there might have a schizophrenia liability gene on 22 chromosome (22q11.2) in our studied pedigrees.

English Abstract↗
PubMed2005

A walk through the management of Parkinson s disease.

INTRODUCTION: Patients with Parkinson s disease are known to develop motor complications after a few years of therapy. Motor fluctuations and dyskinesias develop with increasing severity of disease, and were formerly thought to be an inevitable consequence of the disease. METHODS: Literature review of articles on the aetiopathogenesis of Parkinson s disease, the mechanisms underlying the development of motor fluctuations and dyskinesias, and strategies for delaying the onset of dyskinesias. RESULT: Motor fluctuations develop with increasing severity of the disease, owing to loss of dopaminergic neurons and loss of the buffering capacity of the neurons to fluctuating dopamine levels. Dyskinesias develop as a result of pulsatile stimulation of the receptors, causing changes in plasticity, dysregulation in gene and protein expression and alterations in neuronal firing patterns. Continuous dopaminergic stimulation, through long-acting dopa agonists and frequent administration of levodopa, is known to delay the development of dyskinesias. The use of catechol-O-methyl transferase (COMT) inhibitors likewise increases the bioavailability and brings about a smooth drug profile. The use of dopa agonists is associated with sedation and confusion, particularly in the elderly. CONCLUSIONS: Initiation of therapy in Parkinson s disease should begin with a dopa agonist agent, unless the patient is elderly or has cognitive impairment, in which case levodopa therapy should be given.

Antiparkinson Agents↗
PubMed2005

Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect.

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.

Antiparkinson Agents↗
PubMed2005

[Genetic variation-- important for the clinical effect of opioids?].

The individual variability of opioid pharmacology suggests that the patients' genetic disposition influences the response to opioids. Given the complexity of morphine pharmacology, variability may be caused by several genes. Data suggest that variability in genes encoding the enzyme metabolising morphine (UGT2B7 gene), mu-opioid receptors (OPRM1 gene) and BBB transport of morphine by multidrug resistance transporters (MDR1 gene) influence the clinical efficacy of morphine. Furthermore, variability in an enzyme-degrading catecholamines (COMT gene) may also alter the efficacy of morphine, which shows that genetic variability in non-opioid systems may indirectly influence the clinical opioid efficacy. Results obtained so far strongly suggest that opioid efficacy is partly related to inborn properties caused by genetic variability.

Analgesics, Opioid↗
PubMed2005

[Chromosome 22q11 and schizophrenia].

Several human chromosomal regions have been identified as candidate regions that play a role in schizophrenia. Deletion or duplication of chromosome 22q11 is associated with velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), a disorder associated with high rates of schizophrenia as well as physical abnormalities (i.e., cardiovascular, parathyroid, thymic and craniofacial abnormalities). Recent mouse studies have identified several candidate genes for VCFS/DGS within the mouse homologue chromosome 16. Deletion of Tbx1, Prodh and Comt within mouse chromosome 16 causes several physical and behavioral features of VCFS/DGS. As VCFS/DGS is likely to represent a genetic subtype of schizophrenia, pinpointing the genetic basis for this specific subtype will contribute to a better understanding of this neuropsychiatric disorder.

Animals↗
PubMed2005

[Schizophrenic disorders: current etiologic and clinical knowledge].

Brain anomalies associated with schizophrenic disorders may be of a cognitive, neurophysiological or neurological nature [the latter being relatively minor and nonspecific]. Brain imaging has revealed early anomalies such as cortical-subcortical atrophy and abnormal gyration. These anomalies can also be present in relatives free of schizophrenic symptoms. This raises the question of what determines the transition from vulnerability to clinical onset. There is now evidence that schizophrenic disorders are true brain diseases. This is based on neuropathological studies, brain imaging and clinical findings such as "soft" neurological signs (pyramidal and extrapyramidal symptoms, coordination difficulties, etc.). Cognitive dysfunctions such as attention and memory disorders and abnormal verbal fluency have also been described. Oculomotor pursuit and auditive evoked potentials have identified specific neurophysiological disorders such as N300 and P50 wave modifications. Schizophrenic disorders can also be associated with neuronal abnormalities, notably affecting factors involved in synaptic transmission and plasticity. For example, BDNF protein deficit is linked to certain late-onset forms of schizophrenia. Genetic studies are no longer focusing on a possible disease genotype but rather on phenotypic characteristics determined by simpler genotypes (P50 wave modulation, COMT and BDNF genes). The ultimate objective is to identify high-risk subjects, in order to shorten the treatment delay and thereby improve long-term outcome. The benefit of primary prophylaxis remains to be determined, however.

Brain↗
PubMed2005

[Inter- and intraindividual pharmacokinetic variations in the treatment of Parkinson's disease].

In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.

Antiparkinson Agents↗
PubMedDate not supplied

[Genetic background of ADHD: population studies, genes of the catecholamine system].

Attention-deficit hyperactivity disorder (ADHD) begins in early childhood. In this article we review the studies supporting a genetic background of this disorder. ADHD occurs in 3-10% of the general population. Family studies reveal a 5 times more likely frequency of ADHD among first-degree relatives than in the general population. Monozygotic twin concordance rate for ADHD is 81%, whereas for dizygotic twins it is 29%. One of the ADHD predisposing factors is dopaminergic neurotransmission abnormality. According to other studies there is a relationship between polymorphism of dopamine transporter gene (DAT), dopamine receptors genes: DRD2, DRD3, DRD4, DRD5, dopamine-beta-hydroxylase gene (DBH) and catechol-O-methyltransferase gene (COMT) and ADHD. In other articles authors describe abnormalities of the serotonergic system, such as the polymorphism of the serotonin transporter gene (5HTT/SERT), serotonin receptors genes 5HT2A and 5HT1B in the development ofADHD. Another possible factor in ADHD background is the dysregulation of the adrenergic system. The most frequently studied is the connection between polymorphism of norepinephrine transporter gene (NET), adrenergic receptors genes: alpha 2A (ADRA2A), alpha 1C (ADRA1C), alpha 2C and monoamine oxidase A gene (MAO-A).

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

Levodopa induced motor complications in Thai Parkinson's disease patients.

BACKGROUND: Long-term levodopa usage in Parkinson's disease (PD) patients is known to cause several motor complications. It may be related to several factors such as levodopa dosage, duration of treatment and severity of disease. OBJECTIVE: To study the prevalence of levodopa motor complications and associated factors in Thai Parkinson's disease patients. MATERIAL AND METHOD: The authors prospectively collected baseline characteristics of PD patients, details of treatment and complications from 3 hospitals in various parts of Thailand. These patients were diagnosed by UK PD Brain Bank criteria. RESULTS: A total of 154 patients aged 68.1 +/- 9.5 years were recruited. Age of onset was 61.2 +/- 9.8 years. Most patients were in Hoehn-Yahr stage 1-3. The common clinical features were bradykinesia, rigidity and resting tremor Treatments were levodopa (98.1 per cent), anticholinergic (29.9 per cent), dopamine agonists (26 per cent) and COMT inhibitor (9.1 per cent). Eighty-five per cent of the patients had excellent response to levodopa. However, 25 per cent of patients developed motor complications, which were wearing off (79 per cent), on-off fluctuation (45 per cent), freezing (42 per cent), morning dyskinesia (10.5 per cent) and permanent dyskinesia (23.7 per cent). Twelve patients developed severe levodopa induced chorea. Factors associated with levodopa side effects were earlier age of onset, long duration of disease, advanced stage, higher levodopa dosage and long duration of levodopa treatment. In the present study, age of onset was inversely correlated with H-Y stage, while dosage of levodopa was positively correlated with H-Y stage but inversely correlated with lower ADL score, which may be due to advanced disease state. CONCLUSION: Levodopa motor complications are common in Thai PD patients. Wearing off on-off fluctuation and freezing are common forms of motor complications.

Aged↗
PubMedDate not supplied

Recent advances in the clinical pharmacology of Parkinson's disease.

The introduction of levodopa in the treatment of Parkinson's disease had modified both the prognosis and the current concepts of the disease, Although levodopa remains the most potent drug for the treatment of Parkinson's disease, its long-term use is associated with fluctuations in motor performance, abnormal movements and psychotic hallucinations. These late side-effects remain difficult to treat and thus raise questions as to the benefits and risks of first-time treatment with levodopa. Levodopa mainly alleviates akinesia and rigidity and to a lesser extent, tremor. Levodopa increases life expectancy. This paper reviews some recent developments in the pharmacology of Parkinson's disease. Recent findings indicate that not only central dopamine but also several other central neurotransmitter and receptor changes are involved in the pathophysiology of Parkinson's disease. New data on autonomic dysfunction in Parkinson's disease are presented. New methods of investigation (clinical rating scales, pharmacological tests, imaging techniques, etc.) are reviewed. Finally, future strategies, e.g. the development of potent new symptomatic drugs (selective D2 and D1 agonists, new formulations of apomorphine, COMT inhibitors, new routes of administration, etc.) and etiopathogenic agents (antioxidative and anti-free radical drugs, etc.) are discussed.

Apomorphine↗
PubMed2006

Immunoregulatory role of endogenous catecholamines synthesized by immune cells.

It has been well known that catecholamines (CAs) in the body, including norepinephrine (NE), epinephrine (E) and dopamine (DA), are synthesized and secreted by neurons and endocrine cells and mainly modulate visceral activities such as cardiovascular, respiratory and digestive functions. The studies over the past nearly 30 years have shown that CAs can also regulate immune function. The immunomodulation of CAs is generally considered as a role mediating the regulation of nervous and endocrine systems. However, recent studies reveal that immune cells can also synthesize CAs, which is an update of traditional concept. A classical metabolic pathway of CAs shared by the nervous and endocrine systems is present in the immune cells, i.e., the immunocytes have the enzymes for synthesis of CAs [e.g. tyrosine hydroxylase (TH)] and the enzymes for degradation of CAs [e.g. monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)]. The endogenous CAs synthesized by immune cells can regulate many immune functions, including cellular proliferation, differentiation, apoptosis and cytokine production. These roles of the endogenous CAs may be mediated by an autocrine/paracrine pathway via relevant receptors on the immunocytes and intracellular cAMP. Intracellular oxidative mechanism may also be involved in immunoregulation of endogenous CAs in immune cells. In addition, some metabolic abnormalities of CAs in the immune cells probably induce some autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis. These findings not only provide evidence for the new concept that the immune system is possible to become the third CA system other than the nervous and endocrine systems, but also extend our comprehension on functional significance of the endogenous CAs synthesized by immune cells.

Animals↗
PubMed2006

[Progesterone-modulated proteins in human endometrial cancer cell line Ishikawa].

OBJECTIVE: To identify proteins associated with growth inhibitory effects of progesterone in Ishikawa endometrial adenocarcinoma cell line (Ishikawa). METHODS: The total cellular proteins of the control and megestrol acetate (MA)-treated Ishikawa cells were separated by two-dimensional gel electrophoresis. After colloidal Coomassie G-250 staining and scanning, the gel images were analyzed by PDQuest software. Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and Mascot software were used to identify the differentially expressed protein. RESULTS AND CONCLUSIONS: Well-resolved and reproducible 2-dimensional patterns of both control and MA-treated Ishikawa cells were obtained. Forty-one proteins displayed differential expression after MA treatment, among which 23 were up-regulated and 18 down-regulated. Peptide mass fingerprints (PMF) by MALDI-TOF-MS analysis and search in NCBInr resulted in the identification of 8 proteins. The up-regulated proteins identified were catechol-O-methyltransferase (COMT), glutathione S-transferase, keratin 8, splicing factor 3a (subunit 3), chaperonin containing TCP1 (subunit 6A isoform a, CCT6A), RAB6A protein and AHA1. The down-regulated protein was peptidyl prolyl isomerase A (isoform 1). These findings can be helpful in further investigation of the molecular mechanism of progesterone.

Adenocarcinoma↗
PubMed2006

A review of agitation in mental illness: burden of illness and underlying pathology.

Agitation has been poorly addressed as a unique entity in many psychiatric disorders. Recent medical literature and a range of instruments have measured agitation in various clinical settings. Agitation is a common problem in many patients with schizophrenia, bipolar mania, or dementia. Moreover, agitation adversely impacts many facets of the healing process, including direct patient care, caregiver burden, and community resources. Frontal lobe dysfunction and mutations in the catechol O-methyltransferase (COMT) gene involved in dopamine metabolism and catecholamine inactivation have been linked to agitation in patients with schizophrenia and bipolar disorder. Cerebral impairment and deficits in cognitive function predispose patients with dementia to agitation. In patients with Alzheimer's dementia, both frontal and temporal lobe pathology may be associated with agitation. Addressing agitation as a symptom of psychiatric illness would represent a great opportunity for therapeutic intervention and the alleviation of patient suffering, family burden, and societal costs.

Aggression↗