"Nature versus nurture" and incompletely penetrant mutations.
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Forecasting↗
Biomedical subjects
M T Lin
Publications and source records attributed to M T Lin.
The hypothermic effects of dl-tetrahydropalmatine in rats.
Systemic administration of dl-tetrahydropalmatine (THP; 10-50 mg x kg(-1) intraperitoneally) produced a proportional decrease in both colonic temperature and release of hypothalamic serotonin (5-hydroxytryptamine (5-HT)) in rats at room temperature. The hypothermia was brought about by cutaneous vasodilation and decreased metabolism. The THP- induced hypothermia was significantly attenuated in rats with brain 5-HT depletion produced by control injection of 5,7-dihydroxytryptamine or in rats with 5-HT2A receptor activation produced by 1-(2,5-dimethoxy-4-iodophenyl) -2-aminopropane, or in rats with 5-HT1A receptor antagonist produced by (-)-pindolol. The results suggest involvement of serotoninergic antagonism in the THP-induced hypothermia in rats
Animals↗
Absence of statistically significant correlation between disparity for the minor histocompatibility antigen-HA-1 and outcome after allogeneic hematopoietic cell transplantation.
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Acute Disease↗
Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer.
Early detection of fungal infections in and corresponding early treatment of febrile patients with neutropenia and cancer have been important issues and continue to be major challenges for clinicians. The use of nested PCR to make therapeutic decisions was studied. Sequential blood samples obtained from 42 patients with neutropenia and cancer were tested by nested PCR and culture. Instead of the empirical antifungal therapy strategy, amphotericin B treatment was initiated only for patients who had 2 consecutive positive results by nested PCR. A reduced mortality rate was observed for febrile patients with neutropenia and cancer who had fungal infections. Thus, this strategy, combined with the nested PCR for early detection of fungal infection in febrile patients with neutropenia, may be used as a guideline for antifungal therapy.
Adolescent↗
Stimulatory effect of phenylephrine on the secretion of beta-endorphin from rat adrenal medulla in vitro.
In an attempt to investigate the role of alpha1-adrenoceptors in the regulation of opioid secretion from adrenal gland, phenylephrine was employed to investigate the effect on secretion of beta-endorphin-like immunoreactivity (BER) from adrenal medulla of rat in vitro. Phenylephrine enhanced the BER from isolated adrenal medulla in a concentration-dependent manner and this action was abolished by the antagonists of alpha1-adrenoceptors, prazosin and tamsulosin. Investigations of signal pathway further support that an activation of alpha1-adrenoceptors is responsible for the stimulatory effect of phenylephrine on BER secretion from adrenal medulla. In the presence of U73312, the specific inhibitor of phospholipase C (PLC), phenylephrine-induced change of BER was reduced in a concentration-dependent manner but it was not affected by U73343, the negative control of U73312. Moreover, chelerythrine and GF 109203X diminished the action of phenylephrine at concentration sufficient to inhibit protein kinase C (PKC). In conclusion, our results suggest that an activation of alpha1-adrenoceptors in adrenal medulla by phenylephrine may enhance the secretion of opioids from adrenal gland of rat via signals of PLC-PKC pathway.
Adrenal Medulla↗
Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells. Involvement of phosphatidylinositol 3-kinase/Akt pathway.
Cyclooxygenase 2 (COX-2) has been reported to be commonly expressed in advanced stages of human lung adenocarcinoma. In this study, the COX-2 constitutive expression vector was transfected into a human lung adenocarcinoma cell line CL1.0 and several clones were obtained which stably expressed COX-2. These COX-2-overexpressed clones demonstrated remarkable resistance to apoptosis induced by Ultraviolet B (UVB) irradiation, vinblastine B (VBL) cell lymphoma-2 (Bcl-2), or other anti-cancer drugs. To understand how COX-2 prevents apoptosis, the investigators examined the expression level of Bcl-2 family members. Mcl-1, but not other Bcl-2 members, was significantly up-regulated by COX-2 transfection or prostaglandin E(2) (PGE(2)) treatment. Treatment of COX-2-overexpressed cells (cox-2/cl.4) with two specific COX-2 inhibitors, NS-398 and celecoxib, caused an effective reduction of the increased level of Mcl-1. These data suggest that the expression level of Mcl-1 is tightly regulated by COX-2. Moreover, transfection of cox-2/cl.4 cells with antisense Mcl-1 enhanced apoptosis induced by UVB irradiation, revealing that Mcl-1 plays a crucial role in cell survival activity mediated by COX-2. Furthermore, COX-2 transfection or PGE(2) treatment evidently activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Inhibition of the PI3K pathway by LY294002 or wortmannin effectively attenuated the increased level of Mcl-1 induced by COX-2 or PGE(2). Blocking the PI3K activity with a dominant-negative vector, DN-p85, also greatly diminished the level of Mcl-1 and enhanced UVB-elicited cell death in cells transfected by COX-2. In a similar way, LY294002 inhibited cell survival and Mcl-1 level in PGE(2)-treated CL1.0 cells. These findings suggest that COX-2 promotes cell survival by up-regulating the level of Mcl-1 by activating the PI3K/Akt-dependent pathway.
Adenocarcinoma↗
DL-Tetrahydropalmatine may act through inhibition of amygdaloid release of dopamine to inhibit an epileptic attack in rats.
DL-Tetrahydropalmatine (THP), an active component isolated from corydalis (a Chinese herbal medicine), possesses analgesic effects. Systemic administration of picrotoxin (3-4 mg/kg) produced increases of locomotion (including horizontal motion, vertical motion, and total distance traveled), elevations of turnings (including both clockwise and anticlockwise), and inhibition of postural freezing in freely moving rats, and increases of amygdaloidal release of dopamine in anesthetizes rats. All the afore-mentioned activity measures induced by picrotoxin were suppressed following THP pretreatment. The results indicate that THP may act through inhibition of amygdaloid dopamine release to inhibit an epileptic attack.
Amygdala↗
Loss of plasma glucose lowering response to cold stress in opioid mu-receptor knock-out diabetic mice.
Opioid mu-receptor plays an important role in the regulation of glucose homeostasis in diabetic rats lacking insulin. Opioid mu-receptor knockout mice were employed to identify the essential role of this receptor in the present study. Western blotting analysis characterized the deletion of opioid mu-receptor in liver of knockout mice as compared to that of normal (wild-type) mice. We found that the plasma glucose concentration of diabetic mice induced by intraperitoneal injection of streptozotocin was markedly decreased after exposure to cold-stress in a cold room for 1 h. However, this plasma glucose lowering response to cold-stress was disappeared in diabetic mice lacking opioid mu-receptor. The important role of opioid mu-receptor in the plasma glucose lowering response to cold stress can thus be considered. Moreover, bilateral adrenalectomy abolished this plasma glucose lowering response to cold stress in diabetic mice with opioid mu-receptor, as compared to the shamed-operated animals. Therefore, activation of opioid mu-receptor by opioid from adrenal gland appears to be responsible for the plasma glucose lowering response to cold-stress in diabetic mice with insulin deficiency.
Adrenal Glands↗
Low mutational burden of individual acquired mitochondrial DNA mutations in brain.
Neurons may be particularly susceptible to oxidative damage, which has been proposed to induce somatic mutations, particularly in mitochondrial DNA (mtDNA). Therefore, acquired mtDNA mutations might preferentially accumulate in the brain and could play a role in aging and neurodegenerative disorders. Recently, a somatic T to G mtDNA mutation at noncoding nucleotide position 414 was reported in fibroblasts specifically from elderly subjects, with mutational burdens of up to 50%. We screened for this mutation in brain-derived mtDNA from 8 Alzheimer's disease patients, 27 Parkinson's disease patients, 4 multiple system atrophy patients, and 44 controls using up to three RFLP analyses. A total of 73 of these subjects were over the age of 65. The 414 mutation was absent in all cases. Next, individual mtDNA fragments from 6 elderly subjects were cloned, and a total of 70 clones were sequenced. The 414 mutation was absent in all clones, though occasional sequence variations were identified at other sites in single clones. The 414 mutation also was absent in blood (n = 6) and fibroblasts (n = 11) from elderly subjects. Our data suggest that it is rare for any one particular acquired mtDNA mutation to reach levels in the brain that are functionally significant. This does not exclude the possibility that the cumulative burden of multiple, individually rare, acquired mutations impairs mitochondrial function.
Aged↗
The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6.
Interleukin-6 (IL-6) is a pleitrophic cytokine that not only regulates growth and differentiation of many cell types, but also induces production of acute phase proteins (AAP) in hepatocytes. Our previous works have demonstrated that both PI 3-K/Akt and STAT3 pathways were concomitantly activated and cooperatively mediated the anti-apoptotic effect of IL-6. This investigation reports that IL-6 protected cells against apoptosis induced by a variety of agents including, TGF-beta, UV and retinoic acid (RA) in Hep3B cells, suggesting that IL-6 is a fundamental determinant of hepatic cell survival. Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated by IL-6, with a peak (approximately 3-4-fold) appearing at 4 h. Transient transfection of cells with a mcl-1 antisense vector, resulting in a 50-60% reduction of the anti-apoptotic effect of IL-6, indicating that Mcl-1 is a downstream effector of IL-6. Which signaling pathway transduced by IL-6 responsible for the Mcl-1 up-regulation was further investigated. In Hep3B cells, the JAK/STAT3, ERK, and PI 3-K/Akt pathways were activated by IL-6 stimulation. Blocking JAK/STAT3 activation with a dominant-negative mutant STAT3F or a JAK inhibitor AG490 could not influence IL-6-mediated Mcl-1 up-regulation. Similarly, PD98059 treatment, a MEK specific inhibitor, also failed to inhibit Mcl-1 expression. However, the IL-6-induced Mcl-1 up-regulation was effectively attenuated in the presence of PI 3-K inhibitors, LY294002 and wortmannin. Expression of dominant-negative Akt, but not Etk, could abrogate the IL-6-induced increase of Mcl-1. In conclusion, our results suggest that the anti-apoptotic effect of IL-6 is mediated, at least in part, by Mcl-1 expression and that is mainly through the PI 3-K/ Akt-dependent pathway.
Apoptosis↗
Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in chinese patients with Wilson disease.
BACKGROUND: The defective gene (ATP7B) that causes Wilson disease (WD) codes for a putative copper-transporting P-type adenosine triphosphatase. After cloning of ATP7B, the spectrum of mutations and their clinical consequences have been investigated in patients with WD in different ethnic populations. However, the spectrum of mutations and the correlation of genotype-phenotype in the Chinese population have not been extensively studied. OBJECTIVE: To investigate the characterization of mutations of ATP7B and the correlation between genotype and phenotype in the Chinese population. METHODS: We studied 60 unrelated healthy Chinese and 65 unrelated Chinese families, including 84 patients with WD and 126 parents. Genomic DNA was prepared from peripheral blood leukocytes using a salt-precipitation method. Polymerase chain reaction single-strand conformation polymorphism and subsequent direct sequencing were used to identify the mutations and polymorphisms of ATP7B. Statistical analysis was performed using t test or chi(2) test. RESULTS: We identified 18 mutations (7 novel) and 11 polymorphisms (3 novel). The novel mutations are -36C-->T, Trp650ter, Gln914ter, 2810delT, Thr935Met, Arg1041Pro, and Glu1173Lys. The novel polymorphisms are 1168A-->G (Ile390Val), 2785A-->G (Ile929Val), and 3316G-->A (Val1106Ile). Two mutations, Arg778Leu and Thr935Met, are relatively frequent, representing 37.7% and 10.0% of patients, respectively. To our knowledge, we are the first to report the correlation between the genotype and phenotype of Arg778Leu. The result shows that Arg778Leu homozygotes are associated with the early onset of WD with hepatic presentation. CONCLUSIONS: The Arg778Leu and Thr935Met mutations are hot spots in the Chinese population. The features of mutations of ATP7B differ between the Chinese and Western ethnic populations. The Arg778Leu mutation has severe effects on the function of ATP7B. These findings are valuable for developing a fast and effective method to diagnose the presence of the WD gene.
Adolescent↗
Correlation of histologic subtypes and replication error phenotype with comparative genomic hybridization in gastric cancer.
To characterize phenotypic and genotypic changes in gastric cancer (GC), DNA copy number aberrations (CNAs) were assessed in 53 tumors using comparative genomic hybridization (CGH) and correlated with clinicopathologic characteristics and status of TP53 and replication error (RER). The number of CNAs per tumor was 6.8 (gain 5.3, loss 1.5), and the number of changes was significantly higher in tumors with advanced stage, TP53 mutation, and without RER than in those with early stage (7.7 vs. 3.0), no TP53 mutations (12.4 vs. 4.8) or RER phenotype (8.2 vs. 2.6). Frequent abnormalities included gains on chromosomal arms 8q (43%), 6q (26%), 11q (26%), 13q (24%), 7p (23%), 17q (23%), and 20q (23%), and losses on chromosomal arms 16q (26%), 19p (23%), 5q (19%), 3p (15%), 4q(15%), and 1p (15%). Advanced GC demonstrated a higher prevalence of gains of 8q (51% vs. 10%, P < 0.05) and loss of 16q (33% vs. 0%, P < 0.05) than early GC. Gains on 8q (64% vs. 20%, P < 0.05), 17q (39% vs. 4%, P < 0.05) and losses on 3p (25% vs. 4%, P = 0.05) and 5q (32% vs. 4%, P < 0.05) were higher in intestinal GC than in diffuse GC. On the other hand, gains on 13q were more common in the diffuse type (40% vs. 11%, P < 0.05). As compared with noncardia cancer, cardia cancer showed more gains on 7p (58% vs. 12%, P < 0.05) and 20q (58% vs. 12%, P < 0.05) and more losses on 4q (50% vs. 5%, P < 0.05). The finding of histology-related aberrations and the combination of CGH and molecular data thus provide additional evidence suggesting genetic heterogeneity of GC.
Chromosome Aberrations↗
Involvement of brain glutamate release in pyrogenic fever.
Whether the glutamate release in the organum vasculosum laminae terminalis (OVLT) is attributable to genesis of a pyrogenic fever is unclear. The lack of information led us to evaluate the changes in glutamate concentrations of OVLT during the fever induced by staphylococcal enterotoxin A (SEA) in unanesthetized rabbits. Both the OVLT concentrations of glutamate and the colonic temperatures were simultaneously monitored during systemic injection of SEA, MK801 (an N-methyl-D-aspartate (NMDA) receptor channel blocker), ketamine (an NMDA receptor channel blocker), or normal saline. The extracellular dialysates in the brain were collected using a microdialysis probe previously placed in the OVLT region. The concentrations of glutamate in the microdialysates were measured by a high-pressure liquid chromatography in combination with a fluorescence detector. Systemic administration of SEA (30 ng x kg(-1) I.V.) increased both the concentrations of glutamate in the OVLT and the colonic temperatures. Glutamate appeared to rise slightly earlier than body temperature. Pretreatment or posttreatment with MK801 or ketamine significantly attenuated the SEA-induced augmenting glutamate release in the OVLT and fever in rabbits. The suppression of glutamate release appeared to start slightly earlier than temperature decline. In addition, the SEA-induced fever could be mimicked by direct injection of glutamate or SEA into the OVLT area. The fever induced by intra-OVLT injection of SEA or glutamate was significantly attenuated by pretreatment with an intra-OVLT dose of MK801 (5 microg) or ketamine (10 microg). The results suggest that glutamatergic pathways in the OVLT region are in pyrogenic fever genesis.
Animals↗
Genomics of unrelated-donor hematopoietic cell transplantation.
Unrelated-donor hematopoietic cell transplantation is a proven curative modality for hematologic malignancies. The success of unrelated-donor transplantation has been achieved through a better understanding of the immunobiology of the HLA system and through more precise and comprehensive matching of donors and recipients. The extensive polymorphism of HLA genes confers important biological implications affecting engraftment, graft-versus-host disease and overall survival. Although more-complete HLA identity of the donor and recipient is associated with optimal transplant outcome, new information suggests that not every HLA disparity is functionally relevant. Future advances in unrelated-donor transplantation must include the identification of tolerable HLA mismatches, so that more patients may benefit from this therapeutic modality. Furthermore, the role of cytokine-gene polymorphisms and minor histocompatibility genes in transplant outcome requires investigation. Delineation of the function of these markers as transplantation determinants may provide alternative means for optimizing the results of hematopoietic cell transplantation.
Animals↗
Chemical constituents from Drypetes littoralis.
Chemical investigation of Drypetes littoralis yielded three new tricyclic diterpenes, drypetenones A, B, and C (1--3), and one new xanthone (4). Spectral analyses and chemical correlations established the structures as 10S-12-hydroxy-11-methoxy-13-methylpodocarpa-1,5,8,11,13-pentaene-3,7-dione, (1), 10S-12-hydroxy-11-methoxy-13-methylpodocarpa-5,8,11,13-tetraene-3,7-dione (2), 10S-12-hydroxy-6,11-dimethoxy-13-methylpodocarpa-1,5,8,11,13-pentaene-3,7-dione (3), and 1-hydroxy-7-hydroxymethyl-6-methoxyxanthone (4). Complete (13)C NMR assignment of boehmenan D (5) is also made.
Antineoplastic Agents, Phytogenic↗
Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene: further definition of the IL-1 beta and IL-1Ra polymorphisms in North American Caucasians and Taiwanese Chinese.
Previous studies have suggested that a variable number tandem repeat (VNTR) polymorphism in the second intron of the interleukin-1 receptor antagonist (IL-1Ra) gene and the single nucleotide polymorphisms at positions -511 and +3954 of the IL-1beta gene might be associated with increased risks of chronic inflammatory diseases, autoimmune diseases and gastric cancer. In the present study, IL-1beta and IL-1Ra genotypes were analyzed among Asians in Taiwan and Caucasians in North America. We identified a novel polymorphism with 3 nucleotide substitutions in the IL-1Ra VNTR 2-repeat allele. One of the substitutions corresponds with the fourth 3' end nucleotide of the reverse primer that is often used for analysis of the IL-1Ra-associated VNTR locus. Mismatching between this primer and the 2-repeat allele can cause misleading amplification results when stringent conditions are used for annealing. The estimated haplotype frequencies of the variant IL-1 genes were significantly different between Taiwanese and Caucasians. The frequency of the pro-inflammatory IL-1Ra 2-repeat allele was significantly lower in Taiwanese than in Caucasians. In contrast, the frequencies of the pro-inflammatory IL-1beta -511T allele and +3954C allele were significantly higher among Taiwanese compared with Caucasians.
Asian People↗
A nitric oxide-dopamine link pathway in organum vasculosum laminae terminalis of rat brain exerts control over blood pressure.
1. Experiments were carried out to explore the possible role played by the nitric oxide (NO) and dopamine (DA) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation. 2. Intracerebroventricular (ICV) administration of NO donors such as hydroxylamine or sodium nitroprusside (SNP) caused an up to 59 mmHg decrease in blood pressure (BP) and a decrease in DA release (measured by nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV administration of N(G)-nitro-L-arginine methyl ester (L-NAME; a constitutive NO synthase inhibitor) or 7-nitroindazol (a neuronal NO synthase inhibitor) caused an up to 98 mmHg increase in BP and an increase in DA release in the OVLT. 3. Intra-OVLT injection of amphetamine (0.1 - 0.3 mg), SKF 38393 (a DA D(1) receptor agonist; 0.01 - 0.03 mg), or apomorphine (a DA D(2,3) receptor agonist; 0.01 - 0.03 mg) caused an increase in BP. On the other hand, intra-OVLT injection of SCH23390 (a DA D(1) receptor antagonist; 0.005 - 0.020 mg) or haloperidol (0.005 - 0.020 mg) caused a decrease in BP. 4. The pressor effects induced by intra-OVLT administration of L-NAME were attenuated by pretreatment with intra-OVLT injection of haloperidol, SCF23390, or 6-hydroxydopamine. In the contrast, the hydroxylamine-, 8-Br-cGMP- or SNP-induced depressor effects were attenuated by pretreatment with intra-OVLT injection of amphetamine, SKF 38393 or apomorphine. 5. The data suggest that activation of a NO-DA link pathway within the OVLT of rat brain exerts control over blood pressure.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Differential expression of tissue-specific promoters by gene gun.
BACKGROUND: Tissue-specific promoters are becoming increasingly important in light of their effects on gene expression in gene therapy experiments. The regulation of gene expression may be as important as the delivery of the gene itself. OBJECTIVES: To determine the effects of the involucrin (INV), keratin 14 (K14) and cytomegalovirus (CMV) promoters on the expression of the reporter gene beta-galactosidase. METHODS: In vivo, plasmid DNA was introduced to BALB/c mice by gene gun. Skin biopsies were taken after 24 h for histology and beta-galactosidase staining. In tissue culture cells, plasmid DNA was introduced by transient transfection to cell lines 293 (transformed primary human embryonal kidney cells), NIH 3T3 (immortalized mouse fibroblasts) and human keratinocytes. Reporter gene expression was assayed by histochemical staining and chemiluminescence. RESULTS: The K14 and INV promoter constructs showed beta-galactosidase gene expression only in the epidermis, while the CMV promoter showed gene expression in both the dermis and epidermis. In cell culture, the INV and K14 promoter constructs demonstrated significant beta-galactosidase expression in human keratinocytes, but minimal expression in 293 and NIH 3T3 cell types. CMV promoter constructs demonstrated significant expression in all cell types. CONCLUSIONS: Gene expression can be regulated by different promoters both in vivo and in cell culture. Based on the physiological expression of the different promoters, gene expression can be restricted to certain cell types, tissues and skin layers.
Animals↗