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J Tsai

Publications and source records attributed to J Tsai.

At least 55 records · Page 3Linked to original sources
PubMed1998

Cryptolepis sanguinolenta: an ethnobotanical approach to drug discovery and the isolation of a potentially useful new antihyperglycaemic agent.

Evidence has been published that a wide array of plant-derived active principles, representing numerous classes of chemical compounds, demonstrate activity consistent with their possible use in the treatment of patients with Type 2 diabetes mellitus (DM). Despite these interesting observations, to date, metformin is the only ethical drug approved for treatment of Type 2 DM derived from a medicinal plant. Why is this so, given the fact that higher plants are such a potential source of new drugs? The answer to this rhetorical question may lie in the reliance of most pharmaceutical companies on random, in vitro, mechanism-based, high throughput screening in the initial phases of plant drug research. In this article we describe an alternative pathway to discovery of drugs for the treatment of Type 2 DM: on based on an ethnomedical approach, involving ethnobotany and traditional medicine. In particular, we present evidence that cryptolepine, an indoloquinolone alkaloid isolated from Cryptolepis sanguinolenta, significantly lowers glucose when given orally to a mouse model of diabetes. The antihyperglycaemic effect of cryptolepine leads to a significant decline in plasma insulin concentration, associated with evidence of an enhancement in insulin-mediated glucose disposal. Finally, cryptolepine increases glucose uptake by 3T3-L1 cells. These data permit us to conclude that an ethnobotanical approach to drug discovery can identify a potentially useful drug for the treatment of Type 2 DM.

Adipose Tissue↗
PubMed1998

Nongenetic mouse models of non-insulin-dependent diabetes mellitus.

The purpose of the study was to develop a mouse model of non-insulin-dependent diabetes mellitus (NIDDM) that closely simulates the metabolic abnormalities of the human disease and is also cost-effective compared with the genetic models currently available. For this purpose, insulin resistance was induced in male C57BL/6J or Institute of Cancer Research (ICR) mice by feeding diets enriched in either fructose or fat, and hyperglycemia was induced by injecting these mice with a dose of streptozotocin (STZ) that does not cause diabetes in chow-fed mice. In the case of C57BL/6J mice, insulin levels initially increased in response to the fructose- and fat-enriched diets and then decreased to levels comparable to or still higher than those in chow-fed mice following STZ injection. Associated with the decrease in insulin levels following STZ, fat-fed and fructose-fed C57BL/6J mice became significantly hyperglycemic, reaching values of 388 +/- 38 and 366 +/- 58 mg/dL, respectively. In contrast, neither plasma glucose nor insulin concentrations changed in chow-fed mice injected with an identical amount of STZ. Essentially identical findings were seen before and after STZ injection in fat-fed compared with chow-fed ICR mice. Although a direct comparison was not made, sensitivity to the diabetogenic effects of STZ appeared to be greater in fat-fed ICR compared with fat-fed C57BL/6J mice. Finally, plasma glucose decreased when mice with these experimental models of NIDDM were treated with either metformin or tolbutamide. Given these results, it seems reasonable to suggest that the combination of dietary-induced insulin resistance and relatively low-dose STZ results in mouse models that should be of use in studying the pathophysiology of NIDDM or in evaluating therapeutic compounds for the treatment of NIDDM.

Animals↗
PubMed1998

Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential.

The ribonucleotide reductase (RR) gene has been associated with malignant transformation and metastatic potential. In this report, the significance of the expression of RR mRNA and enzymatic activity to the invasive potential was examined by Boyden chamber invasion assay. Our results suggest that overexpression of RR M2 mRNA and RR enzymatic activity correlates to an increase in cell invasive potential. The drug-induced HURs clone expressed a higher level RR M2 mRNA and enzyme activity which contributes significantly to the 3-fold increase in invasive potential of the cells observed relative to the KB wild-type control. On the contrary, the HUr revertant clone decreased the RR M2 mRNA level and enzymatic activity, concomitantly decreasing their invasive potential. This phenomenon is most likely due to the return of RR to levels comparable to that of the KB wild-type cells. To confirm that this observation was not of a drug-resistance phenotype associated with multiple gene alterations, the panel of RR transfectants (M1-D transfected M1 subunit cDNA, M2-D transfected M2 subunit cDNA, X-D transfected M1/M2 cDNA) characterized in a previous study were also tested in the invasion assay. The M2-D clone expressed 6-fold higher RR M2 mRNA and RR activity and also demonstrated 6-fold higher invasive potential in vitro than either the parental or vector only transfected cell line (KB-V). The X-D clone demonstrated 3-fold higher M2 mRNA expression and revealed 4-fold higher invasive potential than control cells. The M1-D clone, in contrast, expressed a baseline level of RR M2 mRNA and higher M1 mRNA. In contrast to the X-D and M2-D cells, the invasive potential of M1-D reached an even lower level in the invasive assay than the control. These results, therefore, suggest that RR M2 overexpression plays an important role in a tumor's invasiveness.

Carcinoma↗
PubMed1998

Emergency medical resource use in Taipei city.

BACKGROUND: It is a worldwide trend to serve emergency patients at emergency department (EDs) staffed by board-certified emergency physicians (EPs). The question arises as to how many EPs are cost effective? This cannot be answered until utilization of emergency resources in the community is explored, so that appropriate plans for efficient ED use, staffing and training of EPs can be made. METHODS: A prospective randomized chart-review study was conducted from August 1, 1995, until May 31, 1996, in the EDs of eight large hospitals in Taipei City. These included Chung-Hsin Municipal Hospital (CHH), Chung-Shiaw Municipal Hospital (CSH), Ho-Ping Municipal Hospital (HPH), Jen-Ai Municipal (JAH), Mackay Memorial Hospital (MMH), Tri-Service General Hospital (TSGH), Veterans General Hospital-Taipei (VGH-T) and the Yang-Ming Municipal Hospital (YMH). RESULTS: Of 37,889 cases reviewed, the average daily ED census at each hospital was: VGH-T 198; TSGH 148; MMH 224; HPH 62; YMH 84; CHH 41; JAH 102; and CSH 139. At MMH, pediatric patients comprised 38.8% of emergency patients and the elderly comprised 49% of patients of VGH-T. The average age of patients was 56 years in VGH-T and 40 years in other hospitals. There were 71 (11.1%) pediatric patients and 3,087 (1.8%) adult patients taken to hospital by an emergency medical services (EMS) ambulance. A total of 176 pediatric and 2,230 (8.1%) adult patients belonged to triage categories 1 and 2. VGH-T had a much higher percentage of triage 1 and 2 patients (769, 13%) than the other hospitals. A total of 30.7% of pediatric and 17.4% of adult patients were classified as triage 4 (pseudoemergency). Patients requiring advanced life support, referral cases and patients requiring an intensive care unit (ICU) bed accounted for 1.1%, 0.9% and 0.6% of pediatric patients, and 6.8%, 3.4% and 1.8% of adult patients, respectively. These figures increased to 11.1%, 7.7% and 3.5%, respectively, in VGH-T. Among patients requiring ICU admission, 30% of pediatric and 53% of adult patients were not admitted on presentation to the ED. Of 10,099 children and 27,555 adults who were evaluated for case disposition, 651 (6.5%) and 4,061 (14.7%), respectively, were considered for admission. Among these 542 (83.3%) and 2,894 (71.3%), respectively, were admitted. CONCLUSIONS: VGH-T is a favorable training ground for EPs due to its high volume of adult and elderly, advanced life support eligible, ICU and high acuity patients. MMH is an ideal place for training in pediatric emergency medicine. Utilization of the 119 emergency response system is low. The number of patients with high acuity triage in Taipei City is low. However, Taipei City faces a shortage of acute care beds, especially ICU beds.

Adult↗
PubMed1997

Simulating the minimum core for hydrophobic collapse in globular proteins.

To investigate the nature of hydrophobic collapse considered to be the driving force in protein folding, we have simulated aqueous solutions of two model hydrophobic solutes, methane and isobutylene. Using a novel methodology for determining contacts, we can precisely follow hydrophobic aggregation as it proceeds through three stages: dispersed, transition, and collapsed. Theoretical modeling of the cluster formation observed by simulation indicates that this aggregation is cooperative and that the simulations favor the formation of a single cluster midway through the transition stage. This defines a minimum solute hydrophobic core volume. We compare this with protein hydrophobic core volumes determined from solved crystal structures. Our analysis shows that the solute core volume roughly estimates the minimum core size required for independent hydrophobic stabilization of a protein and defines a limiting concentration of nonpolar residues that can cause hydrophobic collapse. These results suggest that the physical forces driving aggregation of hydrophobic molecules in water is indeed responsible for protein folding.

Alkenes↗
PubMed1997

Psoas abscess: making an early diagnosis in the ED.

The variable and nonspecific presentations of psoas abscess, as well as its infrequent incidence in the emergency department (ED), can result in delayed diagnosis or misdiagnosis. Previous reports have not discussed the diagnostic difficulties of psoas abscess from the viewpoint of emergency physicians (EPs), especially in light of the widespread use of ED ultrasonography. This report describes a 1-year experience between November 1993 and October 1994, during which 10 ED patients were diagnosed to have psoas abscess; in 7 cases, diagnoses were established in the ED. Patients' mean age was 64.6 years (range, 46 to 76). Pain was the most frequently encountered symptom (80%), with 5 patients (50%) complaining of flank pain. The triad of fever, flank pain, and limitation of hip movement, which is specific for psoas abscess, was present only in 3 patients (30%). The mean duration of symptoms was 10.6 days (range, 1 to 30 days). The mean time spent to establish the diagnosis was 1.7 days (range, 0 to 7 days). The diagnosis of psoas abscess was established by ultrasound in 6 patients, by computed tomography (CT) in 3 patients, and by surgery in 1 patient. Four patients who presented with either sepsis and nonspecific abdominal/flank pain or sepsis and thigh swelling were diagnosed to have psoas abscess by ultrasound performed by EPs. Only 3 patients were admitted to the ED with an initial diagnosis of psoas abscess. The remaining 7 had the following initial ED diagnoses: 2, fever of unknown origin; 2, septic shock; 1, shock; 1, sepsis; and 1, peritonitis. All but one had manifestations of sepsis. Two patients died of septic shock; these two patients had failed to be drained well. This report also includes a discussion of the role of EPs and ultrasonography in the diagnosis of psoas abscess. With their alertness and their expertise in ultrasonographic techniques, EPs can make an immediate diagnosis and arrange an early drainage procedure. For patients with sepsis of unknown origin, prolonged fever of unknown origin, and some specific manifestations suggestive of psoas abscess, the screening ultrasound should scan not only abdominal solid organs but also peritoneal cavity and retroperitoneal space. In addition, a flow chart is presented for facilitating the diagnosis of psoas abscess in the ED.

Aged↗
PubMed1997

Arterial oxygen desaturation during emergent nonsedated upper gastrointestinal endoscopy in the emergency department.

A prospective study was conducted to see whether emergent esophagogastroduodenoscopy (EGD) in patients with active upper gastrointestinal (GI) bleeding is associated with more oxygen desaturation than nonemergent EGD. Emergent EGD was performed in the study patients with active upper GI bleeding. Nonemergent EGD was performed in the control patients. Determination of oxygen saturation (Sao2) was measured by pulse oximeter. A decrease in Sao2 of > 4% was more frequent in the study patients (26%, 13 of 50) than in controls (6%, 3 of 50) (P < .01). During EGD, mean oxygen saturation decreased significantly in both groups of patients. After EGD, mean oxygen saturation did not recover toward the pre-endoscopy insertion level in the study group (P < .01). A linear association was found that oxygen desaturation = 5.46 + 0.15 (status) -0.06 (baseline oxygen saturation). Emergent EGD for active upper GI bleeding in the emergency department tends to be associated with more frequent significant oxygen desaturation than nonemergent EGD. Continuous oxygen supplementation and oxygen saturation monitoring may be used during emergent nonsedated EGD in the emergency department.

Acute Disease↗
PubMed1997

Buthionine sulphoximine alone and in combination with melphalan (L-PAM) is highly cytotoxic for human neuroblastoma cell lines.

Buthionine sulphoximine (BSO) selectively inhibits glutathione (GSH) synthesis and may enhance the antineuroblastoma activity of melphalan (L-PAM). We determined the cytotoxicity of BSO (dose range 0-1000 microM) alone and in combination with L-PAM (dose range 0-0 microM) in a panel of 18 human neuroblastoma cell lines. BSO alone was highly cytotoxic with 16/18 neuroblastoma cell lines having IC90 values (range 2.1- > 1000 microM) below the clinically achievable steady-state plasma level of 500 microM BSO. Maximal cell killing correlated with GSH levels decreased to less than 10% baseline, and was partially reversed by the addition of exogenous anti-oxidants (GSH, vitamin E and ascorbate). Fluorocytometric analysis of DNA fragments by the Tunnel method detected 92% of a BSO sensitive cell line in apoptosis after a 48 h exposure to 500 microM BSO. The combination of L-PAM and BSO synergistically enhanced the cell killing of L-PAM alone by > 1-3 logs (combination index < 1). We conclude that BSO has significant single-agent cytotoxicity against neuroblastoma and enhances cell killing when combined with L-PAM.

Antineoplastic Agents↗
PubMed1997

Emotion and aging: experience, expression, and control.

Age differences in emotional experience, expression, and control were investigated in 4 studies. A community sample of 127 African Americans and European Americans (ages 19-96 years) was used in Study 1; a community sample of 82 Chinese Americans and European Americans (ages 20-85 years) was used in Study 2; a community sample of 49 Norwegians drawn from 2 age groups (ages 20-35 years and 70+ years) was used in Study 3; and a sample of 1,080 American nuns (ages 24-101 years) was used in Study 4. Across studies, a consistent pattern of age differences emerged. Compared with younger participants, older participants reported fewer negative emotional experiences and greater emotional control. Findings regarding emotional expressivity were less consistent, but when there were age differences, older participants reported lesser expressivity. Results are interpreted in terms of increasingly competent emotion regulation across the life span.

Adult↗
PubMed1997

Protein folding: the endgame.

The last stage of protein folding, the "endgame," involves the ordering of amino acid side-chains into a well defined and closely packed configuration. We review a number of topics related to this process. We first describe how the observed packing in protein crystal structures is measured. Such measurements show that the protein interior is packed exceptionally tightly, more so than the protein surface or surrounding solvent and even more efficiently than crystals of simple organic molecules. In vitro protein folding experiments also show that the protein is close-packed in solution and that the tight packing and intercalation of side-chains is a final and essential step in the folding pathway. These experimental observations, in turn, suggest that a folded protein structure can be described as a kind of three-dimensional jigsaw puzzle and that predicting side-chain packing is possible in the sense of solving this puzzle. The major difficulty that must be overcome in predicting side-chain packing is a combinatorial "explosion" in the number of possible configurations. There has been much recent progress towards overcoming this problem, and we survey a variety of the approaches. These approaches differ principally in whether they use ab initio (physical) or more knowledge-based methods, how they divide up and search conformational space, and how they evaluate candidate configurations (using scoring functions). The accuracy of side-chain prediction depends crucially on the (assumed) positioning of the main-chain. Methods for predicting main-chain conformation are, in a sense, not as developed as that for side-chains. We conclude by surveying these methods. As with side-chain prediction, there are a great variety of approaches, which differ in how they divide up and search space and in how they score candidate conformations.

Animals↗
PubMed1997

Bronchial dilatation in patients with HIV infection: CT assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage.

OBJECTIVE: Symptoms of airway disease occur in patients infected with HIV, and bronchiectasis has been reported in patients with AIDS. We evaluated thin-section thoracic CT scans in HIV-positive individuals for bronchial dilatation and correlated imaging findings with pulmonary function abnormalities and findings at bronchoalveolar lavage (BAL). SUBJECTS AND METHODS: Sixty-one subjects, 50 of whom were HIV-positive and 11 of whom were HIV-negative, underwent thin-section CT, BAL, and pulmonary function tests. Two radiologists evaluated the CT scans on two separate occasions for bronchial dilatation in each lobe. BAL and pulmonary function test data in the subjects with bronchial dilatation were compared with such data in subjects with normal bronchi seen on CT scans. RESULTS: Eighteen of the 50 HIV-positive subjects and none of the HIV-negative subjects had bronchial dilatation revealed by CT. Subjects with bronchial dilatation revealed by CT had significantly higher BAL neutrophil counts (p = .014) and significantly lower diffusing capacity (p = .003) than did subjects with normal bronchi revealed by CT. CONCLUSION: Bronchial dilatation is commonly revealed by CT scans of HIV-positive individuals. The association of elevated levels of BAL neutrophils and decreased diffusing capacity with bronchial dilatation that we found in this study suggests that the neutrophil may be associated with airway damage and lung destruction in patients who are infected with HIV.

Adult↗
PubMed1997

Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide.

Many reports have cited coexpression of platelet-derived growth factor (PDGF) and its receptors by tumor cells or cells supporting tumor growth, suggesting both autocrine and paracrine mechanisms for PDGF-mediated tumor growth. We found that a small organic molecule, N-[4-(trifluoromethyl)phenyl] 5-methylisoxazole-4-carboxamide (SU101, leflunomide), inhibited PDGF-mediated signaling events, including receptor tyrosine phosphorylation, DNA synthesis, cell cycle progression, and cell proliferation. SU101 inhibited PDGF-stimulated tyrosine phosphorylation of PDGF receptor (PDGFR) beta in C6 (rat glioma) and NIH3T3 cells engineered to overexpress human PDGFRbeta (3T3-PDGFRbeta). SU101 blocked both PDGF- and epidermal growth factor (EGF)-stimulated DNA synthesis. Previously, this compound was shown to inhibit pyrimidine biosynthesis by interfering with the enzymatic activity of dihydroorotate dehydrogenase. In the current study, EGF-stimulated DNA synthesis was restored by the addition of saturating quantities of uridine, whereas PDGF-induced DNA synthesis was not, suggesting that the compound demonstrated some selectivity for the PDGFR pathway that was independent of pyrimidine biosynthesis. Selectivity was further demonstrated by the ability of the compound to block the entry of PDGF-stimulated cells into the S phase of the cell cycle, without affecting cell cycle progression of EGF-stimulated cells. In cell growth assays, SU101 selectively inhibited the growth of PDGFRbeta-expressing cell lines more efficiently than it inhibited the growth of PDGFRbeta-negative cell lines. SU101 inhibited the s.c., i.p., and intracerebral growth of a panel of cell lines including cells from glioma, ovarian, and prostate origin. In contrast, SU101 failed to inhibit the in vitro or s.c. growth of A431 and KB tumor cells, both of which express EGF receptor but not PDGFRbeta. SU101 also inhibited the growth of D1B and L1210 (murine leukemia) cells in syngeneic immunocompetent mice, without causing adverse effects on the immune response of the animals. In an i.p. model of tumor growth in syngeneic immunocompetent mice, SU101 prevented tumor growth and induced long-term survivors in animals implanted with 7TD1 (murine B-cell hybridoma) tumor cells. Because PDGFRbeta was detected on most of the tumor cell lines in which in vivo growth was inhibited by SU101, these data suggest that SU101 is an effective inhibitor of PDGF-driven tumor growth in vivo.

3T3 Cells↗
PubMed1996

The National Institute on Aging/Alzheimer's Association recommendations on the application of apolipoprotein E genotyping to Alzheimer's disease.

In a conference held in Chicago during October 1995, a working group of the National Institute of Aging (NIA) and the Alzheimer's Association (AlzA) drafted consensus recommendations on research and clinical applications of APOE genetic susceptibility testing for Alzheimer's disease (AD). The NIA/AlzA Working Group concluded that in considering future applications of APOE genotyping and other knowledge that has been gained about the genetic basis of AD, the interests of AD patients and their family members must be held paramount. The group acknowledged that a robust association exists between possession of the APOE epsilon 4 allele and the risk of late-onset AD and cited evidence that this allele is more strongly associated with AD than any other form of dementia. They recommended against the use of APOE genotyping to predict the-future development of AD in asymptomatic individuals at this time, and warned against the use of the test in isolation as the sole means for diagnosing AD. The group endorsed the concept of discretionary use of APOE genotyping as an adjunct to other AD diagnostic procedures. However, routine clinical use of the test for this purpose was not recommended at this time. Physicians were advised to weigh any potential benefits of testing against the possibility that genotype disclosure could adversely affect the insurability, employability, and social standing of AD patients and their family members. Adequate provisions for pre-test and post-test counseling and psychosocial support were advised for all future clinical and research applications of APOE genotyping. The group called for the development of improved protocols for AD genetic counseling as well as supplemental measures to assure genetic privacy for AD patients and their family members.

Alleles↗
PubMed1996

A conserved HPD sequence of the J-domain is necessary for YDJ1 stimulation of Hsp70 ATPase activity at a site distinct from substrate binding.

The 46-kDa protein YDJ1 is one of several known yeast homologues of the Escherichia coli DnaJ protein. Like all J homologues, it shares homology with the highly conserved NH2-terminal "J-domain" of DnaJ. A component of the DnaK (Hsp70) chaperone machinery that mediates protein folding, DnaJ is necessary for survival at elevated temperatures. It stimulates ATP hydrolysis by DnaK and effects the release of DnaK-bound polypeptides. Previous genetic and biochemical studies indicate that the J-domain is necessary for these functions. Using peptides corresponding to J-domain sequence, we show that a peptide containing the highly conserved His-Pro-Asp sequence at positions 34-36 in the J-domain competes off YDJ1 stimulation of Hsp70 ATPase activity. Inhibitory concentrations of peptide do not prevent binding of folding substrates, therefore YDJ1 must interact with Hsp70 at a site distinct from that for substrate binding. This interaction is critical for Hsp70 activity, since a mutant YDJ1 protein harboring a H34Q change (ydj1Q34) stimulates neither Hsp70 ATPase nor substrate release. The importance of the proper function of this region of the protein is supported by the poor growth and temperature-sensitive phenotype of yeast expressing ydj1Q34.

Adenosine Triphosphatases↗
PubMed1996

Using a hydrophobic contact potential to evaluate native and near-native folds generated by molecular dynamics simulations.

There are several knowledge-based energy functions that can distinguish the native fold from a pool of grossly misfolded decoys for a given sequence of amino acids. These decoys, which are typically generated by mounting, or "threading", the sequence onto the backbones of unrelated protein structures, tend to be non-compact and quite different from the native structure: the root-mean-squared (RMS) deviations from the native are commonly in the range of 15 to 20 angstroms. Effective energy functions should also demonstrate a similar recognition capability when presented with compact decoys that depart only slightly in conformation from the correct structure (i.e. those with RMS deviations of approximately 5 angstroms or less). Recently, we developed a simple yet powerful method for native fold recognition based on the tendency for native folds to form hydrophobic cores. Our energy measure, which we call the hydrophobic fitness score, is challenged to recognize the native fold from 2000 near-native structures generated for each of five small monomeric proteins. First, 1000 conformations for each protein were generated by molecular dynamics simulation at room temperature. The average RMS deviation of this set of 5000 was 1.5 angstroms. A total of 323 decoys had energies lower than native; however, none of these had RMS deviations greater than 2 angstroms. Another 1000 structures were generated for each at high temperature, in which a greater range of conformational space was explored (4.3 angstroms RMS deviation). Out of this set, only seven decoys were misrecognized. The hydrophobic fitness energy of a conformation is strongly dependent upon the RMS deviation. On average our potential yields energy values which are lowest for the population of structures generated at room temperature, intermediate for those produced at high temperature and highest for those constructed by threading methods. In general, the lowest energy decoy conformations have backbones very close to native structure. The possible utility of our method for screening backbone candidates for the purpose of modelling by side-chain packing optimization is discussed.

Protein Folding↗
PubMed1996

Naltrindole, a delta-opioid antagonist, blocks MDMA's ability to enhance pressing for rewarding brain stimulation.

Twelve rats were each fixed with a chronically indwelling bipolar electrode for stimulation of the medial forebrain bundle as it courses through the hypothalamus. These rats were trained to press a bar for intracranial stimulation of 0.3-s trains of 60 Hz sine waves for 10 min daily at three intensities. One intensity was just above threshold for maintaining pressing, one intensity was a high intensity that sustained considerable pressing, but not maximum pressing, and the other was intermediate to the others. After stable rates of pressing were obtained, rats received MDMA daily. MDMA significantly increased rates of pressing. Prior to a day when rats received MDMA, they also received an injection of naltrindole, a selective delta-opioid receptor antagonist. Naltrindole blocked MDMA's enhancement of pressing for reinforcing brain stimulation.

Animals↗