Biomedical subjects

M J Chen

Publications and source records attributed to M J Chen.

At least 55 records · Page 3Linked to original sources

PubMed1998

Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases.

Benzylic alpha,alpha-difluorosulfonates, alpha,alpha-difluorotetrazoles, and alpha,alpha-difluorocarboxylates of type 5 and 6 were synthesized and examined as potential phosphate biosteres for PTP1B inhibition. The alpha,alpha-difluorosulfonates and alpha,alpha-difluorotetrazoles were found to be more effective inhibitors than the analogous compounds bearing the fluoromalonyl group, a phosphate biostere currently being used for PTP inhibition.

Drug Design↗

PubMed1998

A novel fermentation pathway in an Escherichia coli mutant producing succinic acid, acetic acid, and ethanol.

Escherichia coli strain NZN111, which is unable to grow fermentatively because of insertional inactivation of the genes encoding pyruvate: formate lyase and the fermentative lactate dehydrogenase, gave rise spontaneously to a chromosomal mutation that restored its ability to ferment glucose. The mutant strain, named AFP111, fermented glucose more slowly than did its wild-type ancestor, strain W1485, and generated a very different spectrum of products. AFP111 produced succinic acid, acetic acid, and ethanol in proportions of approx 2:1:1. Calculations of carbon and electron balances accounted fully for the observed products; 1 mol of glucose was converted to 1 mol of succinic acid and 0.5 mol each of acetic acid and ethanol. The data support the emergence in E. coli of a novel succinic acid:acetic acid:ethanol fermentation pathway.

Acetic Acid↗

PubMed1998

ATP-sensitive potassium-channel-opening activity of CL-065, a 3-[(substituted-carbonyl)amino]-2H-1-benzopyran, in the rat.

The pharmacological activity of CL-065 (trans-3-acetamido-2,2-dimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran-6- carbonitrite) was investigated in anaesthetized spontaneously hypertensive rats (SHR) and isolated thoracic aorta of Sprague-Dawley rats. The intravenous administration of CL-065 [0.1-2.0 mg kg(-1)] to anaesthetized SHR induced a dose-dependent reduction of mean arterial pressure (MAP) with maximum effect approximately 5 min after injection and which persisted for over 3 h. CL-065 also induced a reflex tachycardia which seemed to parallel the time course of the hypotensive effect. The hypotensive effect of CL-065 was blocked by pretreatment with glibenclamide [5 mg kg(-1), i.v.], a specific ATP-sensitive potassium (KATP) channel blocker. Moreover, CL-065 (0.01-10 microM) resulted in dose-dependent vasodilatory effects on phenylephrine (0.3 microM)-induced vasoconstriction in isolated thoracic aorta. The vasorelaxation elicited by CL-065 was antagonized competitively by pretreatment with glibenclamide (0.1-1.0 microM; pA2 = 6.90+/-0.09; slope = 1.03+/-0.18). Similarly, the other two KATP-channel openers cromakalim (1.0 nM-1.0 microM) and nicorandil (0.1-30 microM) also induced vasorelaxation in thoracic aorta. The EC50 of cromakalim, CL-065 and nicorandil (i.e. the doses having half the maximum effect) were approximately 0.083, 0.17, and 4.5 microM, respectively, for phenylephrine (0.3 microM)-induced vasoconstriction in isolated thoracic aorta. Moreover, increased extracellular potassium levels (20-60 mM) resulted in concentration-dependent attenuation of the vasodilator effect of CL-065. In conclusion, CL-065 induces a depressor effect via activation of KATP channels.

Animals↗

PubMed1998

Recent use of hormone replacement therapy and the prevalence of colorectal adenomas.

The etiological role of hormone replacement therapy (HRT) (including estrogen only, combined estrogen-progesterone, and progesterone only) in colorectal neoplasia remains unclear. Several large studies have reported a reduced risk of colorectal cancer among HRT users; however, other studies have given inconsistent results. We examined the association between HRT and colorectal adenomatous polyps, precursors of colorectal cancer, among female participants in a case-control study. Subjects were members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy in 1991-1993. Participants received an in-person interview and completed a food frequency questionnaire. A total of 187 histologically confirmed cases and 188 controls, ages 50-75 years, were included in the analysis. Compared with women who did not use HRT during the year before sigmoidoscopy, recent users had an adjusted odds ratio of 0.57 (95% confidence interval, 0.35-0.94). Duration of use was inversely related to the prevalence of colorectal adenomas, with a multivariate-adjusted odds ratio of 0.49 (95% confidence interval, 0.25-0.97) for use of 5 years or more. These results support a protective effect of HRT on colorectal adenomatous polyps.

Adenomatous Polyps↗

PubMed1997

d-Amphetamine attenuates decreased cerebral glucose utilization after unilateral sensorimotor cortex contusion in rats.

Unilateral contusion injury to the sensorimotor cortex causes, among other symptoms, a transient contralateral hindlimb hemiparesis in rats. A single i.p. 2 mg/kg dose of d-amphetamine (d-AMPH) 24 h after injury accelerates spontaneous recovery from this particular deficit. The mechanism(s) of spontaneous and d-AMPH enhanced recovery are unknown but alleviation of a neuronal depression has been proposed. This quantitative CMRglu study was designed to determine effects of cortical contusion injury and d-AMPH on CMRglu in cortical and subcortical structures. At 2 days after injury, CMRglu was significantly reduced compared to sham-operated controls only in structures ipsilateral to contusion. Affected structures included the caudate putamen, medial geniculate nucleus, lateral geniculate nucleus and the parietal cortex immediately posterior to injury. By 6 days post-contusion, the hypometabolism partially reversed in all structures. A single low dose of d-AMPH significantly alleviated the post-traumatic CMRglu reduction at 2 days after injury. Importantly, while this alleviation was not significant for any single structure, the main effect of treatment was highly significant. d-AMPH increased CMRglu at 2 days post-injury by 18-33% compared to contused/saline-treated rats. These results suggest that alleviation of neuronal metabolic depression may contribute to spontaneous and d-AMPH enhanced recovery.

Animals↗

PubMed1997

A sigmoidoscopy-based case-control study of polyps: macronutrients, fiber and meat consumption.

We conducted a large, sigmoidoscopy-based case-control study to examine the relation of intake of macronutrients, meat, and fiber to occurrence of adenomas of the large bowel. Cases were subjects diagnosed for the first time with one or more histologically confirmed adenomas. Controls had no polyps of any type at sigmoidoscopy, had no history of polyps, and were individually matched to cases by gender, age, date of sigmoidoscopy, and Kaiser Center. The response rate was 84% for cases and 82% for controls. Complete dietary data for 488 matched pairs were available. All odds ratios are from matched analyses adjusted for energy. We observed positive associations with risk of adenomas for calories, animal fat, saturated fat, red meat, and the ratio of red meat to poultry and fish. Protective effects were observed for vegetable protein, carbohydrates, and dietary fiber. The fiber effects diminished after adjusting for fruits and vegetables. Results after mutually adjusting for the effects of saturated fat, fiber and the ratio of red meat to chicken and fish suggest that each of these variables has an effect on risk of adenomas that is independent of the other 2 exposures.

Aged↗

PubMed1997

Seroprevalences of hepatitis B and C viruses and Helicobacter pylori infection in a small, isolated population at high risk of gastric and liver cancer.

The objective of this study was to examine the seroprevalences of chronic infection with hepatitis B and C viruses and Helicobacter pylori in Matzu, a group of small islets with 5,566 civilian residents who have extremely high mortality from cancers of the stomach and liver. The standardized mortality ratios (SMR) of all cancer sites combined, liver cancer and stomach cancer in 1984-1993 were calculated using the general population in Taiwan as the referent (SMR = 100). The SMRs (95% confidence interval) for all cancer sites combined, liver cancer and stomach cancer were 160 (131-195), 252 (170-360) and 351 (229-516), respectively, in Matzu. A health survey was carried out with 1,485 civilian residents aged 30 years or more, giving a response rate of 69% among those who were eligible. Serum samples were tested for antibodies against Helicobacter pylori (anti-HP) by enzyme-linked immunosorbent assay and hepatitis B surface antigen (HBsAg) and antibodies against hepatitis C virus (anti-HCV) by enzyme immunoassay. The seroprevalence was 61% for anti-HP, 24.7% for HBsAg and 1.8% for anti-HCV in Matzu. While mortality rates of liver and stomach cancers were significantly higher in Matzu than in Taiwan, the seroprevalences of anti-HP, HBsAg and anti-HCV in Matzu were similar to or even lower than those in Taiwan. These findings suggest the existence of risk factors other than microbial agents involved in the development of stomach and liver cancers.

Adult↗

PubMed1997

Molecular contacts between nebulin and actin: cross-linking of nebulin modules to the N-terminus of actin.

Nebulin, a giant actin binding protein, coextends with actin and is thought to form a composite thin filament in the skeletal muscle sarcomere. To understand the molecular interactions between nebulin and actin, we have applied chemical cross-linking techniques to define molecular contacts between actin and ND8, a two-module nebulin fragment that promotes actin polymerization and inhibits depolymerization by binding to both G- and F-actin. The formation of a 1:1 complex with a dissociation constant of 4.9 microM between ND8 and G-actin was demonstrated by fluorescence titration of dansyl-ND8 with G-actin. Treatment with a zero-length cross-linker, l-ethyl-3-[3-(dimethylamino) propyl]carbodiimide (EDC), cross-linked the ND8-G-actin complex covalently without impairing actin's ability to polymerize. End-labeling Western blot and sequence and mass analyses of purified conjugated peptides revealed the cross-linking between lysine 5 of ND8 and the two N-terminal acidic residues of G-actin. Similarly, we have shown by end-labeling that cross-linking of ND8 to F-actin occurred at the N-terminus of actin protomer. The binding of nebulin to the N-terminus of actin is likely to be significant in its ability to affect actin polymerization. Furthermore, the association of nebulin modules with the actin N-terminus in subdomain 1 supports the hypothesis that nebulin wraps around the outer edges of actin filaments where Sl, tropomyosin, and several actin binding proteins are known to interact.

Actins↗

PubMed1997

Efficiency of sex pre-selection of spermatozoa by albumin separation method evaluated by double-labelled fluorescence in-situ hybridization.

To evaluate the separation efficiency of Ericsson's two- and three-layer albumin separation methods, semen samples from 21 healthy males were studied. Seven patients already had two or more sons, another seven had two or more daughters and the other seven had primary infertility due to female factors. The semen samples were divided into three aliquots: one remained unprocessed initially, the other two aliquots went through two- and three-layer albumin separation methods respectively. All samples were then stained with X-Y double staining probes. In each group, four or five samples were processed at room temperature, and two or three at body temperature (37 degrees C). The labelling efficiency of X-Y double staining probe was over 99%. The X:Y sperm ratios were even in the original samples. The ratios of the X and Y spermatozoa were altered slightly but significantly after the two-layer (P < or = 0.05) or the three-layer (P < or = 0.005) separation. The alterations occurred only at room temperature. The X spermatozoa increased and the Y spermatozoa decreased, both to a small degree of difference (1.4-3.5%). Double fluorescence in-situ hybridization analysis therefore showed that albumin separation methods do not enrich Y spermatozoa.

Albumins↗

PubMed1997

Risk factors for primary lung cancer among non-smoking women in Taiwan.

BACKGROUND: Although cigarette smoking is considered to be the most important cause of lung cancer, smoking behaviour cannot fully explain the epidemiological characteristics of lung cancer in Taiwanese women, who rarely smoke but contract lung cancer relatively often. There are other causes of lung cancer that have produced variability in lung cancer incidence. METHODS: A case-control study involving interviews with 117 female patients (including 106 non-smoking) suffering from lung cancer and the same number of individually matched hospital controls was conducted in Kaohsiung, Taiwan between 1992 and 1993. The questionnaire administered to cases and controls collected information on cigarette smoking and suspected risk factors for lung cancer. Multivariate logistic regression analysis was applied to assess smoking for all women and suspected risk factors for non-smoking women. RESULTS: The relationship between cigarette smoking and lung cancer was statistically significant although only a small proportion (9.4%) of female patients had smoked. However, the risk of contracting cancer for non-smoking women appears to be associated with certain cooking practices, especially preparing meals in kitchens not equipped with a fume extractor at cooking age of 20-40 years (odds ratio [OR] = 8.3; 95% confidence interval [CI]: 3.1-22.7. These factors and a history of pulmonary tuberculosis plus low consumption of fresh vegetables explained 78% of the summary attributable risks for non-smoking women in a multivariate logistic regression model. CONCLUSIONS: Exposure to fumes from cooking oils, when not reduced by an extractor, may be an important factor in causing lung cancer in non-smoking Taiwanese women.

Adult↗

PubMed1997

Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2.

Crystal structures have been determined of recombinant human tumor necrosis factor-alpha (TNF-alpha) and its R31D mutant that preferentially binds to TNF receptor R1 with more than seven times the relative affinity of binding to receptor R2. Crystals of the wild-type TNF were of space group P4(1)2(1)2 and had unit cell dimensions of a = b = 94.7 and c = 117.4 A. Refinement of the structure gave an R-factor of 22.3% at 2.5 A resolution. The crystals of TNF R31D mutant diffracted to 2.3 A resolution, and were of identical space group to the wild type with unit cell dimensions of a = b = 95.4 and c = 116.2 A, and the structure was refined to an R-factor of 21.8%. The trimer structures of the wild-type and mutant TNF were similar with a root mean square (r.m.s.) deviation of 0.56 A for Calpha atoms; however, the subunits within each trimer were more variable with an average r.m.s. deviation of 1.00 A on Calpha atoms for pairwise comparison of subunits. Model complexes of TNF with receptors R1 and R2 have been used to predict TNF-receptor interactions. Arg31 in all three subunits of wild-type TNF is predicted to form an ionic interaction with the equivalent glutamic acid in both receptors R1 and R2. Asp31 of the TNF R31D mutant is predicted to interact differently with the two receptors. The side chain of Asp31 in two subunits of the TNF mutant is predicted to form hydrogen bond interactions with Ser59 or Cys70 of R1, while it has no predicted interactions with R2. The loss of three strong ionic interactions of Arg31 and the electrostatic repulsion of Asp31 with Glu in the receptors is consistent with the reduced binding of the R31D mutant to both receptors relative to wild-type TNF. The replacement of these ionic interactions by two weaker hydrogen bond interactions between Asp31 of the R31D mutant and R1, compared with no interactions with R2, is in agreement with the observed preferential binding of the R31D mutant to R1 over R2. Analysis of the structure and function of receptor-discriminating mutants of TNF will help understand the biological role of TNF and facilitate its use as an antitumor agent.

Binding Sites↗

PubMed1997

Leukemia cutis as the initial manifestation of acute nonlymphocytic leukemia in a young child.

A 15-month-old boy was well except for asymptomatic, erythematous, wheal-like papuloplaques, macules, and nodules on his face and four extremities. It was misdiagnosed by a pediatrician and treated as urticaria for six months. Later, he was sent to our hospital for evaluation of prolonged fever. Acute nonlymphocytic leukemia (M5) with leukemia cutis was diagnosed by results of hematologic examination and examination of a skin biopsy specimen. After one course of chemotherapy, all of the skin lesions completely resolved and had not recurred. Five months after acute nonlymphocytic leukemia was diagnosed, bone marrow relapse and central nervous system involvement were noted.

Humans↗

PubMed1996

Alcohol and smoking in relation to the prevalence of adenomatous colorectal polyps detected at sigmoidoscopy.

Cigarette smoking has been associated with adenomatous polyps of the large bowel but not with increased risk of colorectal cancer. Giovannucci et al recently proposed a hypothesis to explain this inconsistency. A key testable aspect of the hypothesis is that smoking in the distant past increases the risk of large polyps. Questions also remain about the association between colorectal polyps and consumption of alcohol. To address these issues, we examined data from 488 cases with adenomatous polyps and 488 controls. Subjects were members of a prepaid health plan in Los Angeles who had a sigmoidoscopy in 1991-1993. As expected, the adjusted odds of polyps in current smokers compared with never-smokers was increased [odds ratio = 2.43; 95% confidence interval (CI) = 1.56-3.79]. For those who had smoked in the distant past (for example, 30 or more pack-years before 20 years ago), the adjusted odds of an adenoma > or = 1 cm, relative to nonsmokers, was 0.88 (95% CI = 0.23-3.42). The adjusted odds of polyps in those consuming > or = 46 gm per day of alcohol compared with nondrinkers was 1.50 (95% CI = 0.72-3.13). Although imprecise, these data do not support the hypothesis that past smoking increases the risk of large polyps, but our results indicate a weak association between alcohol use and risk of adenomatous polyps.

Adenomatous Polyps↗

PubMed1996

Survey on the distribution of Vibrionaceae at the seaport areas in Taiwan, 1991-1994.

A monthly survey on the distribution of human-pathogenic Vibrionaceae of the seawater from five principal harbors in Taiwan was conducted by National Quarantine Service from July, 1991 to February, 1994. Of the total 1,167 Vibrionaceae isolates, strains of Vibrio alginolyticus (449 strains) were the most frequently isolated, followed by Vibrio parahaemolyticus (262) , Aeromonas hydrophila (153), Vibrio cholerae non-O1 (86), and Vibrio vulnificus (67). None of Vibrio cholerae O1 was isolated. The pH, salinity, and water temperature in this study ranged from 5.8 to 8.6, 0.1 to 4.2% , and 15 to 34 degrees C, respectively. It is concluded that the family Vibrionaceae exists autochthonously around the coastal waters in Taiwan.

Hydrogen-Ion Concentration↗

PubMed1996

Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas.

We determined whether intakes of the main dietary carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food-frequency questionnaire and a non-dietary questionnaire from 1991 to 1993. In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.41.1; trend, P= 0.04; ORs compare highest to lowest quartiles0; vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the mutivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta-carotene with colorectal adenomatous polyps.

Adenoma↗

PubMed1995

Action of dexmedetomidine on rat locus coeruleus neurones: intracellular recording in vitro.

The action of dexmedetomidine on rat locus coeruleus neurones was examined using intracellular recordings from the in vitro brain slice preparation. Concentrations of dexmedetomidine from 1 to 1000 nM were tested. At 30 nM, dexmedetomidine produced complete inhibition of firing of all neurones tested (n = 21); this was associated with a 13 mV hyperpolarization (range 2.2-29.7 mV, n = 21) and a 27% reduction in input resistance (range 11.1-46.2%, n = 17). The dexmedetomidine responses reached a plateau phase between 100 and 1000 nM. Based on single-cell recordings, the hyperpolarizing potency of dexmedetomidine was found to be 6 times greater than that of clonidine (n = 10). The reversal potential for the dexmedetomidine-induced hyperpolarization was -106.9 +/- 1.7 mV (n = 9), a value similar to the K+ equilibrium potential; hyperpolarization was blocked by both CsCl and BaCl2. The effect of dexmedetomidine was antagonized by yohimbine, with a dissociation equilibrium constant of 30 nM. In contrast, prazosin, the alpha 1-, alpha 2B- and alpha 2C-adrenoceptor subtype-preferring ligand, did not inhibit the dexmedetomidine effect. Our results also show that low concentrations of oxymetazoline (10-300 nM), an alpha 2A-adrenoceptor subtype-selective drug, cause profound inhibition of neuronal activity in the locus coeruleus. These data therefore suggest that dexmedetomidine binds to alpha 2A-adrenoceptors on the cell membrane of neurones of the locus coeruleus and that this leads to opening of the inwardly rectifying K+ channels, resulting in the observed hyperpolarization of the membrane.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Mapping the domain(s) critical for the binding of human tumor necrosis factor-alpha to its two receptors.

The extracellular domains of the two human tumor necrosis factor (TNF) receptors critical for binding TNF-alpha were examined by deletion mapping. The ligand binding capability of full-length and truncated recombinant soluble TNF receptors (TNFRs) was assessed by ligand blot analysis and their binding affinity determined by Scatchard analysis. The results showed that deletion of the fourth cysteine-rich domain of the p55 receptor (TNFR-1) did not alter ligand binding affinity significantly. Deletion of domains 3 and 4 of TNFR-1 resulted in no ligand binding, suggesting that domain 3, but not 4, of TNFR-1 binds directly to ligand. Deletion of domain 4 of TNFR-2 resulted in drastically reduced protein yield and 3-fold reduction in ligand binding affinity, while deletion of both domains 4 and 3 yielded no protein. Thus, the domain 4 of TNFR-2, but not that of TNFR-1, appears to be involved directly in binding TNF, although it is also possible that the domain 4 of TNFR-2 is involved in the correct folding of other domains. These results suggest that the modes of interaction between TNF-alpha and its dual receptors are different, providing opportunity to modulate each receptor specifically for research and therapeutic purposes.

Animals↗

PubMed1995

Harvesting of the latissimus dorsi muscle: a small animal model for seroma formation.

A common complication of soft tissue dissection and muscle harvesting is seroma formation. In order to manage and understand the formation of seromas, we developed a small animal model for seromas in the Sprague Dawley rat. Skin flaps and subcutaneous tissue were elevated and the latissimus dorsi muscle was harvested in 20 animals. Eighteen of the 20 rats (90%) formed clinically significant seromas. Sixteen animals had associated skin flap necrosis and 12 required serial drainage for recurrent seromas. At necropsy, gross capsular formation occurred in all animals who developed seromas. Microscopically, a fibrous capsule enveloping the seroma was seen associated with a local chronic inflammatory cell infiltrate. We conclude: (1) Elevation of the latissimus dorsi muscle in the rat is a reliable and practical animal model for seroma formation; (2) Sequelae of clinically significant seromas are often as severe as skin flap necrosis; (3) An inflammatory reaction may be associated with seromas.

Animals↗