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K J Chen

Publications and source records attributed to K J Chen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Peroxyacetyl nitrate-induced apoptosis through generation of reactive oxygen species in HL-60 cells.

Peroxyacetyl nitrate (PAN), an ubiquitous air pollutant, induced apoptosis in human leukemia HL-60, human chronic myelogenous leukemia K-562, and mouse monocyte-macrophage RAW 264.7 cell lines. In the HL 60 cells, characteristic apoptosis morphology could be observed 4 h after the cells were treated with 50 microM PAN. Exposure of HL-60 cells to increasing concentrations of PAN (from 1 microM to 100 microM) confirmed the concentration dependence of apoptosis as evidenced by DNA fragmentation in HL-60 cells, chromatin condensation by acridine-orange staining, and the appearance of the DNA apoptotic peak in flow cytometry. During apoptosis in HL-60 cells, 3-nitrotyrosine and 3,5-dinitrotyrosine were detected by high-performance liquid chromatography and liquid chromatography-mass spectrometry-mass spectrometry. We hypothesized that PAN might induce cell death in human leukemia cells by releasing peroxynitrite and other reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Moreover, exogenous superoxide dismutase promoted PAN-induced apoptosis, and in contrast, a combination of superoxide dismutase and catalase suppressed this apoptosis. We also hypothesize that the generation of ROS during PAN-induced apoptosis in HL-60 cells could activate stress-activated protein kinase/jun N-terminal kinase activity. The formation of H2O2 produced from the dismutation of PAN-elicited superoxide anion contributed to the apoptotic mechanism in HL-60 cells through ROS pathways. These findings suggested that induction of apoptosis by the air pollutant PAN might occur as a result of the release of ROS.

Air Pollutants↗
PubMed1999

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Alkyl and Aryl Transferases↗
PubMed1999

Acute hemodynamic effects of tetramethylpyrazine and tetrandrine on cirrhotic rats.

The hemodynamic effects of tetramethylpyrazine (TMP) and tetrandrine (TET), both alkaloids isolated from Chinese herbs Ligusticum wallichii Franch and Stephania tetrandra S. Moore, respectively, were assessed in anesthetized cirrhotic rats. TMP induced dose-dependent decreases of portal venous pressure (P.V.P.) and mean arterial pressure (M.A.P.) after intravenous infusion. The maximum percentage reduction of P.V.P. after TMP was 3.6 +/- 0.8%, 6.8 +/- 0.5%, and 17.8 +/- 0.6% of baseline, respectively, for the dosages given (3.0, 9.9 and 30.0 mg/kg). Similarly, TET induced dose-dependent decreases of P.V.P. and M.A.P. The maximum percentage reduction of P.V.P. after TET was 5.4 +/- 1.0%, 9.2 +/- 0.8%, and 23.7 +/- 1.2% of baseline, respectively, for the dosages given (2.0, 6.6 and 20.0 mg/kg). Total peripheral resistance was also reduced by TMP as well as TET. Our results showed that TMP and TET induced P.V.P. reduction in cirrhotic rats, together with reduction in M.A.P. and total peripheral resistance.

Alkaloids↗
PubMed1999

Haemodynamic effects of chronic tetramethylpyrazine administration on portal hypertensive rats.

OBJECTIVE: The purpose of this study was to investigate the therapeutic effects of tetramethylpyrazine, an alkaloid isolated from a Chinese herb Ligusticum wallichii Franch, on portal hypertensive rats. METHODS: There were three groups of animals: partial portal vein ligated (PVL) rats, bile duct ligated (BDL) rats and sham-operated (Sham) rats. Each rat in every group was given only one of three treatment regimens: tetramethylpyrazine 30 or 50 mg/kg/12 h, or vehicle (0.2 N HCl, 0.7 ml/12 h). There were seven rats allocated to each regimen, with a total of 63 rats studied. Tetramethylpyrazine or vehicle was given via gastric gavage every 12 h for 8 days, starting just after PVL or 3 weeks after BDL, and haemodynamic parameters were measured thereafter. RESULTS: Both PVL and BDL rats exhibited portal hypertensive and hyperdynamic state as compared with Sham rats. Eight-day tetramethylpyrazine treatment induced dose-dependent reductions of portal venous pressure (PVP), mean arterial pressure (MAP), and total peripheral resistance (TPR) in both PVL and BDL rats. Tetramethylpyrazine at 30 and 50 mg/kg/12 h induced PVP reduction by 10.2 and 16.1% in PVL rats, and 10.5 and 14.8% in BDL rats, respectively, as compared with the vehicle group. There were no significant changes of cardiac index or heart rate (HR) after tetramethylpyrazine treatment in either PVL or BDL rats. In the Sham rats, tetramethylpyrazine did not significantly change PVP, MAP, HR or TPR, despite a tendency of reduction. CONCLUSION: Our results showed that 8-day treatment of tetramethylpyrazine induced reductions of both portal venous and systemic arterial pressure in portal hypertensive rats with and without cirrhosis. Overall, the therapeutic effects are neither outstandingly efficacious nor altogether beneficial.

Animals↗
PubMed1999

Beneficial effects of combined terlipressin and tetramethylpyrazine administration on portal hypertensive rats.

The purpose of this study was to investigate the therapeutic effects of terlipressin (TP) alone or in combination with tetramethylpyrazine (TMP) on anesthetized portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL, without cirrhosis) or bile duct ligation (BDL, with cirrhosis) in Sprague-Dawley rats. Each PVL or BDL rat received only one of the two regimens: vehicle for 3 min followed by TP (0.017 mg x kg(-1) x min(-1) for 3 min) or TMP (10 mg x kg(-1) x min(-1) for 3 min) followed by TP. In PVL rats, infusion of vehicle followed by TP induced significant reduction of portal venous pressure (PVP, -15.0+/-1.0%) and prominent elevation of mean arterial pressure (MAP, 57.3+/-8.1%) as well as total peripheral resistance (TPR, 113+/-11%) from baseline, and there was a cardiodepressant response (cardiac index, CI, -26.3+/-1.1%). Infusion of TMP followed by TP induced significant reduction of PVP (-20.3+/-0.4%) and CI (-9.9+/-1.2%) and significant elevation of MAP (31.3+/-2.5%) and TPR (46.0+/-4.1%) from baseline. In BDL rats, infusion of vehicle followed by TP also induced significant reduction of PVP (-13.8+/-1.7%) but an increase in MAP (57.1+/-2.2%) and TPR (101+/-6%) from baseline, and there also was a cardiodepressant response (CI, -21.4+/-2.3%). Infusion of TMP followed by TP induced significant reduction of PVP (-18.9+/-1.4%) and CI (-11.9+/-2.1%), but an increase in MAP (36.2+/-2.5%) and TPR (55.0+/-5.2%). Compared with vehicle followed by TP, TMP not only significantly enhanced portal hypotensive (PVP reduction) effects of TP but also attenuated the systemic pressor (MAP and TPR elevation) and cardiodepressant (CI reduction) effects of TP in both PVL and BDL rats. Our results suggest that TP, alone or in combination with TMP, induced portal hypotensive effects in two models of portal hypertensive rats. Combination of TP and TMP was beneficial in enhancing portal hypotensive effects of TP and ameliorating the systemic pressor and cardiodepressant effects of TP.

Animals↗
PubMed1999

Predicting control mechanisms for human head stabilization by altering the passive mechanics.

The purpose of this study was to clarify the mechanisms controlling head and neck stabilization in the horizontal (yaw) and vertical (pitch) planes by changing the passive mechanics of the head-neck motor system. Angular velocities of the head and trunk in space were recorded in seated subjects during external perturbations of the trunk with pseudorandom sum-of-sines (SSN) stimuli. Four subjects in yaw and nine subjects in pitch actively stabilized their heads in the dark, and performed a mental distraction task in the dark both with and without a weight atop the head. In yaw, the behavior of the head was found to change relatively little with added inertia. As adding inertia to a passive mechanical system should cause substantial changes in dynamics, we inferred that neural mechanisms were invoked to maintain the constant response dynamics. A mathematical model of head-neck control was applied to predict the relative influence of the vestibulocollic and cervicocollic reflexes, and of inertia, stiffness, and viscosity. Using optimization methods to fit the model to experimental data, we identified stiffness and vestibulocollic reflex gain as the primary contributors to the control of head stabilization in space. In pitch, increasing inertia accentuated phase shifts at higher frequencies. Because our pitch model was insufficiently constrained, we only simulated responses due to passive mechanics. Model simulation predicted unstable head motion at all test frequencies. Subjects were able to compensate for trunk motion at most frequencies, however, suggesting that neural components were modulated to exert compensatory responses both with and without additional weight.

Adaptation, Physiological↗
PubMed1998

Inhibitors of farnesyl protein transferase. 4-Amido, 4-carbamoyl, and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine.

The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

3T3 Cells↗
PubMed1998

Effects of tetramethylpyrazine on portal hypertensive rats.

The effects of tetramethylpyrazine, an alkaloid isolated from a Chinese herb Ligusticum wallichii Franch have been assessed in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Two weeks after ligation, when the hyperdynamic state had stabilized, rats were anaesthetized after an overnight fast and cannulated for measurement of mean arterial pressure, portal venous pressure, cardiac index and heart rate. Tetramethylpyrazine (3.0, 9.9 and 30mgkg(-1)) induced dose-dependent reductions of portal venous pressure and mean arterial pressure after intravenous infusion. The maximum percentage reduction of portal venous pressure after tetramethylpyrazine was 6.0+/-0.8, 9.3+/-1.6 and 20+/-2% of baseline for doses of 3.0, 9.9 and 30.0mgkg(-1), respectively. Also, total peripheral resistance was significantly reduced by tetramethylpyrazine and cardiac index was slightly increased. Our results showed that tetramethylpyrazine induced portal pressure reduction in portal hypertensive rats.

Animals↗
PubMed1997

Structure-activity relationship of 3-substituted N-(pyridinylacetyl)-4- (8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene )- piperidine inhibitors of farnesyl-protein transferase: design and synthesis of in vivo active antitumor compounds.

Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.

3T3 Cells↗
PubMed1997

Community-acquired Acinetobacter pneumonia: a case report.

A 35-year-old male with glucose-6-phosphate dehydrogenase (G6PD) deficiency was admitted because of right chest (pleuritic) pain, fever, cough with scarce production of blood-tinged sputum, and generalized yellowish discolouration of skin for 2 days. Radiographic examination revealed right lower lobe necrotizing pneumonia. Hypotension, dyspnoea and severe haemolysis was noted the next day. Echo-guided lung aspiration and sputum cultures both grew Acinetobacter baumannii. Antibiotic therapy was started immediately, but fever persisted and abscess formation was noted 1 week later. After aggressive supportive and antibiotic therapy, he made a slow but complete recovery from the pneumonia, and was then discharged in a stable condition. Acinetobacter baumannii is a well-known causative agent of nosocomial infections, particularly in intensive units. Community-acquired pneumonia, however, is quite rare, and usually has a fulminant course and high case fatality rate.

Acinetobacter↗
PubMed1997

[Clinical study of effect of yizhi capsule on senile vascular dementia].

OBJECTIVE: To assess the efficacy of Yizhi capsule (YZC) in treating senile dementia. METHODS: Sixty-one vascular dementia (VaD) patients were randomly divided into YZC and control groups. There were 32 cases in YZC group, 4 capsules each time three times a day. In control group, there were 29 cases, 2 mg of hydergine were given each time three times a day, single-blind method was used and the treatment course was two months. RESULTS: YZC could remarkably increase mini-mental state examination (MMSE) and Hamilton Depression Scale (HDS) marks of VaD patients. YZC had the effect of improving balance and gait ability of VaD patients. YZC could improve the abnormal blood velocity (BV), as well as improve cerebral blood flow, brain electrical activity monitoring (BEAM) and hemorheological indexes especially for the abnormal case. No side-effect or toxic-effect was observed in the administration period. CONCLUSION: YZC had certain effect on senile VaD, and it was safe in application.

Aged↗
PubMed1997

[Effect of xuefuzhuyu pill on patients with carotid atherosclerosis by colour Doppler ultrasonography].

OBJECTIVE: To observe the effect of Xuefuzhuyu Pill (XFZYP) on carotid atherosclerosis. METHODS: The patients were randomly divided into XFZYP group and aspirin control group. The status of the carotid plaque vessel wall and blood flow were observed by colored Doppler ultrasonography. RESULTS: (1) Plaque of 6 cases regressed, of 6 cases unchanged, of 1 case progressed after treatment of XFZYP. The area of plaques between baseline and after treatment decreased 0.11 +/- 0.05 cm and that of thickness reduced for 0.09 +/- 0.04 cm2 (P < 0.05) in XFZYP group. While plaque of 3 cases regressed, of 6 unchanged, of 2 cases progressed after treatment of aspirin. The area and thickness of plaque were reduced to 0.05 +/- 0.04 cm and 0.04 +/- 0.03 cm respectively. There were no statistic difference in aspirin group. (2) The intima-media thickness of common carotid artery decreased 0.13 +/- 0.03 mm in XFZYP group (P < 0.001 versus baseline), but there were no significant change after treatment of aspirin (P > 0.05). (3) There were no distinct change about peak systole, minimal diastole time average peak, pulsative index, resistive index in common carotid artery and internal carotid artery after treatment of XFZYP and aspirin. CONCLUSION: Colour Doppler ultrasonography of carotid artery provide a noninvasive, safe and valid opportunities for clinical trail. XFZYP can be useful for the treatment of carotid atherosclerosis.

Aged↗
PubMed1996

Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and CYP2D6.

[3H]Loratadine was incubated with human liver microsomes to determine which cytochrome P450 (CYP) enzymes are responsible for its oxidative metabolism. Specific enzymes were identified by correlation analysis, by inhibition studies (chemical and immunoinhibition), and by incubation with various cDNA-expressed human P450 enzymes. Descarboethoxyloratadine (DCL) was the major metabolite of loratadine detected following incubation with pooled human liver microsomes. Although DCL can theoretically form by hydrolysis, the conversion of loratadine to DCL by human liver microsomes was not inhibited by the esterase inhibitor phenylmethylsulfonyl fluoride (PMSF), and was dependent on NADPH. A high correlation (r2 = 0.96, N = 10) was noted between the rate of formation of DCL and testosterone 6 beta-hydroxylation, a CYP3A-mediated reaction. With the addition of ketoconazole (CYP3A4 inhibitor) to the incubation mixtures, the residual rate of formation of DCL correlated (r2 = 0.81) with that for dextromethorphan O-demethylation, a CYP2D6 reaction. Rabbit polyclonal antibodies raised against the rat CYP3A1 enzyme (5 mg IgG/nmol P450) and troleandomycin (0.5 microM), a specific inhibitor of CYP3A4, decreased the formation of DCL by 53 and 75%, respectively, when added to 1.42 microM loratadine microsomal incubations. Quinidine (5 microm), a CYP2D6 inhibitor, inhibited the formation of DCL approximately 20% when added to microsomal incubations of loratadine at concentrations of 7-35 microM. Incubation of loratadine with cDNA-expressed CYP3A4 and CYP2D6 microsomes catalysed the formation of DCL with formation rates of 135 and 633 pmol/min/nmol P450, respectively. The results indicated that loratadine was metabolized to DCL primarily by the CYP3A4 and CYP2D6 enzymes in human liver microsomes. In the presence of a CYP3A4 inhibitor, loratadine was metabolized to DCL by the CYP2D6 enzyme. Conformational and electrostatic analysis of loratadine indicated that its structure is consistent with substrate models for the CYP2D6 enzyme.

Anti-Bacterial Agents↗
PubMed1996

Mechanisms controlling head stabilization in the elderly during random rotations in the vertical plane.

Frequency-related response characteristics of the mechanisms controlling stabilization of the head in 10 elderly subjects were compared with response characteristics in 8 young adults. Angular velocity of the head with respect to the trunk and EMG responses of 2 neck muscles were recorded in 10 seated subjects during pseudorandom rotations of the trunk in the sagittal plane at frequencies of 0.35 to 3.05 Hz. Subjects were required to actively stabilize their heads with (VS) and without (NY) visual feedback so that voluntary mechanisms and the influence of vision could be tested. Reflex mechanisms were examined when subjects were distracted by a mental calculation task during rotations in the dark (MA). Age emerged as an influential factor in the performance of head stabilization mechanisms, and decrements in performance were even more pronounced in the older as compared with younger elderly subjects. Age effects could be seen in the (a) diminished ability to voluntarily stabilize the head, particularly with the absence of vision, (b) impaired ability to stabilize the head when cognitively distracted, and (c) appearance of a resonant response of the head. Control of head stabilization shifted from reflex mechanisms to system mechanics, probably as a result of age-related changes in the integrity of the sensory systems. The elderly's system mechanics could not effectively compensate for the disturbances, however, and instability was the result.

Journal Article↗
PubMed1996

Salmonella infections: a retrospective 10-year analysis of 134 cases in a regional hospital in Taiwan.

A total of 134 cases of salmonella infections have been noted during the past 10 years in our hospital. Cases of non-typhoidal salmonellosis increased gradually but infections due to Salmonella typhi did not show the same trend. Gastroenteritis was the most prevalent diagnosis in patients below 1 year of age and non-typhoidal bacteraemia and localized infections were the most prevalent in patients over 50 years. Diabetes mellitus was an important underlying disease especially in patients with localized infections (86%). Travelling history played an important role in cases of enteric fever. The susceptibility pattern in non-typhoidal salmonella changed markedly over the study period; multiple drug resistance was noted. The susceptibility pattern of S. typhi showed no significant change. Seven deaths due to salmonella infections were noted (5.2%); all due to non-typhoidal salmonellosis, especially serogroup B. Age above 50 years, localized infection, infection with serogroup B and diabetes were poor prognostic factors.

Adolescent↗
PubMed1996

[Effect of concentrated xuefu zhuyu pill on proliferation of vascular smooth muscle cells in experimental atheriosclerosis rabbits observed by serologic pharmacological test].

Two in vitro experiments were performed for comparative study to evaluate the effect of concentrated Xuefu Zhuyu pill (CXZP), a Chinese traditional herbal medicinal mixture, on the proliferation of vascular smooth muscle cells (SMCs) of experimental atherosclerosis rabbits by serologic pharmacological test. The first experiment approach adopted the addition of the rabbit's serum to the culture medium while in the second experiment the CXZP was added to the medium directly. Results showed that both the serum with CXZP and the CXZP extract itself could inhibit the proliferation of SMC significantly and dose-dependently, and the inhibitory action of the latter was more potent than the former one. It suggested that CXZP could inhibit the proliferation of SMC both in vivo and in vitro, the decrease of effectiveness in vivo might be due to the non-absorption of some active ingredient of CXZP or due to metabolic inactivation.

Animals↗