Biomedical subjects

J H Lin

Publications and source records attributed to J H Lin.

At least 37 records · Page 2Linked to original sources

PubMed2001

P450 interaction with farnesyl-protein transferase inhibitors metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes.

Methyl substitution at the 2-position of the imidazole ring greatly improved drug metabolism profiles, in human liver microsomes, of ras farnesyl-protein transferase inhibitor (FTI) candidates for drug development. Methyl substitution markedly reduced the P450 inhibitory potency of non-substituted FTIs for CYP3A4 (by a factor of 12-403) and 2C9 (by a factor of 4.2-28), while it had little effect on the CYP2D6 enzyme. An immunochemical inhibition study demonstrated that CYP3A4 plays a predominant role in the metabolism of both non-substituted and 2-methyl-substituted imidazole-containing FTI candidates. Very strong type II binding spectra with human liver microsomes were observed for all non-substituted FTIs, while methyl substitution markedly weakened type II spectra or shifted the type of spectra from II to I. This indicated that methyl substitution on the imidazole moiety interfered with the substrate-P450 heme interaction, likely due to a steric effect caused by the methyl group. A kinetics study revealed that the methyl substitution increased V(max) and K(m) values to the same extent. These studies suggested that the 2-methyl substitution on the imidazole ring improved its drug metabolism profile by reducing the potential to inhibit CYP3A4-mediated metabolism without affecting intrinsic metabolic clearance (V(max)/K(m)).

Alkyl and Aryl Transferases↗

PubMed2001

Characterization of a delayed rectifier potassium channel in the slowly adapting stretch receptor neuron of crayfish.

Single channel recordings were performed on enzyme-cleaned slowly adapting sensory neurons of crayfish, in cell-attached configuration, with a physiological K(+) gradient across the neuronal membrane. An outward rectifying, voltage-gated K(+) channel with a slope conductance of 13 pS and a K(+) ion permeability of P(K)=6.5 x 10(-14) cm(3)/s was characterized. This 13 pS K(+) channel started to be activated at around 20 mV depolarization. Its open probability increased upon depolarization with V(0.5)= -25.3 mV and P(max)=0.83. The averaged currents showed a delay following the onset of depolarization. The activation time constant was voltage-dependent. The maximal value was 17.0 ms at -25 mV and at +35 mV the time constant was 1.7 ms. Little inactivation was observed throughout the 80- or 1500-ms long depolarization pulses. A sum of two exponentials provided the optimal fit for open time and closed time distribution. At 80-mV depolarization, the open time constants were 0.4 and 10.4 ms; the close time constants were 0.4 and 2.3 ms. The first-latency distribution suggested that at least two closed states preceded two open states. This 13 pS delayed rectifier plays a minor role in the maintenance of the resting membrane potential but contributes to the action potential repolarization. It may also modify the stretch-induced receptor potential and affect the adaptation behaviours in this neuron.

Action Potentials↗

PubMed2001

Expression and function of astrocytic gap junctions in aging.

Astrocytic gap junctions have been implicated in a variety of signaling pathways essential to normal brain function. However, no information exists on the prevalence of gap junction channels and their function in the aging brain. Here we have compared the expression of the two most abundant astrocytic gap junction proteins in young and senescent brains and quantified the extent of functional gap junction coupling. The expression level of Cx43 peaked in 7-month-old mice. The relative numbers of Cx43 immunoreactive plaques were 596+/-61, 734+/-62, and 755+/-114 in 3-, 7-, and 21-month-old mice, whereas plaques size averaged 0.9+/-0.1 microm(2) (3 months), 1.3+/-0.1 microm(2) (7 months), and 0.7+/-0.1 microm(2) (21 months). The expression level of Cx30 was also highest in 7-month-old animals (315+/-49 plaques, size 0.8+/-0.07 microm(2) vs. 585+/-51 plaques, size 0.9+/-0.1 microm(2) in 3- and 7-month-old mice, respectively), but only 262+/-63 plaques (size 0.4+/-0.04 microm(2)) in 21-month-old mice. Western blot analysis revealed that the content of both Cx43 and Cx30 remained relatively constant at 3, 7, and 21 months. The fluorescence recovery of photobleach technique (FRAP) was used to evaluate coupling in freshly prepared hippocampal slices. Gap junction coupling did not change significantly as a function of aging, but a tendency towards reduced coupling was observed as the animals aged. Average fluorescence recovery after 2 min was 63+/-6% in younger animals, 59+/-5% in adult animals, and 54+/-4% in old brain. These observations indicate that although astrocytic gap junction proteins are maintained at high levels through the entire lifespan of mice, aging is associated with changes in the number and size of both Cx30 and Cx43 gap junction plaques.

Aging↗

PubMed2001

Syntheses of hydrated molybdenum bronzes by reduction of MoO3 with NaBH4.

Hydrated molybdenum bronzes have been prepared by reduction reaction of MoO3 with NaBH4 in ethanol and DMSO. The reduction reactions in both solvents occur smoothly; thus, the layered structure of MoO3 is maintained in the product. Divalent cation Ca2+ has been intercalated between the MoO3 layers, which leads to highly reduced molybdenum bronze (Mo5.26+). Solvated molybdenum bronze catalyzes the reduction reaction of DMSO by NaBH4, producing CH3SCH3. The structure model of hydrated sodium molybdenum bronze has also been reinvestigated by using the Rietveld analysis. The hydrated molybdenum bronze crystallizes in an orthorhombic structure, in which the structure of Mo octahedron layers is closely related to that in MoO3. However, the structure refinement reveals that the Mo octahedron in the MoO3 layers is axially distorted, which is different from that in MoO3 but similar to an isoelectron compound H0.33MoO3.

Journal Article↗

PubMed2001

Differential inhibition of progesterone synthesis in bovine luteal cells by estrogens and androgens.

We investigated the roles of estrogens and androgens in the progesterone biosynthesis of bovine luteal cells. The responsiveness of primary luteal cells to the stimulation of tropic agents was observed in a dose-dependent manner. Estrogens and androgens significantly inhibited tropic agent-induced progesterone secretions, but glucocorticoids did not, which indicated the inhibitions were specific. The failure of exogenous 8-Br-cAMP to prevent these inhibitions suggested that took place at the post-cAMP steps. The immunoblot showed that testosterone remarkably decreased the amount of induced P450scc protein after 6-hour treatment, yet 17beta-estradiol did not. The 3beta-HSD activity assays demonstrated that both 17beta-estradiol and testosterone efficiently blocked induced 3beta-HSD activities. Both inhibitory effects of E2 and T on progesterone synthesis were observed one hour after treatment and accompanied with suppressed 3beta-HSD activities. This study presents that estrogens and androgens specifically inhibit bovine luteal function through different mechanisms.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2001

Dynamic biomechanical model of the hand and arm in pistol grip power handtool usage.

The study considers the dynamic nature of the human power handtool operator as a single degree-of-freedom mechanical torsional system. The hand and arm are, therefore, represented as a single mass, spring and damper. The values of these mechanical elements are dependent on the posture used and operator. The apparatus used to quantify these elements measured the free vibration frequency and amplitude decay of a known system due to the external loading of the hand and arm. Twenty-five subjects participated in the investigation. A full factorial experiment tested the effects on the three passive elements in the model when operators exerted maximum effort for gender, horizontal distance (30, 60, 90 cm), and vertical distance (55, 93, 142 190 cm) from the ankles to the handle. The results show that the spring element stiffness and mass moment of inertia changed by 20.6 and 44.5% respectively with vertical location (p<0.01), and 23.6 and 41.2% respectively with horizontal location (p<0.01). Mass moment of inertia and viscous damping for males were 31.1 and 38.5% respectively greater than for females (p<0.01). Tool handle displacement and hand force during torque build-up can, therefore, be predicted based on this model for different tool and workplace parameters. The biomechanical model was validated by recalling five subjects and having them operate a power handtool for varying horizontal distances (30, 60, 90 cm), vertical distances (55, 93, 142 cm), and two torque build-up times (70, 200 ms). Tool reaction displacement was measured using a 3D-motion analysis system. The predictions were closely correlated with these measurements (R = 0.88), although the model underpredicted the response by 27%. This was anticipated since it was unlikely that operators used maximal exertions for operating the tools.

Adult↗

PubMed2001

Involvement of apoptosis during deciduomal regression in pseudopregnant hamsters effect of progesterone.

We determined whether fragmentation of genomic DNA, apoptosis, occurs during deciduomal regression in pseudopregnant hamsters and the effect of progesterone on the apoptotic processes. Artificially induced deciduoma were obtained on different days of pseudopregnancy and separated into mesometrial and antimesometrial tissues. The deciduomal cell cycle progression and population profiles of both sides were compared by flow cytometry. The proportion of sub-G1 peak, which was correlated with the apoptotic cells, were about 10% on day 8 and reached to 40% in both tissues on day 10. Exogenous progesterone treatment by daily injection (2 mg; s.c.) on and after day 8 reduced the percentage of low molecular weight DNA in both tissues on day 10 and day 12 as compared to the nontreated control one, respectively. The appearance of DNA ladder was also delayed at least 24 h by progesterone administration. The intensity of DNA fragmentation was more pronounced in antimesometrial deciduoma. In situ 3'-end labeling of apoptotic cells further substantiated the apoptotic process. The apoptotic cells first appeared in the luminal region in antimesometrial deciduoma on day 8 and spreaded all over the entire deciduomal tissue on day 10. Progesterone treatment stimulated deciduomal proliferating cell nuclear antigen (PCNA) expression, maintained deciduoma until day 14 and retarded the differentiation and regeneration of the uterine epithelium.

Animals↗

PubMed2001

Tpl-2 induces apoptosis by promoting the assembly of protein complexes that contain caspase-9, the adapter protein Tvl-1, and procaspase-3.

The Tpl-2 proto-oncoprotein promotes cellular proliferation when overexpressed in a variety of tumor cell lines. Here, we present evidence that when overexpressed in immortalized non-transformed cells, Tpl-2 induces apoptosis by promoting the activation of caspase-3 via a caspase-9-dependent mechanism, and that apoptosis is enhanced when Tpl-2 is co-expressed with the newly identified ankyrin repeat protein Tvl-1. The activation of caspase-3 by caspase-9 is known to depend on the assembly of a multimolecular complex that includes Apaf-1 and caspase-9. Data presented here show that co-expression of Tpl-2 with Tvl-1 promotes the assembly of a complex that involves several proteins that bind Apaf-1 including Tvl-1, itself, Tpl-2 and phosphorylated procaspase-9. More important, procaspase-3, which under normal growth conditions is not associated with the complex, binds Tvl-1 conditionally in response to Tpl-2-generated apoptotic signals. The conditional association of procaspase-3 with Tvl-1 promotes the in vivo proteolytic maturation of procaspase-3 by caspase-9, a process casually linked to apoptosis.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Structure and immersion behavior of plasma-sprayed apatite-matrix coatings.

The microstructure and properties of a series of plasma-sprayed coatings from sinter-granulated powders fabricated from SiO2, CaO, P2O5 and Na2O-containing HA composite powders on Ti-6Al-4V substrate were reported. The immersion behavior of these coatings in a simulated body fluid (SBF) was also investigated. The results showed that sinter-granulated apatite-matrix powders were irregularly shaped and appeared quite similar. XRD patterns showed that during fabrication of the powders, P2O5 and SiO2 enhanced the decomposition of HA structure, while CaO and Na2O did not. Reasonably high bond strengths (45-50 MPa) were obtained from all coatings. The plasma spray process itself enhanced the decomposition of apatite and chemical reactions among different phases. When immersed in SBF, the intensities of such phases as alpha- and beta-TCP in all coatings decreased with immersion time and an apatite precipitation took place on all coating surfaces. The immersed SiO2- and CaO-containing HA (HSC) coating had the highest rate of apatite precipitation among all coatings. The variations in calcium ion concentration in simulated body fluid indicated that the HSC-immersed solution reached its maximal Ca concentration the earliest, while the HSCP (HA, SiO2, CaO and P2O5)-immersed solution reached its maximum the latest.

Apatites↗

PubMed2001

Analysis of three lupane type triterpenoids in Helicteres angustifolia by high-performance liquid chromatography.

Kang-chih-ma is the dried roots and stems of Helicteres angustifolia (Sterculiaceae) and a commonly used folk herbal drug in Taiwan. It possesses antidotal, analgesic, anti-inflammatory and anti-bacterial effects and is also known as a kind of tumor inhibitory plant. To evaluate the quality of H. angustifolia, a simple, rapid and accurate high-performance liquid chromatographic (HPLC) method was developed for the assay of three lupane type triterpenes: 3beta-acetoxy-27-benzoyloxylup-20(29)-en-28-oic acid methyl ester (methyl helicterate), 3beta-acetoxy-27-benzoyloxylup-20(29)-en-28-oic acid, and 3beta-acetoxy-27-(p-hydroxyl) benzoyloxylup-20(29)-en-28-oic acid methyl ester. The present HPLC system used an Inertsil ODS-2 column by gradient elution with acetonitrile and water as the mobile phase and detected at UV 230 nm. Regression equations revealed good linear relationships (correlation coefficients: 0.9922-0.9997). The relative standard deviations of these three constituents ranged between 1.05-3.14% (intraday) and 2.12-4.38% (interday). The contents of these three constituents of the heartwood and the bark of the roots of H. angustifolia in five different samples have also been determined.

Chromatography, High Pressure Liquid↗

PubMed2001

Temporal expression of nitric oxide synthase isoforms in healing Achilles tendon.

We investigated the temporal expressions of the three nitric oxide synthase (NOS) isoforms by semi-quantitative polymerase chain reaction (PCR) assays and by immunoblot analysis, following Achilles tendon transection in rats. Four days after injury, there were increases in the steady-state levels of mRNA for all three NOS isoforms, with peaks for the inducible isoform (iNOS) (23-fold increase) at day 4, the endothelial isoform (eNOS) (24-fold increase) at day 7 and the neuronal isoform (bNOS) (seven-fold increase) at day 21. The temporal expression of NOS isoforms at a protein level was consistent with the results at the mRNA level. We have previously shown a five-fold increase in the NOS activity, as detected by 3H-arginine to 3H-citrulline conversion, at day 7 postinjury. These findings indicate that all three NOS isoforms are expressed during tendon healing with differential expression patterns during the various phases of tendon healing. These findings may prove clinically relevant with respect to strategies for regulating tendon healing.

Achilles Tendon↗

PubMed2001

Screening of drug candidates for their drug--drug interaction potential.

Within the past year, additional papers have been published that focus on higher-throughput drug-interaction screening. Some papers have described enzyme assays that can be used to evaluate inhibition or induction of the human cytochrome P450s. At the same time, numerous investigators have developed computational (in silico) methods to predict interactions and have validated the approach using in vitro (assay-derived) data. These so called 'in silico--in vitro' correlations have great potential and may complement existing 'in vitro--in vivo' correlations.

Cytochrome P-450 Enzyme Inhibitors↗

PubMed2001

Surface reaction of stoichiometric and calcium-deficient hydroxyapatite in simulated body fluid.

In the present study, the immersion behavior of two kinds of sintered HA with different Ca/P ratios in two different extracellular simulated solutions (Tris buffer and Hank's solutions) was investigated and compared. Results indicated that an as-received Ca-deficient HA (FHA) had a lower Ca/P ratio, larger linear shrinkage and higher density than a stoichiometric HA (MHA). When FHA powder was calcined at 900 degrees C, its Ca-deficient apatite structure was unstable and a significant amount of beta-TCP phase was formed. When heated to 1250 degrees C in air, the highly crystalline apatite structure of MHA was still stable without any noticeable decomposition. The FTIR spectra indicated that both immersed MHA and FHA in Hank's solution were gradually covered with a layer of precipitated apatite during immersion. When immersed in Tris buffer solution, neither HA showed significant changes in their FTIR spectra. SEM observation indicated that the precipitation rate on immersed FHA surface was much higher than that on MHA surface when immersed in Hank's solution. The weight loss and pH data confirmed the higher dissolution rate of FHA than MHA in Hank's solution.

Journal Article↗

PubMed2001

Glutamate release promotes growth of malignant gliomas.

Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative diseases. Although recent data show that cultured glioma cells secrete glutamate, the growth potential of brain tumors has not yet been linked to an excitotoxic mechanism. Using bioluminescence detection of glutamate release from freshly prepared brain slices, we show that implanted glioma cells continue to secrete glutamate. Moreover, gliomas with high glutamate release have a distinct growth advantage in host brain that is not present in vitro. Treatment with the NMDA receptor antagonists MK801 or memantine slowed the growth of glutamate-secreting tumors in situ, suggesting that activation of NMDA receptors facilitates tumor expansion. These findings support a new approach for therapy of brain tumors, based upon antagonizing glutamate secretion or its target receptors.

Amino Acid Transport System X-AG↗

PubMed2001

Interindividual variability in inhibition and induction of cytochrome P450 enzymes.

Drug interactions have always been a major concern in medicine for clinicians and patients. Inhibition and induction of cytochrome P450 (CYP) enzymes are probably the most common causes for documented drug interactions. Today, many pharmaceutical companies are predicting potential interactions of new drug candidates. Can in vivo drug interactions be predicted accurately from in vitro metabolic studies? Should the prediction be qualitative or quantitative? Although some scientists believe that quantitative prediction of drug interactions is possible, others are less optimistic and believe that quantitative prediction would be very difficult. There are many factors that contribute to our inability to quantitatively predict drug interactions. One of the major complicating factors is the large interindividual variability in response to enzyme inhibition and induction. This review examines the sources that are responsible for the interindividual variability in inhibition and induction of cytochrome P450 enzymes.

Algorithms↗

PubMed2001

Heart transplantation and the Batista operation for children with refractory heart failure.

Medically refractory heart failure may be present in children with cardiomyopathy (CMP) or complex congenital heart disease (CHD). In adults, the surgical management of this condition is either heart transplantation or the Batista operation. From March 1995 to January 2000, a total of 6 children, aged from 1 to 16 years, with medically refractory heart failure associated with CMP or complex CHD underwent cardiac transplantation and one of them also had the Batista operation as a bridge to transplantation. One of the 6 patients died of intractable sepsis 17 days after the operation, but the other 5 were discharged with satisfactory hemodynamics. Immunosuppressive agents, including azathioprine, cyclosporin or FK-506, were given. One patient experienced moderate acute rejection, but it was controlled by FK-506, OKT-3 and solumedrol. However, another suffered from lymphoproliferative disease 8 months after transplant, but it was controlled by intravenous immunoglubulin, alpha-interferon and acyclovir. Cardiac function during serial follow-up (range, 1 month to 5 years) revealed normal systolic and diastolic function and none received any anticongestive medications. Almost all patients received an oversized donor heart. The left ventricle (LV) mass was remodeled, initially as an decrease and later as an increase. The patient who underwent the Batista operation was discharged 1 month after the operation with an increased LV ejection fraction (from 10% to 22%). She was successfully bridged to heart transplantation 7 months after the Batista operation. The results of cardiac transplantation in growing children are satisfactory and remain the mainstay of surgical treatment for medically refractory heart failure in these patients. However, with a shortage of donor hearts, the Batista operation may be adopted as a bridge to heart transplant with a fair response.

Adolescent↗

PubMed2001

Acupuncture for general veterinary practice.

Since the International Society of Veterinary Acupuncture (IVAS) was founded in 1974, acupuncture (AP) has received greater acceptance by veterinary professionals throughout the world. This article introduces some important animal diseases that respond well to AP therapy. These include resuscitation of small animals, treatment of anoestrous gilts and sows, bovine reproductive disease, canine vertebral problems and equine backpain, etc. Conventional medicine considers these to be difficult cases to treat. Veterinarians have become more aware of the benefits of AP especially for those diseases, thanks to the efforts of experienced practitioners and scientists, and the many published reports on veterinary AP that have introduced some good indications for AP therapy in veterinary practice. Possible mechanisms behind the effectiveness of AP are discussed. This article aims to introduce veterinarians to good indications for AP to initiate their interest in the practice of AP. Although this is a rapidly expanding field, a long march must begin with one step. We wish this article to be the shoes for such a march. For more information on veterinary AP, contact IVAS , P.O. Box 1478, Longmont, CO.. 80502, USA (http://www.ivas.org), or your national veterinary acupuncture society (http://www.komvet.at/ ivadkom/vapsocs.htm).

Acupuncture↗

PubMed2001

Nitric oxide synthase isoforms during fracture healing.

We have shown previously that nitric oxide (NO) has regulatory effects on fracture healing. Our aim here was to investigate the temporal expression patterns of the three NO synthase (NOS) isoforms that are responsible for the generation of NO by semiquantitative competitive polymerase chain reaction (PCR) and immunoblot analysis after femoral fractures in rats. We found that 4 days after fracture, there were increases in the levels of messenger RNA (mRNA) for all three NOS isoforms, with peaks for the inducible NOS (iNOS; 35-fold increase, p < 0.05) at day 4, the endothelial NOS (eNOS; 5-fold increase, p < 0.05) at day 7, and the neuronal NOS (bNOS; 16-fold increase, p < 0.05) at day 21. At a protein level, the time course expression of NOS isoforms was consistent with the results of those at the mRNA level. In addition, we have previously reported a 2.5-fold increase in NOS activity detected by [3H]arginine to [3H]citrulline conversion at day 15 compared with that at day 4 after fracture. The findings that the expression of NOS isoforms during fracture healing is type specific and time dependent are important and may have clinical applications in the regulation of bone repair by NOS inhibitors or stimulators at different stages after injury.

Animals↗