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Biomedical subjects

H Wang

Publications and source records attributed to H Wang.

At least 1,783 records · Page 99Linked to original sources

A possible involvement of solvent-induced interactions in drug design.

We propose to study a new factor in designing new drugs. Most approaches to the drug design problem focus on the direct interactions between the drug and the corresponding target. We propose to study specific solvent-induced effects that can contribute to the binding Gibbs energy between the drug and its target. We estimate that these indirect effects will contribute significantly to the binding affinity and hopefully improve the clinical efficiency of the drugs.

Amino Acid Chloromethyl Ketones↗

Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells.

Pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) have been used as antioxidants to prevent apoptosis in lymphocytes, neurons, and vascular endothelial cells. We report here that PDTC and NAC induce apoptosis in rat and human smooth muscle cells. In rat aortic smooth muscle cells, PDTC induced cell shrinkage, chromatin condensation, and DNA strand breaks consistent with apoptosis. In addition, overexpression of Bcl-2 suppressed vascular smooth muscle cell death caused by PDTC and NAC. The viability of rat aortic smooth muscle cells decreased within 3 h of treatment with PDTC and was reduced to 30% at 12 h. The effect of PDTC and NAC on smooth muscle cells was not species specific because PDTC and NAC both caused dose-dependent reductions in viability in rat and human aortic smooth muscle cells. In contrast, neither PDTC nor NAC reduced viability in human aortic endothelial cells. The use of antioxidants to induce apoptosis in vascular smooth muscle cells may help prevent their proliferation in arteriosclerotic lesions.

Acetylcysteine↗

Automated analytical system for the examination of protein primary structure.

This paper describes an automated analytical system for the examination of protein primary structure in which (i) the target protein is first purified by immunoaffinity chromatography, (ii) subsequent chromatographic and chemical reaction steps in the sequencing process are directly coupled, (iii) buffer exchange between these unit operations is achieved while the protein is absorbed on a mixed bed of strong ion exchange sorbents, (iv) proteolysis occurs in an immobilized trypsin column having a 10-1000 fold-excess of enzyme, (v) the tryptic digest is directly transferred to a perfusion dilute capture column where it is concentrated and rapidly desalted, and (vi) peptides eluted from the dilute capture column and analytical microbore and capillary perfusion reversed-phase chromatography columns are analyzed by either single-stage mass spectrometry (MS) or tandem MS/MS. Protein structure variants were easily recognized, and in the case of hemoglobin (Hb) S, the site of variation from Hb A0 was verified.

Amino Acid Sequence↗

Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines.

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.

Animals↗

MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation.

MKT-077 (formerly known as FJ-776) is a newly synthesized, highly water-soluble ( > 200 mg/ml) rhodacyanine dye that exhibits significant antitumor activity in a variety of model systems. In culture, MKT-077 inhibits the growth of five human cancer cell lines (colon carcinoma CX-1, breast carcinoma MCF-7, pancreatic carcinoma (CRL 1420, bladder transitional cell carcinoma EJ, and melanoma LOX) but not monkey kidney CV-1, an indicator cell line for normal epithelial cells. In nude mice, MKT-077 inhibits the growth of s.c. implanted human renal carcinoma A498 and human prostate carcinoma DU145 and prolongs the survival of mice bearing i.p. implanted human melanoma LOX (tumor:control = 344%). Subcellular localization indicates that MKT-077 is taken up and retained by mitochondria, and flow cytometric analysis suggests that CX-1 cells take up MKT-077 to a much greater extent than CV-1 cells. Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1 cells accumulate 65-fold more MKT-077 than do CV-1 cells. MKT-077 is the first delocalized lipophilic cation with a favorable pharmacological and toxicological profile in preclinical studies. MKT-077 is now being investigated in Phase I clinical trials.

Animals↗

LTD and LTP induced by transcranial magnetic stimulation in auditory cortex.

Using a system capable of relatively localized and rapidrate transcranial magnetic stimulation (rTMS), evoked trains of complex spikes were studied in rodent auditory cortex. Low rate rTMS from 1 to 10Hz produced a frequency-dependent increase in spike rate. Iterations of rTMS resulted in long-term potentiation (LTP)-like, and more durable long-term depression (LTD)-like changes in evoked spike rate. These observations generate new perspectives for studying mechanisms of learning and memory non-invasively as well as introducing some caveats for use of rTMS in humans.

Animals↗

Down-regulation of HCW9 mRNA in rat hepatocytes during chemical hypoxia involves both transcriptional and posttranscriptional mechanisms.

HCW9 cDNA encodes a rat protein with 95% homology to mouse phospholipase A2 activating protein (PLAP). Its mRNA, which is substantially decreased in rat hepatocytes during chemical hypoxic injury, was found to be expressed in all rat tissues examined, including liver, heart, brain, spleen, lung, skeletal muscle, kidney, and testis. To elucidate the mechanisms responsible for this hypoxia-induced down-regulation of HCW9 mRNA levels, the transcription rate and half-life of HCW9 mRNA were measured. Nuclear run-off assays revealed a 54-57% inhibition in the transcription rate of HCW9 gene during chemical hypoxic injury. The half-life of HCW9 mRNA decreased from approximately 15 min under normoxic conditions to approximately 7 min during chemical hypoxic injury. These findings suggest that HCW9 expression in rat hepatocytes is regulated at both the transcriptional and posttranscriptional levels during chemical hypoxia.

Animals↗

Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells.

Homocysteine is an important and independent risk factor for arteriosclerosis. We showed previously that homocysteine stimulates vascular smooth muscle cell proliferation, a hallmark of arteriosclerosis. We show here that homocysteine and serum increased DNA synthesis synergistically in both human and rat aortic smooth muscle cells (RASMCs). Treatment of quiescent RASMCs with 1 mM homocysteine or 2% calf serum for 36 h increased cyclin A mRNA levels by 8- and 14-fold, respectively, whereas homocysteine plus serum increased cyclin A mRNA levels by 40-fold, indicating a synergistic induction of cyclin A mRNA. Homocysteine did not increase the half-life of cyclin A mRNA (2.9 h), but it did increase the transcriptional rate of the cyclin A gene in nuclear run-on experiments. The positive effect of homocysteine on cyclin A gene transcription was confirmed by our finding that homocysteine increased cyclin A promoter activity and ATF-binding protein levels in RASMCs. Finally, 1 mM homocysteine increased cyclin A protein levels and cyclin A-associated kinase activity by threefold. This homocysteine-induced expression lesions by promoting proliferation of vascular smooth muscle cells.

Activating Transcription Factors↗

Solitary focal demyelination in the brain as a paraneoplastic disorder.

Solitary focal demyelination (SFD) in the brain is an uncommon and poorly understood disorder of uncertain etiology that may represent an intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis. In a few reported cases of SFD, the patient was briefly noted to have a nonneurological malignancy. We studied two patients who had solitary focal lesions in the brain. Utilizing magnetic resonance imaging and tissue biopsy, we found the characteristics of the brain lesions in these two patients to be those of SFD. In our combined experience over the past 10 years, we have encountered no similar brain lesions at our medical center. We found it remarkable that both of these patients also had malignancy outside of the nervous system. One had a seminoma, and the other a lymphoma. We conclude that some cases of SFD in the brain may occur as a paraneoplastic disorder associated with nonneurological malignancies.

Adult↗

Allelotypic and cytogenetic characterization of chemically induced mouse mammary tumors: high frequency of chromosome 4 loss of heterozygosity at advanced stages of progression.

Loss of heterozygosity (LOH) is one of the most common genetic abnormalities in cancer. To define the role of LOH and chromosomal abnormalities at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in CD2F, mice by two basic protocols, the classical multiple-dose 7,12-dimethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combined medroxyprogesterone acetate (MPA) and DMBA. The advantage of the latter protocol is that its latency for tumor development is much shorter and its tumor incidence is higher than those of DMBA alone. To study more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were transplantable into syngeneic hosts. The allelotypic studies were performed by means of microsatellite length polymorphism analysis with a minimum of two simple-sequence repeat markers per chromosome. We observed that MPA-DMBA-induced mammary adenocarcinomas, which in general arose earlier because of the growth promotion exerted by MPA, did not show any significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequency of allelic losses. LOH on chromosome 11 was observed in 30% of the cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumors, respectively. Interestingly, advanced stages of mammary tumor progression, represented by transplantable mammary tumors, showed a much higher level of genomic instability, specifically a very high frequency (66%) of LOH on chromosome 4. These findings indicate that chromosome 4 harbors a gene whose inactivation may play a role in the acquisition of more aggressive characteristics such as autonomous growth and transplantation ability.

9,10-Dimethyl-1,2-benzanthracene↗

Ambulatory esophageal manometry/pH-metry discriminates between patients with different esophageal symptoms.

Ambulatory esophageal manometry/pH-metry has been used primarily in patients with chest pain of presumed esophageal origin, and it is unclear whether the discriminating power of this test applies to other esophageal symptoms. In the present study, prolonged ambulatory manometry/pH recordings were compared in 17 healthy controls, 12 patients with atypical chest pain, and 11 patients with chest pain and nonstructural dysphagia using the Synectics microdigitrapper system. Chest pain patients tended to have higher values for all the pH variables, but their esophageal motility parameters were no different than controls. On the other hand, the chest pain plus dysphagia group was characterized by a significantly lower proportion of propagated contractions between 10 and 5 cm above the lower esophageal sphincter. This group also tended to have a higher frequency of high-amplitude or prolonged-duration contractions. In comparison to the results of standard stationary esophageal manometry, the prolonged ambulatory recordings were more sensitive in detecting esophageal motor dysfunction in the two patient groups. This study suggests that quantitative analysis of ambulatory pH/motility recordings is a sensitive method of evaluating patients with suspected esophageal dysfunction.

Adult↗

OxLDL-induced cytotoxicity and its inhibition by API0134 in cultured porcine aortic endothelial cells.

Protective effects of API0134 on endothelial cells (EC) damaged by oxidatively modified low density lipoprotein (oxLDL) were studied. The results showed that the content of endothelia (ET) and malondialdehyde (MDA) in the media of porcine aortic EC incubated with oxLDL were increased and the cGMP was decreased significantly, and the activity of superoxide dismutase (SOD) was inhibited. The effect of cytotoxicity of oxLDL can be eliminated by API0134. These results suggest that API0134 may protect EC against damages elicited by oxLDL.

Animals↗

Studies on the ossification of compound transplantation of porous TCP ceramics and bone marrow.

Following the culture of human red marrow with porous TCP ceramics in vitro, a large amount culturing marrow cells adhered well to the surface and inner wall of TCP ceramics and spread well over the dish bottom 4 weeks after cultivation. After the compound transplantation of porous TCP ceramics with red marrow into quadriceps femoris muscle of rabbits, a huge amount of new bone and marrow formed in these sites on and in the ceramics 4 weeks after transplantation. These results showed an excellent biocompatibility between TCP ceramics and marrow and an excellent osteogenic effect in the compound transplantation. The mechanism of ossification and clinical significance about the compound transplantation were discussed.

Animals↗

Amperometric detection of heavy metal ions in ion pair chromatography at an array of water/nitrobenzene micro interfaces.

A novel amperometric detector for heavy metal ions has been developed and successfully applied for ion pair chromatography. The detector is based on the electrochemical transfer of the metal ions across an array of water/nitrobenzene micro interfaces. The ion transfer is facilitated by the neutral ionophores methylenebis(diphenylphosphineoxide) and methylenebis(di- phenylphosphinesulfide). More than eight metals are separated in less than 15 min on an RP18 column using octyl sulfonate as ion pair reagent. For the heavy metals, the limits of decision are 19(Pb(2+)), 9(Zn(2+)), 9l (Co(2+)), 8(Cd(2+)) and 1.6(Mn(2+)) microg/L. The applicability of the new method for water samples is demonstrated.

Journal Article↗

Acute cholecystitis. Does the clinical diagnosis correlate with the pathological diagnosis?

BACKGROUND: Most of the literature dealing with the surgical management of acute cholecystitis bases patient selection on pathological diagnosis, either exclusively or using it as a major selection criteria or as a confirmation of diagnosis. The purpose of this study was to examine the correlation between preoperative clinical findings, intraoperative gross findings, and postoperative pathological findings. METHODS: A retrospective review of 493 consecutive laparoscopic cholecystectomies performed by a single surgeon (RJF) in a single institution was done. Four different sets of criteria were used to define four groups of patients as having acute cholecystitis: (1) preoperative acute cholecystitis based on defined criteria (PA); (2) intraoperative gross findings of acute or subacute cholecystitis based on surgeon assessment of inflammation (IA); (3) initial pathological evaluation by a staff pathologist (IP); and (4) expert pathological (EP) review using strictly defined histological criteria. RESULTS: Of 41 patients, 40 (97.6%) were classified as having acute cholecystitis by IA, 21 (51.2%) by IP, and 17 (41.5%) by EP. Of the 75 patients classified as having acute cholecystitis by IA, 40 (53.0%) were classified acute by PA, 34 (45. 0%) by IP, and 17 (22.7%) by EP. Of the 72 IP patients, 34 (47.2%) were classified as acute by IA, 15 (20.8%) by EP, and 24 (33.3%) were PA. Of the 32 EP patients, 21 (65.6%) were classified as acute by IA, 14 (43.8%) by IP, and 18 (56.3%) were PA. CONCLUSION: The correlation between the pathological diagnosis and intraoperative findings is poor. Preoperative clinical findings of acute cholecystitis are highly reliable for predicting intraoperative gross findings. However, intraoperative findings of acute cholecystitis are commonly found in the absence of preoperative clinical signs. Recommendations for surgical therapy should be based on studies which use either operative findings or the preoperative clinical findings as the basis for patient selection.

Adolescent↗

Regulatory effects of acutely repeated nicotine treatment towards central muscarinic receptors.

Sensitivity of brain muscarinic acetylcholine receptors to the agonists was examined in nicotine tolerant animals which were developed by acutely repeated injections of nicotine. In conscious rats, the dose-response curves of muscarinic agonists arecoline and pilocarpine, cholinesterase inhibitors soman and physostigmine rather than GABA receptor antagonist pentylenetetrazol or glycine receptor antagonist strychnine for producing EEG seizures were shifted leftwards by acutely repeated injections of nicotine. This phenomenon could be prevented by nicotinic antagonist mecamylamine. Similar results were obtained in acute nicotine tolerant mice and rabbits. In other experiments, the dose-response curve of arecoline-induced convulsions or oxotremorine-induced tremors was also shifted leftwards, and the durations of arecoline- and oxotremorine-induced tremors were prolonged in acute nicotine tolerant mice. In addition, the effects of arecoline for producing down-regulation of muscarinic receptors of rat cerebrum and hippocampus rather than brain stem were potentiated in acute nicotine tolerant rats. It is concluded that the sensitivity of brain muscarinic receptor to its agonists is increased in acute nicotine tolerant rats, mice and rabbits.

Animals↗

Intrinsic uncertainty and integration efficiency in bisection acuity.

A spatial perturbation paradigm was used to determine equivalent intrinsic uncertainty and spatial integration efficiency in bisection. Specifically, three-line bisection thresholds were measured in the fovea of four normal observers with stimulus lines comprised of discrete dark dots distributed randomly around the mean line position according to a Gaussian function. The standard deviation of the Gaussian distribution (sigma e), the number (N), and the strength (C) of the dots as well as line separation were varied. Bisection thresholds were modeled by an ideal integrator, from which the magnitude of equivalent internal uncertainty (sigma i), the equivalent effective number of dots (k), and equivalent integration efficiency (k/N) were quantified. At the 2 min arc separation, sigma i decreases (down to a few sec arc) as N and/or C increases. The effects of both N and C can be accounted for by the stimulus visibility (V, in multiples of detection threshold). At the 16 min arc separation, sigma i is independent of N, C, or V, and is about 1 min arc. The two different forms of sigma i indicate that bisection judgments are limited by at least two separate sources of limiting noise, consistent with the hypothesis of two separate mechanisms (i.e. spatial filters and local signs). A visibility dependent sigma i at the 2 min arc separation can be explained on the basis of contrast sensitive spatial filter mechanisms. A fixed sigma i at the 16 min arc separation indicates a genuine positional uncertainty, consistent with local-sign mechanisms. Interestingly, equivalent integration efficiency (k/N) is very similar at the two line separations. k/N is critically dependent on, and proportional to C, indicating a common limitation in a detection mechanism.

Depth Perception↗