Biomedical subjects

Y Gu

Publications and source records attributed to Y Gu.

At least 163 records · Page 9Linked to original sources

PubMed1999

MAPK superfamily plays an important role in daunomycin-induced apoptosis of cardiac myocytes.

BACKGROUND: Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment. METHODS AND RESULTS: When cultured cardiac myocytes of neonatal rats were exposed to 1 micromol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH(2)-terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca(2+) chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis. CONCLUSIONS: These results suggest that DM activates MAPKs through reactive oxygen species and Ca(2+) and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.

Animals↗

PubMed1999

An immunodominant conserved region within the variable domain of VlsE, the variable surface antigen of Borrelia burgdorferi.

Antigenic variation is an effective strategy evolved by pathogenic microbes to avoid immune destruction. Variable Ags such as the variable major protein of Borrelia hermsii, the variant surface glycoprotein of African trypanosomes, and the pilin of Neisseria gonorrhoeae include an immunodominant variable domain and one or more invariable domains that are not antigenic. Short, nonantigenic, invariable regions also may be present within the variable domain. VlsE (variable major protein-like sequence, expressed), the variable surface Ag of Borrelia burgdorferi, the Lyme disease spirochete, also contains both variable and invariable domains. In addition, interspersed within the VlsE variable domain there are six invariable regions (IR1-6) that together amount to half of this portion's primary structure. We show here that these IRs are conserved among strains and genospecies of the B. burgdorferi sensu lato complex. Surprisingly, unlike the invariable regions of variable major protein, variant surface glycoprotein, and pilin, which are not antigenic in natural infections, the most conserved of the IRs, IR6, is immunodominant in Lyme disease patients and in monkeys infected with B. burgdorferi. IR6 is exposed on the surface of VlsE, as assessed by immunoprecipitation experiments, but is inaccessible to Ab on the spirochete's outer membrane, as demonstrated by immunofluorescence and in vitro killing assays. VlsE thus significantly departs from the antigenic variation paradigm, whereby immunodominance is only manifest in variable portions. We submit that IR6 may act as a decoy epitope(s) and contribute to divert the Ab response from other, perhaps protective regions of VlsE.

Amino Acid Sequence↗

PubMed1999

Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy.

Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.

Animals↗

PubMed1999

Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition.

BACKGROUND: Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure. METHODS AND RESULTS: CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt(max) was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress. CONCLUSIONS: GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

The van der Waals Interaction between a Spherical Particle and a Cylinder.

Based on the Hamaker approach, this paper presents a general method to compute the retarded van der Waals (vdW) interaction potential and force between a spherical particle and a cylinder. The effects of the relative dimensions of the cylinder to the sphere were examined by this general method. First, the unretarded vdW interaction potential between these two bodies is obtained by pairwise summation of all the relevant intermolecular interactions and evaluated by accurate multiple numerical integrations. The interaction potential is then modified to account for the retardation effect by incorporating a correction factor which depends on the separation distance and the characteristic wavelength of the interactions. The numerical predictions indicate that the vdW interaction between a sphere and a finitely long cylinder can be approximated as the interaction between a sphere and an infinitely long cylinder only if the ratio of the cylinder length to its radius, B = L/R, is greater than a certain lower limit, say, B > 10. At smaller dimensionless separation distances, H = D/a </= 1, the vdW interaction between a sphere and a cylinder can be approximated by that between a sphere and a flat plate. However, such a commonly used flat plate approximation is found to be acceptable only if the ratio of the cylinder radius to the sphere radius, A = R/a, is larger than 10, regardless of the B value. Otherwise, it will seriously overestimate the vdW interaction for the sphere-cylinder system. Copyright 1999 Academic Press.

Journal Article↗

PubMed1999

Amino acid substitutions at positions 207 and 221 contribute to catalytic differences between murine glutathione S-transferase Al-1 and A2-2 toward (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene.

We have previously identified a novel Alpha class murine glutathione (GSH) S-transferase isoenzyme (designated mGSTAl-2) which is exceptionally efficient in catalyzing the GSH conjugation of (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], the ultimate carcinogen of widespread environmental pollutant benzo[a]pyrene. Furthermore, we have demonstrated that the Al-type subunit of this isoenzyme is significantly more active toward (+)-anti-BPDE than the other subunit (mGSTA2). To establish the basis for catalytic differences between mGSTAl and mGSTA2, which differ in their primary structures by 10 amino acids [distributed in three sections (I-III) as clusters of two (residues 65 and 95), three (residues 157, 162, and 169), and five (residues 207, 213, 218, 221, and 222) amino acids], three chimeric enzymes were expressed and tested for their activity toward (+)-anti-BPDE. These studies revealed that amino acid substitution(s) in section III determined the high catalytic activity of mGSTAl. Molecular modeling studies suggested that amino acid substitutions at positions 207 and/or 221, but not at positions 213, 218, and 222, may be responsible for such a difference. To test this possibility, amino acids at positions 207 and 221 of mGSTAl were mutated with the equivalent residues of mGSTA2. Kinetic analysis of the wild type and the mutant enzymes revealed that both methionine-207 and isoleucine-221 are critical for higher activity of mGSTA1-1 toward (+)-anti-BPDE compared with that of mGSTA2-2.

Amino Acid Substitution↗

PubMed1999

Regulation of AML2/CBFA3 in hematopoietic cells through the retinoic acid receptor alpha-dependent signaling pathway.

AML2 is a member of the acute myelogenous leukemia, AML family of transcription factors. The biologic functions of AML1 and AML3 have been well characterized; however, the functional role of AML2 remains unknown. In this study, we found that AML2 protein expressed predominantly in cells of hematopoietic origin is a nuclear serine phosphoprotein associated with the nuclear matrix, and its expression is not cell cycle-related. In HL-60 cells AML2 expression can be induced by all three natural retinoids, all-trans-retinoic acid (RA), 13-cis-RA, and 9-cis-RA in a dose-dependent manner. A synthetic retinoic acid derivative, 4HPR, which neither activates RA receptor (RAR) alpha nor retinoic X receptor alpha was unable to induce the expression of AML2. A RAR-selective activator, TTNPB, induced AML2 expression similar to RA. Our study further showed that AGN193109, a potent RARalpha antagonist, suppressed AML2 expression induced by RA and that a retinoic X receptor pan agonist AGN194204 had no effect on its expression. Taken together, these studies conclusively demonstrated that the expression of AML2 in HL-60 cells is regulated through the RARalpha-specific signaling pathway. Our study further showed that after all-trans-retinoic acid priming, AML2 expression could be augmented by vitamin D(3). Based on these studies we hypothesize that AML2 expression is normally regulated by retinoid/vitamin D nuclear receptors mainly through the RARalpha-dependent signaling pathway and that it may play a role in hematopoietic cell differentiation.

Alitretinoin↗

PubMed1999

Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.

Biomechanical stress is a major stimulus for cardiac hypertrophy and the transition to heart failure. By generating mice that harbor a ventricular restricted knockout of the gp130 cytokine receptor via Cre-IoxP-mediated recombination, we demonstrate a critical role for a gp130-dependent myocyte survival pathway in the transition to heart failure. Such conditional mutant mice have normal cardiac structure and function, but during aortic pressure overload, these mice display rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis versus the control mice that exhibit compensatory hypertrophy. Thus, cardiac myocyte apoptosis is a critical point in the transition between compensatory cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure.

Animals↗

PubMed1999

Characterization of bone marrow laminins and identification of alpha5-containing laminins as adhesive proteins for multipotent hematopoietic FDCP-Mix cells.

Laminins are extracellular matrix glycoproteins that influence the phenotype and functions of many types of cells. Laminins are heterotrimers composed of alpha, beta, and gamma polypeptides. So far five alpha, three beta, and two gamma polypeptide chains, and 11 variants of laminins have been proposed. Laminins interact in vitro with mature blood cells and malignant hematopoietic cells. Most studies have been performed with laminin-1 (alpha1beta1gamma1), and its expression in bone marrow is unclear. Employing an antiserum reacting with most laminin isoforms, we found laminins widely expressed in mouse bone marrow. However, no laminin alpha1 chain but rather laminin alpha2, alpha4, and alpha5 polypeptides were found in bone marrow. Our data suggest presence of laminin-2 (alpha2beta1gamma1), laminin-8 (alpha4beta1gamma1), and laminin-10 (alpha5beta1gamma1) in bone marrow. Northern blot analysis showed expression of laminin alpha1, alpha2, alpha4, and alpha5 chains in long-term bone marrow cultures, indicating upregulation of laminin alpha1 chain expression in vitro. Laminins containing alpha5 chain, in contrast to laminin-1, were strongly adhesive for multipotent hematopoietic FDCP-mix cells. Integrin alpha6 and beta1 chains mediated this adhesion, as shown by antibody perturbation experiments. Our findings indicate that laminins other than laminin-1 are functional in adhesive interactions in bone marrow.

Animals↗

PubMed1999

A post-transcriptional compensatory pathway in heterozygous ventricular myosin light chain 2-deficient mice results in lack of gene dosage effect during normal cardiac growth or hypertrophy.

Our previous study of homozygous mutants of the ventricular specific isoform of myosin light chain 2 (mlc-2v) demonstrated that mlc-2v plays an essential role in murine heart development (Chen, J., Kubalak, S. W., Minamisawa, S., Price, R. L., Becker, K. D., Hickey, R., Ross, J., Jr., and Chien, K. R. (1998) J. Biol. Chem. 273, 1252-1256). As gene dosage of some myofibrillar proteins can affect muscle function, we have analyzed heterozygous mutants in depth. Ventricles of heterozygous mutants displayed a 50% reduction in mlc-2v mRNA, yet expressed normal levels of protein both under basal conditions and following induction of cardiac hypertrophy by aortic constriction. Heterozygous mutants exhibited cardiac function comparable to that of wild-type littermate controls both prior to and following aortic constriction. There were no significant differences in contractility and responses to calcium between wild-type and heterozygous unloaded cardiomyocytes. We conclude that heterozygous mutants show neither a molecular nor a physiological cardiac phenotype either at base line or following hypertrophic stimuli. These results suggest that post-transcriptional compensatory mechanisms play a major role in maintaining the level of MLC-2v protein in murine hearts. In addition, as our mlc-2v knockout mutants were created by a knock-in of Cre recombinase into the endogenous mlc-2v locus, this study demonstrates that heterozygous mlc-2v cre knock-in mice are appropriate for ventricular specific gene targeting.

Animals↗

PubMed1999

Management of pseudo Class III malocclusion in southern Chinese children.

AIM: To illustrate a simple effective method for early treatment of pseudo Class III in the mixed dentition and to highlight the advantages of early treatment by showing a 4-year follow-up of the treatment effects. SUBJECTS: Twenty-one consecutive southern Chinese patients with a mean age of 9.6 years were included in the early treated group with pseudo Class III malocclusion. METHODS: Lateral cephalometric films taken at the beginning and at the end of treatment were analysed. The arithmetic mean and standard deviation (SD) were calculated for each cephalometric variable and paired t-tests were performed to assess the statistical significance of the treatment effects. RESULTS: Anterior crossbites and mandibular displacements were eliminated after the treatment. The angulation of the upper incisors to the maxillary plane showed an increase by a mean of 9.5 degrees (P < 0.001), while the angulation of the lower incisors to the mandibular plane showed a decrease by a mean of 4.9 degrees (P < 0.001). CONCLUSION: In pseudo Class III malocclusion, proclination of upper incisors and/or retroclination of lower incisors with simple fixed appliances contribute to the correction of anterior crossbite and the elimination of mandibular displacement. Proclination of upper incisors, use of Leeway space and arch width increase provide space required for the eruption of the premolars and canines.

Bicuspid↗

PubMed1999

Osteoblasts derived from load-bearing bones of the rat express both L- and T-like voltage-operated calcium channels and mRNA for alpha 1C, alpha 1D and alpha 1G subunits.

Voltage operated calcium channels (VOCCs) are implicated in osteoblastic mechano- and hormonal transduction. Very little, however, is known about the expression of VOCCs in osteoblasts of load-bearing bones. Here we describe two types of whole-cell calcium current in rat femoral explant-derived osteoblasts. The first is high-voltage activated and sensitive to nifedipine, Bay K8644 and FPL 64176. The second is low-voltage activated and is sensitive to micromolar concentrations of Ni2+. The properties of these two currents are consistent with those of L-type and T-type calcium currents respectively. T-type currents were detected in most cells on the day of passage, the level of expression being significantly lower on subsequent days. L-type currents were also most common on the day of passage but were detected consistently throughout the 4-day period of study. The reverse transcription polymerase chain reaction with non-specific primers directed against all L-type VOCC alpha 1 subunits and then with specific primers directed against sequences from rat brain alpha 1C (L-type), alpha 1D (L-type) and alpha 1G (T-type) VOCC subunits detected transcripts of appropriate size in all four cases. Products from the three sets of specific primer pairs (alpha 1C, alpha 1D, alpha 1G) were sequenced and were identical to their respective rat brain templates.

Animals↗

PubMed1999

The quantitative study of the lateral region to the lumbar pedicle.

BACKGROUND: An anatomic study of the lumbar nerve lateral to the pedicle was performed on 12 cadavers. Three courses of the lumbar nerve were noted around the pedicle. The direct measurements, including the angle of the lumbar rami with the spinal cord, the axis of the pedicle with the cord in the coronal plane, and the distance between the lateral border of the pedicle to the rami, were made bilaterally. RESULTS: The results showed that both angles increased as the lumbar spine descended. The spaces between the lumbar rami and the pedicle were found to be less than 5 mm. CONCLUSION: The region latero-superior to the pedicle had a similar relationship with the region medial inferior to the pedicle. Nerve entrapment was observed around the lumbar pedicle.

Aged↗

PubMed1999

Development of a decision support system for trypanocidal drug control of bovine trypanosomosis in Africa.

During this century livestock production has increased massively through the improved ability to diagnose, treat, control and prevent certain diseases. Despite these advances, disease remains a major constraint to livestock production and welfare throughout the world. In many instances, this is a result of failure to properly apply methods that are already available. TrypsChemo is an expert system that attempts to aid the application of veterinary knowledge to disease management. It has been designed to maximise the effectiveness and cost efficiency of the different trypanocidal drug regimens currently available for prophylaxis and treatment of tsetse-transmitted bovine trypanosomosis in Africa. This paper describes the design of TrypsChemo, the properties of the system, and illustrates how it can be used to support decision making for trypanocidal drug control. The system is currently undergoing a structured evaluation by potential users in Africa.

Africa↗

PubMed1999

Rat-tail replantation model.

The authors evaluated the reliability of a rat-tail replantation model Eleven male adult Sprague-Dawley rats were involved. The tails were completely amputated 3 to 6 cm distal to the base. They were then replanted in the following order: fixation of the coccygeal vertebrae; suturing of tendons; anastomosis of the artery; anastomosis of the two dominant veins (or one of them); and skin closure. Tails were inspected daily for 14 postoperative days for color, capillary refill, skin consistency and wound condition. Subsequently, ultrasound Doppler inspection and angiography were carried out to observe the patency of the vessels. All replanted tails were pink, viable, and had normal capillary refill and appearance. Complete survival was achieved. Doppler flow imaging and angiography demonstrated patency of the vessels. This rat-tail replantation is a reliable and reproducible experimental model of microvascular anastomosis. Crucial steps in the procedure are presented.

Animals↗

PubMed1999

Antisense therapeutics in oncology: points to consider in their clinical evaluation.

Novel therapeutics in oncology stem from a rational design of drugs targeting selective pathways that stimulate and maintain tumor cell growth. Many of these agents are cytostatic in action and also have a limited toxicity profile. However, some can be cytotoxic if they successfully modulate molecular pathways of apoptosis, such as bcl-2. This article discusses points to consider in the design of one class of cytostatic agents, antisense therapy. Our purpose is to stimulate designs that answer the question specifically with regard to proof-of-concept, and the concepts proposed should be viewed as ideas in development rather than firm recommendations.

Apoptosis↗

PubMed1999

Tissue-specific expression of messenger ribonucleic acids for insulin-like growth factors and insulin-like growth factor-binding proteins during perinatal development of the rat uterus.

Insulin-like growth factor (IGF)-I and IGF-II play a number of important roles in growth and differentiation, and IGF-binding proteins (IGFBPs) modulate IGF biological activity. IGF-I has been shown previously to be essential for normal uterine development. Therefore, we used in situ hybridization assays to characterize the unique tissue- and developmental stage-specific pattern of expression for each IGF and IGFBP gene in the rat uterus during perinatal development (gestational day [GD]-20 to postnatal day [PND]-24). IGF-I and IGFBP-1 mRNAs were expressed in all uterine tissues throughout this period. IGFBP-3 mRNA was not detectable at GD-20 but became detectable beginning at PND-5, and the signal intensity appeared to increase during stromal and muscle development. IGFBP-4 mRNA was abundant throughout perinatal development in the myometrium and in the stroma, particularly near the luminal epithelium. IGFBP-5 mRNA was abundantly expressed in myometrium throughout perinatal development. IGFBP-6 mRNA was detected throughout perinatal development in both the stroma and myometrium in a diffuse expression pattern. IGF-II and IGFBP-2 mRNAs were not detected in perinatal uteri. Our results suggest that coordinated temporal and spatial expression of IGF-I and its binding proteins (IGFBP-1,-3,-4,-5, and -6) could play important roles in perinatal rodent uterine development.

Animals↗

PubMed1999

Can an enlarged acetabulum cover the femoral head well in Legg-Calvé-Perthes disease?

Changes in the acetabulum play an important role in the final results of Legg-Calvé-Perthes disease (LCPD). To determine the relationship between the acetabulum and the final results, the acetabulum was measured in 108 children with unilateral LCPD. The acetabular radius, depth, width; iliac width and height; and medial joint distance were measured on the radiographs initially and on follow-up. The parameters between the affected and the unaffected sides were compared by using t test. Herring's classification was employed to evaluate the extent of involved femoral head. The results showed that the radius of the acetabulum was the most sensitive measurement representing the pathologic changes in the acetabulum. The acetabular hypertrophy occurred very early in the avascular necrosis stage. It resulted in the lateral subluxation of the femoral head and in loss of containment. During the later stage of the disease, the femoral head overgrew and broke the growth limit of the acetabulum. Coxa magna made it difficult for a hypertrophic acetabulum to contain it.

Acetabulum↗