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Biomedical subjects

J Yu

Publications and source records attributed to J Yu.

At least 559 records · Page 31Linked to original sources
PubMed1997

Pulmonary drug delivery: physiologic and mechanistic aspects.

Peptide and protein drugs are being used increasingly in major research and development programs in the pharmaceutical industry and are also an important class of therapeutic agents due to advances in genetic engineering and biotechnology. Systemic delivery of these macromolecular drugs, however, has been limited to the parenteral route largely because of their extensive presystemic elimination when taken orally. Faced with this dilemma concerning the systemic delivery of these macromolecules with their unique conformational complexity for therapeutic activity, pharmaceutical scientists have evaluated the potential of various non-oral routes of administration as alternatives. Despite the tremendous efforts that have been devoted to this problem, only limited success has been achieved--mostly with small peptides. Growing attention has been given to the potential of a pulmonary route as an alternative non-invasive means for systemic delivery of peptide/protein-based therapeutic agents due to the fact that the lung provides a huge but extremely thin absorptive mucosal membrane. Although current studies show great promise, pulmonary delivery of therapeutic peptides and proteins is complicated by the complexity of the anatomic structure of the human respiratory system and the influence on drug deposition exerted by respiration. This review discusses the fundamental structure and physiology of the human respiratory system, current methodology used to study pulmonary drug absorption, approaches of drug delivery to the distal lung, and recent progress in pulmonary drug delivery by case studies. The mechanisms of pulmonary drug absorption are also discussed.

Absorption↗
PubMed1997

Analysis of clonality of lymphocytic leukemia and lymphoma by T-cell receptor gene rearrangement.

OBJECTIVE: To analyse the relationship between the number of T-cell receptor (TCR) gamma gene rearrangement and clonality of malignant cells in lymphocytic leukemia and lymphoma. METHODS: The TCR gamma gene characteristics of 73 cases of lymphocytic leukemia and lymphoma and other diseases that had presented 1 or 2 prominent bands of amplified TCR gamma VI subgroups-J1/2 gene rearrangement (GR) were detected by polymerase chain reaction-restriction enzymes (PCR-RE), heteroduplex formation (HDF), DNA sequencing and single-strand conformational polymorphism (SSCP). RESULTS: Thirty-four percent patients had 2 of TCR gamma GR (biallelic rearrangement); twenty-six percent had 1 of TCR gamma GR; fifty-four percent of acute lymphocytic leukemia's and nineteen percent of non-Hodgkin's lymphomas (NHL) had 2 of TCR gamma GR. HDF could rapidly confirm more than 1 of alleles while more alleles were difficult to be recognized by restriction analysis. Sense and antisense strands of heteroduplex were composed of 2 of TCR gamma GR respectively. By combining HDF method, oligoclonalities in three patients (2 acute lympholytic leukemia and 1 myelodysplastil syndrome and clone evolution in one NHL were found. CONCLUSIONS: The fact that many patients had 2 of TCR GR means that complications of two neoplastic clones can be affirmed only if more than 2 of TCR GR are found. HDF can be used to detect the clonality, oligoclonality and polyclonality of lymphoid cells in lymphocytic leukemia and lymphoma by analysis of the difference of gene segments. HDF is a reliable method for the clone evolution research of lymphoid malignancies in progression.

Base Sequence↗
PubMed1997

[Changes in densities of hypothalamic mu opioid receptor during cupric acete-induced preovulatory lh surge in rabbit].

Decrease in activity of hypothalamic beta-endorphin (beta-EP) is an important factor for inducing the preovulatory LH surge. To study whether hypothalamic mu opioid receptor is involved in this process, changes in densities of hypothalamic mu opioid receptors were observed in this study by autoradiography and image process during cupric acetate (CuAC)-induced preovulatory LH surge in rabbits. New Zealand female rabbits were injected 1% CuAC 0.9 ml or saline 0.9 ml and sacrificed at different times after the injection. The densities of mu opioid receptor in the medial basal hypothalamus (MBH) and the medial preoptic area (MPO) were measured. A transient increase in densities of MPO mu opioid receptor were observed 1 h after CuAC injection (P < 0.05). The densities of MPO mu opioid receptor decreased significantly before the onset of the LH surge (P < 0.05) and remained at a low level during the surge. The change in densities of mu opioid receptor in the MBH was similar to those in the MPO. No change was observed in the saline control group. There was a negative correlation between the changes in densities of MBH mu opioid receptor and serum LH levels in the process of LH surge. The results suggest that the decrease of hypothalamic mu opioid receptor may be involved in the preovulatory LH surge.

Animals↗
PubMed1997

Presence of methylthioadenosine phosphorylase (MTAP) in hematopoietic stem/progenitor cells: its therapeutic implication for MTAP (-) malignancies.

Methylthioadenosine phosphorylase (MTAP) is important for the salvage of adenine and methionine. Recently, we found frequent deletion of MTAP in T-cell acute lymphoblastic leukemia (T-ALL) patients both at diagnosis and at relapse (A. Batova et al., Blood, 88: 3083-3090, 1996). In addition, MTAP deficiency has been reported in other cancers. Thus, MTAP deficiency in cancer may offer opportunities for developing selective therapy, which would spare normal cells. It is therefore important to document the presence of MTAP activity in hematopoietic stem/progenitor cells. Our approach was to investigate whether hematopoietic stem/progenitor cells can be rescued from the cytotoxicity of an AMP synthesis inhibitor, L-alanosine, by 5'-deoxyadenosine, a process that requires MTAP. Erythroid burst-forming unit, granulocyte/monocyte colony-forming unit, or granulocyte/erythrocyte/macrophage/megakaryocyte colony-forming unit progenitors and the primitive high proliferative potential colony-forming cells in the purified CD34(+) cells were cultured in horse serum-containing medium, and their colony growth was found to be suppressed by incubation with 5 microM or greater concentrations of L-alanosine. However, in the presence of 5-10 microM of 5'-deoxyadenosine, colony formation of hematopoietic stem/primitive progenitors was restored. On the other hand, 5'-deoxy-5'-methylthioadenosine, the endogenous substrate of MTAP, was toxic to hematopoietic stem/progenitors (ID50 < 1 microM), presumably due to inhibition of methylation reactions or polyamine synthesis. We also compared the effects of L-alanosine and 5'-deoxyadenosine on MTAP (+) and MTAP (-) T-ALL cell lines. Treatment of MTAP (+) Molt 4 and MTAP (-) CEM cell lines with L-alanosine in the presence of 5'-deoxyadenosine resulted in killing of MTAP (-), but not MTAP (+) cells. Therefore, our findings demonstrate the presence of MTAP in human hematopoietic stem/progenitor cells and support the possibility of targeting MTAP in the design of an enzyme-selective therapy for T-ALL and other MTAP-deficient malignancies.

Alanine↗
PubMed1997

[Comparison of mechanical properties between human aortic valve and pulmonary arterial valve].

We have investigated the mechanical properties of Chinese aortic and pulmonary valves by means of uniaxial tension. The parameters include the stress-strain curve, the maximum tangent modulus E (the slope of linear segment) in the curve, the tensile strength delta b, and the ultimate strain epsilon b. The results have shown that E, delta b, and epsilon b values between aortic valve and pulmonary valve exist significant differences (significant level = 0.01), but the mechanical property differences between circumferential direction and radial direction in the pulmonary arterial valve are not significant, that means, the valve appears small anisotropic behaviour.

Adult↗
PubMed1997

[Experimental study on the collateral sprouting after end-to-side anastomosis of nerve trunk].

In order to observe the collateral sprouting capacity of the nerve trunk after end-to-side anastomosis, a window was made on the epineurim of the donor nerve through which the result of the end-to-end anastomosis of nerves could be compared. Sixteen SD rats were chosen and divided into 4 groups randomly. Group 1, the peroneal nerve was severed, the epineurium of the tibial nerve was fenestrated and sutured the peroneal stump with the tibial nerve by end-to-side neurorrhaphy. Group 2, operative procedures were almost the same as that of Group 1, but no fenestration on the epineurium was done. Group 3, the distal peroneal nerve stump was sutured in paralell with the tibial nerve without fenestration on the tibial nerve and Group 4, severed the peroneal nerve and sutured the stumps by end-to-end anastomosis immediately. The peroneal function index(PFI) and acetylcholine transferase (ChAT) activity were assessed and the histological examination was performed in all rats. The results showed: between group 1 and 2, there was no difference in PFI and ChAT activity (P > 0.05). The existence of collateral sprouting in all groups was proved by histological examination. Even in Group 3, there were plenty of nerve fibers turned into tiny myelined nerve fibers through collateral sprouting. But the ChAT activity in Group 1 was only two thirds of that in Group 4. It was suggested that the epineurial sheath did not influence the collateral sprouting of the nerve.

Anastomosis, Surgical↗
PubMed1996

Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction.

The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus gene US2 specifies a product capable of dislocating MHC class I molecules from the endoplasmic reticulum to the cytosol and delivering them to the proteasome. This process involves the Sec61 complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.

Adenosine Triphosphate↗
PubMed1996

Cholinergic neurons from different subdivisions of the basal forebrain lack connectional specificity for cerebral cortical target sites in vitro.

Basal forebrain cholinergic neurons send their axons to cerebral cortex in a topographically organized projection. Experiments tested the hypothesis that this topographic organization results from target preferences of the cholinergic neurons. Slices containing either medial septum or substantia innominata were grown in co-culture with slices of lateral neocortex and hippocampus. Cholinergic neurons from septum and from substantia innominata projected axons into neocortex and hippocampus, without obvious differences in pattern or density. These data suggest that basal forebrain cholinergic neurons can innervate any portion of the cerebral mantle.

Acetylcholinesterase↗
PubMed1996

Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy.

Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine and methionine, is deficient in a variety of cancers, including acute lymphoblastic leukemia (ALL). Because the MTAP gene is located adjacent to the tumor-suppressor gene p16 on chromosome 9p21 and more than 60% of T-cell ALL (T-ALL) patients have deletion in the p16 gene, we examined the status of the MTAP gene in T-ALL patients. Quantitative polymerase chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at diagnosis and in 13 of 33 (39.4%) patients at relapse. Southern blot analysis showed that, in addition to deletion of the entire MTAP gene, a common break point was between exons 4 and 5, resulting in deletion of exons 5 through 8. The finding of frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme targeted therapy for T-ALL. MTAP(-) T-ALL-derived cell line, CEM cells were very sensitive to methionine deprivation, with cell viability at 50% of control as early as 48 hours after methionine deprivation. In contrast, methionine deprivation had little effect on the viability of normal lymphocytes or on their proliferative response to phytohemagglutinin. Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines. However, the addition of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity. These findings suggest the possibility of targeting MTAP for selective therapy of T-ALL.

Adenosine Monophosphate↗
PubMed1996

YY1 and c-Myc associate in vivo in a manner that depends on c-Myc levels.

The c-Myc oncoprotein has previously been shown to associate with transcription regulator YY1 and to inhibit its activity. We show herein that endogenous c-Myc and YY1 associate in vivo and that changes in c-Myc levels, which accompany mitogenic stimulation or differentiation of cultured cells, affect the ratio of free to c-Myc-associated YY1. We have also investigated the mechanism by which association with c-Myc inhibits YY1's ability to regulate transcription. c-Myc does not block binding of YY1 to DNA. However, protein association studies suggest that c-Myc interferes with the ability of YY1 to contact basal transcription proteins TATA-binding protein and TFIIB.

3T3 Cells↗
PubMed1996

A knock-out model of paroxysmal nocturnal hemoglobinuria: Pig-a(-) hematopoiesis is reconstituted following intercellular transfer of GPI-anchored proteins.

We created a "knockout" embryonic stem cell via targeted disruption of the phosphatidylinositol glycan class A (Pig-a) gene, resulting in loss of expression of cell surface glycosyl phosphatidylinositol-anchored proteins and reproducing the mutant phenotype of the human disease paroxysmal nocturnal hemoglobinuria. Morphogenesis of Pig-a- embryoid bodies (EB) in vitro was grossly aberrant and, unlike EB derived from normal embryonic stem cells, Pig-A EB produced no secondary hematopoietic colonies. Chimeric EB composed of control plus Pig-A- cells, however, appeared normal, and hematopoiesis from knock-out cells was reconstituted. Transfer in situ of glycosyl phosphatidylinositol-anchored proteins from normal to knock-out cells was demonstrated by two-color fluorescent analysis, suggesting a possible mechanism for these functional effects. Hematopoietic cells with mutated PIG-A genes in humans with paroxysmal nocturnal hemoglobinuria may be subject to comparable pathophysiologic processes and amenable to similar therapeutic protein transfer.

Animals↗
PubMed1996

Effects of intraventricular transplantation of NGF-secreting cells on cholinergic basal forebrain neurons after partial immunolesion.

The aim of the present study was to examine the effects of nerve growth factor on brain cholinergic function after a partial immunolesion to the rat cholinergic basal forebrain neurons (CBFNs) by 192 IgG-saporin. Two weeks after intraventricular injections of 1.3 micrograms of 192 IgG-saporin, about 50% of CBFNs were lost which was associated with 40-60% reductions of choline acetyltransferase (ChAT) and high-affinity choline uptake (HACU) activities throughout the basal forebrain cholinergic system. Two groups of lesioned animals received intraventricular transplantations of mouse 3T3 fibroblasts retrovirally transfected with either the rat NGF gene (3T3NGF+) or the retrovirus alone (3T3NGF-) and were sacrificed eight weeks later. In vivo production of NGF by 3T3NGF+ cells was confirmed by NGF immunohistochemistry on the grafts and NGF immunoassay on cerebrospinal fluid (CSF) samples. Both ChAT and HACU activities returned to normal control levels in the basal forebrain and cortex after 3T3NGF+ transplants, whereas no recovery was observed in 3T3NGF- transplanted animals. There was a 25% increase in the size of remaining CBFNs and an increased staining intensity for NGF immunoreactivity in these cells after NGF treatments. Acetylcholinesterase (AChE) histochemistry revealed that the optical density of AChE-positive fibers in the cerebral cortex and hippocampus were reduced by about 60% in immunolesioned rats which were completely restored by 3T3NGF+ grafts. In addition, decreases in growth-associated protein (GAP)-43 immunoreactivity after immunolesion and increases in synaptophysin immunoreactivity after 3T3NGF+ grafts were observed in the hippocampus. Our results further confirm the notion that transfected NGF-secreting cells are useful in long-term in vivo NGF treatment and NGF can upregulate CBFN function. They also highly suggest that NGF induces terminal sprouting from remaining CBFNs.

3T3 Cells↗
PubMed1996

Sex differences in estrogen receptor and progestin receptor induction in the guinea pig hypothalamus and preoptic area.

Quantitative in vitro autoradiography was used to determine if regional sex differences in estrogen receptor (ER) content and/or estrogen responsiveness, as indicated by an increase in progestin receptor (PR), are present in the adult guinea pig brain. Adult male and female guinea pigs were gonadectomized 1 week before subcutaneous injection of 25 micrograms estradiol benzoate (EB)/kg body wt or the sesame oil vehicle. Animals were killed by decapitation 44 h after injection. Unoccupied PRs, and unoccupied and occupied ERs, were measured in discrete brain regions by quantitative in vitro autoradiography using [3H]R5020 and [3H]estradiol as ligands, respectively. In vehicle-injected controls, a higher level of ER was found in the arcuate nucleus (ARC), dorsal medial nucleus (DMN) and ventrolateral nucleus (VLN) of females as compared to males. At 44 h after EB injection, 32-55% of the ERs were occupied; however, EB treatment caused a marked down-regulation of total receptor (calculated as occupied+ unoccupied receptor) in most of the brain regions examined, including the periventricular preoptic area (PVP), medial preoptic area (MPO), bed nucleus of the stria terminalis, paraventricular nucleus, ARC, ventrolateral hypothalamus (VLH), VLN, and DMN. In EB-treated animals, PR binding was detectable in the PVP, MPO, ARC, VLH, and VLN, with higher levels of binding observed in the PVP, MPO, and VLN of the female as compared to the male. No PR binding was observed in oil-injected control animals. These results demonstrate region-specific sex differences in ER as well as estrogen-induced regulation of progestin and ERs in the guinea pig brain. The discordance between the regional distributions of sex differences in ER and estrogen-induced PR implies that sex differences in ER and estrogen-induced PR implies that sex differences in estrogen response may not be clearly linked to a sex difference in receptor number. Instead, sex differences in response may involve differences in receptor number within specific subpopulations of estrogen target cells or may involve differences in ER dynamics.

Animals↗
PubMed1996

Localization of the homolog of a mouse craniofacial mutant to human chromosome 18q11 and evaluation of linkage to human CLP and CPO.

The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locus ax. To map the human homolog of 9257, a probe from the transgene insertion site was used to screen a human genomic library. Analysis of a cross-hybridizing human clone identified a 3-kb conserved sequence block that does not appear to contain protein coding sequence. Analysis of somatic cell hybrid panels assigned the human locus to 18q11. The polymorphic microsatellite markers D18S1001 and D18S1002 were isolated from the human locus and mapped by linkage analysis using the CEPH pedigrees. The 9257 locus maps close to the centromeres of human chromosome 18q and mouse chromosome 18 at the proximal end of a conserved linkage group. To evaluate the role of this locus in human craniofacial disorders, linkage to D18S1002 was tested in 11 families with autosomal dominant nonsyndromic cleft lip and palate and 3 families with autosomal dominant cleft palate only. Obligatory recombinants were observed in 8 of the families, and negative lod scores from the other families indicated that these disorders are not linked to the chromosome 18 loci.

Alleles↗
PubMed1996

Normal development of mice lacking metablastin (P19), a phosphoprotein implicated in cell cycle regulation.

Metablastin, also called P19, stathmin, prosolin, Lap18, and oncoprotein18, is a highly conserved cytosolic protein that undergoes extracellular factor- and cell cycle-regulated serine phosphorylation and developmentally regulated expression in mammals. It has been implicated in a variety of cellular functions including growth and differentiation, and recent evidence suggests an involvement in cell cycle control. To explore its potential role in mammalian development, we have disrupted the gene encoding metablastin by gene targeting in mice. The metablastin null mutants have no overt phenotype regarding development, growth rate, behavior, T cell maturation, or fertility and do not exhibit an increased predisposition to tumors. SCG10, a protein closely related in structure to metablastin, shows no compensatory up-regulation in metablastin-/- mice. Although the data suggest that metablastin is not essential for mammalian development, the knockout mice should prove valuable in exploring the role of this protein in cell cycle regulation.

Animals↗