Biomedical subjects

J Gao

Publications and source records attributed to J Gao.

At least 91 records · Page 5Linked to original sources

PubMed2001

Human synemin gene generates splice variants encoding two distinct intermediate filament proteins.

Intermediate filament (IF) proteins are constituents of the cytoskeleton, conferring resistance to mechanical stress, and are encoded by a dispersed multigene family. In man we have identified two isoforms (180 and 150 kDa) of the IF protein synemin. Synemin alpha and beta have a very short N-terminal domain of 10 amino acids and a long C-terminal domain consisting of 1243 amino acids for the alpha isoform and 931 amino acids for the beta isoform. An intronic sequence of the synemin beta isoform is used as a coding sequence for synemin alpha. Both mRNA isoforms (6.5 and 7.5 kb) result from alternative splicing of the same gene, which has been assigned to human chromosome 15q26.3. Analyses by Northern and Western blot revealed that isoform beta is the predominant isoform in striated muscles, whereas both isoforms (alpha and beta) are present in almost equal quantities in smooth muscles. Co-transfection and immunolabeling experiments indicate that both synemin isoforms are incorporated with desmin to form heteropolymeric IFs. Furthermore synemin and desmin are found aggregated together in certain pathological situations.

Alternative Splicing↗

PubMed2001

Transport characteristics of peptides and peptidomimetics: I. N-methylated peptides as substrates for the oligopeptide transporter and P-glycoprotein in the intestinal mucosa.

Peptides and peptidomimetics often exhibit poor oral bioavailability due to their metabolic instability and low permeation across the intestinal mucosa. N-Methylation has been used successfully in peptide-based drug design in an attempt to improve the metabolic stability of a peptide-based lead compound. However, the effect of N-methylation on the absorption of peptides through the intestinal mucosa is not well understood, particularly when transporters, i.e. the oligopeptide transporter (OPT) and P-glycoprotein (P-gp), modulate the passive diffusion of these types of molecules. To examine this, terminally free and terminally modified (N-acetylated and C-amidated) analogs of H-Ala-Phe-Ala-OH with N-methyl groups on either the Ala-Phe or Phe-Ala peptide bond were synthesized. Transport studies using Caco-2 cell monolayers, an in vitro model of the intestinal mucosa, showed that N-methylation of the Ala-Phe peptide bond of H-Ala-Phe-Ala-OH stabilized the molecule to protease degradation, and the resulting analog exhibited significant substrate activity for OPT. However, N-methylation of the Phe-Ala peptide bond of H-Ala-Phe-Ala-OH did not stabilize the molecule to protease degradation, and the substrate activity of the resulting molecule for OPT could not be determined. Interestingly, N-methylation of the Phe-Ala peptide bond of the terminally modified tripeptide Ac-Ala-Phe-Ala-NH2 decreased the substrate activity of the molecule for the efflux transporter P-gp. In contrast, N-methylation of the Ala-Phe peptide bond of the terminally modified tripeptide Ac-Ala-Phe-Ala-NH2 increased the substrate activity of the molecule for P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Effect of multiple mutations in the core promoter and pre-core/core region of hepatitis B virus genome on the response to interferon in e antigen-positive chronic hepatitis B.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) genomic mutations may be one of the factors that influence the efficacy of interferon (IFN) therapy. The aim of this study was to investigate the effects of mutations in different parts of the HBV genome on IFN therapy. METHODS: We studied the baseline clinical, biochemical, serologic and virologic parameters in 17 patients with e antigen-positive chronic hepatitis B. The DNA sequence of the X gene and pre-core/core gene in serum samples of these patients was analyzed before the initiation of IFN therapy. RESULTS: All five patients with the T1762-A1764 mutation were IFN responsive, while among the 12 remaining patients, only two responded to therapy. Among five patients with both a pre-core A1896 mutation and a mutation in the epitope aa 107-118 of the core region, four were non-responders whereas the fifth responded to therapy. In three other patients with A1896 mutations, one with simultaneous mutations in five lymphocytic epitopes did not respond to therapy; the two remaining patients with concomitant mutations in one or two epitopes were responsive. Serum HBV-DNA levels were lower and titers of antibody to hepatitis B virus core antigen-immunoglobin M (anti-HBc-IgM) were higher in the responders than in the non-responders. Hepatitis B virus genotypes B and C were found to be in all these Chinese patients. CONCLUSIONS: These results suggest that HBV genomic mutations, serum viral loads and titers of anti-HBc-IgM might be predictive of the efficacy of IFN therapy. These clinical findings should be further investigated by in vivo and in vitro experiments.

Adult↗

PubMed2001

Microencapsulated bovine chromaffin cell xenografts into hemiparkinsonian rats: a drug-induced rotational behavior and histological changes analysis.

Bovine chromaffin cells were microencapsulated within alginate-polylysine-alginate (APA) membranes. Microencapsulated bovine chromaffin cells as well as unencapsulated cells and empty microcapsules were grafted into the brain of hemiparkinsonian rats with 6-hydroxydopamine (6-OHDA) lesions. Apomorphine-induced rotational behavior of the host animals and the survival of the grafted chromaffin cells were examined after transplantation. The animals receiving microencapsulated bovine chromaffin cells showed a significant decrease (17.6--35.6%) in apomorphine-induced rotation 1 week postimplantation that remained stable for the 10 month test period. Fluorescent histochemistry further revealed that microencapsulation increased the chromaffin cell survival with only a minimum host reaction for up to 10 months posttransplantation while the survival of free, unencapsulated chromaffin cells was only modest and was accompanied by a large inflammatory response. The reduction of apomorphine-induced rotations was correlated with the survival of bovine chromaffin cells in the host brain. The data indicate that encapsulation of bovine chromaffin cells in APA membranes reduces the host immune response to the xenograft and prolongs the viability of the grafted cells.

Animals↗

PubMed2001

Morphologic and mechanical characteristics of engineered bovine arteries.

OBJECTIVE: The ideal small-caliber arterial graft remains elusive despite several decades of intense research. A novel approach to the development of small-caliber arterial prostheses with a biomimetic system for in vitro vessel culture has recently been described. In this study we examined the effects of culture time and tissue culture scaffolding on engineered vessel morphology and function and found that these parameters greatly influence the function of engineered vessels. METHODS: This report describes the effects of culture time and scaffold type on vessel morphology, cellular differentiation, and vessel mechanical characteristics. Engineered vessels were cultured from bovine aortic smooth muscle cells (SMCs) and endothelial cells that were seeded onto biodegradable polymer scaffolds and cultured under physiologically pulsatile conditions. Engineered vessels were subjected to histologic, ultrastructural, immunocytochemical, and mechanical analyses. RESULTS: Vessel morphology and mechanical characteristics improved as time in culture increased to 8 weeks. SMCs in the engineered vessel wall were organized into a highly lamellar structure, with cells separated by alternating layers of collagen fibrils. Polymer scaffold remnants were present in vessels cultured for 8 weeks, and SMCs that were in proximity to polymer remnants exhibited a dedifferentiated phenotype. CONCLUSIONS: These findings aid in the systematic understanding of the effects of in vitro parameters on engineered vessels and will be useful for the translation of vessel culture techniques to human cells for the development of autologous human vascular grafts.

Animals↗

PubMed2001

Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway.

Deposition patterns are described of a nasal spray formulation for a novel rhinovirus protease inhibitor. These patterns, which were generated from different nasal spray pumps, were characterized using a multisectional nasal airway model. A human nasal replica was made from an in vivo magnetic resonance imaging (MRI) scan of an adult male human. The nasal replica consisted of 77 acrylic plastic sections, 1.5-mm thick. Our data showed that the aerosols were deposited mainly in the anterior and turbinate regions with little passing beyond the nasopharyngeal region. Detailed deposition information from the turbinate region indicated that deposition was high toward the anterior portion where most deposition was concentrated on the inferior meatus. Spray droplets were also deposited in spots of the middle and posterior portions of the turbinate region, and this nonuniform deposition pattern may be correlated with the flow pattern. The spray angle and droplet size of the nasal spray were found to be important in influencing the deposition pattern in the nasal airway. The droplet size was determined by a laser-diffraction technique and the spray angle by high-speed photography. Larger droplets and a wider spray angle increased deposition in the anterior region of the nasal airway, which prevented more material from depositing in the turbinate region.

Administration, Inhalation↗

PubMed2001

Tissue-engineered fabrication of an osteochondral composite graft using rat bone marrow-derived mesenchymal stem cells.

This study tested the tissue engineering hypothesis that construction of an osteochondral composite graft could be accomplished using multipotent progenitor cells and phenotype-specific biomaterials. Rat bone marrow-derived mesenchymal stem cells (MSCs) were culture-expanded and separately stimulated with transforming growth factor-beta1 (TGF-beta1) for chondrogenic differentiation or with an osteogenic supplement (OS). MSCs exposed to TGF-beta1 were loaded into a sponge composed of a hyaluronan derivative (HYAF-11) for the construction of the cartilage component of the composite graft, and MSCs exposed to OS were loaded into a porous calcium phosphate ceramic component for bone formation. Cell-loaded HYAFF-11 sponge and ceramic were joined together with fibrin sealant, Tisseel, to form a composite osteochondral graft, which was then implanted into a subcutaneous pocket in syngeneic rats. Specimens were harvested at 3 and 6 weeks after implantation, examined with histology for morphologic features, and stained immunohistochemically for type I, II, and X collagen. The two-component composite graft remained as an integrated unit after in vivo implantation and histologic processing. Fibrocartilage was observed in the sponge, and bone was detected in the ceramic component. Observations with polarized light indicated continuity of collagen fibers between the ceramic and HYAFF-11 components in the 6-week specimens. Type I collagen was identified in the neo-tissue in both sponge and ceramic, and type II collagen in the fibrocartilage, especially the pericellular matrix of cells in the sponge. These data suggest that the construction of a tissue-engineered composite osteochondral graft is possible with MSCs and different biomaterials and bioactive factors that support either chondrogenic or osteogenic differentiation.

Animals↗

PubMed2001

Interleukin-6 production by endothelial cells via stimulation of protease-activated receptors is amplified by endotoxin and tumor necrosis factor-alpha.

Human endothelial cells respond to extracellular proteases, endotoxin (lipopolysaccharide, LPS), and inflammatory cytokines. Endothelial cells express several protease-activated receptors (PAR), including the thrombin-activated receptors PAR-1 and PAR-3 and a thrombin-independent, protease-activated receptor, PAR-2. To examine the potential cooperation between PAR and inflammatory stimuli, we investigated the effects of the PAR-1 agonist peptide Ser-Phe-Leu-Leu-Arg-Asn (SFLLRN) and PAR-2 agonist peptide Ser-Leu-Ile-Gly-Lys-Val (SLIGKV) on endothelial cells. Human umbilical vein endothelial cells (HUVEC) were cultured in vitro with SFLLRN or SLIGKV in the presence and absence of LPS or tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels in the culture supernatants were assayed. Both SFLLRN and SLIGKV induced detectable levels of IL-6 production in a dose-dependent fashion, with the PAR-1 receptor agonist being more potent. In the presence of all stimulatory concentrations of LPS or TNF-alpha tested, both peptides were found to further enhance IL-6 production. The effects of SFLLRN and SLIGKV were specific, as related peptides with identical amino acid compositions, but lacking in consensus sequences, were biologically inactive either alone or in the presence of LPS. Both the direct and the amplifying effects of PAR agonist peptides on IL-6 production were pertussis toxin sensitive and caused an increase in the intracellular levels of calcium, implicating G-proteins and calcium mobilization in these pathways. Furthermore, the amplifying effect of LPS or TNF-alpha on PAR-mediated cytokine production was associated with corresponding increases in nuclear NF-kappaB proteins. The results demonstrate significant potentiation of PAR-induced signaling by LPS and TNF-alpha and indicate the potential cooperation of proteases and inflammatory stimuli in amplifying vascular inflammation.

Calcium↗

PubMed2001

Changing access to health services in urban China: implications for equity.

The ongoing reform of public institutions and state-owned enterprises in urban China has had a profound impact on the financing, organization and provision of health services. Access to health care by the urban population has become more inequitable. One of the most pressing concerns is that those who have lost jobs have increasing difficulties accessing health care. Using the data from the national household health surveys conducted in 1993 and 1998, this paper presents empirical results of changing utilization of health care among different income groups. Over 16 000 households and 54 000 individuals in the urban areas were randomly selected to collect information on perceived need of and demand for health care and expenditures on the services. The findings show that the income gap between the highest and lowest income groups increased in real terms from 1993 to 1998. There was a significant decline in the population covered by the government insurance scheme (GIS) and the labour insurance scheme (LIS), while the proportion of the population who had to pay for services out-of-pocket increased from 28% in 1993 to 44% in 1998. There was no statistically significant change in self-reported illness in the 2 weeks prior to survey among the study population over the period. While it was found that more people who reported illness from each income group received medical treatment of some kind, there was a decline in seeking care from a health provider. Among those in the lowest income group who reported illness but did not obtain treatment of any kind, nearly 70% (as compared with 38% in 1993) claimed financial difficulty as the major reason in 1998. The use of in-patient services dropped significantly from 4.5% in 1993 to 3.0% in 1998. The decreased use of in-patient services was more serious in the lowest and lower income groups than in higher and highest income groups. The percentage of patients referred for hospital admission but not being hospitalized had a negative relationship with income level. We can conclude from the data analysis that access of the urban population, particularly the poor, to formal health services has worsened and become more inequitable since the early 1990s. Among possible reasons for this trend are the rapid rise of per capita expenditure on health services and the decline in insurance coverage.

China↗

PubMed2001

DIAN: a novel algorithm for genome ontological classification.

Faced with the determination of many completely sequenced genomes, computational biology is now faced with the challenge of interpreting the significance of these data sets. A multiplicity of data-related problems impedes this goal: Biological annotations associated with raw data are often not normalized, and the data themselves are often poorly interrelated and their interpretation unclear. All of these problems make interpretation of genomic databases increasingly difficult. With the current explosion of sequences now available from the human genome as well as from model organisms, the importance of sorting this vast amount of conceptually unstructured source data into a limited universe of genes, proteins, functions, structures, and pathways has become a bottleneck for the field. To address this problem, we have developed a method of interrelating data sources by applying a novel method of associating biological objects to ontologies. We have developed an intelligent knowledge-based algorithm, to support biological knowledge mapping, and, in particular, to facilitate the interpretation of genomic data. In this respect, the method makes it possible to inventory genomes by collapsing multiple types of annotations and normalizing them to various ontologies. By relying on a conceptual view of the genome, researchers can now easily navigate the human genome in a biologically intuitive, scientifically accurate manner.

Algorithms↗

PubMed2001

Hydrogen peroxide is involved in abscisic acid-induced stomatal closure in Vicia faba.

One of the most important functions of the plant hormone abscisic acid (ABA) is to induce stomatal closure by reducing the turgor of guard cells under water deficit. Under environmental stresses, hydrogen peroxide (H(2)O(2)), an active oxygen species, is widely generated in many biological systems. Here, using an epidermal strip bioassay and laser-scanning confocal microscopy, we provide evidence that H(2)O(2) may function as an intermediate in ABA signaling in Vicia faba guard cells. H(2)O(2) inhibited induced closure of stomata, and this effect was reversed by ascorbic acid at concentrations lower than 10(-5) M. Further, ABA-induced stomatal closure also was abolished partly by addition of exogenous catalase (CAT) and diphenylene iodonium (DPI), which are an H(2)O(2) scavenger and an NADPH oxidase inhibitor, respectively. Time course experiments of single-cell assays based on the fluorescent probe dichlorofluorescein showed that the generation of H(2)O(2) was dependent on ABA concentration and an increase in the fluorescence intensity of the chloroplast occurred significantly earlier than within the other regions of guard cells. The ABA-induced change in fluorescence intensity in guard cells was abolished by the application of CAT and DPI. In addition, ABA microinjected into guard cells markedly induced H(2)O(2) production, which preceded stomatal closure. These effects were abolished by CAT or DPI micro-injection. Our results suggest that guard cells treated with ABA may close the stomata via a pathway with H(2)O(2) production involved, and H(2)O(2) may be an intermediate in ABA signaling.

Abscisic Acid↗

PubMed2001

Preventive effects of isoflavones, genistein and daidzein, on estradiol-17beta-related endometrial carcinogenesis in mice.

The effects of isoflavones (genistein and daidzein) on endometrial carcinogenesis in mice were investigated in two experiments. In the short-term experiment (2 weeks), single subcutaneous (s.c.) administration of genistein [1 mg / 30 g body weight (b.w.)] significantly decreased the levels of estradiol-17beta (E(2)) (5 ppm in diet)-induced expression of c-jun, interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) mRNAs in the uteri of ovariectomized mice (P < 0.005, P < 0.05 and P < 0.01, respectively). Daidzein significantly inhibited E(2)-induced expression of c-fos and IL-1alpha (P < 0.01, P < 0.01 respectively). In the long-term experiment (30 weeks), 140 female ICR mice were given N-methyl-N-nitrosourea-containing solution (1 mg / 100 g b.w.) and normal saline (as controls) into their left and right uterine corpora, respectively. They were divided into six groups; group 1 was given E(2) (in diet) alone. Group 2 was given E(2) and genistein (1 mg / 30 g b.w., s.c., every four weeks). Group 3 was exposed to E(2) and daidzein (1 mg / 30 g b.w., s.c., every four weeks). Groups 4 and 5 respectively received genistein and daidzein, and were kept on the basal diet. Group 6 was kept on the basal diet and served as a control. At the termination of the experiment, incidences of endometrial adenocarcinoma and atypical endometrial hyperplasia of the group given E(2) and genistein or daidzein were significantly lower than of the group with E(2) alone (P < 0.01 and P < 0.05, respectively). It is suggested that both genistein and daidzein have an inhibitory effect on estrogen-related endometrial carcinogenesis in mice, possibly by suppressing expression of estrogen-induced estrogen-related genes c-fos and c-jun, and internal cytokines IL-1alpha and TNF-alpha through a cytokine and estrogen receptor-mediated pathway.

Adenocarcinoma↗

PubMed2001

Interferon action against human parainfluenza virus type 3: involvement of a novel antiviral pathway in the inhibition of transcription.

Interferon (IFN)-induced 2'-5' oligoadenylate synthetase (2-5A synthetase)/RNase L, PKR, and Mx proteins are considered to be the principal antiviral protein pathways through which IFN induces an antiviral state. It was previously reported that human parainfluenza virus type 3 (HPIV3) multiplication was inhibited by IFN-alpha in human lung epithelial cells A549 and that MxA was found to contribute to the inhibition process (Zhao et al., Virology 220:330-338, 1996). Viral primary transcription was dramatically inhibited in A549 cells after IFN-alpha treatment, but a step following primary transcription was inhibited in U87-MxA cells constitutively expressing MxA. Here we have investigated the role of MxA, believed to be cell type specific, and other antiviral pathways in the inhibition of viral primary transcription. Our data indicate that a novel IFN-induced pathway(s) is involved in the inhibition of primary transcription. This is based on the following findings: (i) IFN-alpha inhibited viral primary transcription in U87-MxA and other cell types including cells lacking MxA; (ii) cells constitutively expressing 2-5A synthetase had no antiviral effect against HPIV3; and (iii) primary transcription occurred in the absence of protein synthesis, a step of PKR target. The novel antiviral pathway(s) was induced by both IFN-alpha and IFN-gamma to establish an effective antiviral state against HPIV3. By using IFN-alpha-signaling mutant cells, we found that IFN-gamma could elicit antiviral effect against HPIV3 without cross talk with the IFN-alpha-signaling pathway. These data provide the first evidence that a novel antiviral pathway(s) contributes to the antiviral action of IFN against a nonsegmented negative-strand RNA virus by targeting the primary transcription.

Animals↗

PubMed2001

Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon.

Human parainfluenza virus type 3 (HPIV3) is one of the major causes of bronchiolitis, pneumonia, and croup in newborns and infants. Cellular immunity involving major histocompatibility complex (MHC) class I and class II molecules plays an important role in controlling virus infection. Several viruses have been shown to down-regulate gamma interferon (IFN-gamma)-mediated MHC class II expression. In this communication, we show that HPIV3 strongly inhibits the IFN-gamma-induced MHC class II expression in HT1080 human fibrosarcoma cells. The culture supernatant of HPIV3-infected cells also inhibited IFN-gamma-induced MHC class II expression, a phenomenon that was found to be due, in large part, to alpha/beta interferon (IFN-alpha/beta). Expression of MHC class I and intercellular adhesion molecule 1 occurred efficiently in cells simultaneously infected with HPIV3 and treated with IFN-gamma, indicating that the inhibitory effect of HPIV3 was specific to MHC class II. STAT1 activation was not affected by HPIV3 at early postinfection times but was partially inhibited at later times. These data suggested that the potent inhibition of MHC class II expression was, in major part, due to a defect downstream of STAT1 activation in the IFN-gamma-induced MHC class II expression pathway. Class II transactivator (CIITA) is the unique mediator of IFN-gamma-induced transcription from the MHC class II promoter. By RNase protection analysis, CIITA expression was found to be strongly inhibited in HPIV3-infected cells. The culture supernatant containing IFN-alpha/beta, on the other hand, inhibited MHC class II expression without affecting STAT1 and CIITA expression. These data indicate that HPIV3 inhibits IFN-gamma-induced MHC class II expression primarily by the viral gene products targeting CIITA and additionally by inducing IFN-alpha/beta to target one or more steps further downstream.

Animals↗

PubMed2001

Enhanced PKC beta II translocation and PKC beta II-RACK1 interactions in PKC epsilon-induced heart failure: a role for RACK1.

Recent investigations have established a role for the beta II-isoform of protein kinase C (PKC beta II) in the induction of cardiac hypertrophy and failure. Although receptors for activated C kinase (RACKs) have been shown to direct PKC signal transduction, the mechanism through which RACK1, a selective PKC beta II RACK, participates in PKC beta II-mediated cardiac hypertrophy and failure remains undefined. We have previously reported that PKC epsilon activation modulates the expression of RACKs, and that altered epsilon-isoform of PKC (PKC epsilon)-RACK interactions may facilitate the genesis of cardiac phenotypes in mice. Here, we present evidence that high levels of PKC epsilon activity are commensurate with impaired left ventricular function (dP/dt = 6,074 +/- 248 mmHg/s in control vs. 3,784 +/- 269 mmHg/s in transgenic) and significant myocardial hypertrophy. More importantly, we demonstrate that high levels of PKC epsilon activation induce a significant colocalization of PKC beta II with RACK1 (154 +/- 7% of control) and a marked redistribution of PKC beta II to the particulate fraction (17 +/- 2% of total PKC beta II in control mice vs. 49 +/- 5% of total PKC beta II in hypertrophied mice), without compensatory changes of the other eight PKC isoforms present in the mouse heart. This enhanced PKC beta II activation is coupled with increased RACK1 expression and PKC beta II-RACK1 interactions, demonstrating PKC epsilon-induced PKC beta II signaling via a RACK1-dependent mechanism. Taken together with our previous findings regarding enhanced RACK1 expression and PKC epsilon-RACK1 interactions in the setting of cardiac hypertrophy and failure, these results suggest that RACK1 serves as a nexus for at least two isoforms of PKC, the epsilon-isoform and the beta II-isoform, thus coordinating PKC-mediated hypertrophic signaling.

Actins↗

PubMed2001

Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats.

Melanocortins play a critical role in appetite and body weight regulation, because manipulations of this pathway can lead to the development of obesity in several animal models. The purpose of this study was to use a melanocortin receptor agonist and antagonist to evaluate the involvement of melanocortins in feeding, energy metabolism, and body weight regulation in lean and obese Zucker rats. Central administration of a melanocortin receptor antagonist (SHU9119) elevated food intake and body weight of lean Zucker rats but had little effect in obese Zucker rats. In contrast, the melanocortin receptor agonist MTII reduced food intake in both lean and obese rats but was more potent in the obese Zucker rats. These data indicate the existence of functional melanocortin receptors in both lean and obese Zucker rats but suggest that obese Zucker rats have reduced endogenous melanocortin tone. In addition to its effects on food intake, MTII infusion elevated oxygen consumption and decreased respiratory quotient dose dependently during the light cycle. Our data suggest that a melanocortin receptor agonist can induce weight loss by increasing energy expenditure and promoting body fat utilization in addition to its inhibitory effects on food intake in both obese and lean Zucker rats.

Animals↗

PubMed2001

The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion.

Bone marrow-derived mesenchymal stem cells (MSCs) have the potential to differentiate along different mesenchymal lineages including those forming bone, cartilage, tendon, fat, muscle and marrow stroma that supports hematopoiesis. This differentiation potential makes MSCs candidates for cell-based therapeutic strategies for mesenchymal tissue injuries and for hematopoietic disorders by both local and systemic application. In the present study, rat marrow-derived MSCs were ex vivo culture-expanded, labeled with (111)In-oxine, and infused into syngeneic rats via intra-artery (i.a.), intravenous (i.v.) and intraperitoneal cavity (i.p.) infusions. In addition, for i.a. and i.v. infusions, a vasodilator, sodium nitroprusside, was administered prior to the cell infusion and examined for its effect on MSC circulation. The dynamic distribution of infused MSCs was monitored by real-time imaging using a gamma camera immediately after infusion and at 48 h postinfusion. After 48 h, radioactivity in excised organs, including liver, lungs, kidneys, spleen and long bones, was measured in a gamma well counter and expressed as a percentage of injected doses. After both i.a. and i.v. infusion, radioactivity associated with MSCs was detected primarily in the lungs and then secondarily in the liver and other organs. When sodium nitroprusside was used, more labeled MSCs cleared the lungs resulting in a larger proportion detected in the liver. Most importantly, the homing of labeled MSCs to the marrow of long bones was significantly increased by the pretreatment with vasodilator. These results indicate multiple homing sites for injected MSCs and that the distribution of MSCs can be influenced by administration of vasodilator.

Animals↗

PubMed2001

Formulation and delivery mode affect disposition and activity of tyrphostin-loaded nanoparticles in the rat carotid model.

Poor drug residence in the arterial wall hinders clinical implementation of local drug delivery strategies for the treatment of restenosis. A rat carotid model of vascular injury and intraluminal delivery of tyrphostin-containing polylactic acid (PLA) nanoparticles (NPs) were used to determine the relationship between residence properties and biological activity of different formulations and administration modes. The effects of delivery modes (denudation and delivery time) and formulation variables (adsorbed vs encapsulated drug, and NP size) on arterial drug/NP retention were examined. Antirestenotic effects of large (160 nm) and small (90 nm) tyrphostin-containing NPs, surface-absorbed tyrphostin, and systemic treatment were compared. Fluorescent NPs were used to study the spatial distribution of the carrier in the arterial wall. The decrease in arterial tyrphostin level over time fitted a biexponential model. Delivery time and pressure, endothelium integrity, particle size, and drug-polymer association affected local pharmacokinetics and the antirestenotic results after 14 days. The PLA-based tyrphostin NP formulation ensured a prolonged drug residence at the angioplasty site after single intraluminal application. Several readily adjustable formulation and procedural factors considerably modified arterial ingress of the drug-loaded NPs and governed their subsequent redistribution, tissue binding, elimination, and ensuing antirestenotic effect.

Animals↗