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Biomedical subjects

G Nguyen

Publications and source records attributed to G Nguyen.

At least 19 recordsLinked to original sources
PubMed2006

Renin/prorenin receptors.

The existence of a tissue renin-angiotensin (RAS) system independent of the circulating RAS has prompted the search for cellular binding sites for angiotensinogen and for renin in order to explain their tissue uptake. Two receptors that bind with similar affinity mature renin and prorenin were identified, the mannose-6-phosphate receptor (M6P-R) and a specific receptor. The M6P-R is a clearance receptor that binds exclusively the glycosylated forms of renin and prorenin. Binding of renin and prorenin to the M6P-R is followed by internalization and degradation, and the intracellular proteolysis of prorenin in mature renin did not provoke any generation of intracellular angiotensins. In contrast to the M6P-R, (pro)renin bound to the specific receptor was not degraded. Instead, receptor-bound renin showed increased catalytic activity, and receptor-bound prorenin exhibited full catalytic activity. This 'gain of activity' was explained by a conformational change of the (pro)renin molecule upon binding. Furthermore, (pro)renin binding provoked a rapid activation of the mitogen-activated protein kinases p44/p42, indicating that the receptor has mediated specific, angiotensin II-independent effects of (pro)renin. This receptor represents an elegant concept to explain the existence of active prorenin in vivo, and it provides a pathological role for prorenin in situations with paradoxical low renin and high prorenin concentrations such as in diabetes. Experimental models of rats overexpressing the receptor either in vascular smooth muscle cells and developing high blood pressure or with ubiquitous expression associated with glomerulosclerosis and proteinuria confirm a role for the receptor in cardiovascular and renal diseases.

Animals↗
PubMed2006

Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor?

Interaction between the renin-angiotensin system and cyclooxygenases in the kidney regulates renal microcirculation. Activation of the (pro)renin receptor has profibrotic effects, and now Kaneshiroet al. show that it also increases COX-2 synthesis. These results may have therapeutic implications, as blocking (pro)renin-receptor interaction would prevent the increase of angiotensin generation and prostaglandin synthesis, two phenomena underlying the pathogenesis of diabetic nephropathy.

Animals↗
PubMed2005

[Biochemical evaluation of the results of lipid regulating treatment in France].

The objective of the SPOT study (Study of Practice versus Objectives of Treatment) was the biochemical evaluation of the results of long term lipid regulating treatment in France, compared to the objectives defined by AFSSAPS (French regulatory agency for the safety of medical products) in 2000. A random sample of doctors was recruited in 21 French regions by the Regional Health Observation service. To be included in the SPOT study, the patients had to be on lipid regulating medication for at least six months and consent to biochemical evaluation following a consultation. A sample of 641 doctors examined 2,479 patients treated for 7 years on average. These middle aged patients (aged 63 +/- 11 years) were mostly taking statins (72%). They had an average total cholesterol level of 5.41 +/- 1.01 mmol/L (2.10 +/- 0.39 g/L). and LDL of 3.25 +/- 0.93 mmol/L (1.26 +/- 0.36 g/L), reflecting previous results and confirming the stability of their treatment. In primary prevention and in low risk subjects (with less than 2 associated risk factors), the AFSSAPS objectives were achieved in 95% of cases. In secondary prevention or in very high risk subjects (at least 3 associated risk factors 0), 35% of patients had LDL cholesterol greater than 3.4 mmol/L (1.30 g/L). The SPOT study, performed on subjects who had in theory been stabilised with lipid regulating medication, gave two conclusions: cardiovascular prevention with lipid regulating medication is improving in France, and the subjects at greatest risk attain the recommended objectives less often despite the expected benefit of treatment being higher.

Aged↗
PubMed2004

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma.

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Development of a laser safety hazard evaluation procedure for the research university setting.

Laser safety often receives less attention and fewer resources than other institutional safety and health program elements. This diminished support occurs despite the fact that the potential for laser-related occupational injuries is much greater than the potential for injury from radioactive materials used in biomedical research. Therefore, a small emphasis on laser safety can potentially produce a much greater return on investment than more conventional health physics programs. Developing and implementing a formal laser hazard evaluation procedure provides all efficient mechanism for identifying potential laser safety hazards and offers a great professional development opportunity in this important area of health physics expertise. This paper outlines a process for developing such a university laser hazard evaluation program.

Forms and Records Control↗
PubMed2002

[American pulmonary histoplasmosis. Prospective study with 232 soldiers after a 2-year assignment in Guiana].

The purpose of this report is to describe the results of a prospective study on pulmonary histoplasmosis in French Guiana. Chest radiographs were performed in 232 French legionnaires returning from a two-year assignment in French Guiana. Further examinations were performed in a total of 8 subjects in whom chest radiographs demonstrated the presence of nodules in the lungs. No evidence of cancer or tuberculosis was found. Findings confirmed histoplasmomas in two cases and demonstrated probable histoplasmosis nodules in 6 cases including three involving calcified lesions. Five of these eight patients had been in high-risk rain forest environments. Pulmonary histoplasmosis should be considered as a possible diagnosis in subjects returning from endemic zones. Confirmation depends on a spectrum of findings. Calcified nodules require only radiographic surveillance with follow-up at six months. Non-calcified nodules require further investigation including CT-scan, bronchoscopy, and serological tests. Surgical biopsy may be necessary to achieve exact histological and mycological identification of the lesion and is recommended in smokers.

Adult↗
PubMed2001

Accuracy of glucose meter use in gestational diabetes.

Glucose monitoring is essential for the successful management of gestational diabetes. The accuracy of glucose meters is typically determined over a much wider range of glucose values than that commonly encountered in gestational diabetes. The objective of our study was to look at the accuracy of self-monitoring glucose meters in a clinic setting over a range of glucose values seen in gestational diabetes. We retrospectively analyzed 107 case records of subjects with gestational diabetes, each of whom had three simultaneous laboratory and glucose meter glucose tests. The results were compared using the performance goals that (1) all of glucose meters should have readings within 10% of the reference value and (2) the error grid analysis in the standard format and a modified version suitable for gestational diabetes. We also examined the range of the differences from the reference value. Nearly half of the values (47%) were in excess of 10% of the reference range (either above or below). Close to 15% were in excess of 20% difference from the reference range. Standard error grid analysis showed that 96% of the values fell within sections A of the error grid which are considered acceptable, and 100% fell within sections A and B, differences which are generally considered to have no major impact on care. The modified version of the error grid analysis demonstrated that 39% of the values were outside the acceptable range. Within subjects, a substantial number (26%) had a range of differences that exceeded 20% difference between each other. Although the meters give reasonable results that might be acceptable for general diabetes care, the results provide some cause for concern in the management of gestational diabetes. Given the need for precision in the setting of pregnancy particularly in making the decision of whether to start or withhold insulin therapy, caregivers need to be cognizant of these inaccuracies.

Blood Chemical Analysis↗
PubMed2000

In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain.

The development of an in vivo procedure for the induction of massive proliferation, directed migration, and neurodifferentiation (PMD) in the damaged adult central nervous system would hold promise for the treatment of human neurodegenerative disorders such as Parkinson's disease. We investigated the in vivo induction of PMD in the forebrain of the adult rat by using a combination of 6-hydroxydopamine lesion of the substantia nigra dopaminergic neurons and infusions of transforming growth factor alpha (TGFalpha) into forebrain structures. Only in animals with both lesion and infusion of TGFalpha was there a rapid proliferation of forebrain stem cells followed by a timed migration of a ridge of neuronal and glial progenitors directed toward the region of the TGFalpha infusion site. Subsequently, increasing numbers of differentiated neurons were observed in the striatum. In behavioral experiments, there was a significant reduction of apomorphine-induced rotations in animals receiving the TGFalpha infusions. These results show that the brain contains stem cells capable of PMD in response to an exogenously administered growth factor. This finding has significant implications with respect to the development of treatments for both acute neural trauma and neurodegenerative diseases.

Animals↗
PubMed2000

Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation.

Matrix metalloproteinase 2 (MMP2) has been reported to be secreted by collagen-stimulated platelets, and active MMP2 has been shown to play a role in platelet aggregation. It has been demonstrated that MMP2 activation is dependent on the complex (membrane type 1 [MT1]-MMP/tissue inhibitor of MMP2 [TIMP2]) receptor and MMP2. We have investigated human platelets as a possible source of MT1-MMP, and we have studied its role in MMP2 activation and in platelet aggregation. Gelatin zymograms showed the existence of MMP2 at proforms (68 kd) and activated-enzyme forms (62-59 kd) in supernatants of resting and activated platelets, respectively. No gelatinolytic activity was associated with the platelet pellet after aggregation, suggesting a total release of MMP2 during cell activation. By Western blot analysis in nonreduced conditions, MT1-MMP was found on resting platelet membranes in 2 forms-the inactive 45-kd form and an apparent 89-kd form, which totally disappeared under reduced conditions. After platelet degranulation, only the 45-kd form was detected. Reverse transcription-polymerase chain reaction experiments showed the expression in platelets of messenger RNA encoding for MMP2, MT1-MMP, and TIMP2. Flow cytometry analysis showed that MT1-MMP, MMP2, and TIMP2 expressions were enhanced at the activated platelet surface. MMP inhibitors, recombinant TIMP2, and synthetic BB94 inhibited collagen-induced platelet aggregation in a concentration-dependent manner, indicating the role of activated MT1-MMP in the modulation of platelet function. In conclusion, our results demonstrate the expression of the trimolecular complex components (MT1-MMP/TIMP2/MMP2) by blood platelets as well as the ability of MMP inhibitors to modulate the aggregating response.

Blood Platelets↗
PubMed2000

Characterization of load-length-velocity relationships of nine different skeletal muscles.

A three-dimensional characterization of muscle load, length and velocity was obtained from nine muscles in the cat's hind limb through contractions where the muscles shortened against inertial-gravitational loads. A model based on the load-length characteristic and second-order dynamics describes shortening velocity related to load and length under these conditions. We conclude that this model describes well contraction velocity as function of length and load under inertial-gravitational load conditions, with correlation coefficients higher than 0.9 in most of the tested muscles.

Animals↗
PubMed2000

Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis.

Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. The progression of renal lesions to fibrosis involves several mechanisms, among which the inhibition of extracellular matrix (ECM) degradation appears to play an important role. Two interrelated proteolytic systems are involved in matrix degradation: the plasminogen activation system and the matrix metalloproteinase system. The plasminogen activator inhibitor type 1 (PAI-1), as the main inhibitor of plasminogen activation, regulates fibrinolysis and the plasmin-mediated matrix metalloproteinase activation. PAI-1 is also a component of the ECM, where it binds to vitronectin. PAI-1 is not expressed in the normal human kidney but is strongly induced in various forms of kidney diseases, leading to renal fibrosis and terminal renal failure. Thrombin, angiotensin II, and transforming growth factor-beta are potent in vitro and in vivo agonists in increasing PAI-1 synthesis. Several experimental and clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis, diabetic nephropathy, focal segmental glomerulosclerosis, and other fibrotic renal diseases. Experimental models of renal diseases in PAI-1-deficient animals are in progress, and preliminary results indicate a role for PAI-1 in renal fibrogenesis. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic antagonists, antisense oligonucleotides, or decoy oligonucleotides has been obtained in vitro, but needs to be evaluated in vivo for the prevention or the treatment of renal fibrosis.

Animals↗
PubMed2000

[Assessment of the management of arterial hypertension in a population of (type 2) diabetic patients undergoing hospitalization. Diabetes and prognostic factors in the control of arterial hypertension].

The control of hypertension in diabetic hypertensive patients prevents micro and macroangiopathy complications. Our prospective study was designed to evaluate the level of treatment of hypertension in type II diabetic patients at the time of referral to our endocrinology unit and after a mean follow-up of 9.2 months. Five hundred and sixty four patients (sex ratio: 1.15, mean age of 56 +/- 13, mean BMI of 28 +/- 15, mean duration of diabetes of 11.3 +/- 9.9) were referred to our unit. Among these, 42% had an antihypertensive drug (58% under monotherapy, 42% under combinations) and 92% had a documented history of CHD. Glycemic and blood pressure controls were stable during follow-up. HbA1c remained unchanged (8.95% at admission, 8.8% at 9 months) BP decreased from 143/84 +/- 26/13 mmHg to 142/82 +/- 23/13 mmHg. Fifty six percent reached a BP goal of 140/90 mmHg whereas 42% achieved a BP goal of 130/85 mmHg at 9 months compared to respectively 56% and 39% at admission. A multivariate logistic regression analysis showed that initial value of SBP (p < 0.0001), age (p < 0.0001), BMI (p = 0.006), HbA1c (p = 0.018) were independent factors of non control of hypertension. In conclusion, follow-up of hypertension diabetic patients would be focussed on identified and modifiable factors.

Age Factors↗
PubMed1999

Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals.

Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1-infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin's lymphoma (NHL). The SDF1-3'A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3'A/3'A homozygotes and 22 (10%) of 202 SDF1-+/3'A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-triangle up32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3'A frequency may contribute to the lower risk of HIV-1-associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1-infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL.

Acquired Immunodeficiency Syndrome↗
PubMed1998

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HRIs) have been recently shown to prevent atherosclerosis progression. Clinical benefit results from combined actions on various components of the atherosclerotic lesion. This study was designed to identify the effects of HRI on one of these components, the endothelial fibrinolytic system. Aortas isolated from rats treated for 2 days with lovastatin (4 mg/kg body wt per day) showed a 3-fold increase in tissue plasminogen activator (tPA) activity. In a rat aortic endothelial cell line (SVARECs) and in human nontransformed endothelial cells (HUVECs), HRI induced an increase in tPA activity and antigen in a time- and concentration-dependent manner. In SVARECs, the maximal response was observed when cells were incubated for 48 hours with 50 micromol/L HRI. An increase of tPA mRNA was also in evidence. In contrast, HRI inhibited plasminogen activator inhibitor-1 activity and mRNA. The effects of HRI were reversed by mevalonate and geranylgeranyl pyrophosphate, but not by LDL cholesterol and farnesyl pyrophosphate, and were not induced by alpha-hydroxyfarnesyl phosphonic acid, an inhibitor of protein farnesyl transferase. C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho protein, reproduced the effect of lovastatin on tPA and plasminogen activator inhibitor-1 activity and blocked its reversal by geranylgeranyl pyrophosphate. The effect of HRI was associated with a disruption of cellular actin filaments without modification of microtubules. A disrupter of actin filaments, cytochalasin D, induced the same effect as lovastatin on tPA, whereas a disrupter of microtubules, nocodazole, did not. In conclusion, HRI can modify the fibrinolytic potential of endothelial cells, likely via inhibition of geranylgeranylated Rho protein and disruption of the actin filaments. The resulting increase of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis.

Animals↗
PubMed1998

Soluble latent membrane-type 1 matrix metalloprotease secreted by human mesangial cells is activated by urokinase.

BACKGROUND: Matrix metalloprotease 2 (MMP2) is secreted in a latent inactive form (pro-MMP2) that is activated on the cell surface by a membrane-type 1 MMP (MT1-MMP) in the presence of the tissue inhibitor of MMP (TIMP2). In spite of evidence for the synthesis of MT1-MMP shown by immunoblotting, immunocytochemistry and RT-PCR, and of TIMP2, MMP2 was found exclusively in a latent form in human mesangial cells (HMC) serum-free culture medium. METHODS AND RESULTS: On purified membranes of HMC, MT1-MMP was found in a 63 kD latent form and as a faint band of 55 kD. The 55 kD band was also present in the ultracentrifuged conditioned medium and likely represented MT1-MMP cleaved from its transmembrane domain, since Northern blot analysis showed only one transcription product. The addition of urokinase plasminogen activator (uPA, 100 nM) to HMC membranes induced the activation of pro-MMP2 via the activation of latent membrane-associated MT1-MMP as reflected by the cleavage of the 63 and 55 kD forms. In addition, when the conditioned medium was successively incubated with uPA and alpha 2-macroglobulin and analyzed by immunoblotting, MT1-MMP decreased, indicating that the soluble MT1-MMP was in a latent form and was activated by uPA. CONCLUSION: Our results provide the first evidence, to our knowledge, of the existence of a soluble latent form of MT1-MMP secreted by primary human cells in culture, confirming that MT1-MMP is an ectoenzyme, and show that uPA can regulate MT1-MMP activity in a soluble phase.

Cell Membrane↗
PubMed1998

PAI-1 secretion and matrix deposition in human peritoneal mesothelial cell cultures: transcriptional regulation by TGF-beta 1.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of plasminogen activators in plasma and in peritoneum, impairs plasmin formation that is essential for the repair processes of the mesothelium damaged by peritoneal dialysis fluids and peritonitis. The fibrogenetic cytokine transforming growth factor-beta (TGF-beta) displays variable effects on extracellular matrix remodeling enzymes and their inhibitors depending on tissues and cell lines. We previously found an unexpected stimulating effect of TGF-beta 1 on matrix metalloproteinase-9 in peritoneal mesothelial cells. In this study, we analyzed the effects of TGF-beta 1 on PAI-1 production and deposition in extracellular matrix. METHODS: We used primary cultured mesothelial cells and a recently established human peritoneal mesothelial cell line (HMrSV5). Cell-associated and secreted plasminogen activators and their inhibitors were detected and characterized by substrate gel zymography. PAI-1 was identified by reverse zymography and by Western blotting, and total PAI-1 was measured by ELISA. Secreted and cell-associated PA activity was measured by its ability to activate plasminogen into plasmin, that is, by the release of paranitroaniline from the plasmin synthetic substrate S-2251. PAI-1 mRNA accumulation was assessed by Northern blot. In vitro nuclear run-on assays were carried out to determine whether TGF-beta 1 had transcriptional effects on PAI-1 expression. Finally, the subcellular distribution of PAI-1 was analyzed by immunofluorescence and by immunogold silver staining. RESULTS: TGF-beta 1 increased PAI-1 antigen in the conditioned media of HMrSV5 cells, in a time- and concentration-dependent manner. This induced a dramatic decrease of free tPA in the cell medium and of membrane-bound uPA, and a parallel increase of high molecular weight PA-PAI complexes. Consequently, secreted and cell-associated plasminogen activator activities were considerably reduced. In primary cultured peritoneal mesothelial cells, TGF-beta 1 also induced PAI-1 secretion and the shift of tPA toward high molecular weight complexes. TGF-beta 1 increased PAI-1 mRNA in a time- and concentration-dependent manner. This effect was at least in part transcriptional since an approximately threefold increase in the rate of PAI-1 gene transcription was observed in nuclei sampled after a four-hour cell exposure to 5 ng/ml TGF-beta 1. Finally, TGF-beta 1 substantially increased the amount of intracellular and matrix-associated PAI-1. CONCLUSIONS: These results suggest that excessive TGF-beta 1 stimulated PAI-1 could prevent appropriate peritoneal healing by impairing the degradation of fibrin and of unorganized matrix components, and by interfering with cell migration.

Blotting, Northern↗