Letter: delta-aminolevulinic acid dehydratase.
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5-Aminolevulinate Synthetase↗
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Fibroblasts: what's new in cellular biology?
This paper briefly examines the fibroblast network with particular emphasis on the exceptionally complex pattern of specific interactions and their effects on dermal integrity and homeostasis regulation systems. It will be some time before we have a full understanding of the cellular biology mechanisms involved in the operation of lasers, flashlamps, peels, mechanical dermabrasions, fillers or topicals on the skin.
Cellular Senescence↗
Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells.
Langerhans cells (LCs) are dendritic cells (DCs) that are present in the epidermis, bronchi, and mucosae. Although LCs originate in bone marrow, little is known about their lineage of origin. In this study, we demonstrate that in vitro LCs may originate from monocytes. Adult peripheral blood CD14+ monocytes differentiate into LCs (CD1a+, E-cadherin+, cutaneous lymphocyte-associated antigen+, Birbeck granules+, Lag+) in the presence of granulocyte/macrophage colony-stimulating factor, interleukin 4, and transforming growth factor beta1 (TGF-beta1). This process occurs with virtually no cell proliferation and is not impaired by 30 Gy irradiation. Selection of monocyte subpopulations is ruled out since monocyte-derived DCs can further differentiate into LCs. Our data suggest that in vivo LC differentiation may be induced peripherally, from a nonproliferating myeloid precursor, i.e., the monocyte, in response to a TGF-beta1-rich microenvironment, as found in the skin and epithelia. Therefore, the monocyte may represent a circulating precursor critical to the immune response in vivo.
Cell Differentiation↗
Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping.
Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.
Adolescent↗
An experimental test of the dose-dependent effect of carotenoids and immune activation on sexual signals and antioxidant activity.
Carotenoid-based sexual traits are thought to be reliable indicators of male quality because they might be scarce and therefore might indicate the ability of males to gather high-quality food and because they are involved in important physiological functions (as immune enhancers and antioxidants). We performed an experiment where male and female zebra finches (Taeniopygia guttata) were provided with increasing carotenoid doses in the drinking water during 4 weeks (bill color of this species is a carotenoid-based sexual signal). Simultaneously, birds were split into two groups: one receiving weekly injections of Escherichia coli lipopolysaccharide in order to activate the immune system, the other being injected with the same volume of phosphate buffered saline. We assessed how carotenoid availability and immune activation affected the amount of circulating plasma carotenoids, the beak color, and the antioxidant defenses (assessed as the resistance of red blood cells to a controlled free radical attack). Carotenoid availability affected the amount of circulating carotenoids and beak color; both variables reached a plateau at the highest carotenoid doses. Immune activation diverted carotenoids from plasma, and this in turn affected the expression of the sexual trait. Finally, we found a positive correlation between the change in circulating carotenoids and antioxidant defenses. These results support the idea that carotenoids have important physiological properties that ensure the honesty of carotenoid-based sexual traits.
Animal Communication↗
Fungemia due to Saccharomyces species in a patient treated with enteral Saccharomyces boulardii.
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Aged↗
Contractility and retrograde flow in lamellipodium motion.
We present a phenomenological description of cell locomotion on a solid substrate. The material properties of the actin cytoskeleton in the lamellipodium are described by the constitutive equations of a viscous polar gel with intrinsic activity. The polymerization of the gel takes place in a localized region near the leading edge. Using a simple two-dimensional description, we calculate in the steady state the thickness profile of the lamellipodium which at the rear connects to the cell body; we also calculate the flow profiles and the forces exerted on the substrate. The cell velocity is estimated as a function of externally applied forces. Our description is consistent with experimentally observed properties of motile cells such as the existence of a retrograde flow in the lamellipodium and a dipolar force distribution exerted by the cell on the substrate.
Actins↗
n-3 polyunsaturated fatty acids raise low-density lipoproteins, high-density lipoprotein 2, and plasminogen-activator inhibitor in healthy young men.
The effects of a moderate supplementation in n-3 polyunsaturated fatty acids (PUFAs) were investigated in 36 young healthy adult males. Factors investigated were lipoprotein (including HDL subfractions and apolipoproteins) and hemostasis indexes, assessed by platelet aggregation and plasminogen-activator-inhibitor (PAI) activity. Fat-controlled diets were prescribed, one with and one without a fish-oil supplement (control diet), successively during 3 wk in random order. Total calorie, fat, and cholesterol intakes were similar in the two diets. Triglycerides in serum and very-low-density lipoproteins were lower and high-density-lipoprotein 2 cholesterol was higher with the n-3 PUFA-supplemented diet. These effects as well as a significant decrease in platelet aggregation can be considered beneficial in terms of cardiovascular risk. However, significant increases in low-density-lipoprotein cholesterol and PAI activity occurred and were correlated. This latter effect could be detrimental.
Adult↗
Hepatic storage and transport of n-3 and n-6 polyunsaturated fatty acids by very-low-density lipoproteins in growing rats fed low- or adequate-protein diets with sunflower, soybean, coconut, and salmon oils.
Protein and essential fatty acid (EFA) deficiencies may both occur in chronic malnutrition and have common symptoms. To determine the interactions between dietary protein intake and EFA availability, rats were fed purified diets containing 20% or 2% casein and 5% as one of four fats (sunflower, soybean, coconut, or salmon oil) that differed particularly in their n-6 and n-3 polyunsaturated fatty acids (PUFAs). Protein malnutrition enhanced hepatic triacylglycerol and cholesterol concentrations while decreasing hepatic protein and phospholipid contents and mass and components of very-low-density lipoprotein (VLDL). The ratio of PUFAs to saturated fatty acids (SFAs) was consistently depressed by protein malnutrition in liver and VLDL triacylglycerol and phospholipid. Total n-6 and n-3 fatty acids were diminished by protein malnutrition, except with salmon oil, with which a decrease in 20:5n-3 was compensated for by an increase in 22:6n-3. The ratio of 20:4n-6 to 18:2n-6 was enhanced in liver phospholipid and VLDL triacylglycerol, and modified little in liver triacylglycerol. Generally, the ratio of 20:3n-9 to 20:4n-6, an index for EFA deficiency, was raised with protein malnutrition in liver triacylglycerol and phospholipid and in VLDL triacylglycerol. The extent of changes in each fatty acid proportion varied according to the oil fed. Overall, VLDL-apolipoprotein concentrations were, in general, strongly reduced with protein malnutrition. In conclusion, protein malnutrition may accelerate marginal EFA deficiency and decrease long-chain PUFA bioavailability and thus increase EFA requirement.
Animals↗
Acute effects of tertatolol and nadolol on systemic and renal hemodynamics in patients with essential hypertension.
The acute systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta-blocker without partial agonist activity, were compared to those of an equipotent dose of nadolol in eight patients with essential hypertension. Tertatolol (5 mg) or nadolol (80 mg) were administered orally at an interval of 1 week in a random order as a double-blind, cross-over study. Cardiac output was measured by Doppler echography, and renal blood flow and glomerular filtration rate were measured by constant infusion techniques using 123I-iodohippurate and 51CR-EDTA, respectively. Measurements were performed before and then successively 2 and 4 hours after ingestion of the drugs. Both nadolol and tertatolol decreased blood pressure and cardiac output to a comparable extent. Renal blood flow remained unchanged, so that the renal fraction of cardiac output increased from 14.4 +/- 1.5% to 21.3 +/- 2% after nadolol and from 14.8 +/- 2.4% to 20.5 +/- 1.8% after tertatolol (mean +/- SE, P less than 0.01 before vs. after; nadolol vs. tertatolol was not significant). The glomerular filtration rate remained unchanged, from 68 +/- 9 to 64 +/- 6 mL/min.m2 after nadolol and from 71 +/- 8 to 67 +/- 7 mL/min.m2 after tertatolol (before vs. after and nadolol vs. tertatolol levels were not significant). These results show that both tertatolol and nadolol redistribute cardiac output to the kidneys in patients with essential hypertension.
Adult↗
Effect of tertatolol on glomerular hemodynamics in the normal Munich-Wistar rat.
Administration of beta-blockers is frequently associated with decreases in both renal plasma flow and glomerular filtration rate (GFR). Tertatolol, a new non-selective beta-blocker, has demonstrated similar systemic effects to other conventional beta-blockers, but tertatolol produces increases in both renal plasma flow and glomerular filtration rate. To evaluate the renal hemodynamic mechanism responsible for the increase in GFR, micropuncture experiments were performed in normal Munich-Wistar rats. Intravenous injection of tertatolol produced a significant increase in GFR and urinary sodium excretion in spite of a decrease in systemic blood pressure. Single nephron glomerular filtration rate was significantly increased due to an increase in single nephron plasma flow related to parallel afferent and efferent arteriolar dilatation. No significant changes in glomerular hydrostatic pressure, transcapillary hydrostatic pressure gradient or the ultrafiltration coefficient were demonstrated with tertatolol. The capacity of tertatolol to increase glomerular filtration rate and to promote sodium excretion without modifying critical glomerular pressures makes this agent a highly attractive antihypertensive drug.
Adrenergic beta-Antagonists↗
Selective infusion of tertatolol into the renal artery induces a local vasodilator effect in humans. Demonstration by the continuous thermodilution method.
The effects of tertatolol on renal circulation were studied in 8 patients with normal renal function. Left renal blood flow was measured by the continuous thermodilution method before (t0), and 5 (t1), 10 (t2) and 20 (t3) min after a selective infusion of 0.25 mg of tertatolol into the left renal artery. During the study, cardiac output, heart rate, aortic and right atrial pressures, systemic vascular resistances and the systemic arteriovenous oxygen difference were not significantly altered. Plasma renin activity and plasma aldosterone in arterial and renal venous blood started to decrease at t1. At t3, renal blood flow was increased (from 463 +/- 28 mL/min at t0, to 549 +/- 22 mL/min, P less than .001), renal vascular resistance was reduced (from 188 +/- 17 mm Hg/L/min at t0 to 156 +/- 15 mm Hg/L/min, P less than .01) and the arteriovenous oxygen difference was decreased (from 1.6 +/- 0.2 mL/100 mL at t0 to 1.1 +/- 0.1 100 mL, P less than .01). The renal/cardiac flow ratio increased from 10.0 +/- 2.2% to 11.7 +/- 2.1% (P less than .05) and the renal/systemic vascular resistance ratio decreased from 10.5 +/- 2.0 to 8.7 +/- 1.4 (P less than .01). These data show that selective infusion of a low dose of tertatolol into the renal artery results in an increase in renal blood flow which is delayed and occurs without concomitant changes in systemic hemodynamics. This suggests an intrarenal mechanism of action in humans supporting the previously observed renal vasodilation induced by tertatolol in isolated perfused animal kidneys.
Adult↗
The Tertatolol International Multicenter Study (T.I.M.S.). Predicting factors of an efficient therapy.
The Tertatolol International Multicenter Study (T.I.M.S.) was aimed at assessing the efficacy and tolerability of 5 mg tertatolol (T) once daily over a one year period and at finding, among the clinical variables before treatment, parameters predicting a successful single beta-blocking therapy. The study was carried out in 230 patients (96 men, 134 women, mean age +/- standard error of the mean: (51.5 +/- 0.7 years) suffering from uncomplicated mild to moderate hypertension. After a one-month placebo run-in period (M0-M1) and a one-month double-blind placebo-controlled period (M1-M2), 213 patients entered and 166 completed the one-year open period (M2-M14). A diuretic (D) was added if blood pressure (BP) was inadequately controlled with the single therapy. After one year, 88.5% of patients were controlled (sitting diastolic BP less than or equal to 90 mm Hg): 56.3% on single therapy (T) and 32.2% on dual therapy (T + D), respectively. Statistical analysis performed on the controlled subjects showed that patients who were controlled with T alone had an initially lower standing diastolic BP and a higher standing heart rate, were younger and had a lower sitting systolic BP than those controlled with T + D. Using such discriminant parameters which are predictors, 83.5% patients (single therapy group) and 49% patients (dual therapy group) were classified in the therapeutic group to which they really belonged. This study confirms the antihypertensive efficacy of tertatolol, and highlights relevant parameters for a successful single beta-blocker therapy in clinical practice.
Adrenergic beta-Antagonists↗
Life survival and cardiovascular structures following selective beta-blockade in spontaneously hypertensive rats.
The aim of this study was to assess life survival, and arterial and cardiac structural changes following chronic selective beta-blockade in spontaneously hypertensive rats (SHR). Twenty-two SHR aged 3 months and 20 SHR aged 18 months were treated with the beta 1-blocking agent bisoprolol (10 mg/kg/day) or placebo for a period of 2 months. At the end of this period left and right ventricular weight and morphometric parameters of five different arterial segments (thoracic and abdominal aorta, renal, mesenteric, and carotid arteries) were evaluated. In younger SHR, systolic blood pressure (tail-cuff method) was significantly lower in drug-treated animals (225 +/- 15 v 185 +/- 10 mm Hg in placebo-treated animals; P < .001); left ventricular weight was significantly lower in drug-treated rats (0.845 +/- 0.02 v 0.932 +/- 0.03 g; P < .05); medial thickness was significantly lower in the bisoprolol-treated rats at the site of the thoracic (-22%) and abdominal (-17%) aorta, and mesenteric artery (-29%); in the renal and carotid arteries, no change in medial thickness was observed. In older SHR, cardiovascular morbidity and mortality were significantly higher (P < .01) in the placebo group. In bisoprolol-treated animals, systolic blood pressure did not change and was even significantly higher than in controls. Heart weight and medial thickness of the thoracic aorta and the renal arteries were significantly lower in the Bisoprolol group. These results provide evidence that 2 months of selective beta-blockade in adult SHR has an important antihypertrophic cardiac and vascular effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Use of gas-liquid chromatography with glass capillary columns for steroid trace analysis in tissues.
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Adrenal Glands↗
The molecular basis of the specificity of action of K(ATP) channel openers.
K(ATP) channels incorporate a regulatory subunit of the ATP-binding cassette (ABC) transporter family, the sulfonylurea receptor (SUR), which defines their pharmacology. The therapeutically important K(+) channel openers (e.g. pinacidil, cromakalim, nicorandil) act specifically on the SUR2 muscle isoforms but, except for diazoxide, remain ineffective on the SUR1 neuronal/pancreatic isoform. This SUR1/2 dichotomy underpinned a chimeric strategy designed to identify the structural determinants of opener action, which led to a minimal set of two residues within the last transmembrane helix of SUR. Transfer of either residue from SUR2A to SUR1 conferred opener sensitivity to SUR1, while the reverse operation abolished SUR2A sensitivity. It is therefore likely that these residues form part of the site of interaction of openers with the channel. Thus, openers would target a region that, in other ABC transporters, is known to be tightly involved with the binding of substrates and other ligands. This first glimpse of the site of action of pharmacological openers should permit rapid progress towards understanding the structural determinants of their affinity and specificity.
ATP-Binding Cassette Transporters↗
A syndecan-4/CXCR4 complex expressed on human primary lymphocytes and macrophages and HeLa cell line binds the CXC chemokine stromal cell-derived factor-1 (SDF-1).
The stromal cell-derived factor-1 (SDF-1) is a CXC chemokine, which plays critical roles in migration, proliferation, and differentiation of leukocytes. SDF-1 is the only known ligand of CXCR4, the coreceptor of X4 HIV strains. We show that SDF-1 binds to high- and low-affinity sites on HeLa cells. Coimmunoprecipitation studies demonstrate that glycanated and oligomerized syndecan-4 but neither syndecan-1, syndecan-2, betaglycan, nor CD44 forms complexes with SDF-1 and CXCR4 on these cells as well as on primary lymphocytes or macrophages. Moreover, biotinylated SDF-1 directly binds in a glycosaminoglycans (GAGs)-dependent manner to electroblotted syndecan-4, and colocalization of SDF-1 with syndecan-4 was visualized by confocal microscopy. Glycosaminidases pretreatment of the HeLa cells or the macrophages decreases the binding of syndecan-4 to the complex formed by it and SDF-1. In addition, this treatment also decreases the binding of the chemokine to CXCR4 on the primary macrophages but not on the HeLa cells. Therefore GAGs-dependent binding of SDF-1 to the cells facilitates SDF-1 binding to CXCR4 on primary macrophages but not on HeLa cell line. Finally, an SDF-1-independent heteromeric complex between syndecan-4 and CXCR4 was visualized on HeLa cells by confocal microscopy as well as by electron microscopy. Moreover, syndecan-4 from lymphocytes, monocyte derived-macrophages, and HeLa cells coimmunoprecipitated with CXCR4. This syndecan-4/CXCR4 complex is likely a functional unit involved in SDF-1 binding. The role of these interactions in the pathophysiology of SDF-1 deserves further study.
Chemokine CXCL12↗
RANTES (CCL5) induces a CCR5-dependent accelerated shedding of syndecan-1 (CD138) and syndecan-4 from HeLa cells and forms complexes with the shed ectodomains of these proteoglycans as well as with those of CD44.
We recently demonstrated that RANTES forms complexes with CCR5, syndecan-1 (SD-1), SD-4, and CD44 expressed by human primary macrophages and that SD-1 and SD-4 but neither CD44 nor SD-2 coimmunoprecipitate with CCR5. Here we show that RANTES directly binds in a glycosaminoglycan-dependent manner to SD-1, SD-4, and CD44. Moreover, RANTES accelerates the shedding of SD-1 and SD-4 ectodomains from HeLa cells expressing CCR5 and, by contrast, has no effect on the constitutive shedding of CD44 from these cells. These accelerated sheddings are prevented by the MEK1/2 inhibitor, U0126, and by the protein kinase C inhibitor bisindolylmaleimide I. This indicates that both MAP kinase--and protein kinase C-dependent signaling pathways are involved in these RANTES-induced accelerated sheddings. RANTES also induces a decreased expression of SD-1 and SD-4 by HeLa cells expressing CCR5 and on the contrary an increased expression of CD44 by these cells. By contrast, RANTES neither accelerates the shedding of SD-1 and SD-4 ectodomains from HeLa cells lacking CCR5, nor changes the SD-1-, SD-4-, and CD44-plasma membrane expressions of these cells. CCR5 is therefore involved in the RANTES-induced accelerated shedding of SD-1 and SD-4 ectodomains. Nevertheless, the fact that RANTES stimulates in Hela cells (expressing or lacking CCR5) the mRNA synthesis of SD-1 and SD-4 indicates that the molecular events that follow the synthesis of these proteoglycans differ, according to the presence or not of CCR5. Finally, RANTES forms GAG-dependent complexes with the shed ectodomains of SD-1 and SD-4 as well as with those of CD44. The role of these events in the pathophysiology of RANTES deserves further study.
Chemokine CCL5↗