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PubMed1995

Iron species in iron homeostasis and toxicity.

Iron homeostasis in prokaryotic cells appears to be regulated essentially at the level of the genome by the Fur protein. When iron is in short supply the uptake and assimilation pathways are de-repressed and siderophores are synthesized together with the outer, inner (plasma) membrane, periplasmic and cytosolic components necessary for the uptake of ferri-siderophores. When iron is no longer limiting the Fe2+ the Fur complex acts as a transcriptional repressor, and shuts down the synthesis of all the components of iron assimilation. In euykarotic cells, iron homeostasis is dependent upon the iron regulatory factor (IRF), a cytoplasmic protein that can bind to specific stem loops, iron responsive elements (IREs) on the messenger ribonucleic acid molecules (mRNAs) of proteins involved in iron storage (ferritin), utilization (erythroid delta-aminolaevulinate synthase, AIS), and uptake (transferrin receptor). During ion depletion the IRE is in a high affinity form, which, by binding strongly to the corresponding mRNAs, down regulates iron storage and utilization, while up-regulating transferrin receptor expression. When the cells are iron replete, IRF binding to IREs is weak, allowing transferrin receptor mRNA to be degraded. In this paper it is shown that in physiological conditions of iron overload and depletion, IRF functions in vivo in the manner already described for in vitro models. The nature and the speciation of the various iron species within the low molecular weight pool of eukaryotic cells remains unclear.

Animals↗

PubMed2004

Association of cyclic adenosine monophosphate with permeability barrier homeostasis of murine skin.

Activation of Gs protein increases the intracellular cyclic adenosine monophosphate (cAMP) level, and the Gs protein-linked receptor has been implicated in the skin barrier homeostasis. In this study, we investigated the role of cAMP in epidermal barrier function. The barrier was disrupted by tape stripping or treatment with acetone. Immediately after barrier disruption, reagents affecting the cAMP level were topically applied. Topical application of forskolin, which activates cAMP synthesis delayed barrier recovery, whereas application of the antagonist of cAMP, cAMP-Rp, accelerated barrier recovery. Moreover, application of 9-cyclopentyladenine, an inhibitor of cAMP synthesis also accelerated barrier recovery. Tape stripping was found to increase the cAMP in the epidermis. Light and electron microscopic observations showed the delay of lamellar body secretion by forskolin and acceleration of the lamellar body secretion by cAMP-Rp. Application of an inhibitor of protein kinase A did not affect the barrier recovery rate. The delay of barrier recovery induced by forskolin was blocked by the voltage-gated calcium channel blockers, nifedipine and verapamil. In cultured keratinocytes, forskolin increased the intracellular calcium concentration and both nifedipine and verapamil blocked the increase. These results suggest that intracellular cAMP in the epidermis is involved in skin barrier homeostasis.

Animals↗

PubMed2001

Intrathecal anaesthesia alters intracellular Ca2+/Mg2+ homeostasis in the spinal cord neurones of experimental rats.

BACKGROUND AND OBJECTIVE: The effect of anaesthesia induced by intrathecal injection of 6.3% MgSO4 or 4% lidocaine on intracellular electrolyte homeostasis in spinal cord neurones of a rat model was investigated. METHODS: Intracellular Ca2+, Mg2+, Na+ and K+ concentrations were determined at different times after intrathecal administration of NaCl (saline, a control group), MgSO4 or lidocaine. RESULTS: In both thoracic and lumbar spinal cord segments, Ca2+ concentrations rose significantly 30 min and 2 h after 6.3% MgSO4 injection, and after 24 h were still significantly increased compared with the values obtained from the control group which were subjected to sham 'anaesthesia' by saline injection (172, 121 and 108 ng mg-1 protein vs. control 23 ng mg-1 protein, respectively, in the thoracic segment and 222, 229 and 176 ng mg-1 protein vs. control 43 ng mg-1 protein, respectively, in the lumbar segment). Lidocaine injection also produced a significant increase in intracellular Ca2+ in the thoracic and lumbar spinal cord segments (69, 64 and 53 ng mg-1 protein vs. control 33.4 ng mg-1 protein and 26, 94 and 46 ng mg-1 protein vs. 23 ng mg-1 protein respectively). Only a modest rise in intracellular Mg2+ was observed after intrathecal MgSO4 or lidocaine injection (27 ng mg-1 protein vs. 23 ng mg-1 protein). Na+ and K+ concentrations decreased 24 h after MgSO4 and 1 h after lidocaine injection. CONCLUSION: Intrathecal anaesthesia by MgSO4 or lidocaine alters intracellular electrolyte homeostasis in spinal cord neurones of experimental rats. A possible common mechanism of action via Ca2+ ion channels is discussed.

Anesthesia, Spinal↗

PubMed1998

Glutathione homeostasis is disturbed in CD4-positive lymphocytes of HIV-seropositive individuals.

BACKGROUND: Numerous in vitro tests have suggested that a disturbed cellular glutathione homeostasis plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. METHODS: Using validated high-performance liquid chromatography (HPLC) methods, glutathione concentrations were determined in plasma and in cytosol of CD4+ lymphocytes and CD14+ cells of HIV-seropositive individuals and healthy control subjects. We measured concentrations of total glutathione, which is the sum of reduced (GSH) and oxidised (GSSG) glutathione and mixed disulphides of which there are two fractions: soluble mixed disulphides (GSSR) and protein bound glutathione (ProSSG). Also, non-protein-bound glutathione was measured, which is the sum of GSH, GSSG and GSSR. Thirty-five healthy control subjects and 35 HIV-infected individuals participated in the study. RESULTS: We found that in CD4+ lymphocytes from HIV-seropositive individuals, total glutathione levels were significantly higher than in healthy control subjects, whereas the fraction of non-protein-bound glutathione was not different. This can only be explained by an increase in the protein-bound fraction of glutathione indicating the presence of oxidative stress in CD4+ lymphocytes of HIV-seropositive individuals. Glutathione measurements of cytosol of CD14+ cells and plasma were, however, not compatible with significant increased oxidation. Glutathione precursors (cysteine, cysteinylglycine, glutamylcysteine and homocysteine) and products of lipid peroxidation (thiobarbituric acid-reactive substances) were also measured in plasma and did not differ between healthy control subjects and HIV-seropositive individuals. CONCLUSION: We conclude that the glutathione homeostasis is disturbed in CD4+ lymphocytes of HIV-seropositive individuals. The glutathione redox dysbalance in CD4+ lymphocytes could be important in the pathogenesis of HIV infection and have implications for therapy.

Adult↗

PubMed1999

Changes of cardiac calcium homeostasis in spontaneously hypertensive rats.

The aim of the present study was to assess the alterations in cardiac Ca2+ homeostasis induced by hypertension using electrically paced right ventricular strips from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2 Basal contractile force was higher in SHR than in WKY. Similarly, the beta-adrenoceptor agonist isoprenaline (10 nM-10 microM) induced a concentration-dependent positive inotropic effect that was higher in SHR than in WKY, which was in turn inhibited by the beta-adrenoceptor antagonist propranolol (1 microM) in both strains. 3 Preincubation of strips with the L-type Ca2+ channel blockers, nifedipine (1 microM) or verapamil (10 microM), markedly inhibited the isoprenaline response, the inhibition being higher in SHR than in WKY. However, this inhibition was minor by the T-type Ca2+ channel blocker mibefradil (10 microM). 4 Bay K 8644 (10 nM-10 microM), a L-type Ca2+ channel activator induced a concentration-dependent positive inotropic effect, that was greater in SHR than WKY. 5 Nifedipine and verapamil (both 0.1 nM-10 microM) inhibited in a concentration-dependent way the inotropic effect induced by 0.3 microM isoprenaline or 1 microM Bay K 8644. The inhibition was higher in SHR than in WKY. Mibefradil (0.1 nM-10 microM) only clearly inhibited the isoprenaline and Bay K 8644 inotropic effects at 10 microM in both strains. 6 The inhibitor of the sarcoplasmic reticulum Ca2+ release, ryanodine (10 nM-10 microM), was a more effective depressor of isoprenaline-induced response in SHR than in WKY. 7 These results suggest that cardiac Ca2+ homeostasis in SHR ventricular strips is altered compared with those of WKY, showing an increased Ca2+ entry through L-type Ca2+ channels and release from sarcoplasmic reticulum; the participation of T-type Ca2+ channels are irrelevant in this tissue.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2003

Changes in hydrogen peroxide homeostasis trigger an active cell death process in tobacco.

In transgenic tobacco plants with reduced catalase activity, high levels of hydrogen peroxide (H2O2) can accumulate under photorespiratory conditions. Such a perturbation in H2O2 homeostasis induced cell death in clusters of palisade parenchyma cells, primarily along the veins. Ultrastructural alterations, such as chromatin condensation and disruption of mitochondrial integrity, took place before cell death. Furthermore, enhanced transcript levels of mitochondrial defense genes accompanied these mitochondrial changes. Pharmacological data indicated that the initiation and execution of cell death require de novo protein synthesis and that the signal transduction pathway leading to cell death involved changes in ion homeostasis, (de)phosphorylation events and an oxidative burst, as observed during hypersensitive responses. This oxidase-dependent oxidative burst is essential for cell death, but it is not required for the accumulation of defense proteins, suggesting a more prominent role for the oxidative burst in abiotic stress-induced cell death.

Apoptosis↗

PubMed2004

Cross-species microarray transcript profiling reveals high constitutive expression of metal homeostasis genes in shoots of the zinc hyperaccumulator Arabidopsis halleri.

Arabidopsis halleri ssp. halleri (accession Langelsheim) is a naturally selected zinc (Zn)- and cadmium-tolerant Zn hyperaccumulator. This plant differs strikingly from its close relative A. thaliana by accumulating Zn specifically in above-ground tissues. A. thaliana GeneChips were used in order to identify, on a transcriptome-wide scale, genes with a potential involvement in cellular metal uptake or detoxification in the shoots of A. halleri. Compared to A. thaliana, transcript abundance of several genes was found and confirmed to be substantially higher in A. halleri after 4 days of exposure to low as well as high Zn concentrations in the hydroponic culture medium. The identified candidate genes encode proteins closely related to the following A. thaliana proteins: AtZIP6, a putative cellular Zn uptake system and member of the zinc-regulated transporter (ZRT)-iron regulated transporter (IRT)-like protein (ZIP)-family of metal transporters, the putative P-type metal ATPase AtHMA3, the cation diffusion facilitator ZAT/AtCDF1, and the nicotianamine synthase AtNAS3. Heterologous expression in mutant strains of the yeast Saccharomyces cerevisiae suggested that AhHMA3, AhCDF1-3, and AhNAS3 can function in cellular Zn detoxification. Our data indicate that, at the transcript level, the Zn tolerance strategy of A. halleri involves high constitutive expression of metal homeostasis genes in the shoots to accommodate higher basal levels of Zn accumulation, and possibly to prepare for sudden increases in Zn influx into shoot cells. Furthermore, profiling of metal homeostasis gene transcripts in shoot and root tissues by real-time RT-PCR indicated that A. halleri and A. thaliana respond differently to changes in plant Zn status.

Arabidopsis↗

PubMed2002

Intracellular pH homeostasis in the filamentous fungus Aspergillus niger.

Intracellular pH homeostasis in the filamentous fungus Aspergillus niger was measured in real time by 31P NMR during perfusion in the NMR tube of fungal biomass immobilized in Ca2+-alginate beads. The fungus maintained constant cytoplasmic pH (pH(cyt)) and vacuolar pH (pH(vac)) values of 7.6 and 6.2, respectively, when the extracellular pH (pH(ex)) was varied between 1.5 and 7.0 in the presence of citrate. Intracellular metabolism did not collapse until a Delta pH over the cytoplasmic membrane of 6.6-6.7 was reached (pH(ex) 0.7-0.8). Maintenance of these large pH differences was possible without increased respiration compared to pH(ex) 5.8. Perfusion in the presence of various hexoses and pentoses (pH(ex) 5.8) revealed that the magnitude of Delta pH values over the cytoplasmic and vacuolar membrane could be linked to the carbon catabolite repressing properties of the carbon source. Also, larger Delta pH values coincided with a higher degree of respiration and increased accumulation of polyphosphate. Addition of protonophore (carbonyl cyanide m-chlorophenylhydrazone, CCCP) to the perfusion buffer led to decreased ATP levels, increased respiration and a partial (1 microm CCCP), transient (2 microm CCCP) or permanent (10 microm CCCP) collapse of the vacuolar membrane Delta pH. Nonlethal levels of the metabolic inhibitor azide (N3-, 0.1 mm) caused a transient decrease in pH(cyt) that was closely paralleled by a transient vacuolar acidification. Vacuolar H+ influx in response to cytoplasmic acidification, also observed during extreme medium acidification, indicates a role in pH homeostasis for this organelle. Finally, 31P NMR spectra of citric acid producing A. niger mycelium showed that despite a combination of low pH(ex) (1.8) and a high acid-secreting capacity, pH(cyt) and pH(vac) values were still well maintained (pH 7.5 and 6.4, respectively).

Antimetabolites↗

PubMedDate not supplied

Angiotensin and osmoreceptor inputs to the area postrema: role in long-term control of fluid homeostasis and arterial pressure.

1. The role of the area postrema (AP) in the long-term control of body fluid homeostasis and arterial pressure under conditions of increased dietary salt intake is reviewed. A model is proposed in which sympathetic nerve activity is suppressed when dietary salt is increased. It is hypothesized that the AP acts as an essential integrative site in the hind-brain for this response. 2. An essential component of the hypothesis is that basal levels of circulating angiotensin II support arterial pressure in animals consuming a normal salt diet by acting on the AP to drive sympathetic nerve activity. This hypothesis is supported by the observation that the long-term hypotensive response to losartan, the AT1 receptor antagonist, is attenuated in AP-lesioned (APx) rats. 3. The role of hepatoportal sodium receptors in signalling the AP about changes in dietary salt intake is discussed. Intragastric hypertonic saline infusion increases portal venous, but not systemic plasma, osmolality and increases Fos-like immunoreactivity in the AP, nucleus tractus solitarius and the supraoptic, paraventricular and lateral parabrachial nuclei. Other studies have shown that stimulation of these receptors decreases renal sympathetic nerve activity. 4. The hypothesis that the AP is critical in long-term control of arterial pressure and body fluid homeostasis under conditions of altered dietary salt intake was studied. The responses of arterial pressure and sodium and water balance to changes in dietary salt intake were measured in intact and APx rats. Contrary to the hypothesis, APx rats did not exhibit impaired regulation of arterial pressure or water balance. However, APx rats did demonstrate an impaired ability to excrete sodium when salt intake was elevated. 5. Based on these observations, it is concluded that the AP is important in the control of sodium balance, but not arterial pressure, when dietary salt intake is altered.

Angiotensin II↗

PubMed2003

Significance of endothelin on volume homeostasis in obese Zucker rats.

1. The present study explored the impact of endothelin (ET) and its interaction with renal sympathetic nerves in the control of volume homeostasis in obesity. 2. Groups of lean and obese Zucker rats with innervated and denervated kidneys were subjected to an acute isotonic saline volume expansion (VE), 10% bodyweight and renal haemodynamics and excretory function were evaluated following administration of SB209670 (a non-selective ET antagonist) or UK 350 926 (a selective ETA receptor antagonist). 3. Volume expansion in untreated obese rats resulted in a blunted cumulative urine sodium excretion (CuUNaV) after 40 min, VE compared with untreated lean rats being 36 and 51% in the denervated and innervated kidneys, respectively (both P < 0.001). 4. In lean rats, both SB209670 and UK 350 926 caused a depressed ability to excrete the saline load and CuUNaV after 40 min, VE compared with untreated being decreased by 51 and 60% in the denervated and innervated kidneys, respectively (both P < 0.001). 5. SB209670 and UK 350 926 given to obese rats reduced (both P < 0.001) CuUNaV after VE by 43% in denervated kidneys compared with untreated obese rats, whereas they were without effect on the magnitude of the excretory response in innervated kidneys. 6. These findings show that the blunted renal excretory responses to VE present in obese rats were not mediated by ET. Conversely, ET, acting through ETA receptors, plays a role as a diuretic and natriuretic factor in maintaining volume homeostasis by, at least in lean rats, renal nerve-independent mechanisms.

Animals↗

PubMed1996

beta 25-35 alters calcium homeostasis and induces neurotoxicity in cerebellar granule cells.

We studied the neurotoxic effects of beta 25-35 amyloid fragment (beta 25-35) on cerebellar granule cells and the intracellular mechanisms involved. Treatment for 3 days with peptide greatly reduced the survival of 1 day in vitro (DIV) cultures kept in 5 mM KCI but slightly modified the survival of 25 mM KCI-cultured cerebellar granule cells. We also studied the effect of glutamate on survival of undifferentiated cerebellar granules. We report no neurotoxic effect of glutamate on 3-DIV-treated cultures; whereas in beta 25-35-pretreated cells, a significant glutamate toxicity was observed. Treatment of 6-DIV cells with beta 25-35, performed with 25 mM KCI, induced a late but significant neurotoxic effect after 5 days of exposure, and death occurred within 8 days. Differentiated cerebellar granule cells were also sensitive to glutamate-related neurotoxicity, and this effect was enhanced by beta 25-35 pretreatment. To study the molecular mechanisms underlying the neurotoxic effects of beta 25-35, changes in calcium homeostasis after glutamate stimulation were evaluated in control and beta 25-35-treated cells. beta 25-35 did not affect basal [Ca2+]i but modified glutamate-induced [Ca2+]i increase, causing a sustained plateau phase that persisted even after the removal of the agonist. These results show that beta 25-35 induces neurotoxicity in cerebellar granule cells and that this effect is related to modifications in the control of calcium homeostasis.

Amyloid beta-Peptides↗

PubMed1997

Nitric oxide disrupts Ca2+ homeostasis in hippocampal neurons.

Nitric oxide has been recognized in recent years as an important mediator of neuronal toxicity, which in many cases involves alterations of the cytoplasmic Ca2+ concentration ([Ca2+]i). In [Ca2+]i fluorimetric experiments on cultured hippocampal neurons, the nitric oxide-releasing agent S-nitrosocysteine produced a delayed rise in [Ca2+]i over a 20-min exposure, which was accompanied by a progressive slowing of the kinetics of recovery from depolarization-induced [Ca2+]i transients. These effects were blocked by oxyhemoglobin and by superoxide dismutase, confirming nitric oxide as the responsible agent, and suggesting that they involved peroxynitrite formation. Similar alterations of [Ca2+]i homeostasis were produced by the mitochondrial ATP synthase inhibitor oligomycin, and when an ATP-regenerating system was supplied via the patch pipette in combined whole-cell patch-clamp-[Ca2+]i fluorimetry experiments, S-nitrosocysteine had no effect on the resting [Ca2+]i or on the recovery kinetics of [Ca2+]i transients induced by direct depolarization. We conclude that prolonged exposure to nitric oxide disrupts [Ca2+]i homeostasis in hippocampal neurons by impairing Ca2+ removal from the cytoplasm, possibly as a result of ATP depletion. The resulting persistent alterations in [Ca2+]i may contribute to the delayed neurotoxicity of nitric oxide.

Animals↗

PubMed1997

A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide.

Peroxidation of membrane lipids results in release of the aldehyde 4-hydroxynonenal (HNE), which is known to conjugate to specific amino acids of proteins and may alter their function. Because accumulating data indicate that free radicals mediate injury and death of neurons in Alzheimer's disease (AD) and because amyloid beta-peptide (A beta) can promote free radical production, we tested the hypothesis that HNE mediates A beta 25-35-induced disruption of neuronal ion homeostasis and cell death. A beta induced large increases in levels of free and protein-bound HNE in cultured hippocampal cells. HNE was neurotoxic in a time- and concentration-dependent manner, and this toxicity was specific in that other aldehydic lipid peroxidation products were not neurotoxic. HNE impaired Na+, K(+)-ATPase activity and induced an increase of neuronal intracellular free Ca2+ concentration. HNE increased neuronal vulnerability to glutamate toxicity, and HNE toxicity was partially attenuated by NMDA receptor antagonists, suggesting an excitotoxic component to HNE neurotoxicity. Glutathione, which was previously shown to play a key role in HNE metabolism in nonneuronal cells, attenuated the neurotoxicities of both A beta and HNE. The antioxidant propyl gallate protected neurons against A beta toxicity but was less effective in protecting against HNE toxicity. Collectively, the data suggest that HNE mediates A beta-induced oxidative damage to neuronal membrane proteins, which, in turn, leads to disruption of ion homeostasis and cell degeneration.

Aldehydes↗

PubMed1997

Disrupted [Ca2+]i homeostasis contributes to the toxicity of nitric oxide in cultured hippocampal neurons.

Nitric oxide (NO) has been shown to be an important mediator in several forms of neurotoxicity. We previously reported that NO alters intracellular Ca2+ concentration ([Ca2+]i) homeostasis in cultured hippocampal neurons during 20-min exposures. In this study, we examine the relationship between late alterations of [Ca2+]i homeostasis and the delayed toxicity produced by NO. The NO-releasing agent S-nitrosocysteine (SNOC; 300 microM) reduced survival by about one half 1 day after 20-min exposures, as did other NO-releasing agents. SNOC also was found to produce prolonged elevations of [Ca2+]i, persisting at 2 and 6 h. Hemoglobin, a scavenger of NO, blocked both the late [Ca2+]i elevation and the delayed toxicity of SNOC. Removal of extracellular Ca2+ during the 20-min SNOC treatment failed to prevent the late [Ca2+]i elevations and did not prevent the delayed toxicity, but removal of extracellular Ca2+ for the 6 h after exposure as well blocked most of the toxicity. Western blots showed that SNOC exposure resulted in an increased proteolytic breakdown of the structural protein spectrin, generating a fragment with immunoreactivity suggesting activity of the Ca2+-activated protease calpain. The spectrin breakdown and the toxicity of SNOC were inhibited by treatment with calpain antagonists. We conclude that exposures to toxic levels of NO cause prolonged disruption of [Ca2+]i homeostatic mechanisms, and that the resulting persistent [Ca2+]i elevations contribute to the delayed neurotoxicity of NO.

2-Amino-5-phosphonovalerate↗

PubMed1998

The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis.

During development, the interaction of stem cell factor (SCF) with its receptor, KIT, is critical for the survival of melanocytes. Limited in vivo human studies have suggested a possible activating role of SCF on adult human melanocytes. In order to study the impact of this pathway on normal melanocyte homeostasis, human skin xenografts were treated with serial injections of recombinant human SCF or a KIT-inhibitory antibody (K44.2). On histologic evaluation, SCF injection increased, whereas KIT inhibition decreased the number, size, and dendricity of melanocytes. Immunohistochemical expression of melanocyte differentiation antigens, including tyrosinase-related-protein-1 and gp100/pmel17, was markedly increased by treatment with SCF, and decreased by K44.2 treatment. The number of Ki67-positive melanocytes was increased in the SCF-treated tissue, suggesting a direct proliferative effect of SCF; conversely, treatment with K44.2 resulted in melanocyte loss, which did not appear reversible with prolonged treatment. These findings demonstrate that the SCF/KIT pathway remains critical in adult human skin, and that pharmacologic modulation of this single pathway can control cutaneous melanocyte homeostasis.

Animals↗

PubMed2001

Testosterone perturbs epidermal permeability barrier homeostasis.

Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerate whereas testosterone retards barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates. Moreover, prenatal administration of the androgen receptor antagonist, flutamide, equalizes developmental rates in male and female fetuses. Therefore, we evaluated the effects of changes in testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal mice (whether by castration or by treatment with systemic flutamide) displayed significantly faster barrier recovery at 3, 6, and 12 h than did controls, and testosterone replacement slowed barrier recovery in castrated mice. Moreover, testosterone directly effects the skin, as topical flutamide also accelerated barrier recovery in normal male mice. These findings appear to be of physiologic significance, since prepubertal male mice (age 5 wk) displayed accelerated barrier recovery in comparison with adult postpubertal (11 wk) males. These studies also appear to be relevant for humans, as a hypopituitary human subject demonstrated repeated changes in barrier recovery in parallel with peaks and nadirs in serum testosterone levels during intermittent testosterone replacement. Mechanistic studies showed that differences in epidermal lipid synthesis do not account for the testosterone-induced functional alterations. Instead, epidermal lamellar body (LB) formation and secretion both decrease, resulting in decreased extracellular lamellar bilayers in testosterone-replete animals. These studies demonstrate that fluctuations in testosterone modulate barrier function, and that testosterone repletion can have negative consequences for permeability barrier homeostasis.

Animals↗

PubMed2003

NMDA-type glutamate receptor is associated with cutaneous barrier homeostasis.

Glutamate receptors play an important role in the excitatory synaptic action of the central nervous system. In this study, effects of glutamate receptor agonists and antagonists on skin barrier homeostasis were studied using hairless mouse. Topical application of L-glutamic acid, L-aspartic acid (non-specific glutamate receptor agonists) and N-methyl-D-aspartate (NMDA, NMDA type receptor agonist) delayed the barrier recovery rate after barrier disruption with tape stripping. On the other hand, topical application of D-glutamic acid (non-specific antagonist of glutamate receptor), MK 801 and D-AP5, (NMDA-type receptor antagonists) accelerated the barrier repair. The non-NMDA type receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), did not affect the barrier recovery. Topical application of MK-801 also promoted the healing of epidermal hyperplasia induced by acetone treatment under low environmental humidity. Immediately after barrier disruption on skin organ culture, secretion of glutamic acid from skin was significantly increased. Immunohistochemistry, reverse transcription polymearse chain reaction (RT-PCR) and in situ hybridization showed an expression of NMDA-type receptor-like protein on hairless mouse epidermis. NMDA increased intercellular calcium in cultured human keratinocytes and the increase was blocked by MK 801. These results suggest that glutamate plays an important role as a signal of cutaneous barrier homeostasis and epidermal hyperplasia induced by barrier disruption.

Animals↗

PubMed2004

[Is the ileal bile acid-binding protein (I-BABP) gene involved in cholesterol homeostasis?].

In the body, cholesterol balance results from an equilibrium between supplies (diet and cellular de novo synthesis), and losses (cellular use and elimination in feces, essentially as bile acids). Bile acids are synthesized from cholesterol in the liver. After conjugation to glycine or taurine, bile acids are secreted with bile in the intestinal lumen where they actively participate to the digestion and absorption of dietary fat and lipid-soluble vitamins. In healthy subjects, more than 95% of bile acids are reabsorbed throughout the small intestine and returned by the portal vein to the liver, where they are secreted again into bile. This enterohepatic circulation is essential for maintenance of bile acids balance, and hence, for cholesterol homeostasis. Indeed, the bile acids not reclaimed by intestinal absorption constitute the main physiological way to eliminate a cholesterol excess. Little is known about the molecular mechanisms controlling bile acids reabsorption by the small intestine. The intestinal bile acids uptake mainly takes place through an active transport located in the distal part of the small intestine. To date, four unrelated proteins exhibiting a high affinity for bile acids have been identified in the ileum, and only one, the ileal bile acid-binding protein (I-BABP) is a soluble protein. Therefore, it is thought to be essential for efficient bile acids desorption from the apical plasma membrane, as well as for bile acids intracellular trafficking and targeting towards the basolateral membrane. If this assumption is correct, the I-BABP expression level might be rate limiting for the enterohepatic bile acids circulation, and hence, for cholesterol homeostasis. It was found that both bile acids and cholesterol, probably via oxysterols, are able to up-regulate the transcription rate of I-BABP gene. The fact that intracellular sterol sensors (FXR, LXR, and SREBP1c) are involved in the control of the I-BABP gene expression strongly suggests that I-BABP exerts an important role in maintenance of cholesterol balance.

Animals↗