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At least 973 records · Page 54Linked to original sources
PubMed1986

Bile acid secretion in cystic fibrosis: evidence for a defect unrelated to fat malabsorption.

In order to define basic biliary defects not related to steatorrhoea in cystic fibrosis, we studied 12 control and 18 cystic fibrosis subjects, with a wide range of pancreatic function. Duodenal aspirates were collected over three consecutive 20 minute periods, during continuous intravenous infusion of cholecystokinin and secretin using a marker perfusion technique, and analysed for pancreatic enzyme output (colipase, lipase, trypsin), bile acid output and concentration, and biliary lipids. Cystic fibrosis patients, at all levels of pancreatic function, had significantly reduced total bile acid output (mumol/kg/h) with delayed appearance of the bile acid peak, compared with control subjects. Actual duodenal bile acid concentrations were significantly higher in cystic fibrosis subjects than in controls, however, probably because of the markedly reduced water output shown in these patients. The lithogenic index was not raised in cystic fibrosis patients at any level of pancreatic function. The reduced bile acid output and the delayed peak appearance probably reflect a defect in gall bladder responsiveness which is independent of pancreatic function and steatorrhoea. Whether this defect is related to gall bladder filling or a defective peptide hormone response awaits further study.

Adolescent↗
PubMed1998

Genetic defects in the control of growth hormone secretion.

Since growth hormone deficiency (GHD) causes short stature and metabolic derangements, the processes which control its release are important physiologically. These processes can be illuminated by an understanding of genetically determined GHD. In 2 Indian Moslem cousins from a consanguineous family, GHD resistant to growth hormone releasing hormone (GHRH) stimulation was found. No mutations were found in the growth hormone gene (GH1) (J. Phillips). The receptor for GHRH (GHRHR), implicated in the dwarfism of the little mouse, thus becomes a candidate gene to explain their GHD. Amplification and sequencing a region of GHRHR homologous to that mutated in the little mouse showed a mutation (265G*T) leading to a stop codon at position 72 which would completely prevent GHRHR expression. Subsequently, Maheshwari et al. found an identical mutation in a multiplex kindred from Sindh, Pakistan, about 800 km from the place of origin of our patients. GHD is more commonly caused by recessive or dominant mutations of GH1. The latter are of great interest in understanding the mechanism of GH secretion. In a large kindred with dominant GHD we found a heterozygous 666G*A mutation replacing of Arg with His at amino acid 183. We speculate that the introduced histidine interferes with interactions necessary for correct GH secretion.

Adolescent↗
PubMed1993

Characterization of defective phorbol ester responses in a low secreting rat basophilic leukemia (RBL-2H3) cell variant.

The role of protein kinase C (PKC) in the signaling mechanism that stimulates the release of mediators from rat mast cells, for which the RBL-2H3 cell line is a model, is at present unresolved. Current evidence suggests that PKC activation alone is an insufficient stimulus, although it can modulate mast cell exocytosis induced by other agents. In this article we characterize a variant of the RBL-2H3 cell line that has a reduced capacity for mediator secretion in response to an IgE-mediated antigen-induced stimulation. The outcome of our study suggests that at least two PKC isotypes are active in RBL-2H3 cells, and affect the positive and negative modulation of the secretory response.

Actins↗
PubMed1989

Vasopressin secretion in the DIDMOAD (Wolfram) syndrome.

The diabetes insipidus which accompanies the DIDMOAD (Wolfram) syndrome is thought to be hypothalamic in origin, though no formal study of vasopressin secretion in the syndrome has been published, and some data in the literature suggest a renal tubular defect. We have studied vasopressin secretion in seven patients with the Wolfram/DIDMOAD syndrome during three dynamic stimuli: an osmotic stimulus (hypertonic saline infusion), hypoglycaemia (insulin tolerance test) and a baroregulatory stimulus (trimetaphan infusion). Hypertonic saline infusion demonstrated three patients to have complete and four to have partial hypothalamic diabetes insipidus; administration of (per nasal) desmopressin excluded nephrogenic diabetes insipidus in all seven patients. Insulin hypoglycaemia failed to stimulate vasopressin release, but trimetaphan-induced hypotension produced significant though subnormal rises in plasma vasopressin in three patients with partial diabetes insipidus, though it produced a negligible rise and no rise in plasma vasopressin in two patients with complete diabetes insipidus. The data suggest a much greater frequency of hypothalamic diabetes insipidus in the Wolfram/DIDMOAD syndrome than is reported, but did not identify nephrogenic diabetes insipidus. The absence of vasopressin responses to non-osmotic stimuli in patients with complete diabetes insipidus suggests global lack of vasopressin secreting neurones, rather than an isolated osmoreceptor defect or selective vasopressin secreting neuronal loss, as the lesion producing diabetes insipidus in the DIDMOAD syndrome.

Adult↗
PubMed1999

P-type ATPase spf1 mutants show a novel resistance mechanism for the killer toxin SMKT.

SMKT, a killer toxin produced by the halotolerant yeast Pichia farinosa KK1, consists of alpha and beta subunits with folding remarkably similar to that of the fungal killer toxin KP4, a Ca2+ channel inhibitor. The budding yeast Saccharomyces cerevisiae is sensitive to SMKT. To understand the killing mechanism of SMKT, we isolated SMKT-resistant mutants of S. cerevisiae and characterized them. Five spf mutants (sensitivity to the P. farinosa killer toxin) fell into a single genetic complementation group, designated spf1. The SPF1 gene was cloned by complementation of the mutant phenotype. The SPF1 gene encodes a putative P-type ATPase of 1215 amino acid residues that contains 12 membrane-spanning regions. Gene disruption revealed that the SPF1 gene is not essential for viability but is required for the sensitivity to SMKT. The spf1 disruptant showed some phenotypes characteristic of glycosylation-defective mutants and secreted underglycosylated invertase. Fluorescence-activated cell-sorting analysis and indirect immunofluorescence microscopy showed that SMKT interacts with the cell surface of the resistant cells but not with that of sensitive cells, suggesting a novel resistance mechanism for this toxin. The glycosylation-defective phenotype and possible killer-resistant mechanisms are discussed in comparison with the Golgi Ca2+ pump Pmr1p.

ATP-Binding Cassette Transporters↗
PubMed2006

Type IV pili-mediated secretion modulates Francisella virulence.

Francisella tularensis are the causative agent of the zoonotic disease, tularaemia. Among four F. tularensis subspecies, ssp. novicida (F. novicida) is pathogenic only for immunocompromised individuals, while all four subspecies are pathogenic for mice. This study utilized proteomic and bioinformatic approaches to identify seven F. novicida secreted proteins and the corresponding Type IV pilus (T4P) secretion system. The secreted proteins were predicted to encode two chitinases, a chitin binding protein, a protease (PepO), and a beta-glucosidase (BglX). The transcription of F. novicida pepO and bglX was regulated by the virulence regulator MglA. Intradermal infection of mice with F. novicida mutants defective in T4P secretion system or PepO resulted in enhanced F. novicida spread to systemic sites. Infection with F. novicida pepO mutants also resulted in increased neutrophil infiltration into the mouse airways. PepO is a zinc protease that is homologous to mammalian endothelin-converting enzyme ECE-1. Therefore, secretion of PepO likely results in increased production of endothelin and increased vasoconstriction at the infection site in skin that limits the F. novicida spread. Francisella human pathogenic strains contain a mutation in pepO predicted to abolish its secretion. Loss of PepO function may have contributed to evolution of highly virulent Francisellae.

Animals↗
PubMed1993

Developmental and sex-related changes of the growth hormone axis in lean and obese Zucker rats.

The development and sex-related changes in the hypothalamic-pituitary GH axis were examined in lean and obese Zucker male and female rats from 6 to 12 weeks of age. Pituitary GH content was not different in any phenotype/sex group at 6 weeks. GH content increased with age in male rats, but at 10 and 12 weeks content was decreased in obese male rats relative to lean rats. GH content did not increase in female rats and there was no difference in content between lean and obese female rats. Hypothalamic GHRH content was not different between the groups. Hypothalamic SS content was decreased in obese male rats compared to lean male rats (95%) and in obese female rats compared to lean female rats (78%). Individual 6-hour plasma GH profiles from rats 6-7 weeks of age showed the characteristic sexually dimorphic GH secretory patterns. However, spontaneous GH secretion was dramatically reduced in obese animals when compared to sex-matched lean rats. GH peak amplitude (25% of lean) and mean GH concentration (19% of lean) were decreased in obese male rats without a significant alteration in GH peak frequency or baseline level. In obese female rats, the number of GH peaks, peak amplitude, baseline GH, and mean GH concentration were all decreased compared to lean. The reduction in peak amplitude (14% of lean) and in mean GH concentration (20% of lean) was similar to the reduction in obese male rats. Serum IGF-I concentrations were not different among the groups at 6 weeks. IGF-I levels in male rats increased with age but were not different between lean and obese rats. IGF-I concentrations in female rats were unchanged with time and were not different between lean and obese rats. Serum insulin was increased in obese male and female rats at 6 through 12 weeks. We conclude (1) GH secretion is depressed at 6-7 weeks in obese male and female rats with the magnitude of reduction similar to previous observations in male rats 12 weeks or older; (2) pituitary GH content is depressed only in obese male rats and occurs after the defect in GH secretion; (3) hypothalamic GHRH content is unchanged and hypothalamic SS is slightly to moderately decreased in obese rats; (4) serum IGF-I is not different between lean and obese rats; (5) obese male and female rats were hyperinsulinemic.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed2002

Dendritic cells in innate immune responses against HIV.

Dendritic cells (DCs) were recently found to be innate immunity effectors against tumoral cells and viruses. (i) In response to most viruses, including HIV, plasmacytoid DCs are responsible for most of the type I IFN secretion, which is strongly anti-viral and induces TH1 type responses. Myeloid DCs secrete IL-12, which is also important for TH1-type and cytotoxic responses. In HIV patient blood, both DC population numbers decrease as early as the primary stage. Plasmacytoid DC numbers correlate with type I IFN secretion, which is a prognosis predictor, particularly under treatment. IL-12 secretion is also defective. Immunotherapies to replace the defective cytokines or to restore a potentially defective DC-T lymphocyte feed-back might help patients restore their immune responses under antiviral therapy. (ii) After measles and other viral infections, or incubation with dsRNA, DCs become cytotoxic and consequently exhibit natural killer function, through upregulation of type I IFN secretion which enhances TRAIL expression. In HIV infection, this mechanism was not demonstrated yet, but it might a) be responsible for the massive apoptosis of uninfected lymphocytes, and b) increase specific immunity through cross-presentation of antigens from infected cells killed by DCs. (iii) DCs direct expansion and effector functions of NK cells in the absence of adaptive-type cytokines and modulate NKT cell IFN-gamma production. Reciprocally, NK activation triggers DC maturation. HIV-1 Tat inhibits NK cell cytotoxicity directly and probably through inhibition of IL-12 secretion by DC. Therefore, understanding the functions of DCs in innate immune responses and in pathogenesis will help obtain better HIV replication control.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Glucose metabolism in obese subjects: lessons from OGTT, IVGTT and clamp studies.

Impaired glucose tolerance and overt diabetes are more frequent in presence than in absence of obesity. In obese subjects, glucose tolerance can be maintained within the normal range by compensating for insulin resistance by peripheral hyperinsulinism, the latter resulting from both increased insulin secretion and reduced insulin clearance. Impaired glucose tolerance is observed when insulin resistance is associated to impaired first-phase insulin response, which results in a significant increase in plasma glucose levels and a late insulin hyperresponsiveness. Both hyperinsulinaemia and hyperglycaemia are then able to overcome peripheral insulin resistance and impaired glucose disposal. When a more marked defect in insulin secretion is present, hyperglycaemia progresses, probably due to an additional participation of impaired suppression of hepatic glucose output. Overt diabetes then occurs with persistent post-absorptive hyperglycaemia. All these abnormalities can be reversed after a marked weight loss and recovery of ideal body weight, arguing for acquired rather than inherited metabolic defects in presence of morbid obesity. If a sufficient weight reduction can not be obtained, pharmacological approaches may be considered to improve insulin resistance of obese subjects, especially those with impaired glucose tolerance or overt diabetes.

Blood Glucose↗
PubMed1982

Acquired distal renal tubular acidosis in man.

Distal renal tubular acidosis (dRTA) may complicate renal transplantation, liver cirrhosis, and obstructive uropathy. Indeed, its occurrence may be an early clue to an episode of rejection of the graft or to obstructive uropathy. The mechanism in most patients with dRTA is impaired distal secretion of protons. In some patients, however, back leak of protons from tubular lumen to blood may abolish distal tubular ability to maintain urine to blood proton gradients. In patients with obstructive uropathy the spectrum of tubular acidosis is widened by the occurrence of additional defects in tubular secretion of potassium and impairment of hydrogen ion secretion secondary to hypoaldosteronism. Hyperkalemia is also seen in "voltage dependent" states such as following the administration of lithium and amiloride. Hyperkalemia per se is conducive to acidosis by a combination of extrarenal and several intrarenal mechanisms.

Acidosis, Renal Tubular↗
PubMed1995

Mutational analysis of the Yersinia enterocolitica virC operon: characterization of yscE, F, G, I, J, K required for Yop secretion and yscH encoding YopR.

Pathogenic yersiniae secrete the Yop anti-host proteins using a type-III secretion pathway. The components of the secretion machinery are encoded by three loci on the pYV plasmid: virA, virB, and virC. In this paper we describe the characterization of eight non-polar mutants of the virC locus, constructed by allelic exchange. The yscE, FG, I, J and K mutants were defective in Yop secretion and independent of Ca2+ (CI) for their growth at 37 degrees C. Substitution of the 12 N-terminal amino-acid residues of YscF impaired secretion of YopB and YopD only and led also to a CI phenotype. The culture supernatant of the yscH mutant contained all the Yops except the 18 kDa YopR. Complementation experiments and an immunoblot analysis confirmed that YopR is encoded by the yscH gene. The LD50 for the mouse of the yscH mutant was 10-fold higher than that of the parental strain indicating that YopR is involved in pathogenesis. The phenotype of the yscM mutant was similar to that of the wild-type strain. However, overproduction of YscM from a multicopy plasmid in wild-type Yersinia enterocolitica prevented Yop secretion and synthesis. A hybrid YopH-LacZ' protein, encoded by a gene transcribed from the lac promoter, was secreted by a strain overexpressing YscM, showing that the secretion machinery was still functional. These results indicate that YscM plays a role in the feedback inhibition of Yop synthesis when secretion is compromised by acting as a negative regulator of Yop synthesis.

Bacterial Proteins↗
PubMed1995

Functions of the internal pre-S domain of the large surface protein in hepatitis B virus particle morphogenesis.

The large hepatitis B virus (HBV) surface protein (L) forms two isomers which display their N-terminal pre-S domain at the internal and external side of the viral envelope, respectively. The external pre-S domain has been implicated in binding to a virus receptor. To investigate functions of the internal pre-S domain, a secretion signal sequence was fused to the N terminus of L (sigL), causing exclusive expression of external pre-S domains. A fusion construct with a nonfunctional signal (s25L), which corresponds in its primary sequence to sigL cleaved by signal peptidase, was used as a control. SigL was N glycosylated in transfected COS cells at both potential sites in pre-S in contrast to s25L or wild-type L, confirming the expected transmembrane topologies of sigL and s25L. Phenotypic characterization revealed the following points. (i) SigL lost the inhibitory effect of L or s25L on secretion of subviral hepatitis B surface antigen particles, suggesting that the retention signal mapped to the N terminus of L is recognized in the cytosol and not in the lumen of the endoplasmic reticulum. (ii) SigL was secreted into the culture medium even in the absence of the major HBV surface protein (S), while release of an L mutant lacking the retention signal was still dependent on S coexpression. (iii) s25L but not sigL could complement an L-negative HBV genome defective for virion secretion in cotransfections. This suggests that the cytosolic pre-S domain, like a matrix protein, is involved in the interaction of the viral envelope with preformed cytosolic nucleocapsids during virion assembly.

Animals↗
PubMed1993

Constitutive hypersecretion and insensitivity to neurotransmitters by cystic fibrosis tracheal gland cells.

Submucosal glands are the major mucus-secreting cells in the tracheobronchial tree, and they appear to be affected in cystic fibrosis (CF). To study the dysregulation of pulmonary secretion in CF, human tracheal glandular (HTG) cells were isolated from tracheal mucosa of CF patients undergoing bipulmonary transplantation and compared with normal HTG cells. The cells were cultured in Dulbecco's modified Eagle's-Ham's F-12 medium supplemented with Ultroser G, on collagen type 1-coated dishes. We observed that the secretion rates for the three specific serous secretory markers: bronchial inhibitor (BrI), lysozyme, and lactoferrin were 10, 20, and 50 times higher, respectively, in CF-HTG cells than in normal HTG cells. Furthermore, the two physiological neurotransmitters: acetylcholine and norepinephrine, which have opposite actions on the secretion of BrI (suggesting that these neurotransmitters acted as regulators of secretion) did not induce the significant modification of protein secretion observed with normal HTG cells. In combination with forskolin and calcium ionophore A23187, secretion of BrI was minimally modified, indicating a lack of responsiveness of CF-HTG cells to these agonists. In conclusion, CF-HTG cells in culture show a constitutive hypersecretion and an hyporesponsiveness to agonists. They provide a useful tool to study the regulation defect of bronchial secretion observed in CF.

Acetylcholine↗
PubMed2002

Protein S Gla-domain mutations causing impaired Ca(2+)-induced phospholipid binding and severe functional protein S deficiency.

We have identified 2 PROS1 missense mutations in the exon that encodes the vitamin K-dependent Gla domain of protein S (Gly11Asp and Thr37Met) in kindred with phenotypic protein S deficiency and thrombosis. In studies using recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor Va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (P <.001) and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (P <.0001) and decreased affinity for an antibody specific for the Ca(2+)-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only a modest 1.5-fold (P <.001), reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterization of natural protein S Gla-domain variants highlights the importance of the high affinity protein S-phospholipid interaction for its anticoagulant role.

Alleles↗
PubMed2000

A proposed model for the assembly of chylomicrons.

The intestine synthesizes very low density lipoproteins (VLDL) and chylomicrons (CM) to transport fat and fat-soluble vitamins into the blood. VLDL assembly occurs constitutively whereas CM assembly is a characteristic property of the enterocytes during the postprandial state. The secretion of CM is specifically inhibited by Pluronic L81. CM are very heterogeneously-sized particles that consist of a core of triglycerides (TG) and cholesterol esters and a monolayer of phospholipids (PL), cholesterol and proteins. The fatty acid composition of TG, but not PL, in CM mirrors the fatty acid composition of fat in the diet. CM assembly is deficient in abetalipoproteinemia and CM retention disease. Abetalipoproteinemia results due to mutation in the mttp gene and is characterized by the virtual absence of apoB-containing lipoproteins in the plasma. Patients suffer from neurologic disorders, visual impairment, and exhibit acanthocytosis. CM retention disease, an inherited recessive disorder, is characterized by chronic diarrhea with steatorrhea in infancy, abdominal distention and failure to thrive. It is caused by a specific defect in the secretion of intestinal lipoproteins; secretion of lipoproteins by the liver is not affected. Besides human disorders, mice that do not assemble intestinal lipoproteins have been developed. These mice are normal at birth, but defective in fat and fat-soluble vitamin absorption, and fail to thrive. Thus, fat and fat-soluble vitamin transport by the intestinal lipoproteins is essential for proper growth and development of neonates. Recently, differentiated Caco-2 cells and rabbit primary enterocytes have been described that synthesize and secrete CM. These cells can be valuable in distinguishing between the two different models proposed for the assembly of CM. In the first model, the assembly of VLDL and CM is proposed to occur by two 'independent' pathways. Second, CM assembly is proposed to be a product of 'core expansion' that results in the synthesis of lipoproteins of different sizes. According to this model, intestinal lipoprotein assembly begins with the synthesis of 'primordial' lipoprotein particles and involves release of the nascent apoB with PL derived from the endoplasmic reticulum (ER) membrane. In addition, TG-rich 'lipid droplets' of different sizes are formed independent of apoB synthesis. The fusion of lipid droplets and primordial lipoproteins results in the formation of different size lipoproteins due to the 'core expansion' of the primordial lipoproteins.

Animals↗
PubMed1989

[Clinical value of inhibin in women].

Inhibin is a peptide secreted in women by the granulosa cells, the corpus luteum and the placenta. This hormone specifically inhibits pituitary FSH secretion. Recent studies have shown that the serum concentration of bioactive and immunoactive inhibin may represent a valuable marker of follicular and luteal functions. Inhibin may also contribute with estrogen and progesterone to FSH suppression during the luteal phase and in pregnancy. Evidence was found that a defect in inhibin secretion is involved in premature ovarian failure and the menopause but not in the polycystic ovary syndrome.

Female↗
PubMed1993

Both somatostatin and insulin responses to glucose are impaired in the perfused pancreas of the spontaneously noninsulin-dependent diabetic GK (Goto-Kakizaki) rats.

We have studied the responses of insulin and somatostatin to glucose and arginine in the perfused pancreas of GK rats, which spontaneously develop mild noninsulin-dependent diabetes without concomitant obesity. Our GK rats have been obtained after at least 42 generations of inbreeding of Wistar rats with initial selection for increased blood glucose levels during glucose tolerance tests. During perfusion with a high (16.7 mmol l-1) glucose concentration, normal responses of insulin and somatostatin were found in pancreata from non-diabetic control rats. In GK pancreata, however, these responses were virtually abolished. When the glucose concentration of the perfusion medium was switched from 16.7 to 3.3 mmol l-1 glucose, a transient increase- 'off-response' -in both insulin and somatostatin secretion was noted in GK but not in control pancreata. During the subsequent stimulation with arginine (20 mmol l-1), insulin and somatostatin responses were similar in pancreata from non-diabetic and GK rats. The pancreatic content of insulin did not differ between non-diabetic and GK rats, whereas the content of somatostatin was increased by 56% (P < 0.025) in GK glands. In conclusion, abnormalities assigned to pancreatic hormone secretion in the GK rat comprise not only markedly impaired insulin but also somatostatin response to glucose. Since there was no decrease in pancreatic content of these hormones in GK rats, the cause of glucose insensitivity of the hormone-producing cells is likely to reside in a defective stimulus-secretion coupling rather than decreased availability of the hormones.

Animals↗