SEARCH · PubMed Health

Results for “Type VII secretion”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

159 records · Page 9Linked to original sources

PubMed1999

Compound heterozygosity (554-589 del, C515-T transition) in the platelet glycoprotein Ib alpha gene in a patient with a severe bleeding tendency.

Giant platelets in the blood smear, absent in vitro platelet agglutination in response to ristocetin, and normal aggregation, ATP secretion and thromboxane B2 formation were found in a young patient with a life-long bleeding tendency. Ristocetin-induced von Willebrand factor binding to her platelets was less than 10% of normal. Flow cytometric analysis with monoclonal antibodies LJ-Ib-1, LJ-Ib-10, and LJ-P3 was consistent with the latter finding. SDS-PAGE analysis of solubilized platelets showed a marked reduction of the platelet glycoprotein (GP) Ibalpha. Genetic characterisation demonstrated that the patient and her father were heterozygous for a deletion of 36 nucleotides (positions 554-589) leading to a mutant GPIalpha (deletion of aminoacids from residue 169 to 180 and a Glu --> Lys substitution at residue 181). In addition, a C --> T transition at nucleotide 515 in the other allele of the GPIbalpha gene was found in the patient and in her mother that results in the substitution of alanine for valine in codon 156 (Bernard-Soulier type Bolzano). These variations occurred within the VI and VII leucine-rich repeats. The novel variant of Bernard-Soulier syndrome identified further suggests that the integrity of leucine-rich repeats is important for normal function of the GP Ib-IX-V receptor complex.

Adult↗

PubMed2006

Encapsulation cell therapy for mucopolysaccharidosis type VII using genetically engineered immortalized human amniotic epithelial cells.

Mucopolysaccharidosis type VII (MPSVII) is a lysosomal storage disease resulted from a deficiency of the enzyme beta-glucuronidase (GUSB), which is necessary for degradation of glycosaminoglycans (GAGs). The deficiency of GUSB causes progressive accumulation of GAGs and subsequent lysosomal distension in multiple tissues, including the central nervous system (CNS). In murine experiments, bone marrow transplant, enzyme replacement, viral vectors, and genetically modified cells were successfully used for correction of the visceral accumulation of GAGs, but little improvement was seen in the brain, because these therapeutic agents cannot cross the blood-brain barrier (BBB). Although direct intracerebral injection of GUSB-encoding viral vectors has been developed to bypass the BBB, the possibility of tumor formation and the toxicity of over-expressed GUSB have been reported. In this study, we generated immortalized human amniotic epithelial (IHAE) cells to maintain the effect of implantation, and encapsulated these cells to prevent harmful immunological response and tumor formation and to regulate the level of GUSB expression within the host. Moreover, we generated IHAE cells that over-express and secrete human GUSB following transduction with an adenoviral vector encoding human GUSB. Therapeutic efficacy for MPSVII was evaluated in and ex vivo experiments using these encapsulated genetically engineered GUSB-encoding IHAE cells. We confirmed that encapsulated genetically engineered IHAE cells could secrete significant amounts of GUSB outside the capsule in vitro and into the cerebral parenchyma of C3H mice seven days after the capsule implantation. Thus, encapsulation cell therapy using genetically engineered IHAE cells is an effective armamentarium for the treatment of MPSVII.

Amnion↗

PubMedDate not supplied

Pathophysiology of impaired pulsatile insulin release.

Plasma insulin displays 5-10 min oscillations. In Type 2 diabetes the regularity of the oscillations disappears, which may lead to insulin receptor down-regulation and glucose intolerance and explain why pulsatile delivery of the hormone has a greater hypoglycemic effect than continuous delivery. The rhythm is intrinsic to the islet. Variations in metabolism, cytoplasmic Ca(2+) concentration ([Ca(2+)](i)), other hormones, neuronal signaling and possibly beta-cell insulin receptor expression have been implicated in the regulation of plasma insulin oscillations. Most of these factors are important for amplitude-regulation of the insulin pulses. Although evidence exists supporting a role of both metabolism and [Ca(2+)](i) as pacemakers of the pulses, metabolic oscillations probably have a primary role and [Ca(2+)](i) oscillations a permissive role. Results from islets from animal models of diabetes suggest that altered plasma insulin pattern could be due to lowering of pulse amplitude of insulin oscillations rather than alterations in their frequency. Supporting a role of metabolism, altered plasma insulin oscillations were found in MODY2, MIDD and glycogenosis Type VII, which are linked to alterations in glucokinase, mitochondrial tRNALeu(UUR) and phosphofructokinase. Plasma insulin oscillations require coordination of islet secretory activities in the pancreas. The intrapancreatic ganglia have been suggested as coordinators. The diabetes-associated neuropathy may contribute to the deranged pattern as indicated by glucose intolerance in chagasic patients. Continued investigation of the role and regulation of pulsatile insulin release will lead to better understanding of the pathophysiology of impaired pulsatile insulin release, which could lead to new approaches to restore normal plasma insulin oscillations in diabetes and related diseases.

Activity Cycles↗

PubMedDate not supplied

Human islets of Langerhans express the delta(C) isoform of calcium/calmodulin-dependent protein kinase II.

BACKGROUND: There is considerable evidence that calcium/calmodulin-dependent protein kinase II (CaM kinase II) plays a key role in insulin secretion and the enzyme provides a candidate gene for Type 2 diabetes. Since several isoforms of the enzyme exist, it is essential to define which are expressed by the beta-cell. METHODS: A human islet cDNA library in lambdaZAPII was screened with a probe for the 5'-end of human gamma CaM kinase II. Since this region is very homologous between the different isoforms, it is expected that isoforms other than gamma would be detected. From each of the six positive clones obtained, DNA was prepared and subjected to PCR using primers spanning the variable region in which the main variability of CaM kinase II isoforms resides. PCR products were purified and sequenced in both directions. The beta-cell line MIN6 was screened for CaM kinase II delta by reverse transcriptase-polymerase chain reaction (RT-PCR) and by Western blotting. RESULTS: The sequences of five of the human islet PCR products indicated that the clones corresponded to the gamma(B) isoform whose expression in human islets we have previously documented. The other PCR product, however, gave a sequence containing the variable domains II and VII characteristic of CaM kinase II delta. This sequence and the absence of other domains in this region identified the clone as CaM kinase II delta(C). The expression of CaM kinase II delta in MIN6 beta-cells was confirmed by RT-PCR and by Western blotting. CONCLUSIONS: Human islets of Langerhans express the delta(C) isoform of CaM kinase II.

Amino Acid Sequence↗

PubMed1993

Identification, ontogeny, and regulation of an interleukin-6-like factor in the rat seminiferous tubule.

The present study's aims are to search for the presence of interleukin-6 bioactivity (IL-6) in medium conditioned by various testicular cell types and to investigate the cellular and hormonal regulation of testicular IL-6 production. Sertoli cells prepared from rats of increasing ages (20, 35, and 45 days) secreted IL-6 in vitro, whereas medium conditioned by pachytene spermatocytes, early spermatids, and peritubular cells showed no activity. Lipopolysaccharide (LPS) and latex beads, two known stimulators of monocyte/macrophage IL-6 production, markedly stimulated IL-6 secretion by Sertoli cells at all the ages investigated. Maximum levels of IL-6 were reached after 6 h of culture of Sertoli cells with LPS and after 24 h with latex beads. When Sertoli cells were cocultured with pachytene spermatocytes, early spermatids, or fractions containing residual bodies and cytoplasts from elongated spermatids, only the latter significantly stimulated IL-6 levels. Maximum levels of IL-6 were attained by adding 2 x 10(6) residual bodies to Sertoli cells; a significant increase in IL-6 secretion was seen after 6 h, and maximum levels were observed after 24 h. The levels of IL-6 varied throughout different stages of the seminiferous epithelium cycle; highest levels were observed in stages II-VI and lowest in stages VII-VIII. IL-6 bioactivities induced by LPS and residual bodies and cytoplasts from elongated spermatids could be totally neutralized with a specific monoclonal antibody at all of the ages studied. FSH, phorbol myristate acetate, and IL-1 alpha augmented Sertoli cell IL-6 secretion in a dose-dependent manner. Furthermore, FSH and (Bu)2cAMP differentially stimulated IL-6 secretion during the seminiferous epithelial cycle. It is concluded that the release of IL-6 from Sertoli cells is regulated by a complex interplay between residual bodies and humoral factors.

Aging↗

PubMed1996

Central nervous system cell transplantation: a novel therapy for storage diseases?

Many methods of gene transfer to the brain are under study. One employs a neural stem cell based strategy. Transplanting neural progenitor cells that intrinsically secrete missing or therapeutic gene products, or are genetically engineered ex vivo to do so, may provide a strategy for long-term treatment of central nervous system manifestations of a number of neurogenetic diseases. Multipotent neural progenitors or stem cells (or cells that mimic their behavior) are capable of differentiating along multiple central nervous system cell-type lineages. They can engraft as integral members of normal structures throughout the host central nervous system without disturbing other neurobiological processes. They can also be easily genetically manipulated ex vivo. By exploiting their basic biological properties, these cells may be able to deliver therapeutic gene products in a sustained, direct, and perhaps regulated fashion throughout the central nervous system. Furthermore, although they may disseminate these gene products throughout the brain, they nevertheless restrict that distribution to only the central nervous system. Thus, these vehicles may overcome many of the limitations of viral and non-neural cellular vectors, as well as pharmacologic and genetic interventions. The feasibility of this neural stem cell-based strategy has been demonstrated by correcting the widespread central nervous system pathology of a murine model of a prototypical inherited neurodegenerative disease, mucopolysaccharidosis type VII. These studies have helped to establish the use of such cells as a paradigm for transferring other molecules of therapeutic or developmental interest throughout the central nervous system at many ages.

Animals↗

PubMed1994

Gene therapy for lysosomal disorders.

Genetic defects of lysosomal hydrolases result in severe storage diseases and treatments based on enzyme replacement have been proposed. In mice lacking beta-glucuronidase, which develop a disease homologous to human mucopolysaccharidosis type VII (MPS VII, sly syndrome), we have used autologous implants of genetically-modified cells for the continuous in vivo production of the enzyme. A retroviral vector containing the human beta-glucuronidase cDNA under the control of the mouse phosphoglycerate kinase promoter was used to infect primary skin fibroblasts, bone marrow cells, or myoblasts from mutant MPS VII animals. The fibroblasts were embedded into collagen lattices and reimplanted into the peritoneal cavity of recipient MPS VII mice. All animals, when analysed 10 to 155 days later, expressed beta-glucuronidase from the vascularised neo-organs that developed after implantation, and accumulated the enzyme in their tissues. A complete disappearance of the lysosomal storage lesions was observed in their liver and spleen. This procedure has been scaled up for long term lysosomal enzyme delivery in dogs. The bone marrow cells were used for partial hematopoietic reconstruction of sublethally irradiated MPS VII mice. Five months after gene transfer, animals in which under 5% of genetically-modified hematopoietic cells were detected in the spleen showed a drastic reduction of lysosomal storage lesions in the liver and spleen. Genetically-modified myoblasts were transplanted into injured muscles, where they participated in the regeneration of a significant proportion of muscle fibers. Enzyme secretion and liver uptake were observed for at least one month.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group.

AIMS/HYPOTHESIS: Induction of tolerance to insulin is achievable in animal models of Type I (insulin-dependent) Diabetes mellitus by oral treatment with this hormone, which can lead to prevention of the disease. In the Diabetes Prevention Trial of Type I diabetes (DPT-1), oral insulin is given with the aim of preventing disease insurgence. We investigated whether if given at diagnosis of Type I diabetes in humans, oral insulin can still act as a tolerogen and therefore preserve residual beta-cell function, which is known to be substantial at diagnosis. METHODS: A double-blind trial was carried out in patients (mean age +/- SD: 14 +/- 8 years) with recent-onset Type I diabetes to whom oral insulin (5 mg daily) or placebo was given for 12 months in addition to intensive subcutaneous insulin therapy. A total of 82 patients with clinical Type I diabetes ( < 4 weeks duration) were studied. Basal C peptide and glycated haemoglobin were measured and the insulin requirement monitored every 3 months up to 1 year. Insulin antibodies were also measured in 27 patients treated with oral insulin and in 18 patients receiving placebo at the beginning of the trial and after 3, 6 and 12 months of treatment. RESULTS: The trial was completed by 80 patients. Overall and without distinction between age at diagnosis, at 3, 6, 9 and 12 months baseline mean C-peptide secretion in patients treated with oral insulin did not differ from that of those patients treated with placebo. In patients younger than 15 years a tendency for lower C-peptide values at 9 and 12 months was observed in the oral insulin group. Insulin requirement at 1 year was similar between the two groups as well as the percentage of glycated haemoglobin. Finally, IgG insulin antibodies were similar in the two groups at each time point. CONCLUSION/INTERPRETATION: The results of this study indicate that the addition of 5 mg of oral insulin does not modify the course of the disease in the first year after diagnosis and probably does not statistically affect the humoral immune response against insulin.

Administration, Oral↗

PubMed1992

Biotypes of Haemophilus parainfluenzae from the respiratory secretions in chronic bronchitis.

A total of 2401 isolates of Haemophilus parainfluenzae was isolated from respiratory secretions of 36 healthy adults and 128 patients with chronic bronchitis over a period of 1 year. The isolates were allocated to eight biotypes, by their production of indole, urease and ornithine decarboxylase. Biotypes I and II constituted most of the isolates of H. parainfluenzae from the oropharynx of controls (75%) and chronic bronchitics (c. 90%). Among the patients, there was no difference in the isolation rate between oropharyngeal swabs and sputum specimens. Biotypes III, IV, VI, VII and VIII were isolated less frequently, as was a new taxon defined here as biotype V which does not produce indole, urease or ornithine decarboxylase. Biotype III was isolated significantly less frequently from cases of chronic bronchitis than from controls, whereas biotype II was isolated somewhat more frequently from the patients, especially during acute episodes.

Adult↗

PubMed1977

Morphological aspects of the hypothalamic-hypophyseal system. VII. The tanycytes: Their relation to the hypophyseal adrenocorticotrophic function. An ultrastructural study.

The ultrastruct of the tanycyte ependyma in male 160-180 g Wistar albino rats was studied under normal conditions and in experiments involving long-term suppression of ACTH secretion and its long-term stimulation. The former was accomplished by daily (for 8 days) intraperitoneal administration of dexamethasone phosphate at low (5 microgram/100 g) and high (100 microgram/100 g) concentrations. The effectiveness of suppression of the hypothalamic-hypophyseal-adrenal system in the experimental animals was judged by their reaction to two-minute ether stress (determination of plasma corticosterone) and by the results of measurement of the adrenal weights. Stimulation of ACTH secretion was achieved by bilateral adrenalectomy; the animals were examined on days 8, 10, 14, and 22 following the operation. The results obtained were in agreement with the previously established fact that there is a negative correlation between tanycyte activity and hypophyseal adrenocorticotropic function (Akmayed and Fidelina, 1974). They also testified to the predominant involvement of the median eminence tanycyte ependyma (beta-tanycytes according to the author's nomenclature) in these relationships. It is supposed that correlations are regulated by a feedback mechanism and attest to the involvement of beta-tanycytes in the inhibiting control of hypophyseal adrenocorticotrophic function. The mechanism of this control may be explained alternatively: either the tanycytes transport ACTH-suppression substances (catecholamines, corticosteroids, ACTH) from the CSF to the hypophyseal portal system or they themselves secrete substances possessing ACTH-suppressive activity. The authors distinguish several types of vesicles in the beta-tanycytes, the number of which changed with experimentally induced shifts in hypophyseal adrenocorticotrophic function. These vesicles are discussed in connection with the transport and secretory activity of the tanycytes and are considered to be a possible substrate of the hypothalamic inhibiting effect on ACTH secretion.

Adrenalectomy↗

PubMed1994

Factor VII Mie: homozygous asymptomatic type I deficiency caused by an amino acid substitution of His (CAC) for Arg(247) (CGC) in the catalytic domain.

We found hereditary factor VII deficiency in a clinically asymptomatic family, and characterized their factor VII gene and the abnormal molecule using recombinant DNA techniques. The propositus was a 45-year-old woman who was noted to have a prolonged prothrombin time. The level of factor VII antigen of the patient was 25.9% of that of normal individuals and the level of factor VII activity was 28% and 24%, when tested using rabbit brain tissue factor and human placental tissue factor in a one-stage clotting assay, respectively. Two of her sisters had almost the same reduced levels of factor VII antigen and activity, and her parents who are first cousins, a son, a daughter and a niece had moderately reduced leves of both factor VII activity and antigen. To identify the mutation site, all the coding exons and exon-intron boundaries of the factor VII gene of the propositus were amplified using the polymerase chain reaction (PCR), then subcloned and sequenced. One missense mutation (G to A) was identified in exon VII of the gene resulting in an amino acid substitution of His(CAC) for Arg(247)(CGC) in the gene product. PCR using a mutagenic primer to introduce a new ApaL I site into the mutant allele of the patient's factor VII gene revealed that this allele was inherited in the affected individuals in the pedigree. Transient expression assays using BHK cells transfected with an expression vector containing the mutant factor VII cDNA suggested that this mutation leads to factor VII deficiency by impairing secretion of the mutated factor VII.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1998

Murine mucopolysaccharidosis type VII: the impact of therapies on the clinical course and pathology in a murine model of lysosomal storage disease.

Murine mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a recessively inherited deficiency of the lysosomal enzyme beta-glucuronidase. Affected mice have clinical, biochemical and pathological findings similar to those seen in humans with MPS VII (Sly syndrome), including growth retardation, facial dysmorphism, deafness, behavioural deficits and widespread glycosaminoglycan storage in lysosomes in the viscera, skeleton and brain. This mouse model is a useful tool for the evaluation of the effectiveness and experimental therapies for the MPS disorders. Syngeneic bone marrow transplantation performed in newborn MPS VII animals--before clinical evidence of disease is pronounced--prolongs life, improves hearing and bone growth, and prevents lysosomal storage in many sites, but does not correct the central nervous system disease. Enzyme therapy with beta-glucuronidase from the first days of life does reduce lysosomal storage in the brain in murine MPS VII. The enzyme-replaced mice also have reduced visceral lysosomal storage, impressive normalization of their phenotype and an improved life span. The effectiveness of gene therapy for the treatment of lysosomal storage disease has also been tested using the MPS VII model. When transplanted into MPS VII mice, syngeneic haematopoietic stem cells or mouse skin fibroblasts infected with retrovirus expressing beta-glucuronidase decreased storage, but only in the liver and spleen. Injection of an adenovirus vector expressing beta-glucuronidase into the vitreous of the MPS VII mice reduced storage in the retinal pigment epithelium and corneal endothelium. Intravenous administration of the adenovirus vector transduced with the beta-glucuronidase gene reduced liver and spleen storage and, when instilled into the cerebral ventricles, this viral vector caused beta-glucuronidase production in epithelial cells lining the ventricles. Recently, retroviral vector-corrected MPS VII fibroblasts secreting high levels of beta-glucuronidase were engrafted directly into the brains of adult MPS VII mice with resultant reduction in storage in neurons and glia adjacent to the grafts. Future efforts aimed at prolonging expression of the beta-glucuronidase gene by viral vectors and more precisely directing the therapeutic effect to the skeleton and brain will be important in optimizing treatments for murine MPS VII and extending the results of such therapies to humans with MPS.

Animals↗

PubMed2003

Procollagen VII self-assembly depends on site-specific interactions and is promoted by cleavage of the NC2 domain with procollagen C-proteinase.

Procollagen VII is a homotrimer of 350-kDa proalpha1(VII) chains. Each chain has a central collagenous domain flanked by a noncollagenous amino-terminal NC1 domain and a carboxy-terminal NC2 domain. After secretion from cells, procollagen VII molecules form antiparallel dimers with a 60 nm overlap. These dimers are stabilized by disulfide bonds formed between cysteines present in the NC2 domain and cysteines present in the triple-helical domain. Electron microscopy has provided direct evidence for the existence of collagen VII dimers, but the dynamic process of dimer formation is not well understood. In the present study, we tested the hypothesis that, during dimer formation, the NC2 domain of one procollagen VII molecule specifically recognizes and binds to the triple-helical region adjacent to Cys-2625 of another procollagen VII molecule. We also investigated the role of processing of the NC2 domain by the procollagen C-proteinase/BMP-1 in dimer assembly. We engineered mini mouse procollagen VII variants consisting of intact NC1 and NC2 domains and a shortened triple helix in which the C-terminal region encompassing Cys-2625 was either preserved or substituted with the region encompassing Cys-1448 derived from the N-terminal part of the triple-helical domain. The results indicate that procollagen VII self-assembly depends on site-specific interactions between the NC2 domain and the triple-helical region adjacent to Cys-2625 and that this process is promoted by the cleavage of the NC2 by procollagen C-proteinase/BMP1.

Amino Acid Sequence↗

PubMed2004

Distinctive effects of red wine and diet on haemostatic cardiovascular risk factors.

The aim of this study was to compare the effects of Mediterranean-type diet (MD), high-fat diet (HFD), and red wine supplementation on plasma concentration of emergent haemostatic cardiovascular risk factors (HCVRF) and on variables of primary haemostasis (bleeding time, plasma von Willebrand factor and platelet aggregation/secretion). In a controlled prospective intervention study, two groups (21 healthy males each) received either MD or HFD during 90 days. Between days 30-60, both diets were supplemented with 240 ml/ day of red wine. After adjusting by baseline values, MD was associated with: lower plasma fibrinogen (p =0.03), factor VIIc (p=0.034) and factor VIIIc (p=0.0057); higher levels of protein S (p=0.013); longer bleeding time (p=0.017); and marginal increases in platelet serotonin aggregation and secretion after stimulation with epinephrine. Red wine supplementation, in both diets, resulted in decreased plasma fibrinogen (p=0.001) and factor VIIc (p=0.05), and in increased t-PA (p=0.01) and PAI-1 (p=0.0003). The effects of wine on antithrombin III (p=0.01) were divergent: there was a decrease in the HFD group but it increased slightly in the MD group. No effects of diet or wine were detected in plasma protein C, C-reactive protein or von Willebrand factor. BT did not change significantly with wine supplementation. Wine intake resulted in a significant increase in ex vivo platelet aggregation and secretion after stimulation with collagen (1 and 2 microg/ml, p < or = 0.01). MD and moderate consumption of red wine have complementary, mostly beneficial effects on haemostatic CV risk factors. The longer BT in individuals on MD, obtained independently of red wine, denotes less interaction of platelets with the vascular wall, which could be beneficial from the point of view of CV risk.

Bleeding Time↗

PubMed2002

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs.

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2-3 days of age with a retroviral vector (RV) expressing canine beta-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5-60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6-17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.

Animals↗