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PubMed2005

Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic beta-cells.

Dysfunction of pancreatic beta-cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of beta-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic beta-cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K(+) (K(ATP)) and voltage-dependent Ca(2+) currents, and depolarized the resting membrane potential in primary beta-cells. When stimulated by high glucose, genistein-treated beta-cells exhibited a time delay of both depolarization and Ca(2+) influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca(2+) influx and a loss of Ca(2+) oscillations. Semiquantitative PCR analysis revealed decreased expression of K(ATP) and L-type Ca(2+) channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca(2+) current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic beta-cell dysfunction and may be involved in the etiology of type 2 diabetes.

Animals↗
PubMed1991

Effect of cell density on growth hormone release from, cyclic AMP levels in and peptide alpha-amidation activity of primary cultured rat anterior pituitary cells.

To investigate the effect of cell density on rat somatotrophs, dispersed adult rat anterior pituitary cells were plated at several densities (0.6, 1.2, 2.4 and 6.0 x 10(5) cells/cm2) or at two densities (6.07 x 10(5) and 1.21 x 10(5) cells/cm2) as high and low densities respectively. A static incubation system was used to study the release of GH and peptidyl glycine alpha-amidating enzyme (PAM; a component of secretory granules) and the cellular concentration of cyclic AMP (cAMP) in basal and stimulated cells. In addition, a perifusion system was used to characterize the sensitivity to GH-releasing factor (GRF) at both high and low densities. The high density of cells in both the static incubation and perifusion systems caused a low basal secretion rate of GH and PAM. When the cultured cells were stimulated with human GRF (hGRF) in perifusion, GH secretion from cells at high density was markedly higher than that from cells at low density. The cAMP content in the static incubation system showed a similar tendency to that observed for basal and stimulated GH secretion; that is, the basal cAMP content was increased as the cell density decreased. The cellular concentration of cAMP was increased by about threefold by 1 nmol hGFR/l and by more than tenfold by 10 nmol hGRF/l. When the medium from cells cultured at low density was replaced by that from the cells at high density, there was no change in the basal cellular cAMP content of the cells at low density.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Different regulated expression of the tyrosine phosphatase-like proteins IA-2 and phogrin by glucose and insulin in pancreatic islets: relationship to development of insulin secretory responses in early life.

IA-2 and phogrin are tyrosine phosphatase-like proteins that may mediate interactions between secretory granules and cytoskeleton in islets and neuroendocrine tissues. We investigated factors that regulate IA-2 and phogrin expression and their relationship to maturation of insulin secretory responses that occur after birth. Islet content of IA-2, but not phogrin, increased during the first 10 days of life in rats, when insulin secretion in response to glucose increased to adult levels. In cultured 5-day-old rat islets, IA-2 protein and mRNA was increased by glucose and agents that potentiate insulin secretion by the cAMP pathway. Addition of insulin increased IA-2 protein levels and insulin biosynthesis without affecting IA-2 mRNA. Blocking insulin secretion with diazoxide or insulin action with insulin receptor antibodies inhibited glucose-induced increases in IA-2 protein, but not those of mRNA. Phogrin expression was unchanged by all agents. Thus, IA-2 is regulated at the mRNA level by glucose and elevated cAMP, whereas locally secreted insulin modulates IA-2 protein levels by stimulating biosynthesis. In contrast, phogrin expression is insensitive to factors that modify beta-cell function. These results demonstrate differential regulation of two closely related secretory granule components and identify IA-2 as a granule membrane protein subject to autocrine regulation by insulin.

Age Factors↗
PubMed2002

Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion.

IA-2 is a major autoantigen in type 1 diabetes. Autoantibodies to IA-2 appear years before the development of clinical disease and are being widely used as predictive markers to identify individuals at risk for developing type 1 diabetes. IA-2 is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is an integral component of secretory granules in neuroendocrine cells. To study its function, we generated IA-2-deficient mice. Northern and Western blot analysis showed that neither IA-2 mRNA nor protein was expressed. Physical examination of the IA-2(- /-) animals and histological examination of tissues failed to reveal any abnormalities. Nonfasting blood glucose levels, measured over 6 months, were slightly elevated in male IA-2(-/-) as compared to IA-2(+ /+) littermates, but remained within the nondiabetic range. Glucose tolerance tests, however, revealed statistically significant elevation of glucose in both male and female IA-2(-/-) mice and depressed insulin release. In vitro glucose stimulation of isolated islets showed that male and female mice carrying the disrupted gene released 48% (P < 0.001) and 42% (P < 0.01) less insulin, respectively, than mice carrying the wild-type gene. We concluded that IA-2 is involved in glucose-stimulated insulin secretion.

Animals↗
PubMed1984

Ovarian and uterine morphology and function in Angus and Brahman cows.

Ovarian characteristics, daily serum progesterone (P4) and estradiol-17 beta (E2) concentrations (d 7 through 17) and uterine luminal secretory protein components and histological variables were evaluated in parous Bos taurus (Angus, n = 20) and Bos indicus (Brahman, n = 19) cows. Cows were slaughtered on d 17 (estrus = d 0) for measurement of ovarian structures, flushing of uteri and removal of uterine tissue for histological evaluation. Cows were placed into one of three reproductive categories: nonpregnant, remnant (flushings contained remnants of embryonic tissue) or pregnant. For ovarian and uterine variables, there were only a few differences among reproductive categories within breeds. For combined categories, weight of the active ovary (containing the corpus luteum) was similar between breeds, but inactive ovarian (P less than .001) and follicular fluid (P less than .01) weights, stromal weight (P less than .01) and number of follicles less than 5 mm in diameter (P less than .01) for both ovaries combined were greater in Brahman than Angus cows. Corpus luteum weight (P less than .001), luteal P4 content (P less than .08) and number of follicles greater than 5 mm in diameter for both ovaries combined (P less than .05) were greater for Angus than for Brahman cows. Overall, mean serum P4 concentrations were greater in nonpregnant (P less than .05), pregnant (P less than .005) and combined (P less than .025) reproductive categories for Angus than corresponding categories of Brahman cows and mean serum E2 concentrations were greater in remnant (P less than .025) and combined (P less than .05) reproductive categories for Angus than corresponding categories of Brahman cows. Mean total uterine luminal protein was greater (P less than .05) in Angus than in Brahman cows for pregnant (23.4 vs 14.7 mg, respectively) and combined reproductive categories (22.4 vs 16.1 mg, respectively). Using electrophoretic analyses, percentage composition of three uterine specific cathode migrating protein bands and quantitative estimates of proteins with molecular weights (MW, X 10(-3)) of 9, 15.5, 34.2, 41.3, 46.2 and 183.1 were greater (P less than .05 to P less than .001) in uterine flushings from Angus than from Brahman cows. Uterine, myometrial and endometrial thicknesses, number of glands/microscopic field and uterine luminal epithelial cell height variables were generally greater (P less than .05 to P less than .001) in pregnant and combined reproductive categories for Angus than for Brahman cows.

Animals↗
PubMedDate not supplied

Monoclonal antibody (Mab) markers for subpopulations of rat tracheal epithelial (RTE) cells.

We sought monoclonal antibodies (Mabs) that would recognize distinct subsets of rat tracheal epithelial (RTE) cells. Mice were immunized with pronase-dissociated RTE cells and hybridomas whose supernatants immunocytochemically stained subpopulations of tracheal cells were selected. We report the immunohistochemical staining properties of the antibodies and give the results of preliminary biochemical characterization of the antigens. Four different types of antibodies were produced. Antibody RTE 1 stained most RTE cells. Three antibodies (RTE 2, 7, and 13) recognized a subpopulation of nonciliated cells, both columnar and basal cells. Antibody RTE 3 intensely labeled the surface of ciliated cells. Three antibodies reacted with granule components of secretory cells; antibodies RTE 9 and 11 reacted with mucous-type secretory cells and antibody RTE 12 stained all tracheal surface secretory cells. As described in detail, some antibodies were RTE cell specific while others also reacted with cells and secretions in other organs; the antibodies did not cross react with guinea pig or rabbit tissues. Periodate sensitivity of the antigens suggested that some antibodies recognized carbohydrate moieties while others detected peptide epitopes. In some cases, Western blotting revealed the molecular weights of the antigens, but some antigens were denatured by sodium dodecyl sulfate (SDS) and heat treatment. These antibody probes provide a useful means to immunochemically study changes in cell type distribution and/or epitope expression during development, injury, and regeneration.

Animals↗
PubMed1991

Pancreastatin--a novel regulatory peptide?

Pancreastatin is a 49 amino acid peptide originally isolated from porcine pancreas on the basis of its C-terminal glycinamide as isolation criterion. It is derived by proteolytic processing from chromogranin A, an acidic protein component of secretory granules in endocrine and neuronal cells. The primary structures of human, porcine, bovine and rat pancreastatin have been determined on the protein or cDNA level and show 70% sequence homology. By immunocytochemistry, pancreastatin has been detected in the pituitary, adrenal gland, pancreas, CNS and throughout the gastrointestinal tract. In pancreatic islets, pancreastatin is co-localized with insulin, glucagon and somatostatin. The principle biological activities of this peptide are: inhibition of insulin release and of exocrine pancreatic secretion. These effects which can be assigned to the amidated C-terminal part of the molecule have been demonstrated in several species. Whether or not pancreastatin can be classified as a novel peptide hormone that under physiological conditions plays a role in the regulation of the endocrine and exocrine pancreas, is still a matter of controversy.

Amino Acid Sequence↗
PubMed1988

Selectivity, specificity and kinetics of the androgen regulation of the ocular secretory immune system.

The purpose of the present investigation was to determine the selectivity, specificity and kinetics of the androgen regulation of the ocular secretory immune system. To examine the mucosal selectivity of hormone action, tears, saliva, respiratory and intestinal secretions, urine and serum were collected from orchiectomized rats following four days of treatment with saline or testosterone. Androgen administration significantly increased the tear levels of IgA and free SC. In contrast, this combined hormone response was not duplicated in other mucosal secretions or serum. Consequently, it appears that the androgen control of the ocular secretory immune system is unique to the eye. To evaluate androgenic specificity, orchiectomized rats were treated for four days with saline, testosterone, 5 alpha-androstan-17 beta-o1 ('5 alpha'), 4-estren-7 alpha-methyl-17 beta-o1-3-one ('4-E') or the synthetic analogue, danazol. Results demonstrated that testosterone and '4-E', a potent androgen, both stimulated the accumulation of tear IgA and free SC, compared to amounts in tears of saline-treated controls. The weak androgen '5 alpha' induced a slight rise in tear free SC, but not IgA, levels, whereas danazol had no effect on the ocular secretory immune system. These findings indicate that androgen structure is of critical importance in modulation of mucosal immunity in the eye. Lastly, to assess the kinetics of hormone action on tear IgA and free SC, orchiectomized rats were acutely (0, 1.5, 4, 7, 12, or 24 hours) or chronically (0, 4, 7, 11, 14, or 17 days) exposed to testosterone. Acute androgen exposure for less than 12 hours did not elicit any change in the tear content of IgA or free SC. In comparison, chronic androgen treatment induced a progressive and dramatic rise in the levels of both tear proteins. By 17 days of hormone exposure, the IgA and free SC concentrations in tears had increased by 14- and 18-fold amounts, respectively, relative to amounts in placebo-treated controls. Of interest, the temporal pattern of accumulation of tear IgA and free SC were different. Overall, these results show prolonged, but not abbreviated, exposure to androgens has a profound impact on the IgA and free SC profile in tears.

Androgens↗
PubMedDate not supplied

Nutritional modulation of intestinal mucosal immunity.

Protein-energy malnutrition results in an increased risk of gastrointestinal infection. This can be attributed in part to impaired immune responses. Cell-mediated immunity is decreased as judged by reduced number and function of thymus-dependent lymphocytes, impaired delayed cutaneous hypersensitivity reactions, and decreased production of lymphokines. Concentration of secretory IgA is reduced and there are fewer intraepithelial lymphocytes. Antibody responses following viral vaccine administration are reduced and there is decrease in natural killer cell activity. In addition, the number of bacteria binding to epithelial cells is increased. These changes are observed also in certain selected nutrient deficiencies, such as that of vitamin A. It is suggested that impaired systemic and mucosal immunity contributes to the increased frequency and severity of intestinal infections seen in undernourished individuals.

Animals↗
PubMed1983

[On The Applicability Of Partially Purified Antigenic Preparations Of Paragonimus Westermani]

In order to obtain more specific antigenic preparation for the diagnosis of human paragonimasis, crude saline extract of whole worm (=PwWWE), secretory-excretory components (PwSEC) and secretion-excretion-free somatic extract (PwSM) of 12 week-old Paragonimus westermani were filtrated through Sephadex G-200 gel column. The adult Paragonimus worms were obtained from experimentally infected dogs. A total of 11 antigenic solutions was lyophilized or diluted to adjust protein content of 1 mg/ml. To evaluate the antigenicity of crude antigens and fractions, micro-ELISA was done with the sera from P. westermani infected cases, C. sinensis infected cases and non-infected control cases to detect Paragonimus specific IgG antibody. The results were as follows: When the PwWWE was filtrated through Sephadex G-200 gel, it was separated into three fractions; PwWWE Fr. 1, PwWWE Fr. 2 and PwWWE Fr. 3. The percentage of protein content was 28.0 %, 21.6 % and 50.4 % respectively. The PwSM was also separated into three fractions; PwSM Fr. 1, PwSM Fr. 2, PwSM Fr. 3 and their percentage of protein content was 41.3 %, 38.6 % and 20.1 %. However, the PwSEC showed different fractionation pattern; i.e. fraction 1 (=PwSEC Fr. 1) and 3 (PwSEC Fr. 3) without fraction 2. The percentage of protein content was 14.0 % in PwSEC Fr. 1 and 86.0 % in PwSEC Fr. 3. When the antigenicity of each Paragonimus crude antigen and fractionated antigen was evaluated for specific IgG antibody by micro-ELISA in 10 human paragonimiasis sera, PwSEC Fr. 1 was the most potent antigen showing the mean absorbance 1.98. The PwWWE Fr. 1, PwSEC, PwWWE were next to that; their mean absorbance were 1.72, 1.38 and 0.83, respectively. The antigenicity of fractions 2 and 3 was much weaker in binding specific IgG antibody. When the antigens were reacted in micro-ELISA with 10 human clonorchiasis sera, most antigens showed weak reactivity. Each fraction 1 of crude antigens reacted higher than other fractions or crude antigens; the mean absorbance was 0.17 in fraction 1, but in others the absorbances were about 0.06. With non-infected control sera, the result of micro-ELISA revealed almost same pattern with those of the clonorchiasis sera. From the above results, it became apparent that PwWWE Fr. 1, especially PwSEC Fr. 1 was the most potent antigen reacted with Paragonimus specifc IgG antibody.

Journal Article↗
PubMed2004

Targeting of secretory IgA to Peyer's patch dendritic and T cells after transport by intestinal M cells.

In addition to being instrumental to the protection of mucosal epithelia, secretory IgA (SIgA) adheres to and is transported by intestinal Peyer's patch (PP) M cells. The possible functional reason for this transport is unknown. We have thus examined in mice the outcome of SIgA delivered from the intestinal lumen to the cells present in the underlying organized mucosa-associated lymphoreticular tissue. We show selective association of SIgA with dendritic cells and CD4(+) T and B lymphocytes recovered from PP in vitro. In vivo, exogenously delivered SIgA is able to enter into multiple PP lining the intestine. In PP, SIgA associates with and is internalized by dendritic cells in the subepithelial dome region, whereas the interaction with CD4(+) T cells is limited to surface binding. Interaction between cells and SIgA is mediated by the IgA moiety and occurs for polymeric and monomeric molecular forms. Thus, although immune exclusion represents the main function of SIgA, transport of the Ab by M cells might promote Ag sampling under neutralizing conditions essential to the homeostasis of mucosal surfaces.

Animals↗
PubMed1999

Polymerization of IgA and IgM: roles of Cys309/Cys414 and the secretory tailpiece.

We have investigated how the secretory tailpiece (tp), Cys414 and the amino acids flanking Cys414 or Cys309 are involved in regulating the different polymerization of IgM and IgA to pentamers and dimers/monomers, respectively. Whereas changing the tp of IgM to that of IgA has little effect on IgM polymerization, introducing the mu tp to IgA leads to the formation of larger than wild-type IgA polymers, including pentamers and hexamer. This shows that the secretory tp can differentially regulate polymerization depending on the heavy chain context. Cys414, which is engaged in intermonomeric disulfide bonds in IgM, is not crucial for the difference in IgM and IgA polymerization; IgM with a C414S mutation forms more large polymers than IgA. Also, IgA with IgM-like mutations in the five amino acids flanking Cys309, which is homologous to Cys414, oligomerize similarly as IgA wild type. Thus, IgA appears to have an inherent tendency to form monomers and dimers that is partially regulated by the tp, while the Cys309 region has only a minor effect. We also show that complement activation by IgM is sensitive to alterations in the polymeric structure, while IgA is inactive in classical complement activation even for polymers such as pentamers and hexamers.

Amino Acid Sequence↗
PubMedDate not supplied

[The secretory IgA. The local secretory immunitary system (author's transl)].

The Authors take into examine the local secretory immunitary system (L.S.I.S.) starting from the presence of antibody-molecules in secretions: they study origin, characteristics, action and excitement procedures of this class of molecules, also compared with the immunitary central system.

Antibodies↗
PubMed1999

Induction of mucosal immunity by inactivated poliovirus vaccine is dependent on previous mucosal contact with live virus.

The inactivated poliovirus vaccine (IPV) is used for protection against poliomyelitis in The Netherlands. It is not clear, however, whether IPV vaccination can lead to priming of the mucosal immune system and the induction of IgA. It has been demonstrated that IPV vaccination is able to induce strong memory IgA responses in the serum of persons who have been naturally exposed to wild-type poliovirus. This has led to the hypothesis that IPV vaccination is able to induce poliovirus-specific IgA at mucosal sites in persons who have been previously primed with live poliovirus at mucosal sites. To test this hypothesis, the kinetics of the IgA response in serum and saliva after IPV vaccination were examined in persons previously vaccinated with oral poliovirus vaccine (OPV) or IPV. ELISA and enzyme-linked immunospot assays were used for the detection of poliovirus-specific IgA responses. In addition, B cell populations were separated on the basis of the expression of mucosal (alpha4beta7 integrin) and peripheral homing receptors (L-selectin). Parenteral IPV vaccination was able to boost systemic and mucosal IgA responses in previously OPV-vaccinated persons only. None of the previously vaccinated IPV recipients responded with the production of IgA in saliva. In agreement with this finding, a large percentage of the poliovirus-specific IgA-producing lymphocytes detected in previous OPV recipients expressed the alpha4beta7 integrin. It is concluded that IPV vaccination alone is insufficient to induce a mucosal IgA response against poliovirus. In mucosally (OPV-) primed individuals, however, booster vaccination with IPV leads to a strong mucosal IgA response.

Adult↗