Isolation and characterization of novel intestinal polypeptides of the enteroinsular and brain-gut axes and of macrophages
Author: Chen, Zheng-wang
Date: 1997-12-12
Location: Farmakologens föreläsningssal
Time: 10.00
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
Abstract
The gastrointestinal tract has been recognized as our largest endocrine organ, from which many peptide hormones, neuropeptides and growth factors have been isolated. There is also increasing evidence that the gastrointestinal tract can be considered as our largest immune organ, from which many antibacterial peptides, cytokines, cytotoxins and chemokines have been characterized. Different entero-endocrine cells, peptidergic nerve terminals and immune cells are found in this organ. This thesis describes the isolation and characterization, from intestinal tissues, of seven polypeptides, five porcine [daintain/AIF1, diazepam binding inhibitor (DBI), dopuin, pancreatic polypeptide (PP), vimentin-37] and two from chicken (DBI1-86 and DBI35-86). These peptides were first detected in chromatographic peptide fractions that influenced the glucose-induced secretion of insulin from rat, isolated pancreatic glands or islets.
Purification was guided by monitoring this effect or chemically by analysis for the presence of cyst(e)ine peptides. The polypeptides dopuin (do, many; pu, proline) and daintain- /AIF1 (da, big; in, influencing; tai, peptide; in, insulin secretion /allograft inflammatory factor 1) represent novel structures. The multifunctional peptide DBI and the peptide hormone PP have now been isolated from intestinal tissues, while chicken DBI and its novel, processed form DBI35-86 represent peptides now isolated from avian sources. Both of the purified chicken DBI forms inhibit glucose-induced insulin release in vitro, and were not known in structure earlier. Dopuin is a 62-residue polypeptide with a high content of pro-line in its N-terminal part and a high proportion of histidine in its C-terminal part. Both proline and histidine are important residues for specific structures and specialized functions. Six half-cystine residues are present and shown to be involved in three intrachain di-sulphide bridges (Cys22-25, 23-54, 35-44) which contribute to a tightly folded core segment in the molecular structure. At 10 nM concentration, the peptide has an inhibitory tendency on glucose induced insulin release in vitro. Daintain/AIFI consists of 146 amino acid residues and is N-terminally acetyl blocked.
An internal 44-residue segment with a sequence pattern (---KR--- KK---GKR---) resembles that found in the structural theme of peptide hormone precursors and of the GKR segment for C-terminal amide formation during the processing of peptide hormones. Daintain/AIFIis immunohistochemically localized to microglial cells in the central nervous system, to macrophages, and to tissue-specialized macrophages such as dendritic or Kupffer's cells in the immune system of different tissues. Its weakly insulin-suppressing activity in vitro, dual influence on glucose-stimulated insulin secretion in vivo and relative abundance in macrophages of the pancreatic islets of prediabetic and newly diabetic BB rats raise the possibility that daintain/AIFI has a role in the pathogenesis of insulin dependent diabetes mellitus and other autoimmune diseases.
Purification was guided by monitoring this effect or chemically by analysis for the presence of cyst(e)ine peptides. The polypeptides dopuin (do, many; pu, proline) and daintain- /AIF1 (da, big; in, influencing; tai, peptide; in, insulin secretion /allograft inflammatory factor 1) represent novel structures. The multifunctional peptide DBI and the peptide hormone PP have now been isolated from intestinal tissues, while chicken DBI and its novel, processed form DBI35-86 represent peptides now isolated from avian sources. Both of the purified chicken DBI forms inhibit glucose-induced insulin release in vitro, and were not known in structure earlier. Dopuin is a 62-residue polypeptide with a high content of pro-line in its N-terminal part and a high proportion of histidine in its C-terminal part. Both proline and histidine are important residues for specific structures and specialized functions. Six half-cystine residues are present and shown to be involved in three intrachain di-sulphide bridges (Cys22-25, 23-54, 35-44) which contribute to a tightly folded core segment in the molecular structure. At 10 nM concentration, the peptide has an inhibitory tendency on glucose induced insulin release in vitro. Daintain/AIFI consists of 146 amino acid residues and is N-terminally acetyl blocked.
An internal 44-residue segment with a sequence pattern (---KR--- KK---GKR---) resembles that found in the structural theme of peptide hormone precursors and of the GKR segment for C-terminal amide formation during the processing of peptide hormones. Daintain/AIFIis immunohistochemically localized to microglial cells in the central nervous system, to macrophages, and to tissue-specialized macrophages such as dendritic or Kupffer's cells in the immune system of different tissues. Its weakly insulin-suppressing activity in vitro, dual influence on glucose-stimulated insulin secretion in vivo and relative abundance in macrophages of the pancreatic islets of prediabetic and newly diabetic BB rats raise the possibility that daintain/AIFI has a role in the pathogenesis of insulin dependent diabetes mellitus and other autoimmune diseases.
Issue date: 1997-11-21
Publication year: 1997
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