ABSTRACT
In the fasted gastrointestinal (GI) tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occurs in an ultradian rhythm, at 90-120 min time intervals, in many species. However, the underlying mechanism directing this ultradian rhythmic MMC pattern is yet to be completely elucidated. Therefore, this study aimed to identify the possible causes or factors that involve in the occurrence of the fasting gastric contractions by using Suncus murinus a small model animal featuring almost the same rhythmic MMC as that found in humans and dogs. We observed that either intraduodenal infusion of saline at pH 8 evoked the strong gastric contraction or continuously lowering duodenal pH to 3-evoked gastric phase II-like and phase III-like contractions, and both strong contractions were essentially abolished by the intravenous administration of MA 2029 (motilin receptor antagonist) and D-Lys3-GHRP6 (ghrelin receptor antagonist) in a vagus-independent manner. Moreover, we observed that the prostaglandin E2-alpha (PGE2-α) and serotonin type 4 (5HT4) receptors play important roles as intermediate molecules in changes in GI pH and motilin release. These results suggest a clear insight mechanism that change in the duodenal pH to alkaline condition is an essential factor for stimulating the endogenous release of motilin and governs the fasting MMC in a vagus-independent manner. Finally, we believe that the changes in duodenal pH triggered by flowing gastric acid and the release of duodenal bicarbonate through the involvement of PGE2-α and 5HT4 receptor are the key events in the occurrence of the MMC.
Subject(s)
Gastrointestinal Motility/drug effects , Hydrogen-Ion Concentration/drug effects , Myoelectric Complex, Migrating/physiology , Oligopeptides/antagonists & inhibitors , Receptors, Gastrointestinal Hormone/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Stomach/chemistry , Acetamides/administration & dosage , Acetamides/pharmacology , Administration, Intravenous , Animals , Dinoprostone/metabolism , Duodenum/chemistry , Duodenum/physiology , Fasting/physiology , Female , Gastrointestinal Motility/physiology , Imines/administration & dosage , Imines/pharmacology , Male , Motilin/administration & dosage , Motilin/metabolism , Motilin/pharmacology , Myoelectric Complex, Migrating/drug effects , Oligopeptides/administration & dosage , Receptors, Gastrointestinal Hormone/administration & dosage , Receptors, Neuropeptide/administration & dosage , Shrews , Stomach/physiology , Vagotomy , Vagus Nerve/physiologyABSTRACT
No disponible
Subject(s)
Humans , Female , Neurotransmitter Agents/analysis , Neurotransmitter Agents/history , Gonadotropin-Releasing Hormone/analysis , Gonadotropin-Releasing Hormone/history , Receptors, LHRH/administration & dosage , Receptors, LHRH/antagonists & inhibitors , Receptors, LHRH/biosynthesis , Receptors, Neuropeptide/administration & dosage , Receptors, Neuropeptide/therapeutic useABSTRACT
G-protein coupled receptors (GPCRs) play a major role in a number of physiological and pathological processes. Thus, GPCRs have become the most frequent targets for development of new therapeutic drugs. In this context, the availability of highly specific antibodies may be decisive to obtain reliable findings on localization, function and medical relevance of GPCRs. However, the rapid and easy generation of highly selective anti-GPCR antibodies is still a challenge. Herein, we report that highly specific antibodies suitable for detection of GPCRs in native and unfolded forms can be elicited by immunizing animals against purified full length denatured recombinant GPCRs. Contrasting with the currently admitted postulate, our study shows that an active and well-folded GPCR is not required for the production of specific anti-GPCR antibodies. This new immunizing strategy validated with three different human GPCR (µ-opioid, κ-opioid, neuropeptide FF2 receptors) might be generalized to other members of the GPCR family.
Subject(s)
Antibodies/immunology , Immunoglobulin G/biosynthesis , Receptors, Neuropeptide/immunology , Receptors, Opioid, kappa/immunology , Receptors, Opioid, mu/immunology , Amino Acid Sequence , Animals , Antibodies/isolation & purification , Humans , Immunization , Immunoglobulin G/immunology , Immunoglobulin G/isolation & purification , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Pichia/genetics , Protein Denaturation , Protein Folding , Receptors, Neuropeptide/administration & dosage , Receptors, Neuropeptide/genetics , Receptors, Opioid, kappa/administration & dosage , Receptors, Opioid, kappa/genetics , Receptors, Opioid, mu/administration & dosage , Receptors, Opioid, mu/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/immunologyABSTRACT
Targeted therapy may be a promising approach against cancer because its focus of attention is to enhance the efficacy and to reduce the side effects of antitumor agents through high selectivity. One of targeted strategies is to use tumor-specific ligands as targeting moieties to carry drugs into tumor cells, and use the receptors that expressed on tumor cells as target sites to bind with peptide ligands. The fact that the distributions of reproductive hormone receptors are relatively limited in normal tissues makes it possible to use them as targeted sites and use hormone peptides as targeting moieties for cancer treatment. Until now many tumor targeting approaches with reproductive hormone peptides have been developed, and some of them have been introduced into clinical trials. Here a review is given to discuss the targeted antitumor therapeutic strategies based on gonadotropin-releasing hormone, follicle-stimulating hormones, luteinizing hormone, human chorionic gonadotropin and their receptors.