Pharmacologically Active Tripeptide Leu-Ile-Lys in Indomethacin-Induced Gastric Ulcer

The aim of the study was to examine the effect of a new tripeptide, Leu-Ile-Lys, on an experimental indometacin-induced gastric ulcer in rats. Materials and Methods: The experiment was performed with 24 male Wistar rats (average weight of 150 g). Rats were randomly divided into 3 groups: Group 1(n=8) – the ulcer control group (IIGU), Group 2 (n=8) – the experimental group (IIGU+pre-treating with the tripeptide Leu-Ile-Lys), and Group 3 (n=8) – the comparison group (IIGU+pre-treating with omeprazole). The model of IIGU in rats was performed by a single intragastric administration of indomethacin (60mg/kg in 1ml of physiological saline). In Group 1, indomethacin caused the appearance of severe injuries of the mucosa with the presence of extensive edema and leukocyte infiltration in the submucosal layer. In animals of Group 2, which were pre-treated with the tripeptide Leu-Ile-Lys, macroscopically gastric mucosa also looked smooth and atrophic changes were not found. Destructive changes were not severe; they appeared only in the form of small spot erosions. The number of spot erosions was 2.6 times less than in Group 1. The average erosion depth was 6.8 times less than in Group 1, and 2.0 times less than in Group 3. Conclusion: Results of this study demonstrated the high, comparable to the action of omeprazole, gastroprotective activity of the new tripeptide Leu-Ile-Lys

The Roles of MIST1 and RAB26 in Zymogenic (Chief) Cell Differentiation and Subcellular Organization

Little is known about how differentiating cells reorganize their cellular structure to perform specialized physiological functions. Specifically, exocrine cells like pancreatic acinar and zymogenic chief cells have a highly developed secretory architecture that is rapidly established upon differentiation. What is known in these cells is that the evolutionarily conserved transcription factor MIST1 is required for final maturation. We hypothesized that MIST1 directly regulates specific subcellular components that facilitate functional maturation of secretory cells. We show that MIST1 binds to conserved CATATG E-boxes to activate transcription of 6 genes, including the small GTPases RAB26 and RAB3D. We next demonstrate that RAB26 and RAB3D expression is significantly downregulated in Mist1-/- ZCs and upregulated in gastric cancer cell lines stably expressing MIST1 and induced to form secretory granules. Moreover, granule formation in these MIST1-expressing cells requires Rab activity because treatment with a Rab prenylation inhibitor or transfection of dominant negative RAB26 abrogates granule formation. We next sought to elucidate how a scaling factor like MIST1 rearranges cellular architecture through transcriptional targets, specifically RAB26. We confirm that RAB26 expression was tissue specific and confined to acinar secretory cells. Functional studies in gastric cell lines showed RAB26 association with lysosomes but not with secretory granules. In addition, increasing RAB26 expression caused lysosomes to coalesce in a central, perinuclear region, causing redistribution of other organelles including mitochondria into distinct subcellular neighborhoods. In mouse exocrine cells that are null for Mist1 and lack RAB26, we found lysosomes to be similarly abnormally distributed. Normally, lysosomes cluster centrally and basally away from secretory granules, whereas in Mist1-/- cells, they rapidly accumulate apically and degrade secretory vesicles. We confirmed active granule degradation when much of the vesicle phenotype in Mist1-/- mice was rescued upon crossing with mice deficient in the lysosome acid hydrolase processing enzyme, GlcNAc-1-phosphotransferase, alpha and beta subunits (Gntpab-/-). Taken together, we propose that MIST1 promotes normal maturation of secretory granules through blocking their targeting by the cellular degradation/recycling machinery. These results illustrate how a transcription factor can regulate cell architecture and have implications for disease processes like acute pancreatitis where MIST1 is lost, and secretory vesicles are targeted to lysosomes

日本医科大学研究業績年報 第51巻 平成16(2004年度)

日本医科大

Skills in Rheumatology

This Open Access book presents practical approaches to managing patients affected by various rheumatological diseases, allowing readers to gain a better understanding of the various clinical expressions and problems experienced by these patients. Discussing rheumatology from an organ systems perspective, it highlights the importance ofdetailed musculoskeletal examinations when treating patients affected by rheumatological diseases. The book first explores the latest diagnostic approaches and offers key tips for accurate musculoskeletal examinations before addressing the various treatment modalities, with a particular focus on the most common joints involved in rheumatoid arthritis: the wrists and the metacarpophalangeal joints (2nd and 3rd). Featuring easy-to-understand flow diagrams and explaining the common medical problems associated with rheumatic disease, such as shortness of breath and anemia, it is not only a valuable resource to rheumatologists, but will also appeal to medical students, junior residents, and primary healthcare physicians

Skills in Rheumatology

This Open Access book presents practical approaches to managing patients affected by various rheumatological diseases, allowing readers to gain a better understanding of the various clinical expressions and problems experienced by these patients. Discussing rheumatology from an organ systems perspective, it highlights the importance ofdetailed musculoskeletal examinations when treating patients affected by rheumatological diseases. The book first explores the latest diagnostic approaches and offers key tips for accurate musculoskeletal examinations before addressing the various treatment modalities, with a particular focus on the most common joints involved in rheumatoid arthritis: the wrists and the metacarpophalangeal joints (2nd and 3rd). Featuring easy-to-understand flow diagrams and explaining the common medical problems associated with rheumatic disease, such as shortness of breath and anemia, it is not only a valuable resource to rheumatologists, but will also appeal to medical students, junior residents, and primary healthcare physicians