Wyniki wyszukiwania

1

Regulation of gastrointestinal mucosal growth during aging

100%

Majumdar A. P. N.

Journal of Physiology and Pharmacology. Supplement

|

2003

|

tom 54

|

nr 4

143-154

The increase in the aging population has led to a growing interest in achieving a better understanding of the aging process and of diseases that are predominantly expressed during advancing age. Since the structural and, in turn, the functional integrity of the mucosa of the gastrointestinal tract (GI) are maintained by constant renewal of cells, a detailed knowledge of the events that initiate and regulate mucosal proliferative processes is essential for a better understanding of the normal aging process as well as age-associated dysfunctions, including malignancy that represent disorders of tissue growth. In Fischer-344 rats, aging is associated with increased mucosal proliferative activity in much of the GI tract. On the other hand, the functional properties are either decreased or remain unchanged during advancing age. Basal gastric acid and pepsin output decline during aging, as is gastrin secretion. In contrast, antral gastrin levels increase during this period, as is mucosal histidine decarboxylase activity. The age-related decline in gastrin secretion could partly be attributed to a higher ratio of somatostatin (D) to gastrin (G) cells in the antral mucosa. The age-related rise in GI mucosal proliferative activity could not be attributed to the trophic action of either gastrin or bombesin, since they caused no significant change in mucosal proliferation in aged rats. On the other hand, EGF and TGF-alphalpha appear to be involved in regulating mucosal proliferation during aging. Aging is associated with increased activation of EGF-receptor (EGFR), the common receptor for EGF and TGF-alpha. This could be due to (a) increased levels of membrane-bound precursor form(s) of TGF-alpha resulting in increased activation EGFR signaling processes through an autocrine/paracrine mechanism, (b) heightened sensitivity of mucosal EGFR to EGF and TGF-alpha such that comparatively lower levels of these peptides are required to activate EGFR in aged than in young animals and/or (c) loss of EGFR regulatory factor(s) such as ERRP (EGFR Related Protein), a "negative regulator" of EGFR.

2

Experimental studies as an inspiration for clinical investigation

51%

Malecka-Panas E., Talar-Wojnarowska R., Kotynia J., Majumdar A. P. N.

Journal of Physiology and Pharmacology. Supplement

|

2004

|

tom 55

|

nr 2

139-150

This study represents an attempt of showing own author's example of using basic research data as an inspiration for the clinical studies. The project evaluates the role of gastrin in colorectal carcinogenesis as well as the differences of its action in proximal and distal colon. Colonocytes were isolated from Fischer-344 rats and incubated for 2 minutes with gastrin (10-8M). This treatment resulted with 60-70% rise in tyrosine kinase (Tyr-k) and 150-200% - in phospholipase C activity as regards to basal levels. In vivo infusion of gastrin for 5 days to Fischer-344 rats resulted with 90-150% increase in distal but not proximal colonic mucosal proliferative activity as well as tyrosine phosphorylation of several colonic mucosal proteins. In clinical study, the mean fasting gastrin level in the control group was significantly lower (p<0.01) than in patients with colorectal cancer before surgery. Mean plasma gastrin level in patients with distal tumor yielded 105,31 ± 12,5 µ U/l and was significantly higher than in patients with the proximal tumor site (42, 2 ± 3,1 µU/l) (p<0,001). We conclude, that Tyr-k is involved in the mechanism of the trophic action of gastrin, particularly in distal colon. The differences in gastrin concentration in patients with distal and proximal tumors may probably contribute to the distinct pathogenesis and biological properties of those cancers.

3

Gastrin activates tyrosine kinase and phospholipase C in isolated rat colonocytes

51%

Malecka-Panas E., Tureaud J., Majumdar A. P. N.

Acta Biochimica Polonica

|

1996

|

tom 43

|

nr 3

Postreceptor regulation of the trophic action of gastrin is not fully elucidated. Tyrosine kinase (Tyr-kinase) has been associated with receptors of a number of growth factors and plays an important role in regulation of cellular growth within the gastrointestinal tract. The aim of this study was to determine, whether Tyr-kinase plays a role in mediating the growth promoting action of gastrin and whether phospholipase C (PLC) is involved in the signal transduction pathway. Colonocytes isolated from Fischer 344 rats were incubated for 2 min with gastrin (10-8 M) and assayed for Tyr-kinase and PLC activities. Incubations with gastrin resulted in 60%-70% rise in Tyr-kinase and 150%-200% rise in PLC activities over the corresponding basal levels. When processed separately, in proximal colon Tyr-kinase activation by gastrin was 15%-20%, while in distal colon 70%-80% as compared to the buffer control. Gastrin activation of both Tyr-kinase and PLC was abolished by Tyr-kinase inhibitor, tyrphostin-25 (3.2 nM) and was not affected by staurosporine (20 ng/ml). We conclude that Tyr-kinase is involved in the mechanism of trophic action of gastrin, and PLC activation appears to be the next step in the signal transduction pathway.

Ograniczanie wyników

2 Journal of Physiology and Pharmacology. Supplement

1 Acta Biochimica Polonica

3 Majumdar A. P. N.

2 Malecka-Panas E.

1 Kotynia J.

1 Talar-Wojnarowska R.

1 Tureaud J.

1 2004

1 2003

1 1996

Regulation of gastrointestinal mucosal growth during aging

Experimental studies as an inspiration for clinical investigation

Gastrin activates tyrosine kinase and phospholipase C in isolated rat colonocytes