Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chronic toxicity of FUT-187, a synthetic protease inhibitor, was investigated in Sprague-Dawley rats. FUT-187 was given orally to the rats at doses of 0.4, 2, 10, 50 and 250 mg/kg/day for 52 weeks. The drug was then withdrawn for 5 weeks. The results are summarized as follows: There were no deaths or toxic signs caused by the drug throughout the experimental period. There were no drug-related changes in food consumption, ophthalmological examination, hematology or blood chemistry. Slight suppression of growth was observed in males in the 250 mg/kg group. This change was reversed on withdrawal of the drug. Drug crystals were observed in the urinary sediments of both sexes in the 250 mg/kg group, but this change disappeared on withdrawal of the drug. Gross pathological examination revealed the following changes: enlargement and nodule formation in the pancreas in both sexes given more than 10 mg/kg of the drug; dark red spots in the glandular stomach in males in the 250 mg/kg group; thickening of the small intestinal walls in both sexes given more than 50 mg/kg. Of these organs, no changes were observed in the stomach and small intestine at the end of the recovery period. Increased pancreas weight was observed in both sexes given more than 50 mg/kg of the drug. Examination at the end of the recovery period suggested reversibility, showing a lesser degree of change. Histopathological examination revealed the following changes in the pancreatic acinar cells: acidophilic foci and nodules in both sexes given more than 10 mg/kg of the drug; adenoma in one male in the 250 mg/kg group; increased zymogen granules in both sexes given more than 50 mg/kg of drug; fine vacuolization in females in the 250 mg/kg group. At the end of the recovery period, increased zymogen granules and fine vacuolization of the acinar cells were not found. Furthermore, erosion or healed erosion in the glandular stomach, duodenum and jejunum was observed in a few males or females in the 250 mg/kg group, but those changes disappeared after the recovery period. In the liver, altered cell foci was observed more frequently in males in the 250 mg/kg group than the other groups, but this change also disappeared after the recovery period. In addition, brown pigmentation in the proximal renal tubules of the kidney was observed in both sexes in the 250 mg/kg group, but lesions observed in the examination after the recovery period were less noticeable than in the examination at the end of the administration period.
 ...
PMID:[A 52-week oral chronic toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in rats with a recovery period of 5 weeks. 129 21

The author describes how his interest in the nutritional value of soybeans led to a trail of research that had many ramifications. In an attempt to account for the poor nutritional value of raw soybeans and the beneficial effect of heat treatment, a protein displaying hemagglutinating activity and capable of inhibiting the growth of rats was isolated and characterized. This protein subsequently proved to be an example of a class of proteins that were later referred to as "lectins". Lectins were also isolated from kidney beans and shown to be even more toxic than the soybean lectin. Concurrent studies with the soybean trypsin inhibitors revealed that these proteins inhibited growth by stimulating the secretory activity of the pancreas and could in the long term cause acinar cell adenoma of the pancreas. Acute experiments with human subjects showed that the human pancreas also responded to the stimulatory effects of the so-called Bowman-Birk soybean inhibitor. The studies on soybean trypsin inhibitors were expanded to include a protease inhibitor present in blood, alpha-1-antitrypsin, a deficiency of which leads to emphysema in humans. The mechanism whereby this protein inhibits leucocyte elastase was investigated. On the basis of these results the intratracheal administration of a synthetic peptide inhibitor of elastase attached to albumin microspheres was found to prevent elastase-induced emphysema in hamsters.
 ...
PMID:A trail of research revisted. 1238 Nov 54

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.
 ...
PMID:Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells. 1831 48

Serine protease inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is involved in inflammation, cell proliferation and carcinogenesis. The role and association between SPINK1, EGFR and Ki-67 in colorectal adenoma (CRA) and colorectal cancer (CRC) are still unknown. In this study, we used immunohistochemical stain to evaluate expression of SPINK1, EGFR and Ki-67 proteins in 30 CRA and 53 CRC patients semiquantitatively, and then analyzed their correlation with clinicopathologic parameters. Our results revealed that SPINK1 expression was noted in the upper and basal parts of the crypts in CRA and was more intensely related with cellular atypia. EGFR expression was found in 13 out of 30 adenomas, including 9 out of 15 adenomas with dysplasia or synchronous CRC (60 %), and 4 out of 15 adenomas without dysplasia (26.7 %). In CRC, high SPINK1 expression was significantly associated with males (p = 0.041) and advanced disease stage (p = 0.015). EGFR positivity was significantly correlated with higher T stage (p = 0.004) and disease stage (stage I-IV, p = 0.017; early vs. late, p = 0.015). Pearson's correlation showed positive correlation between the SPINK1 intensity and EGFR immunoreactivity (p = 0.011), and Ki-67 and SPINK1 intensity or percentage (p = 0.017 and p = 0.039 respectively). In Kaplan-Meier analyses, patients with high SPINK1 intensity tended to have shorter overall survival (p = 0.03). Concomitant expression of high SPINK1 intensity and EGFR was also identified as being associated with poor prognosis (p = 0.015). In conclusion, high SPINK1 expression is associated with advanced stage and poor prognosis. There is positive correlation between high SPINK1 expression, EGFR immunoreactivity, and high Ki-67 labeling index. The SPINK1 protein seems to play a role in tumor proliferation and malignant transformation through the EGFR pathway. SPINK1 may serve as a prognostic biomarker in therapeutic targeting in the future.
 ...
PMID:Serine Protease Inhibitor Kazal Type 1 (SPINK1) Promotes Proliferation of Colorectal Cancer Through the Epidermal Growth Factor as a Prognostic Marker. 2603 68