The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors.

BACKGROUND & AIMS: The WNT-adenomatous polyposis coli system controls cell fate in the intestinal epithelium, where compartment-specific genes tightly regulate proliferation, migration, and differentiation. Nuclear receptors are transcription factors functioning as sensors of hormones and nutrients that are known to contribute to colon cancer progression. Here we mapped the messenger RNA (mRNA) abundance and the epithelial localization of the entire nuclear receptor family in mouse and human intestine. METHODS: We used complementary high-resolution in situ hybridization and systematic real-time quantitative polymerase chain reaction in samples of normal distal ileum and proximal colon mucosa and tumors obtained from mouse and human adenomatous polyposis coli-initiated tumor models (ie, Apc(Min/+) mice and familial adenomatous polyposis patients) and in cellular models of human colon cancer. RESULTS: We first defined for each receptor an expression pattern based on its transcript localization in the distal ileum and the proximal colon. Then, we compared the mRNA levels between normal intestinal epithelium and neoplastic intestinal tissue. After analyzing the correspondence between mouse and human tumor samples plus genetically modified human colon cancer cells, we used complementary graphic and statistical approaches to present a comprehensive overview with several classification trees for the nuclear hormone receptor intestinal transcriptome. CONCLUSIONS: We defined the intestinal nuclear hormone receptor map, which indicates that the localization pattern of a receptor in normal intestine predicts the modulation of its expression in tumors. Our results are useful to select those nuclear receptors that could be used eventually as early diagnostic markers or targeted for clinical intervention in intestinal polyposis and cancer.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials.

BACKGROUND: A recent clinical trial showed harmful renal effects with the combined use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) in people with diabetes or vascular disease. We examined the benefits and risks of these agents in people with albuminuria and one or more cardiovascular risk factors. METHODS: MEDLINE, EMBASE and Renal Health Library were searched for trials comparing ACEI, ARB or their combination with placebo or with one another in people with albuminuria and one or more cardiovascular risk factor. RESULTS: Eighty-five trials (21,708 patients) were included. There was no significant reduction in the risk of all-cause mortality or fatal cardiac-cerebrovascular outcomes with ACEI versus placebo, ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. There was a significant reduction in the risk of nonfatal cardiovascular events with ACEI versus placebo but not with ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI + ARB versus monotherapy. Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were reduced significantly with ACEI versus placebo and ARB versus placebo but not with combined therapy with ACEI + ARB versus monotherapy. CONCLUSIONS: ACEI and ARB exert independent renal and nonfatal cardiovascular benefits while their effects on mortality and fatal cardiovascular disease are uncertain. There is a lack of evidence to support the use of combination therapy. A comparative clinical trial with ACE, ARB and its combination in people with albuminuria and a cardiovascular risk factor is warranted.