Drug discovery today. Disease mechanisms最新文献

Critical physiological roles of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) include the regulation glucose and lipid homeostasis, cellular differentiation and modulation of inflammation. The potential for targeting PPARβ/δ for the prevention and treatment of metabolic diseases or cancer, is compromised because of major inconsistencies in the literature. This is due primarily to uncertainty regarding the effect of PPARβ/δ and its activation on cell proliferation, apoptosis and cell survival. This review summarizes both the confirmed and conflicting mechanisms that have been described for PPARβ/δ and the potential for targeting this nuclear receptor for the prevention and treatment of colon cancer.

Colorectal cancer is a major health problem in developed countries. Chronic intestinal inflammation predisposes individuals to the development of colorectal cancer. The intracellular NOD-like receptors (NLRs) have emerged as crucial regulators of intestinal inflammation and colorectal tumorigenesis. Activation of several NLRs leads to the formation of a protein complex called the inflammasome, which then triggers the activation of the cysteine protease caspase-1 and the downstream maturation and secretion of the inflammatory cytokines interleukin (IL)-1β and -18. Defective inflammasome signaling in the gut contributes to colitis and colorectal tumorigenesis by increasing the permeability of the epithelial barrier, dysregulating the proliferation of epithelial cells, and inducing oncogenic mediators. In this review, we discuss our current knowledge on how the inflammasome protects against colorectal tumorigenesis.

MicroRNAs are small noncoding RNAs that control gene expression. In doing so, they functionally contribute to the maintenance of cellular processes as well as several important features related to cancer development and progression such as cell growth control, differentiation and apoptosis. In fact, recent studies have shown that microRNAs are suitable and effective cancer-related biomarkers because they display altered expression profiles in cancers versus normal tissue. In addition, microRNAs have been associated with cancer progression and outcome. In this review, the current state of knowledge of microRNA expression and function in relation to gastroenterological cancers will be addressed. Moreover, the mechanisms to alter their expression and the potential application of microRNAs in clinical settings will also be highlighted. Finally, the challenges involved in translating microRNA research to the clinic will be discussed.

IL-17 is an important proinflammatory cytokine in autoimmune diseases. The constant presence of IL-17 in the intestinal tract raises the possibility that it may be a critical enhancer of intestinal tumorigenesis. Yet the role of IL-17 in cancer development is controversial. Animal studies and clinical studies suggest that the role of IL-17 may be differential depending on type of cancer and tumor microenvironment. The role of IL-17 in intestinal tumorigenesis is largely proinflammatory and likely affects Treg function. Thus, targeting IL-17 in intestinal tumorigenesis may be an effective approach for treating cancer.

Inappropriate activation of the Toll-IL-1R (TLR-IL-1R) signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases and colitis-associated cancer. Recent studies have identified Single Immunoglobulin IL-1 Receptor Related molecule (SIGIRR) as a negative regulator of TLR-IL-1R signaling. It dampens intestinal inflammation and tumorigenesis in the colon. In this review, we will discuss the role of SIGIRR in different cell types and the mechanisms underlying its tumor suppressor function.

A growing body of evidence supports the role of toll-like receptor (TLR) signaling in the intestinal mucosa and its role in inflammation and tumorigenesis. Patients with chronic intestinal inflammation, as is the case with inflammatory bowel disease (IBD), and a subset of patients with inflammatory and sporadic colorectal neoplasia, have increased expression of TLRs, especially TLR4, on colonic epithelial cells. Mouse models of colitis and cancer are useful to understand the role of TLRs and bacteria in the development of colon cancer. Clear differences in bacterial colonization patterns are noted between normal and dysplastic colonic mucosa. TLRs offer a potential prognostic and therapeutic target, serving as the link between bacterial ligands and epithelial inflammation.

Red blood cells, currently obtained from donors, represent the most common form of cell-based therapy. A better understanding of normal erythropoiesis is leading to improved multi-step protocols for the in vitro generation of fully mature red cells. The extensive in vitro expansion of embryonic erythroblasts and development of erythroid precursors as a potential transfusion product may help to deal with issues of scale and eventually find a place in the treatment of patients with acute and chronic anemias.

Thrombocytopenia is common in HIV and SIV infection, and is often associated with disease progression. HIV and SIV-associated thrombocytopenia arise through multiple mechanisms, including decreased platelet production, increased platelet destruction due to HIV-mimetic anti-platelet antibodies, and increased use of activated platelets. Activated platelets have the potential to contribute to the pathogenesis of HIV and SIV by interacting directly with inflammatory cells and endothelium and by releasing soluble immunomodulatory cytokines.