br Modulators of the GUCY C

Modulators of the GUCY2C/cGMP/PDEs signaling pathways for CRC prevention and therapy (pre-clinical and clinical development) Several modulators of the GUCY2C/cGMP/PDEs signaling pathways, including GUCY2C agonists and PDEs inhibitors, have been developed and explored as chemopreventive agents for CRC. Some of these agents are at various stages of their preclinical and clinical development (Table 1, Fig. 1, Fig. 2). Exisulind, a sulindac derivative with PDE inhibition activity, suppressed tumorigenesis in familial adenomatous polyposis (FAP) in patients. Due to adverse effects, however, this agent was not approved by the FDA [42]. However, linaclotide, plecanatide, and dolcanatide (some of the GUCY2C agonists), and sildenafil and vardenafil (PDEs inhibitors) have been reported to possess prominent chemopreventive potential against CRC [43].
Concluding remarks and future perspectives CRC tumorigenesis is a complex process, and many of the underlying histopathologic and molecular processes involved in the transition from normal epithelium to an invasive adenocarcinoma are unknown. Disruption of intestinal TCS 359 is associated with tumorigenesis, which results from dysregulation of several signaling processes, including the GUCY2C/cGMP/PDEs pathway [7,12,58,61]. The molecular link between the GUCY2C pathway and obesity-induced tumorigenesis of CRC is also well established. The GUCY2C/cGMP/PDEs/PKG pathway regulates several tumor-suppressive (APC, PTEN, p27, and p21) and oncogenic (AKT) mediators. Genetic and pharmacologic modulation of mediators of the GUCY2C/cGMP/PDEs pathway is associated with either chemoprevention or tumorigenesis of CRC. Hence, mediators of this pathway (GUCY2C, cGMP, PDEs and PKG) have been considered as biomarkers and/or preventive targets for CRC.
Conflict of interest
Acknowledgements Dr. C.V. Rao acknowledges R01CA 213987, N01-CN-55003-47, and VA Merit Award for financial support. We would like to acknowledge Kathy J. Kyler for editorial help.
Introduction Inherited retinal diseases (IRDs) are usually characterized by heterogeneity both at the clinical and genetic levels (Hartong et al., 2006, Rivolta et al., 2002). The most common IRD phenotype is retinitis pigmentosa (RP, MIM #268000) that is characterized by a rod > cone pattern of dysfunction often leading to marked visual loss (Berson, 1993). Leber congenital amaurosis (LCA- MIM #204000) is a congenital retinal dysfunction characterized by blindness or severe visual impairment at birth or within the first month of life, congenital nystagmus and extinguished or severely impaired electroretinography (ERG) amplitudes. Cone-rod dystrophy (CRD) on the other hand is characterized by a cone > rod pattern, often exhibiting macular involvement and accompanied by loss of visual acuity (Hamel, 2007, Roosing et al., 2014). RP is estimated to affect approximately 1 in about 3500 individuals (Bundey and Crews, 1984, Bunker et al., 1984, Haim, 2002, Rosenberg, 2003, Sharon and Banin, 2015), while the prevalence of LCA and CRD is much lower [estimated as 1 in 40,000 (Hamel, 2007, Koenekoop, 2004)]. The unexpected discovery of a missense mutation in a rod-specific gene, rhodopsin, as the cause of autosomal dominant RP (adRP) (Dryja et al., 1990), in which cones degenerate as well, opened the gate for the discovery of complicated and unexpected disease mechanisms in IRDs. Different mutations in rhodopsin, for example, were later on reported to cause RP in an autosomal recessive (AR) pattern of inheritance (Rosenfeld et al., 1992), or even a non-degenerative disease, congenital stationary night blindness (CSNB) (Dryja et al., 1993). Since IRDs are considered as one of the most heterogeneous groups of diseases in humans, rare and highly interesting inheritance patterns were identified, such as biallelic and triallelic digenic inheritance patterns (Kajiwara et al., 1994, Katsanis et al., 2001). The current number of genes in which mutations can cause IRDs (including syndromic forms) is estimated at 300 (RETNET website at https://sph.uth.edu/retnet/) and is growing rapidly, mainly due to recent use of next generation sequencing (NGS) techniques in which large sets of genes are being analyzed simultaneously. A recent review contains a comprehensive description of the genetic techniques used to identify and analyze IRD genes (Broadgate et al., 2017).