Angiogenesis is the formation of new blood vessels from existing ones and an underlying cause of numerous human diseases, including cancer and inflammation. A large body of evidence indicates that angiogenic inhibitors have therapeutic potential in the treatment of vascular diseases. However, detrimental side effects and low efficacy hinder their use in clinical practice. Members of the corticotropin-releasing hormone (CRH) family, which comprises CRH, urocortin I-III, and CRH receptors (CRHR) 1 and 2, are broadly expressed in the brain and peripheral tissues, including the intestine and cardiovascular system. The CRH family regulates stress-related responses through the hypothalamic-pituitary-adrenal axis. Therapeutic agents that target CRH family members offer a new approach to the treatment of various gastrointestinal disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer. Since the discovery that CRHR 2 has anti-angiogenic activity during postnatal development in mice, studies have focused on the role of the CRH system in the modulation of blood vessel formation and cardiovascular function. This review will outline the basic biological functions of the CRH family members and the implications for the development of novel anti-angiogenic therapies.
Angiogenesis Inhibitors ; Animals ; Axis, Cervical Vertebra ; Biodiversity* ; Blood Vessels ; Brain ; Cardiovascular System ; Colorectal Neoplasms ; Corticotropin-Releasing Hormone* ; Humans ; Inflammation ; Inflammatory Bowel Diseases ; Intestines ; Irritable Bowel Syndrome ; Mice ; Receptors, Corticotropin-Releasing Hormone ; Urocortins ; Vascular Diseases

The family of corticotropin-releasing factor (CRF) composed of 4 ligands including CRF, urocortin (Ucn) 1, Ucn2, and Ucn3 is expressed both in the central nervous system and the periphery including the gastrointestinal tract. Two different forms of G protein coupled receptors, CRF1 and CRF2, differentially recognize CRF family members, mediating various biological functions. A large body of evidence suggests that the CRF family plays an important role in regulating inflammation and angiogenesis. Of particular interest is a contrasting role of the CRF family during inflammatory processes. The CRF family can exert both pro- and anti-inflammatory functions depending on the type of receptors, the tissues, and the disease phases. In addition, there has been a growing interest in a possible role of the CRF family in angiogenesis. Regulation of angiogenesis by the CRF family has been shown to modulate endogenous blood vessel formation, inflammatory neovascularization and cardiovascular function. This review outlines the effect of the CRF family and its receptors on 2 major biological events: inflammation and angiogenesis, and provides a possibility of their application for the treatment of inflammatory vascular diseases.
Angiogenesis Inducing Agents ; Blood Vessels ; Central Nervous System ; Corticotropin-Releasing Hormone* ; Gastrointestinal Tract ; Humans ; Inflammation* ; Ligands ; Negotiating ; Receptors, G-Protein-Coupled ; Urocortins ; Vascular Diseases

PURPOSE: This study aimed to validate instruments to classify the frailty of Korean elderly people in community. METHODS: For this study, 632 elders were selected from community-based elderly houses and home visiting registries, and data on frailty were collected using three instruments during November, 2008. The Korean Frail Scale (KFS) was composed of 10 domains with the maximum score of 20. The Edmonton Frail Scale (EFS) had 10 domains with the maximum score of 17. The 25_Japan Frail Scale (25_JFS) was composed of 6 domains with the maximum score of 25. Internal consistency was measured with Cronbach's alpha. Sensitivity, specificity and area under the curve (AUC) of ROC were measured to see validity with long-term care insurance grade as a gold standard. RESULTS: The Cronbach's alpha was .72 for KFS, .55 for EFS, and .80 for 25_JFS. Sensitivity, specificity, and AUC were 70.0%, 83.2%, and .83, respectively, at cutting point 10.5 for the KFS, 50.0%, 80.9%, and .66, respectively, at 8.5 for EFS, and 80.0%, 85.9%, and .86, respectively, at 12.5 for 25_JFS. CONCLUSION: KFS and three JFS showed favorable internal consistency and predictive validity. Further longitudinal studies are recommended to confirm predictive validity.
Aged* ; Area Under Curve ; Frail Elderly ; House Calls ; Humans ; Insurance, Long-Term Care ; Longitudinal Studies ; Registries ; Sensitivity and Specificity

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.