A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity.

The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases.

A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines.

Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine.

The high-fat high-fructose hamster as an animal model for niacin's biological activities in humans.

Objective: Niacin has been used for more than 50 years to treat dyslipidemia, yet the mechanisms underlying its lipid-modifying effects remain unknown, a situation stemming at least in part from a lack of validated animal models. The objective of this study was to determine if the dyslipidemic hamster could serve as such a model.

Materials/methods: Dyslipidemia was induced in Golden Syrian hamsters by feeding them a high-fat, high-cholesterol, and high-fructose (HF/HF) diet.

Comparative effects of platelet-derived growth factor-BB and insulin-like growth factor-I, individually and in combination, on periodontal regeneration in Macaca fascicularis.

Platelet-derived growth factor (PDGF) and insulin-like growth factor I (IGF-I) in combination have previously been shown to enhance periodontal regeneration. The objective of this study was to further characterize the biological effects of this combination of growth factors in non-human primates and compare the effects to those of each growth factor individually. Ligature-induced periodontitis was initiated in 10 cynomolgus monkeys.

Combination of platelet-derived growth factor-BB and insulin-like growth factor-I is more effective than platelet-derived growth factor-BB alone in stimulating complete healing of full-thickness wounds in "older" diabetic mice.

Platelet-derived growth factor and insulin-like growth factor-I have been shown to interact synergistically to enhance repair of skin wounds in normal healing swine. Platelet-derived growth factor alone has shown promise in treating human chronic ulcers. The objective of this study was to compare the wound healing effects of platelet-derived growth factor-BB alone with those of a combination of platelet-derived growth factor-BB and insulin-like growth factor-I in an improved model with the use of "older" animals with diabetes.

The combination of platelet-derived growth factor-BB and insulin-like growth factor-I stimulates bone repair in adult Yucatan miniature pigs.

The combination of insulin-like growth factor-I and platelet-derived growth factor-BB has previously been shown to stimulate healing of soft tissue wounds and the formation of bone and ligament around teeth. The purpose of the present study was to evaluate the effects of platelet-derived growth factor-BB and insulin-like growth factor-I individually and in combination on the healing of osseous wounds. Four standardized cortical wounds were created in each tibia of 11 adult Yucatan miniature pigs.

p53 expression during normal tissue regeneration in response to acute cutaneous injury in swine.

The present studies investigated the in vivo expression of the p53 suppressor gene and protein product in response to acute cutaneous injury in swine, along with the parallel expression of the c-sis/PDGF-B mitogen and its receptor beta (PDGF-R beta). p53 expression was shown to be suppressed during the period of active cellular proliferation in the injured tissue and to reemerge during the stages of healing. In contrast, c-sis/PDGF-B and PDGF-R beta were expressed during the early phase of active cellular proliferation and they were suppressed upon healing.

Expression of growth factor and receptor mRNAs in skin epithelial cells following acute cutaneous injury.

We report that acute injury induces the expression of selective growth factor and growth factor receptors in the epithelial cells of the wounded tissue. In situ hybridization analysis of skin biopsy specimens obtained after cutaneous injury in swine demonstrated the induction of the expression of transforming growth factor-alpha, its receptor, epidermal growth factor-R, acidic fibroblast growth factor, and basic fibroblast growth factor messenger RNAs in the skin epithelial cells of the wounded tissue. There was no significant expression in the epithelial cells of control, uninjured tissues.

Role of growth factors in cutaneous wound healing: a review.

The well-orchestrated, complex series of events resulting in the repair of cutaneous wounds are, at least in part, regulated by polypeptide growth factors. This review provides a detailed overview of the known functions, interactions, and mechanisms of action of growth factors in the context of the overall repair process in cutaneous wounds. An overview of the cellular and molecular events involved in soft tissue repair is initially presented, followed by a review of widely studied growth factors and a discussion of commonly utilized preclinical animal models.

The effects of short-term application of a combination of platelet-derived and insulin-like growth factors on periodontal wound healing.

Polypeptide growth factors are a class of potent natural biologic mediators which regulate many of the activities of wound healing including cell proliferation, migration, and metabolism. Platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I) have been shown to regulate DNA and protein synthesis in bone cells in vitro and to interact synergistically to enhance soft tissue wound healing in vivo. We have hypothesized that the combination of PDGF and IGF-I may, therefore, enhance regeneration of both the soft and hard tissue components of the periodontium.

Injury induces in vivo expression of platelet-derived growth factor (PDGF) and PDGF receptor mRNAs in skin epithelial cells and PDGF mRNA in connective tissue fibroblasts.

Platelet-derived growth factor (PDGF) stimulates many of the processes important in tissue repair, including proliferation of fibroblasts and synthesis of extracellular matrices. In this study we have demonstrated with in situ hybridization and immunocytochemistry the reversible expression of c-sis/PDGF-2 and PDGF receptor (PDGF-R) b mRNAs and their respective protein products in epithelial cells and fibroblasts following cutaneous injury in pigs. Epithelial cells in control, unwounded skin did not express c-sis and PDGF-R mRNAs, and fibroblasts expressed only PDGF-R mRNA.