Zebrafish phenotypic screen identifies novel Notch antagonists.

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

Utilizing Zebrafish to Identify Anti-(Lymph)Angiogenic Compounds for Cancer Treatment: Promise and Future Challenges.

Cancer metastasis which predominantly occurs through blood and lymphatic vessels, is the leading cause of death in cancer patients. Consequently, several anti-angiogenic agents have been approved as therapeutic agents for human cancers such as metastatic renal cell carcinoma. Also, anti-lymphangiogenic drugs such as monoclonal antibodies VGX-100 and IMC-3C5 have undergone phase I clinical trials for advanced and metastatic solid tumors. Although anti-tumor-associated angiogenesis has proven to be a promising therapeutic strategy for human cancers, this approach is fraught with toxicities and development of drug resistance. This emphasizes the need for alternative anti-(lymph)angiogenic drugs. The use of zebrafish has become accepted as an established model for high-throughput screening, vascular biology, and cancer research. Importantly, various zebrafish transgenic lines have now been generated that can readily discriminate different vascular compartments. This now enables detailed in vivo studies that are relevant to both human physiological and tumor (lymph)angiogenesis to be conducted in zebrafish. This review highlights recent advancements in the zebrafish anti-vascular screening platform and showcases promising new anti-(lymph)angiogenic compounds that have been derived from this model. In addition, this review discusses the promises and challenges of the zebrafish model in the context of anti-(lymph)angiogenic compound discovery for cancer treatment.

The Association of Self-Perception of Aging and Quality of Life in Older Adults: A Systematic Review.

BACKGROUND AND OBJECTIVES: Self-perception of aging is an important psychosocial factor that can influence quality of life in older age. This review aimed to synthesize findings on the association between self-perception of aging and quality of life among older adults aged 60 and above. RESEARCH DESIGN AND METHODS: A systematic search was conducted in 4 electronic databases (Ovid Medline, PsycInfo, CINAHL, and Web of Science). Studies conducted in English and including measures on the perception of aging and quality of life were included in this review. A total of 32 observational studies (21 cross-sectional, 8 longitudinal, 2 mixed-method, and 1 qualitative) met the inclusion criteria. Outcomes reported in the included studies were quality of life, physical health and functioning, psychological health, mental health, and general well-being. RESULTS: Overall, 20 quantitative studies indicated a strong association between positive perception of aging and increased quality of life. Similarly, 9 quantitative studies demonstrated that negative perception of aging is associated with lower quality of life. Results of the mixed-method and qualitative studies indicated that older adults with higher morale and good physical capability had more positive perceptions of health. DISCUSSION AND IMPLICATIONS: These results suggest that promoting a positive perception of aging and a self-care attitude would help to enhance older adults' quality of life and should be incorporated into future health promotions and interventions.

Stem Cells Derived from Amniotic Fluid: A Potential Pluripotent-Like Cell Source for Cellular Therapy?

BACKGROUND: Regenerative medicine aims to provide therapeutic treatment for disease or injury, and cell-based therapy is a newer therapeutic approach different from conventional medicine. Ethical issues that rose by the utilisation of human embryonic stem cells (hESC) and the limited capacity of adult stem cells, however, hinder the application of these stem cells in regenerative medicine. Recently, isolation and characterisation of c-kit positive cells from human amniotic fluid, which possess intermediate characteristics between hESCs and adult stem cells, provided a new approach towards realising their promise for fetal and adult regenerative medicine. Despite the number of studies that have been initiated to characterize their molecular signature, research on developing approaches to maintain and enhance their regenerative potential is urgently needed and must be developed. AIM: Thus, this review is focused on understanding their potential uses and factors influencing their pluripotent status in vitro. CONCLUSION: In short, this cell source could be an ideal cellular resource for pluripotent cells for potential applications in allogeneic cellular replacement therapies, fetal tissue engineering, pharmaceutical screening, and in disease modelling.