Continually reported human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection create heightened threat to public health, due to the disease severity and high lethality. Acute respiratory syndrome (ARDS) has been found to be the most severe form of acute lung injury caused by H5N1 virus infection. Studies have highlighted that the unusually high virulence of H5N1 virus infection is associated with the cytokine dysregulation and enhanced viral replication in the host. In reference to the past experience during Spanish 1918 influenza pandemic and SARS, it is crucial that a novel therapeutic target is explored and employed in time for the effective control of emerging diseases. The pandemic potential of H5N1 influenza virus urges well preparedness not only in terms of containment measures, but also in the treatment aspect of the severe human H5N1 disease. To date, therapeutic approaches are limited to the use of vaccine, antiviral drugs and corticosteroids. It has been suggested that commercially available antiviral drugs are prone to induce resistance mutations; and are effective in the protection against influenza virus infection only if administered during the early course of disease development. Moreover, vaccine development does not grant a promising therapeutic strategy at the time of a pandemic as it takes time for the development and distribution of safe and reliable vaccine. In attempts to search for a novel adjunctive therapy in addition to currently available agents, indirubin-3’-oxime (IDO) and indirubin derivative, E804 have been tested to show the effect in cytokine suppression and antiviral activity against H5N1 influenza virus infection in vitro. These compounds have been extracted and purified from a natural herb called Isatis tinctoria which is frequently used for herbal remedy in treating respiratory symptoms in traditional Chinese medicine. In this study, it was demonstrated that IDO and E804 treatment in H5N1 influenza virus infected human alveolar epithelial cells effectively inhibit the proinflammatory cytokine induction and viral replication. This physiologically relevant in vitro alveolar epithelial cell model and the efficacy of IDO and E804 provide new insights to the development of new treatment option for severe human H5N1 disease. / published_or_final_version / Microbiology / Master / Master of Medical Sciences

Discovering novel compounds that stimulate or abrogate angiogenesis can lead to development of new therapeutic agents that may effectively treat diseases with pathological angiogenesis. The zebrafish model allows for a whole-organism approach to drug discovery. Advantages over other animal models include small embryo size, fecundity, rapid embryonic development, optical clarity and easy accessibility of the embryos. My goal is to validate the therapeutic efficacy and identify the molecular mechanisms of action of three compounds identified from our previous chemical genetic screens. Fenretinide promoted angiogenesis in zebrafish embryos but inhibited the angiogenesis-dependent process of fin regeneration. The pro-angiogenic effects of fenretinide appear secondary to the stimulation of somitogenesis. I3M potently inhibited angiogenesis and fin regeneration, and may act partially through the notch pathway. Lastly, I validated the anti-angiogenic effect of a novel compound DHM. Comprehensively, my studies support the utility of zebrafish as a versatile tool for anti-angiogenic drug discovery.

Discovering novel compounds that stimulate or abrogate angiogenesis can lead to development of new therapeutic agents that may effectively treat diseases with pathological angiogenesis. The zebrafish model allows for a whole-organism approach to drug discovery. Advantages over other animal models include small embryo size, fecundity, rapid embryonic development, optical clarity and easy accessibility of the embryos. My goal is to validate the therapeutic efficacy and identify the molecular mechanisms of action of three compounds identified from our previous chemical genetic screens. Fenretinide promoted angiogenesis in zebrafish embryos but inhibited the angiogenesis-dependent process of fin regeneration. The pro-angiogenic effects of fenretinide appear secondary to the stimulation of somitogenesis. I3M potently inhibited angiogenesis and fin regeneration, and may act partially through the notch pathway. Lastly, I validated the anti-angiogenic effect of a novel compound DHM. Comprehensively, my studies support the utility of zebrafish as a versatile tool for anti-angiogenic drug discovery.