Finally, HAL+AMB and AQ+AMB efficiently reduced lethality and fungal burden in the lungs and brain, in murine cryptococcosis. Further, the combinations showed reduced toxicity to murine macrophages. Interestingly, the amphotericin B (AMB) fungicidal concentrations were ∼ 10 times lower when combined with ATMs, demonstrating a synergistic interaction. A comprehensive chemical-genetic analysis using two mutant libraries demonstrated that the deletion of genes involved in synthesizing components of the plasma membrane and cell wall, and oxidative stress responses are essential for fungal susceptibility to ATMs. gattii, revealing a dynamic effect on fungal physiology. ATMs reduced fungal growth, induced oxidative and nitrosative stresses, and altered ergosterol content, melanin production, and polysaccharide capsule size in C. is susceptible to reactive oxygen species and that iron is essential for metabolism, we tested the repurposing of ATMs to treat cryptococcosis. The antimalarials (ATMs) halofantrine (HAL) and amodiaquine (AQ) block Plasmodium heme polymerase, while artesunate (ART) induces oxidative stresses. Cryptococcosis and malaria pathogens are eukaryotic organisms and have a high incidence in Sub-Saharan Africa. However, this limited arsenal is toxic and associated with antifungal resistance. neoformans are the main etiological agents of cryptococcosis, an invasive mycosis treated with amphotericin B, 5-fluorocytosine, and fluconazole. NS/PCs expressing 圜D-UPRT can be applied for safe regenerative medicine without the concern for tumorigenesis.Ĭryptococcus gattii and C. Furthermore, after 5-fluorocytosine (5-FC) administration, 5-fluorouracil converted from 5-FC selectively eliminated undifferentiated NS/PCs while preserving the adjacent neuronal structures. During the chronic phase, cerebral atrophy and ventricle enlargement were significantly less evident in the treatment group. The injury area visualized by extravasation of Evans blue was smaller in the treatment group compared with the control group, suggesting the prevention of secondary brain injury. During the subacute phase, performances in both beam walking test and accelerating rotarod test were significantly improved in the treatment group transplanted with genome-edited iPSC-derived NS/PCs compared with the control group. In vivo bioluminescent imaging and histopathological analysis demonstrated that NS/PCs concentrated around the damaged cortex of the TBI mouse model. NS/PCs derived from human iPSCs displayed stable and high transgene expression of 圜D-UPRT following CRISPR/Cas9-mediated genome editing. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (圜D-UPRT). Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI).
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