Chunxiao Meng

Cryptococcus neoformans is a significant and pathogenic encapsulated basidiomycete fungus responsible for cryptococcosis, particularly in immunocompromised individuals. With increasing incidence rates globally, there is an urgent need for improved therapeutic strategies. This study presents the development of a fungal-targeted nanodrug delivery system utilizing a calcofluor white-phosphatidylethanolamine conjugate (CFW-PEc) to enhance the delivery and efficacy of amphotericin B against C. neoformans . We successfully formulated AmB-loaded CFW-PEc-ethosomes, which demonstrated favorable physicochemical properties, including suitable particle size, zeta potential, and high drug entrapment efficiency. In vitro antifungal assessments revealed that CFW-PEc-AmB-ethosomes exhibited superior antifungal activity compared to conventional AmB formulations, maintaining high inhibition rates at lower concentrations, while also demonstrating a favorable safety profile with reduced cytotoxicity. Additionally, in vivo studies in a mouse model of cryptococcal pneumonia illustrated remarkable reductions in fungal burdens and improved histopathological outcomes, attributing these effects to effective targeting of C. neoformans via CFW-PEc. Our findings underscore the potential of CFW-PEc in enhancing the therapeutic efficacy and safety profile of antifungal treatments, paving the way for advanced treatment strategies against cryptococcal pneumonia. IMPORTANCE: Cryptococcal pneumonia presents a significant global health burden with limited therapeutic options due to inherent toxicity and suboptimal bioavailability of conventional antifungal agents. This investigation demonstrates the innovative application of calcofluor white-phosphatidylethanolamine conjugate (CFW-PEc) to enhance amphotericin B (AmB) delivery via ethosomes for cryptococcal infection treatment. Our findings elucidate that CFW-PEc significantly potentiates the antifungal efficacy of AmB-loaded ethosomes against Cryptococcus neoformans while concomitantly mitigating associated cytotoxicity at optimal concentrations. In murine models of pulmonary cryptococcosis, this novel formulation achieved a remarkable 10-fold reduction in fungal burden compared to controls, while preserving pulmonary histoarchitecture and attenuating inflammatory responses. This delivery system’s integrated strategy of increasing antifungal effectiveness while reducing adverse effects marks a significant leap forward in developing safer and more targeted nanomaterial-mediated antifungal treatments. These results have profound implications for developing more efficacious and less toxic treatment modalities for cryptococcal pneumonia and potentially other invasive fungal infections.

Aurantiochytrium sp., a heterotrophic microorganism, has received increasing attention for its high production of polyunsaturated fatty acids and has been widely applied in various industries. This study intended to optimize the carotenoid synthesis pathway in Aurantiochytrium sp. by metabolic engineering to increase the carotenoid content. Multi-sourced key enzyme genes involved in lipid synthesis (LPAAT and DGAT) and astaxanthin synthesis (crtZ and crtW) were selected to construct single-gene expression vectors and transformed into Aurantiochytrium sp. The results showed that the overexpression of LPAAT of Phaeodactylum tricornutum in Aurantiochytrium sp. caused an increase of 39.3% in astaxanthin, 424.7% in β-carotene, 901.8% in canthaxanthin, and 575.9% in lutein, as well as a down-regulation of 15.3% in the fatty acid content. Transcriptomics analysis revealed enhanced expression of genes involved in purine and amino acid metabolism in the transformed strains, and the down-regulation of the citric acid cycle led to an increase in the source of acetyl coenzyme A for the production of fatty acids. This study provides strong experimental evidence to support the application of increasing carotenoid levels in Aurantiochytrium sp.

Background: Amphora coffeaeformis, a unicellular diatom, can accumulate large amounts of lipids under nitrogen (N) limitation, because of which it can act as a promising raw material for biodiesel production. However, the molecular mechanism underlying lipid accumulation in A. coffeaeformis remains unknown. Results: In this study, we investigated the mechanism underlying lipid accumulation under N deprivation conditions in A. coffeaeformis using RNA-seq. The results showed that the total lipid (TL) content of A. coffeaeformis in normal f/2 medium was 28.22% (TL/DW), which increased to 44.05% after 5 days of N deprivation, while the neutral lipid triacylglycerol (TAG) content increased from 10.41% (TAG/DW) to 25.21%. The transcriptional profile showed that 591 genes were up-regulated, with false discovery rate cutoff of 0.1%, and 1,021 genes were down-regulated, indicating that N deprivation induced wide-ranging reprogramming of regulation, and that most physiological activities were repressed. In addition, ribosome biogenesis, carbon fixation, and photosynthesis in A. coffeaeformis were considerably affected by N deprivation. Conclusions: In summary, the findings initially clarified the molecular mechanism of TAG accumulation and revealed the key genes involved in lipid metabolism in A. coffeaeformis, which will be useful in designing strategies for improving microalgal biodiesel production.

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.