The filamentous fungus Aspergillus oryzae (A. oryzae) has been extensively used for the biosynthesis of numerous secondary metabolites with significant applications in agriculture and food and medical industries, among others. However, the identification and functional prediction of metabolites through genome mining in A. oryzae are hindered by the complex regulatory mechanisms of secondary metabolite biosynthesis and the inactivity of most of the biosynthetic gene clusters involved. The global regulatory factors, pathway-specific regulatory factors, epigenetics, and environmental signals significantly impact the production of secondary metabolites, indicating that appropriate gene-level modulations are expected to promote the biosynthesis of secondary metabolites in A. oryzae. This review mainly focuses on illuminating the molecular regulatory mechanisms for the activation of potentially unexpressed pathways, possibly revealing the effects of transcriptional, epigenetic, and environmental signal regulation. By gaining a comprehensive understanding of the regulatory mechanisms of secondary metabolite biosynthesis, strategies can be developed to enhance the production and utilization of these metabolites, and potential functions can be fully exploited.

Cordyceps militaris is considered to be of great medicinal potential due to its remarkable pharmacological effects, safety, and edible characteristics. With the completion of the genome sequence and the advancement of efficient gene-editing technologies, coupled with the identification of gene functions in Cordyceps militaris, this fungus is poised to emerge as an outstanding strain for medicinal engineering applications. This review focuses on the development and application of genomic editing techniques, including Agrobacterium tumefaciens-mediated transformation (ATMT), PEG-mediated protoplast transformation (PMT), and CRISPR/Cas9. Through the application of these techniques, researchers can engineer the biosynthetic pathways of valuable secondary metabolites to boost yields; such metabolites include cordycepin, polysaccharides, and ergothioneine. Furthermore, by identifying and modifying genes that influence the growth, disease resistance, and tolerance to environmental stress in Cordyceps militaris, it is possible to stimulate growth, enhance desirable traits, and increase resilience to unfavorable conditions. Finally, the green sustainable industrial development of C. militaris using agricultural waste to produce high-value-added products and the future research directions of C. militaris were discussed. This review will provide future directions for the large-scale production of bioactive ingredients, molecular breeding, and sustainable development of C. militaris.

The synthetic DSPE-PEG₂₀₀₀-C3 peptide and DSPE-PEG₂₀₀₀-TPP were designed to modify the exosomes (EXO) by incubation, through which guide the C3/TPP-EXO to target the injured mitochondria of neurons. Then, C3/TPP-EXO was further used to encapsulate the curcumin (CUR) to enhance the solubility and bioavailability of the drug. By intravenously injected (i.v) into tau^p301s mutant transgenic (Tg) mice, C3/TPP-EXO facilitated the CUR to target the mitochondria of neurons and increase the entry efficiency of medication. To further reveal the mechanisms of drug entry, sodium azide (NaN₃), an energy inhibitor, was used to treat HT22 cells. The results demonstrated that the entrance efficiency of the engineered EXO is significantly affected suggesting that C3/TPP-EXO may target mitochondria through energy routes. To deeply study the exact molecular mechanisms of C3/TPP-EXO-CUR in treating AD, RNA-Seq was used to identify the relevant molecules. Through GO annotation, many genes are enriched in the pathways of mitochondria functions. Based on these RNA-Seq data, C3/TPP-EXO-CUR showed neuroprotective effects via modulating the protein expression of Bcl-2, Bax and caspase-3 in HT22 cells. To further confirm the in vitro results, the in vivo results revealed that C3/TPP-EXO-CUR treatment inhibited the phosphorylation of tau and protected neurons by inhibiting the apoptotic genes, leading to improve the memory decline of tau^p301s mice. Collectively, the current study revealed the benefits and mechanisms of C3/TPP-EXO-CUR for treating AD, which might provide a novel and effective therapeutic approach for the disease.

Background: Skin whitening agents often face challenges such as poor stability and low permeability. To overcome these issues, a novel 4-butylresorcinol (4-BR)/D-a- Tocopherol Polyethylene Glycol Succinate (TPGS) deep eutectic solvent (DES) system was developed, which can self-assemble into carrier-free nanoparticles (NPs). Methods: The 4-BR/TPGS DES was synthesized and characterized by theoretical calculations, DSC, FTIR, 1H-NMR, and 2D NMR to confirm its successful formation. Results: The self-assembled 4-BR/TPGS DES NPs showed a 3.46-fold increase in skin permeability, a 1.53-fold improvement in 4-BR stability, a 1.55-fold increase in melanin inhibition in B16 cells, and a 2.16-fold higher melanin suppression in zebrafish compared with traditional 4-BR oil-based formulations. These results indicated the excellent whitening efficacy and transdermal delivery potential of this formulation. Conclusions: The combination of TPGS-based DES and self-assembly technology represents a revolutionary approach for advanced transdermal delivery and the development of skin care products.