Derivatives of sarcodonin A isolated from Sarcodon scabrosus reversed LPS-induced M1 polarization in microglia through MAPK/NF-κB pathway.

Emerging evidence suggests the regulation of microglial phenotype balance between M1 and M2 will be a potential therapeutic strategy for microglia-mediated neuroinflammation in Alzheimer's disease (AD). Herein, we evaluated the anti-neuroinflammatory effects and the underlying mechanism of a natural cyathane diterpenoid sarcodonin A (1) derived from the mushroom Sarcodon scabrosus and its six new derivatives (2-7). Lipopolysaccharide (LPS)-activated primary microglia and microglia cell lines were used as models. The nitrite test and immunostaining showed that the derivative named 6 was more effective in inhibiting neuroinflammation. qRT-PCR, ELISA, and western blotting revealed that 6 showed more significant suppression on mRNA and protein expression of proinflammatory M1 markers of TNF-α, IL-6, IL-1ß, iNOS, and COX-2, while more obvious potentiation on mRNA and protein levels of anti-inflammatory M2 markers of IL-10 and ARG-1. In mechanism, western blotting demonstrated that 6 inhibited LPS-induced activation of MAPK, and prevented LPS-stimulated nuclear translocation of NF-κB p65. Molecular docking revealed that 1 and 6 constructed interactions with iNOS. Collectively, the present study indicated that 1 and 6 might support neuroprotection by reversing LPS-induced microglia M1 polarization, implying that sarcodonin A can be a promising candidate for developing new therapeutics against AD by targeting microglia-mediated neuroinflammation.

Erinacine A and related cyathane diterpenoids: Molecular diversity and mechanisms underlying their neuroprotection and anticancer activities.

The presence of a fused 5/6/7 tricyclic core characterizes the group of cyathane diterpene natural products, that include more than 170 compounds, isolated from fungi such as Cyathus africanus and Hericium erinaceus. These compounds have a common biosynthetic precursor (cyatha-3,12-diene) and can be produced bio- or hemi-synthetically, or via total syntheses. Cyathane diterpenes display a range of pharmacological properties, including anti-inflammatory (possibly through binding to the iNOS protein) and neuroprotective effects. Many cyathanes like cyahookerin C, cyathin Q and cyafranines B and G can stimulate neurite outgrowth in cells, whereas conversely a few molecules (such as scabronine M) inhibit NGF-stimulated neurite outgrowth. The main anticancer cyathanes are erinacine A and cyathins Q and R, with a capacity to trigger cancer cell death dependent on the production of reactive oxygen species (ROS). These compounds, active both in vitro and in vivo, activate different signaling pathways in tumor cells to induce apoptosis (and autophagy) and to upregulate the expression of several proteins implicated in the organization and functioning of the actin cytoskeleton. An analysis of the functional analogy between erinacine A and other natural products known to interfere with the actin network in a ROS-dependent manner (notably cucurbitacin B) further supports the idea that erinacine A functions as a perturbator of the cytoskeleton organization. Collectively, we provide an overview of the molecular diversity of cyathane diterpenes and the main mechanisms of action of the lead compounds, with the objective to encourage further research with these fungal products. The anticancer potential of erinacine A deserves further attention but it will be necessary to better characterize the implicated targets and signaling pathways.

Natural and engineered xylosyl products from microbial source.

Glycosylation is a prevalent post-modification found in natural products and has a significant impact on the structural diversity and activity variation of natural products. Glucosylation is the most common type of glycosylation, whereas xylosylation is relatively rare. Despite their unique chemical structures and beneficial activities, xylosylated natural products from microorganisms have received little attention. This review provides, for the first time, a comprehensive summary of 126 microbial-derived xylosylated natural products, including xylosyl-cyathane diterpenes, xylosylated triterpenes, xylosyl aromatic compounds, and others. Among these compounds, xylosyl-cyathane diterpenes represent the highest number of derivatives, followed by xylosylated triterpenes. Xylosyl compounds from bacterial sources have less defined structural profiles compared to those from fungi. The characterization of xylosyltransferase EriJ from Basidiomycota extended the structural diversity of xylosyl cyathane diterpenes. This work provides a valuable reference for the research and use of xylosyltransferase for drug discovery and synthetic chemistry. Further work is needed to explore the potential applications of microbial derived xylosyl compounds and to develop novel xylosyl transferases. With the deepening of genomic sequencing of medicinal fungi, more biosynthesis of bioactive xylosyl compounds is expected to be elucidated in the future.

Comparative Genomic Analysis and Metabolic Potential Profiling of a Novel Culinary-Medicinal Mushroom, Hericium rajendrae (Basidiomycota).

Hericium rajendrae is an emerging species in the genus Hericium with few members. Despite being highly regarded due to its rarity, knowledge about H. rajendrae remains limited. In this study, we sequenced, de novo assembled, and annotated the complete genome of H. rajendrae NPCB A08, isolated from the Qinling Mountains in Shaanxi, China, using the Illumina NovaSeq and Nanopore PromethION technologies. Comparative genomic analysis revealed similarities and differences among the genomes of H. rajendrae, H. erinaceus, and H. coralloides. Phylogenomic analysis revealed the divergence time of the Hericium genus, while transposon analysis revealed evolutionary characteristics of the genus. Gene family variation reflected the expansion and contraction of orthologous genes among Hericium species. Based on genomic bioinformation, we identified the candidate genes associated with the mating system, carbohydrate-active enzymes, and secondary metabolite biosynthesis. Furthermore, metabolite profiling and comparative gene clusters analysis provided strong evidence for the biosynthetic pathway of erinacines in H. rajendrae. This work provides the genome of H. rajendrae for the first time, and enriches the genomic content of the genus Hericium. These findings also facilitate the application of H. rajendrae in complementary drug research and functional food manufacturing, advancing the field of pharmaceutical and functional food production involving H. rajendrae.