Antifungal Activity and Multi-Target Mechanism of Action of Methylaervine on Candida albicans.

The discovery of a lead compound against Candida albicans is urgently needed because of the lack of clinically available antifungal drugs and the increase in drug resistance. Herein, a ß-carboline alkaloid methylaervine (MET) exhibited potential activity against C. albicans (MIC = 16-128 µg/mL), no hemolytic toxicity, and a low tendency to induce drug resistance. An antifungal mechanism study indicated that MET effectively inhibited the biofilm formation and disrupted the mature biofilm. Moreover, filamentation formation and spore germination were also weakened. The electron microscopy analysis revealed that MET could damage the cell structure, including the cell wall, membrane, and cytoplasm. In particular, the permeability and integrity of the cell membrane were destroyed. When it entered the fungi cell, it interfered with the redox homeostasis and DNA function. Overall, MET can inhibit the growth of C. albicans from multiple channels, such as biofilm, filamentation, cell structure, and intracellular targets, which are difficult to mutate at the same time to generate drug resistance. This work provides a promising lead compound for the creation of new antifungal agents against C. albicans.

Combined therapeutic strategy based on blocking the deleterious effects of AGEs for accelerating diabetic wound healing.

Diabetic foot ulcer is a serious complication of diabetes. Excessive accumulation of advanced glycation end products (AGEs) is one of the critical pathogenic factors in postponing diabetic wound healing. The main pathogenic mechanisms of AGEs include inducing cellular dysfunction, prolonging inflammatory response, increasing oxidative stress and reducing endogenous nitric oxide (NO) production. Combination therapy of blocking the deleterious effects of AGEs and supplementing exogenous NO is hypothesized to promote diabetic wound healing. Here, we presented nanoparticles/hydrogel composite dressings to co-delivery rosiglitazone and S-nitroso glutathione into the wound bed. The designed co-delivery system augmented the survival of fibroblasts, reduced oxidative stress levels, reversed the change of mitochondrial membrane potential and decreased the proinflammatory cytokine expression. Local sustained release of therapeutic agents significantly improved the wound healing of diabetic rats including increasing the wound closure rate, alleviating inflammation, promoting collagen fiber production and angiogenesis. Our finding indicated this local deliver strategy aimed at inhibiting the toxic effects of AGEs has great clinical potential for diabetic wound treatment.

Quaternized antimicrobial peptide mimics based on harmane as potent anti-MRSA agents by multi-target mechanism covering cell wall, cell membrane and intracellular targets.

Infectious disease caused by methicillin-resistant Staphylococcus aureus (MRSA) seriously threatens public health. The design of antimicrobial peptide mimics (AMPMs) based on natural products (NPs) is a new strategy to kill MRSA and slow the development of drug resistance recently. Here, we reported the design and synthesis of novel AMPMs based on harmane skeleton. Notably, compound 9b exhibited comparable or even better anti-MRSA activity in vitro and in vivo with minimum inhibitory concentration (MIC) of 0.5-2 µg/mL than the positive drug vancomycin. The highly active compound 9b not only showed low cytotoxicity, no obvious hemolysis and good plasma stability, but also presented low tendency of developing resistance. Anti-MRSA mechanism revealed that compound 9b could destroy cell wall structure by interacting with lipoteichoic acid and peptidoglycan, cause membrane damage by depolarization, increased permeability and destructed integrity, reduce cell metabolic activity by binding to lactate dehydrogenase (LDH), interfere cellular redox homeostasis, and bind to DNA. Overall, compound 9b killed the MRSA by multi-target mechanism, which provide a promising light for combating the growing MRSA resistance.

Screening of cell-virus, cell-cell, gene-gene crosstalk among animal kingdom at single cell resolution.

BACKGROUND: The exact animal origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains obscure and understanding its host range is vital for preventing interspecies transmission. METHODS: Herein, we applied single-cell sequencing to multiple tissues of 20 species (30 data sets) and integrated them with public resources (45 data sets covering 26 species) to expand the virus receptor distribution investigation. While the binding affinity between virus and receptor is essential for viral infectivity, understanding the receptor distribution could predict the permissive organs and tissues when infection occurs. RESULTS: Based on the transcriptomic data, the expression profiles of receptor or associated entry factors for viruses capable of causing respiratory, blood, and brain diseases were described in detail. Conserved cellular connectomes and regulomes were also identified, revealing fundamental cell-cell and gene-gene cross-talks from reptiles to humans. CONCLUSIONS: Overall, our study provides a resource of the single-cell atlas of the animal kingdom which could help to identify the potential host range and tissue tropism of viruses and reveal the host-virus co-evolution.

Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level.

Pigs are valuable large animal models for biomedical and genetic research, but insights into the tissue- and cell-type-specific transcriptome and heterogeneity remain limited. By leveraging single-cell RNA sequencing, we generate a multiple-organ single-cell transcriptomic map containing over 200,000 pig cells from 20 tissues/organs. We comprehensively characterize the heterogeneity of cells in tissues and identify 234 cell clusters, representing 58 major cell types. In-depth integrative analysis of endothelial cells reveals a high degree of heterogeneity. We identify several functionally distinct endothelial cell phenotypes, including an endothelial to mesenchymal transition subtype in adipose tissues. Intercellular communication analysis predicts tissue- and cell type-specific crosstalk between endothelial cells and other cell types through the VEGF, PDGF, TGF-ß, and BMP pathways. Regulon analysis of single-cell transcriptome of microglia in pig and 12 other species further identifies MEF2C as an evolutionally conserved regulon in the microglia. Our work describes the landscape of single-cell transcriptomes within diverse pig organs and identifies the heterogeneity of endothelial cells and evolutionally conserved regulon in microglia.

VThunter: a database for single-cell screening of virus target cells in the animal kingdom.

Viral infectious diseases are a devastating and continuing threat to human and animal health. Receptor binding is the key step for viral entry into host cells. Therefore, recognizing viral receptors is fundamental for understanding the potential tissue tropism or host range of these pathogens. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology has paved the way for studying the expression of viral receptors in different tissues of animal species at single-cell resolution, resulting in huge scRNA-seq datasets. However, effectively integrating or sharing these datasets among the research community is challenging, especially for laboratory scientists. In this study, we manually curated up-to-date datasets generated in animal scRNA-seq studies, analyzed them using a unified processing pipeline, and comprehensively annotated 107 viral receptors in 142 viruses and obtained accurate expression signatures in 2 100 962 cells from 47 animal species. Thus, the VThunter database provides a user-friendly interface for the research community to explore the expression signatures of viral receptors. VThunter offers an informative and convenient resource for scientists to better understand the interactions between viral receptors and animal viruses and to assess viral pathogenesis and transmission in species. Database URL: https://db.cngb.org/VThunter/.