Aim: SARS-coronavirus 2 main protease (Mpro) and host toll-like receptors (TLRs) were targeted to screen potential inhibitors among traditional antiviral medicinal plants. Materials & methods: LeDo...

The enzymatic activity of CD26/DPP4 (dipeptidyl peptidase 4/DPP4) is highlighted in multiple studies to play a vital role in glucose metabolism by cleaving and inactivating the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). A large number of studies demonstrate that CD26 also plays an integral role in the immune system, particularly in T cell activation. CD26 is extensively expressed in immune cells, such as T cells, B cells, NK cells, dendritic cells, and macrophages. The enzymatic activity of CD26 cleaves and regulates numerous chomokines and cytokines. CD26 inhibitors have been widely used for the treatment of diabetes mellitus, while it is still under investigation as a therapy for immune-mediated diseases. In addition, CD26’s involvement in cancer immunology was also described. The review aims to summarize the therapeutic effects of CD26 inhibitors on immune-mediated diseases, as well as the mechanisms that underpin them.

The monkeypox outbreak has become a global public health emergency. The lack of valid and safe medicine is a crucial obstacle hindering the extermination of orthopoxvirus infections. The identification of potential inhibitors from natural products, including Traditional Chinese Medicine (TCM), by molecular modeling could expand the arsenal of antiviral chemotherapeutic agents. Monkeypox DNA topoisomerase I (TOP1) is a highly conserved viral DNA repair enzyme with a small size and low homology to human proteins. The protein model of viral DNA TOP1 was obtained by homology modeling. The reliability of the TOP1 model was validated by analyzing its Ramachandran plot and by determining the compatibility of the 3D model with its sequence using the Verify 3D and PROCHECK services. In order to identify potential inhibitors of TOP1, an integrated library of 4103 natural products was screened via Glide docking. Surface Plasmon Resonance (SPR) was further implemented to assay the complex binding affinity. Molecular dynamics simulations (100 ns) were combined with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations to reveal the binding mechanisms of the complex. As a result, three natural compounds were highlighted as potential inhibitors via docking-based virtual screening. Rosmarinic acid, myricitrin, quercitrin, and ofloxacin can bind TOP1 with KD values of 2.16 μM, 3.54 μM, 4.77 μM, and 5.46 μM, respectively, indicating a good inhibitory effect against MPXV. The MM/PBSA calculations revealed that rosmarinic acid had the lowest binding free energy at −16.18 kcal/mol. Myricitrin had a binding free energy of −13.87 kcal/mol, quercitrin had a binding free energy of −9.40 kcal/mol, and ofloxacin had a binding free energy of −9.64 kcal/mol. The outputs (RMSD/RMSF/Rg/SASA) also indicated that the systems were well-behaved towards the complex. The selected compounds formed several key hydrogen bonds with TOP1 residues (TYR274, LYS167, GLY132, LYS133, etc.) via the binding mode analysis. TYR274 was predicted to be a pivotal residue for compound interactions in the binding pocket of TOP1. The results of the enrichment analyses illustrated the potential pharmacological networks of rosmarinic acid. The molecular modeling approach may be acceptable for the identification and design of novel poxvirus inhibitors; however, further studies are warranted to evaluate their therapeutic potential.

It is widely accepted that N⁶-methyladenosine (m⁶A) exhibits significant intercellular specificity, which poses challenges for its detection using existing m⁶A quantitative methods. In this study, we introduced Single-cell m⁶A Analysis (Scm⁶A), a machine learning-based approach for single-cell m⁶A quantification. Scm⁶A leverages input features derived from the expression levels of m⁶A trans regulators and cis sequence features, and offers remarkable prediction efficiency and reliability. To further validate the robustness and precision of Scm⁶A, we applied a winscore-based m⁶A calculation method to conduct N⁶-methyladenosine sequencing (m⁶A-seq) analysis on CD4⁺ and CD8⁺ T-cells isolated through magnetic-activated cell sorting (MACS). Subsequently, we employed Scm⁶A for analysis on the same samples. Notably, the m⁶A levels calculated by Scm⁶A exhibited a significant positive correlation with m⁶A quantified through m⁶A-seq in different cells isolated by MACS, providing compelling evidence for Scm⁶A’s reliability. Additionally, we performed single-cell level m⁶A analysis on lung cancer tissues as well as blood samples from the coronavirus disease 2019 (COVID-19) patients, and demonstrated the landscape and regulatory mechanisms of m⁶A in different T-cell subtypes from these diseases. In summary, our work has yielded a novel, dependable, and accurate method for single-cell m⁶A detection. We are confident that Scm⁶A have broad applications in the realm of m⁶A-related research.

Intermittent fasting (IF) has emerged as a potential cancer treatment modality, although its tumor-suppressive effects are limited. Glioblastoma (GBM) can be classified into CDKN2A subtype and TP53 subtype. Here, we discover that the efficacy of IF is correlated with tumor subtypes of GBM. IF significantly inhibite GBM progression in mice with the Tp53 GBM model, whereas its inhibitory effect is not significant in the Cdkn2a GBM model. Multi-omics sequencing is performed in the IF-responsive Tp53 GBM mouse model, delineating a comprehensive molecular profiling of IF that including the spatial transcriptome, spatial metabolome, single-cell transcriptome, single-cell RNA methylation, metabolome, and microbiome. Through systematic biological analysis and rescue experiments conducted in IF-responsive Tp53 GBM mice model, we demonstrate that the efficacy of IF is primarily mediated by alterations in the gut microbiota, which subsequently modulate the production of the microbial metabolite methionine sulfoxide. Methionine sulfoxide, by regulating m⁶A modification, inhibits the TGF-β signaling pathway, resulting in suppressing GBM progression. This study proposes a genotype-based hypothesis for the therapeutic effects of IF on tumors, and elucidates the potential RNA modification-related molecular mechanisms underlying the effective suppression of GBM by IF.