In recent years, the FDA has approved numerous anti-cancer drugs that are mutation-based for clinical use. These drugs have improved the precision of treatment and reduced adverse effects and side effects. Personalized therapy is a prominent and hot topic of current medicine and also represents the future direction of development. With the continuous advancements in gene sequencing and high-throughput screening, research and development strategies for personalized clinical drugs have developed rapidly. This review elaborates the recent personalized treatment strategies, which include artificial intelligence, multi-omics analysis, chemical proteomics, and computation-aided drug design. These technologies rely on the molecular classification of diseases, the global signaling network within organisms, and new models for all targets, which significantly support the development of personalized medicine. Meanwhile, we summarize chemical drugs, such as lorlatinib, osimertinib, and other natural products, that deliver personalized therapeutic effects based on genetic mutations. This review also highlights potential challenges in interpreting genetic mutations and combining drugs, while providing new ideas for the development of personalized medicine and pharmacogenomics in cancer study.

Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many similarities in the structure and function of different viral polymerases, so inhibitors designed for a certain viral polymerase have acted as effective universal inhibitors on other types of viruses. The present review describes the development of classical antiviral drugs targeting polymerases, summarizes a variety of viral polymerase inhibitors from the perspective of chemically synthesized drugs and natural product drugs, describes novel approaches, and proposes promising development strategies for antiviral drugs.

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.

Epitranscriptomic modifications can affect every aspect of RNA biology, including stability, transport, splicing, and translation, participate in global intracellular mRNA metabolism, and regulate gene expression and a variety of biological processes. N6-methyladenosine (m6A) as the most prevalent modification contributes to normal embryonic brain development and memory formation. However, changes in the level of m6A modification and the expression of its related proteins cause abnormal nervous system functions, including brain tissue development retardation, axon regeneration disorders, memory changes, and neural stem cell renewal and differentiation disorders. Recent studies have revealed that m6A modification and its related proteins play key roles in the development of various neuropsychiatric disorders, such as depression, Alzheimer’s disease, and Parkinson’s disease. In this review, we summarize the research progresses of the m6A modification regulation mechanism in the central nervous system and discuss the effects of gene expression regulation mediated by m6A modification on the biological functions of the neuropsychiatric disorders, thereby providing some insight into new research targets and treatment directions for human diseases.

Hypericin, one of the major antidepressant constituents of St. John’s wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

Background: Suicidal behaviors have become a serious public health concern globally due to the economic and human cost of suicidal behavior to individuals, families, communities, and society. However, the underlying etiology and biological mechanism of suicidal behavior remains poorly understood. Methods: We collected different single omic data, including single-cell RNA sequencing (scRNA-seq), bulk mRNA-seq, DNA methylation microarrays from the cortex of Major Depressive Disorder (MDD) in suicide subjects’ studies, as well as fluoxetine-treated rats brains. We matched subject IDs that overlapped between the transcriptome dataset and the methylation dataset. The differential expression genes and differentially methylated regions were calculated with a 2-group comparison analysis. Cross-omics analysis was performed to calculate the correlation between the methylated and transcript levels of differentially methylated CpG sites and mapped transcripts. Additionally, we performed a deconvolution analysis for bulk mRNA-seq and DNA methylation profiling with scRNA-seq as the reference profiles. Results: Difference in cell type proportions among 7 cell types. Meanwhile, our analysis of single-cell sequence from the antidepressant-treated rats found that drug-specific differential expression genes were enriched into biological pathways, including ion channels and glutamatergic receptors. Conclusions: This study identified some important dysregulated genes influenced by DNA methylation in 2 brain regions of depression and suicide patients. Interestingly, we found that oligodendrocyte precursor cells (OPCs) have the most contributors for cell-type proportions related to differential expression genes and methylated sites in suicidal behavior.