Targeting epigenetic mechanisms in amyloid-β-mediated Alzheimer’s pathophysiology:unveiling therapeutic potential

Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

Constructing Artificial Nucleobase Compilation to Enable Precise Molecular Medicine

Nucleic acids are the hereditary information storage medium of life. Due to its high programmability and good biocompatibility, the applications of nucleic acids are not limited to their natural function. However, the efficiency of nucleic acids is often hampered by inherent limitations in numerous practical applications, including limited access to complex functional patterns due to only four building blocks, facile degradation by nucleases, rapid renal clearance, poor pharmacokinetic properties, and so on. To end this, the researchers developed unnatural base pairs (UBPs) and numerous artificial analogues of nucleosides and oligonucleotides in recent decades. The developed UBPs and nucleoside base analogues together constitute artificial nucleobase compilation, which promotes the development of biomedical sciences. Here, we describe the development of artificial nucleobase compilation and summarized its applications in precise molecular medicine, including PCR-based diagnostics, aptamer-based diagnostics, nucleobase analogue drugs construction, ASO modification, aptamer-based therapeutics and biomaterials construction. This review provides an overview of current opportunities and challenges of artificial nucleobase-related precise molecular medicine.

The aryl hydrocarbon receptor and the gut–brain axis

The aryl hydrocarbon receptor(AHR)is a ligand-activated transcription factor initially identified as the receptor for dioxin.Almost half a century after its discovery,AHR is now recognized as a receptor for multiple physiological ligands,with important roles in health and disease.In this review,we discuss the role of AHR in the gut–brain axis and its potential value as a therapeutic target for immune-mediated diseases.

The biomarkers of immune dysregulation and inflammation response in Parkinson disease

Parkinson’s disease(PD)is referring to the multi-systemicα-synucleinopathy with Lewy bodies deposited in midbrain.In ageing,the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration,especially in dopaminergic neurons.As a series of biomarkers,the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation.Furthermore,dopaminergic drugs change the biological characteristic of T lymphatic cells,affect theα-synuclein presentation pathway,and inhibit T lymphatic cells to release cytotoxicity in PD development.Taking together,the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.

Systems-based approaches to study immunometabolism

Technical advances at the interface of biology and computation,such as single-cell RNA-sequencing(scRNA-seq),reveal new layers of complexity in cellular systems.An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells.The diverse spectra of immune cell phenotypes,sparsity of immune cell numbers in vivo,limitations in the number of metabolites identified,dynamic nature of cellular metabolism and metabolic fluxes,tissue specificity,and high dependence on the local milieu make investigations in immunometabolism challenging,especially at the single-cell level.In this review,we define the systemic nature of immunometabolism,summarize cell-and system-based approaches,and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells.We close the review by discussing the applications and shortcomings of metabolic modeling techniques.With systems-oriented studies of metabolism expected to become a mainstay of immunological research,an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.