Inefficient differentiation of oligodendrocyte precursor cells (OPCs) is one of the significant pathological obstacles of myelin repair and provides an essential therapeutic target against behavioral dysfunction in various neurodegenerative diseases, especially in secondary progressive multiple sclerosis (SPMS). Ginsenoside Rg1 (Rg1) has traditionally been recognized as a protector of neuronal damages, preventing its degeneration. We investigated the effects of Rg1 on myelin regeneration-mediated by OPCs and its therapeutic significance in SPMS. A cuprizone (CPZ) model was established and then administered with Rg1 specific for evaluations of functional recovery and remyelination. In vitro, the primary mouse OPCs were isolated and cultured for examining their ability of myelin repair. Furthermore, a chronic experimental autoimmune encephalomyelitis (EAE) model was utilized to assess the therapeutic value on SPMS. We found that Rg1 promoted functional recovery of the demyelinated mice, including spatial memory, motor function, and anxiety-like behavior. Histologically, Rg1 enhanced myelin-genesis as proven by myelin staining and microstructures of myelin observed by transmission electron microscope. Furthermore, Rg1 significantly increased Olig2+ oligodendrocyte lineage cells in callosum, implying that the pro-remyelination effect of Rg1 was closely correlated to the enhanced differentiation of OPCs. We further demonstrated that Rg1 increased the survival and proliferation of OPCs as well as induced maturation in oligodendrocytes (OLs). Molecular analysis showed that Rg1 transduced the pro-differentiation signaling programmed by the GSK3β/β-Catenin pathway. Notably, relying on its pro-remyelination effects, Rg1 ameliorated severity and histopathology of EAE disease. By paving the way for OPCs differentiation, Rg1 could maintain the integrity of myelin and is a promising candidate for functional recovery in demyelinating diseases.

Ferroptosis is a novel form of cell demise characterized primarily by the reduction of trivalent iron to divalent iron, leading to the release of reactive oxygen species (ROS) and consequent induction of intense oxidative stress. In atherosclerosis (AS), highly accumulated lipids are modified by ROS to promote the formation of lipid peroxides, further amplifying cellular oxidative stress damage to influence all stages of atherosclerotic development. Macrophages are regarded as pivotal executors in the progression of AS and the handling of iron, thus targeting macrophage iron metabolism holds significant guiding implications for exploring potential therapeutic strategies against AS. In this comprehensive review, we elucidate the potential interplay among iron overload, inflammation, and lipid dysregulation, summarizing the potential mechanisms underlying the suppression of AS by alleviating iron overload. Furthermore, the application of Traditional Chinese Medicine (TCM) is increasingly widespread. Based on extant research and the pharmacological foundations of active compounds of TCM, we propose alternative therapeutic agents for AS in the context of iron overload, aiming to diversify the therapeutic avenues.

Boosting myelin repair is widely recognized as one of the most powerful approaches for demyelinating therapy, essentially contributing to the recovery of neurological functions. Maintaining immune homeostasis in microglia is a prerequisite for creating a reparative environment for myelin. Dihydroartemisinin (DHA) is clinically effective in reshaping immunological status and implies potential in treating demyelinating disease. However, its relevance to pro-remyelination remains unclear. We first evaluated the effects of DHA on neurofunctional recovery and white matter integrity in chronic experimental autoimmune encephalomyelitis (EAE), an ideal model for secondary progressive multiple sclerosis (SPMS) characterized by remyelination deficiency. Single-cell sequencing and microglial depletion with PLX3397 in vivo were used to reveal the dependency between DHA and microglia. The effect of DHA on the reparative phenotype of microglia, particularly on cholesterol recycling and differentiation of oligodendrocyte progenitor cells (OPCs), was evaluated in microglia-OPCs unit either in vitro or in vivo challenged with myelin debris. Finally, to broaden the clinical application for DHA in myelin repair, it was tested in the cuprizone (CPZ) model which shows remyelination failure, a condition common in various neurodegenerative diseases. We demonstrated for the first time that DHA enhanced white matter integrity and OPCs proliferation and differentiation. This effect is dependent on the transition of microglia to a reparative phenotype. Specifically, DHA increased the secretion of inflammatory-resolving and neurotrophic cytokines. It further functionalized cholesterol recycling and provided metabolic support for myelin regeneration predominantly mediated by liver X receptor (LXR) in microglia. This was evidenced by the promotion of myelin debris uptake, cholesterol catabolism, efflux and transport. Notably, DHA promoted remyelination and neurological functional recovery in CPZ-induced demyelinating model, supporting its potential application in neurodegenerative diseases featuring insufficient remyelination. By highlighting the importance of microglia in promoting myelin regeneration, our study proved DHA as a promising candidate for promoting remyelination. A schematic diagram illustrates that DHA enhances remyelination by inducing a reparative phenotype of microglia mainly through its function in cholesterol recycling, thereby creating a permissive immune environment for OPCs proliferation and differentiation.