Naotaifang formula attenuates OGD/R-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through BMP6/SMADs signaling pathway.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI), a subsequent injury caused by thrombolytic reperfusion post ischemic stroke (IS). Naotaifang (NTF) formula, a novel traditional Chinese medicine (TCM) remedy against IS, was shown to exert beneficial effects in inhibiting inflammation and inhibiting lipid peroxide synthesis in our previous research. PURPOSE: This study aimed to further explore the role of NTF in attenuating oxygen-glucose deprivation//reoxygenation (OGD/R)-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through the bone morphogenetic protein 6（BMP6）/SMADs signaling pathway. METHODS: BV2 microglia were used to establish an OGD/R model. The effects of NTF on inflammation and ferroptosis in OGD/R-injured BV2 cells were separately detected by immunofluorescence assay, fluorescent probe, DCFH-DA flow cytometry, enzyme-linked immunosorbent assay, and western-blot. RESULTS: The present results revealed that the M1 phenotype of microglia promoted the secretion of pro-inflammatory cytokines and aggravated ferroptosis and brain damage following OGD/R. However, an inhibitor of BMP6, LND-193189, reversed the aforementioned effects. Similarly, NTF promoted the shift of microglia from M1 to M2. Besides, NTF treatment effectively inhibited the expression of hepcidin, BMP6, SMADs and promoted the expression of ferroportin (FPN, SLC40A1) and γ-L-glutamyl-L-cysteinylglycine (glutathione or GSH) peroxidase 4 (GPX4). CONCLUSION: Microglial M1/M2 polarization plays a pivotal role in inflammation and ferroptosis during OGD/R. The BMP6/SMADs signaling pathway is a potential therapeutical target of inflammation and ferroptosis induced by the transformation of microglia. Moreover, NTF could alleviate inflammation and ferroptosis through the BMP6/SMADs signaling pathway in OGD/R-injured microglia.

[Advances in epigenetics in ischemic stroke].

Ischemic stroke is one of the main causes of death and long-term disability worldwide, which seriously affects the quality of life of patients and brings a heavy economic burden to families and society. Epidemiological studies have shown that stroke has become the second leading cause of death and major disabling disease in the world, with the characteristics of high morbidity, high recurrence, and high mortality. Epigenetic mechanism is the molecular process where gene expression and function in each cell are dynamically regulated and interconnected and a biological mechanism that changes genetic performance without changing the DNA sequence, including DNA methylation, histone modifications, and non-coding RNA. However, the research on epigenetics is currently focused on other diseases such as tumors. Recent studies have found that epigenetics has received extensive attention in the past few decades as a key factor involved in the pathophysiological process of ischemic stroke. The present study introduced the mediation of epigenetics in the induction of stroke, summarized the potential drug targets for these mechanisms in the treatment of stroke, and further explored the significance of traditional Chinese medicine(TCM) against cerebral ischemia injury based on TCM classification of stroke.