In hypoxic-ischemic brain damage (HIBD), the programmed cell death known as ferroptosis is significantly activated. Microglial cells demonstrate a high level of sensitivity to iron accumulation. Understanding how to regulate the dual role of microglia and transforming the microglial ferroptosis to a moderate and controllable process has considerable implications for the targeted treatment in HIBD. This paper serves as an overview of microglia-mediated ferroptosis in HIBD as a disease model. We discuss various aspects centered around microglia, including pathophysiological mechanisms, polarization and functions of microglia, molecular mechanisms of ferroptosis, signaling pathways, and therapeutic strategies. The review aims to provide a reference for studies of ferroptosis in microglia.
Microglia/physiology* ; Ferroptosis/physiology* ; Humans ; Animals ; Hypoxia-Ischemia, Brain/pathology* ; Signal Transduction

OBJECTIVES: To evaluate the therapeutic effect of gastrodin against hypoxic-ischemic brain damage (HIBD) in neonatal mice and explore the role of GPX4/SLC7A11/FTH1 signaling in mediating its effect. METHODS: Twenty-four 9- to 11-day-old C57BL/6J mice were randomized equally into 4 groups for sham operation, HIBD modeling by right common carotid artery ligation and subsequent exposure to hypoxia for 1 h, or gastrodin treatment at 100 or 200 mg/kg before and at 1 and 2 days after modeling. The mice then underwent neurological assessment (Zea-Longa scores), and the cerebral cortical penumbra tissue were collected for HE and Nissl staining, detection of ferroptosis biomarkers and protein expressions of GPX4, SLC7A11, and FTH1 with Western blotting and immunofluorescence co-localization, and observation of mitochondrial ultrastructure with electron microscopy. In cultured HT22 neuronal cells with oxygen-glucose deprivation (OGD) for 2 h, the effects of pretreatments with 0.5 mmol/L gastrodin, 10 μmol/L RSL3 (a GPX4 inhibitor), alone or in combination, were analyzed on expressions of ferroptosis-related proteins, cellular Fe²⁺, ROS, lipid peroxidation, MDA, and GSH levels, mitochondrial membrane potential (JC-1), and cell viability. RESULTS: Gastrodin treatment at the two doses both significantly ameliorated HIBD and neurological deficits of the mice, reduced mitochondrial damage and Fe²⁺, MDA and ROS levels, increased GSH level, and upregulated GPX4, SLC7A11, and FTH1 protein expressions. In HT22 cells, gastrodin pretreatment obviously attenuated OGD-induced ferroptosis and improved cell viability and mitochondrial function. Co-treatment with RSL3 potently abrogated the inhibitory effects of gastrodin on Fe²⁺, ROS, BODIPY-C11, and MDA levels and attenuated its protective effects on GSH level, cell viability, and mitochondrial membrane potential. CONCLUSIONS Gastrodin provides neuroprotective effects in neonatal mice with HIBD by suppressing neuronal ferroptosis via upregulating the GPX4/SLC7A11/FTH1 signaling pathway.
Animals ; Ferroptosis/drug effects* ; Hypoxia-Ischemia, Brain/drug therapy* ; Mice ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Glucosides/pharmacology* ; Animals, Newborn ; Benzyl Alcohols/pharmacology* ; Amino Acid Transport System y+/metabolism*

Objective To investigate the mechanisms of protective effects of dexmedetomidine on lungs in patients of sepsis complicated with acute respiratory distress syndrome (ARDS). Methods The adult patients with sepsis complicated with ARDS, the oxygenation index (PaO2/FiO2) was 150-200 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluationⅡ (APACHEⅡ) score was 10-20, need mechanical ventilation (MV) treatment > 72 hours, and admitted to intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from September 2013 to June 2017 were enrolled. According to the random number table method, the patients were divided into three groups (n = 80): no sedation group, propofol group (0.3-4.0 mg·kg-1·h-1) and dexmedetomidine group (0.2-0.7 μg·kg-1·h-1). The three groups were adequately analgesic treated with remifentanil. The sedation target was -1-0 of Richmond agitation-sedation score (RASS). The levels of interlenkin-6 (IL-6) and tumor necrosis factor-α (INF-α) were determined by enzyme linked immunosorbent assay (ELISA) before sedation, and 24, 48, 72 hours after sedation. The expressions of inflammatory signaling proteins in bronchoalveolar lavage fluid (BALF) were determined by Western Blot before sedation and 72 hours after sedation. Results There were no significant changes for inflammatory factors in serum, and inflammatory signaling proteins and anti-apoptotic signaling proteins in alveolar exfoliated cells in no sedation group. The levels of IL-6 and TNF-α in serum and the expressions of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and phosphorylated c-Jun N-terminal kinase (p-JNK) in alveolar cells in propofol group and dexmedetomidine group were all significantly reduced after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group [48 hours: TNF-α (ng/L) was 153.76±29.16 vs. 179.82±30.28;72 hours: IL-6 (ng/L) was 272.18±42.76 vs. 304.49±44.93, TNF-α (ng/L) was 102.18±30.25 vs. 140.28±28.92, TLR4 (IA value) was 0.288±0.034 vs. 0.648±0.029, MyD88 (IA value): 0.356±0.030 vs. 0.752±0.044, p-JNK (IA value): 0.256±0.027 vs. 0.303±0.034, all 1 < 0.05]. The expression of p-Akt in alveolar cells in propofol group and dexmedetomidine group was all significant increased after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group (IA value: 1.032±0.030 vs. 0.743±0.028, 1 < 0.05). Conclusion Dexmedetomidine exerts the protective effects on lungs in patients of sepsis complicated with ARDS through the TLR4-MyD88-JNK signaling pathway.