Yang Qu

Oxidative stress is a key cause of ischemic stroke and an initiator of neuronal dysfunction and death, mainly through the overproduction of peroxides and the depletion of antioxidants. Ferroptosis/oxytosis is a unique, oxidative stress-induced cell death pathway characterized by lipid peroxidation and glutathione depletion. Both oxidative stress and ferroptosis/oxytosis have common molecular pathways. This review summarizes the possible targets and the mechanisms underlying the crosstalk between oxidative stress and ferroptosis/oxytosis in ischemic stroke. This knowledge might help to further understand the pathophysiology of ischemic stroke and open new perspectives for the treatment of ischemic stroke.

BACKGROUNDS: The prevalence of diabetes has increased with the increase of obesity, and finding indicators to predict diabetes risk has become an urgent need. The purpose of this study is to compare the correlation between four anthropometric indices and the prevalence of diabetes. METHODS: A total of 4052 participants aged 40 years and above were selected in Dehui City, Jilin Province, using a multistage stratified whole group sampling method. Face-to-face interviews and physical examinations were conducted. Multivariate logistic analysis was used. The values of BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were divided into quartiles (Q1: <25%; Q2: ~25%; Q3: ~50%; and Q4: ~75%). The median of each quartile was used for a linear trend test. RESULTS: For all four body fat-measuring indices of body mass index (adjusted OR: 3.300, 95% CI: 2.370, 4.595), WC (adjusted OR: 5.131, 95% CI: 3.433, 7.669), WHR (adjusted OR: 3.327, 95% CI: 2.386, 4.638), and WHtR (adjusted OR: 5.959, 95% CI: 3.922, 9.054), patients in the highest quartile were more likely to have diabetes than those in the lowest quartile. The areas under the curve of WHtR, WC, WHR, and BMI for diabetes were 0.683, 0.669, 0.654, and 0.629, respectively. In female participants, the areas under the curve of the waist-height ratio and WC were 0.710 (95% CI: 0.679-0.741) and 0.701 (95% CI: 0.670-0.732), respectively. CONCLUSIONS: The WC and WHtR were more closely related to diabetes than BMI and WHR among study participants ≥ 40 years of age, especially in females.

Stroke is a major cerebrovascular disease threatening human health and life with high morbidity, disability and mortality. We aimed to find effective biomarkers for the early diagnosis on stroke. Nine previously reported stroke-associated miRNAs (miR-21, miR-23a, miR-29b, miR-124, miR-145, miR-210, miR-221, miR-223 and miR-483-5p) were measured by quantitative real time-PCR, and plasma high-sensitivity C-reactive protein (hs-CRP) and serum interleukin 6 (IL-6), the pro-inflammation markers in brain injury, were examined by enzyme-linked immunosorbent assay in 146 acute ischemic stroke patients and 96 healthy blood donors. We found that serum miR-145 was significantly increased within 24 h after stroke onset and serum miR-23a and miR-221 were decreased in patients. Moreover, serum miR-145 was strong positively correlated with plasma hs-CRP and moderate positively correlated with serum IL-6. Meanwhile, serum miR-23a and miR-221 were moderate negatively correlated with plasma hs-CRP but not serum IL-6. Importantly, the combination of hs-CRP and serum miR-145 gained a better sensitivity/spectivity for prediction of acute ischemia stroke (area under receiver operating characteristic curve from 0.794 to 0.896). Conclusively, our preliminary findings indicate that serum miR-145 upregulated in acute ischemic stroke might be a new biomarker for acute ischemia stroke evaluation.

Intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease with high morbidity and mortality, for which no effective therapies are currently available. Brain tissue damage caused by ICH is mediated by a newly identified form of non-apoptotic programmed cell death, called ferroptosis. Ferroptosis is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS cause damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. Numerous biological processes are involved in ferroptosis, including iron metabolism, lipid peroxidation, and glutathione biosynthesis; therefore, iron chelators, lipophilic antioxidants, and other specific inhibitors can suppress ferroptosis, suggesting that these modulators are beneficial for treating brain injury due to ICH. Accumulating evidence indicates that ferroptosis differs from other types of programmed cell death, such as necroptosis, apoptosis, oxytosis, and pyroptosis, in terms of ultrastructural characteristics, signaling pathways, and outcomes. Although several studies have emphasized the importance of ferroptosis due to ICH, the detailed mechanism underlying ferroptosis remains unclear. This review summarizes the available evidence on the mechanism underlying ferroptosis and its relationship with other types of cell death, with the aim to identify therapeutic targets and potential interventions for ICH.

BACKGROUND: Disruption of the blood-brain barrier (BBB) is a major contributor to hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) following intravenous thrombolysis (IVT). However, the clinical therapies aimed at BBB protection after IVT remain limited. METHODS: One hundred patients with AIS who underwent IVT were enrolled (42 with HT and 58 without HT 24 h after IVT). Based on the cytokine chip, the serum levels of several AIS-related proteins, including LCN2, ferritin, matrix metalloproteinase-3, vascular endothelial-derived growth factor, and X-linked inhibitor of apoptosis, were detected upon admission, and their associations with HT were analyzed. After finding that LCN2 was related to HT in patients with IVT, we clarified whether the modulation of LCN2 influenced BBB dysfunction and HT after thrombolysis and investigated the potential mechanism. RESULTS: In patients with AIS following IVT, logistic regression analysis showed that baseline serum LCN2 (p = 0.023) and ferritin (p = 0.046) levels were independently associated with HT. A positive correlation between serum LCN2 and ferritin levels was identified in patients with HT. In experimental studies, recombinant LCN2 (rLCN2) significantly aggravated BBB dysfunction and HT in the thromboembolic stroke rats after thrombolysis, whereas LCN2 inhibition by ZINC006440089 exerted opposite effects. Further mechanistic studies showed that, LCN2 promoted endothelial cell ferroptosis, accompanied by the induction of high mobility group box 1 (HMGB1) and the inhibition of nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Ferroptosis inhibitor ferrostatin-1 (fer-1) significantly restricted the LCN2-mediated BBB disruption. Transfection of LCN2 and HMGB1 siRNA inhibited the endothelial cell ferroptosis, and this effects was reversed by Nrf2 siRNA. CONCLUSION: LCN2 aggravated BBB disruption after thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway, this may provide a promising therapeutic target for the prevention of HT after IVT.