Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke.

BACKGROUND: Stroke is a devastating disease affecting populations worldwide and is the primary cause of long-term disability. The inflammatory storm plays a crucial role in the progression of stroke. In the acute phase of ischemic stroke, there is a transient increase in anti-inflammatory M2 microglia followed by a rapid decline. Due to the abundant phospholipid in brain tissue, lipid peroxidation is a notable characteristic of ischemia/reperfusion (I/R), constituting a structural foundation for ferroptosis in M2 microglia. Slowing down the decrease in M2 microglia numbers and controlling the inflammatory microenvironment holds significant potential for enhancing stroke recovery. RESULTS: We found that the ferroptosis inhibitor can modulate inflammatory response in MCAO mice, characterizing that the level of M2 microglia-related cytokines was increased. We then confirmed that different subtypes of microglia exhibit distinct sensitivities to I/R-induced ferroptosis. Adipose-derived stem cells derived exosome (ADSC-Exo) effectively decreased the susceptibility of M2 microglia to ferroptosis via Fxr2/Atf3/Slc7a11, suppressing the inflammatory microenvironment and promoting neuronal survival. Furthermore, through plasmid engineering, a more efficient M2 microglia-targeted exosome, termed M2pep-ADSC-Exo, was developed. In vivo and in vitro experiments demonstrated that M2pep-ADSC-Exo exhibits significant targeting specificity for M2 microglia, further inhibiting M2 microglia ferroptosis and improving neurological function in ischemic stroke mice. CONCLUSION: Collectively, we illustrated a novel potential therapeutic mechanism that Fxr2 in ADSC-Exo could alleviate the M2 microglia ferroptosis via regulating Atf3/Slc7all expression, hence inhibiting the inflammatory microenvironment, improving neurofunction recovery in cerebral I/R injury. We obtained a novel exosome, M2pep-ADSC-Exo, through engineered modification, which exhibits improved targeting capabilities toward M2 microglia. This provides a new avenue for the treatment of stroke.

Prognosis of patients with coexisting obesity and malnutrition after ischemic stroke: A cohort study.

BACKGROUND: The double burden of malnutrition, defined as the coexistence of obesity and malnutrition, is an increasing global health concern and is unclear in patients after ischemic stroke. The current study explored the combined impacts of obesity and malnutrition on patients with ischemic stroke. METHODS: We conducted a single-center prospective cohort study with patients with ischemic stroke enrolled in Minhang Hospital in China between January 2018 and December 2022. Patients were stratified into four categories based on their obesity (defined by body mass index) and nutritional status (classified according to the Controlling Nutritional Status score): (1) nourished nonobese, (2) malnourished nonobese, (3) nourished obese, and (4) malnourished obese. The primary end points were poor outcomes and all-cause mortality at 3 months. RESULTS: A total of 3160 participants with ischemic stroke were included in our study, of which 64.7% were male and the mean age was 69 years. Over 50% of patients were malnourished. At 3-month follow-up, the malnourished nonobese had the worst outcomes (34.4%), followed by the malnourished obese (33.2%), nourished nonobese (25.1%), and nourished obese (21.8%; P < 0.001). In multivariable analyses, with nourished nonobese group as the reference, the malnourished nonobese group displayed poorer outcomes (odds ratio [OR], 1.395 [95% CI, 1.169-1.664], P < 0.001) and higher all-cause mortality (OR, 1.541 [95% CI, 1.054-2.253], P = 0.026), but only a nonsignificant increase in poor prognosis rate (33.2% vs. 25.1%, P = 0.102) and mortality (4.2% vs. 3.6%, P = 0.902) were observed in the malnourished obese group. CONCLUSION: A high prevalence of malnutrition is observed in the large population suffering from ischemic attack, even in the obese. Malnourished patients have the worst prognosis particularly in those with severe nutritional status regardless of obesity, while the best functional outcomes and the lowest mortality are demonstrated in nourished obese participants.

High serum lactate dehydrogenase to albumin ratio is associated with increased risk of poor prognosis after ischemic stroke.

BACKGROUND: Lactate dehydrogenase to albumin ratio (LAR) is a comprehensive biomarker for anaerobiosis, inflammation, and nutritional status, but its prognostic value for ischemic stroke has rarely been reported. We aimed to prospectively investigate whether serum LAR is associated with the prognosis of ischemic stroke patients in a large-scale cohort study. MATERIALS AND METHODS: Serum LAR levels were measured among 6634 patients with ischemic stroke admitted at Minhang hospital from January 2018 to December 2022. The primary outcome was the composite of major disability and death (modified Rankin Scale score [mRS] ≥ 3) at 3-month follow up. Secondary outcomes included death and the ordered 7-level category score of mRS. Multivariate logistic regression and restricted cubic splines were adopted to evaluate the associations between serum LAR levels and adverse clinical outcomes of ischemic stroke. RESULTS: During 3 months of follow-up period, a total of 2125 patients experienced primary outcome. After multivariate adjustment, the highest quartile of serum LAR was associated with an increased risk of primary outcome (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.27-1.83; P for trend < 0.001). Each standard deviation higher log-transformed serum LAR resulted in a 20% (95% CI, 12%-28%) increased risk of primary outcome. Furthermore, multivariable-adjusted restricted cubic spline analyses showed a linear association between the serum LAR level with primary outcome (P for linearity < 0.001). Finally, the addition of serum LAR to conventional risk factors significantly improved risk predictive abilities for the primary outcome (net reclassification improvement [NRI]: 18.35%, P < 0.001; integrated discrimination improvement [IDI]: 0.35%, P < 0.001) at 3-month follow up in patients with ischemic stroke. CONCLUSION: High serum LAR level was independently associated with an increased risk of adverse clinical outcomes among patients with ischemic stroke, indicating that serum LAR may be a valuable prognostic biomarker for ischemic stroke.

Preconditioned MSCs Alleviate Cerebral Ischemia-Reperfusion Injury in Rats by Improving the Neurological Function and the Inhibition of Apoptosis.

Mesenchymal stem cells (MSCs) have great application prospects in the treatment of ischemic injury. However, their long-time cultivation before transplantation and poor survival after transplantation greatly limit the therapeutic effect and applications. This study aimed to investigate whether MSCs under the ischemic microenvironment could improve their survival and better alleviate cerebral ischemic injury. Firstly, we used ischemic brain tissue to culture MSCs and evaluated the functional changes of MSCs. Then a middle cerebral artery occlusion (MCAO) model was induced in rats, and the pretreated MSCs were injected via the tail vein. The adhesive removal test, rotarod test, modified neurological severity score, and pathological analyses were applied to assess the rats' neurological function. Then the expression of neuron and apoptosis related markers was detected. The results indicated that ischemic brain tissue pretreated MSCs promoted the proliferation and the release of the growth factors of MSCs. Meanwhile, in MCAO model rats, transplantation of pretreated MSCs enhanced the neurogenesis, attenuated behavioral changes, reduced infarct size, and inhibited apoptosis. The expression of B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), NF-L, and NeuN were increased, while BCL2-Associated X (Bax) and Caspase-3 decreased. Our results suggest that MSCs pretreatment with stroke brain tissue could be an effective strategy in treating cerebral ischemic injury.

Drip-and-Ship Model for Thrombectomy in Stroke Patients with Large-Vessel Occlusion.

BACKGROUND: Previous studies have demonstrated the efficacy of the "drip-and-ship" model in acute ischemic stroke (AIS) patients treated with intravenous (IV) thrombolysis. We investigated and report the outcomes of the safety and efficacy of the "drip-and-ship" model in AIS patients with acute large-vessel occlusion (LVO) in the anterior circulation who underwent endovascular treatment. METHODS: A total of 92 AIS patients with LVO who underwent endovascular treatment enrolled from April 2017 to July 2018 at a single academic comprehensive stroke center (CSC) were included. Patients were divided into 2 groups: a front-door group (directly admitted to the CSC) and a drip-and-ship group (transferred to the CSC from other hospital). Logistic regression model was used to evaluate the functional outcome, mortality, and symptomatic intracranial hemorrhage (sICH) at 90 days. RESULTS: After adjusting for age, gender, occlusion site, National Institutes of Health Stroke Scale (NIHSS) score, and other potential covariates, we did not see difference in modified Rankin Scale (mRS) score between the 2 groups at 90 days. The rate of excellent functional outcome (defined as mRS 0-1) in the drip-and-ship group is lower than the front-door group (p = 0.017); however, functional outcomes (defined as mRS 0-2) have no difference (p = 0.117). There was no significant difference in sICH (p = 0.909) and mortality (p = 0.319) between the 2 groups. CONCLUSIONS: The "drip-and-ship" model has the potential to be a feasible model for patients with LVO in the anterior circulation to undergo endovascular treatment. Further large-scale prospective studies are warranted to confirm these findings.