High Plasma Sarcosine Levels Are Associated with Decreased Risks of Adverse Outcomes After Ischemic Stroke: A Multicenter Prospective Study

血浆肌氨酸水平升高与缺血性卒中后不良结局风险降低相关：一项多中心前瞻性研究

Sarcosine has been reported to improve ischemic tolerance in animal models of brain ischemia, but population-based evidence from patients with ischemic stroke is lacking. We conducted a multicenter prospective study to investigate the associations between plasma sarcosine levels and adverse outcomes among patients with ischemic stroke. We measured plasma sarcosine levels among 3473 patients with ischemic stroke from 26 hospitals across China. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale [mRS] score, 3-6) at 3 months after ischemic stroke. Secondary outcomes were major disability (mRS score, 3-5), death (mRS score, 6), and cardiovascular events. During 3 months of follow-up, 853 participants experienced the primary outcome. Compared with the lowest quartile of sarcosine, the multivariable-adjusted odds ratios or hazard ratios of the highest quartile were 0.59 (Ptrend < 0.001) for primary outcome, 0.70 (Ptrend = 0.002) for major disability, 0.20 (Ptrend < 0.001) for death, and 0.43 (Ptrend = 0.017) for cardiovascular events. Multivariable-adjusted spline regression model showed linear associations of sarcosine with adverse outcomes (all Plinearity < 0.05). Adding sarcosine to conventional prognostic factors modestly improved the risk reclassification of adverse outcomes after ischemic stroke, as evidenced by net reclassification improvement and integrated discrimination improvement (all P < 0.05). Additionally, there was a strong combined effect of sarcosine and glycine on the risks of adverse outcomes after ischemic stroke. High plasma sarcosine levels were associated with low risks of adverse outcomes after ischemic stroke, suggesting that sarcosine might serve as a valuable prognostic biomarker for ischemic stroke.

有报道称，肌氨酸可提高脑缺血动物模型的缺血耐受性，但缺乏基于缺血性卒中患者群体的证据。我们开展了一项多中心前瞻性研究，以探究缺血性卒中患者血浆肌氨酸水平与不良结局之间的关联。我们对来自中国 26 家医院的 3473 例缺血性卒中患者的血浆肌氨酸水平进行了检测。主要结局为缺血性卒中后 3 个月时死亡或严重残疾（改良 Rankin 量表 [mRS] 评分 3 - 6 分）的复合结局。次要结局包括严重残疾（mRS 评分 3 - 5 分）、死亡（mRS 评分 6 分）和心血管事件。在 3 个月的随访期间，853 名参与者出现了主要结局。与肌氨酸水平最低四分位数组相比，最高四分位数组主要结局的多变量调整比值比或风险比为 0.59（趋势 P < 0.001），严重残疾为 0.70（趋势 P = 0.002），死亡为 0.20（趋势 P < 0.001），心血管事件为 0.43（趋势 P = 0.017）。多变量调整的样条回归模型显示，肌氨酸与不良结局呈线性关联（所有线性 P < 0.05）。将肌氨酸纳入传统预后因素后，可适度改善缺血性卒中后不良结局的风险重分类，净重新分类改善和综合区分改善均证实了这一点（所有 P < 0.05）。此外，肌氨酸和甘氨酸对缺血性卒中后不良结局的风险存在显著的联合作用。血浆肌氨酸水平高与缺血性卒中后不良结局风险低相关，这表明肌氨酸可能是一种有价值的缺血性卒中预后生物标志物。

REF: Sun L, Guo D, Chang X, et al. High Plasma Sarcosine Levels Are Associated with Decreased Risks of Adverse Outcomes After Ischemic Stroke: A Multicenter Prospective Study. Transl Stroke Res. Published online July 25, 2025. doi:10.1007/s12975-025-01370-0 PMID: 40715975

FLT1 as a Protective Factor in Ischemic Stroke: Insights from Real-World Pharmacovigilance and Genetic Evidence

FLT1作为缺血性卒中的保护因素：来自真实世界药物警戒和遗传学证据的见解

Ischemic stroke contributes substantially to global death and disability, yet effective molecular targets remain scarce. This study integrates real-world pharmacovigilance data, molecular databases, and genetic evidence to support the discovery and validation of novel therapeutic targets. A stepwise analytic pipeline combined adverse event signals from the FDA Adverse Event Reporting System (FAERS), drug-target data from DrugBank, and Mendelian randomization (MR) using proteomic instruments from the UK Biobank Pharma Proteomics Project (UKB PPP). Disproportionality analyses identified drugs with signals for ischemic stroke. The top 30 drugs were cross-referenced in DrugBank to identify molecular targets, which were subjected to protein interaction and pathway enrichment analyses. MR analysis assessed the causal effects of plasma proteins on ischemic stroke using GWAS data from GIGASTROKE (discovery) and FinnGen (validation). Among 88,313 ischemic stroke-related reports in FAERS, 701 drugs showed consistent signals, with the top 30 prioritized for target identification. FLT1 was the only overlapping protein between MR-significant proteins and FAERS-associated drug targets. MR analysis showed a significant inverse causal relationship between plasma FLT1 levels and ischemic stroke in both the discovery (OR, 0.864; 95% CI, 0.774-0.965) and validation (OR, 0.829; 95% CI, 0.788-0.871) datasets. FLT1 was enriched in pathways such as MAPK and PI3K-Akt, implicated in stroke-related molecular processes. FLT1 was identified as a potential protective factor against ischemic stroke through a triangulated approach combining pharmacovigilance, target bioinformatics, and MR analysis. These findings offer mechanistic insights and a promising direction for targeted intervention.

缺血性中风在全球范围内导致大量死亡和残疾，但有效的分子靶点仍然匮乏。本研究整合了真实世界药物警戒数据、分子数据库和遗传学证据，以支持新型治疗靶点的发现和验证。一个逐步分析流程结合了来自美国食品药品监督管理局不良事件报告系统（FAERS）的不良事件信号、来自DrugBank的药物靶点数据，以及利用英国生物银行药物蛋白质组学项目（UKB PPP）的蛋白质组学工具进行的孟德尔随机化（MR）分析。比例失调分析确定了与缺血性中风有信号关联的药物。在DrugBank中对排名前30的药物进行交叉引用，以确定分子靶点，并对这些靶点进行蛋白质相互作用和通路富集分析。MR分析利用来自GIGASTROKE（发现阶段）和FinnGen（验证阶段）的全基因组关联研究（GWAS）数据，评估血浆蛋白质对缺血性中风的因果效应。在FAERS的88313份缺血性中风相关报告中，701种药物显示出一致的信号，其中排名前30的药物被优先用于靶点识别。FLT1是MR分析有显著意义的蛋白质与FAERS相关药物靶点中唯一重叠的蛋白质。MR分析显示，在发现阶段（比值比[OR]为0.864；95%置信区间[CI]为0.774 - 0.965）和验证阶段（OR为0.829；95% CI为0.788 - 0.871）的数据集中，血浆FLT1水平与缺血性中风之间均存在显著的反向因果关系。FLT1在如MAPK和PI3K - Akt等与中风相关分子过程有关的通路中富集。通过结合药物警戒、靶点生物信息学和MR分析的三角验证方法，FLT1被确定为缺血性中风的潜在保护因素。这些发现提供了机制方面的见解，并为靶向干预提供了一个有前景的方向。

REF: Chen H, Yang J, Li Z, Gao F. FLT1 as a Protective Factor in Ischemic Stroke: Insights from Real-World Pharmacovigilance and Genetic Evidence. Transl Stroke Res. Published online July 18, 2025. doi:10.1007/s12975-025-01369-7 PMID: 40679760

Modified Intracranial Aneurysm Rupture Rat Model with Angiographic Imaging

改良颅内动脉瘤破裂大鼠模型及血管造影成像

Intracranial aneurysms (IAs) are a major cause of spontaneous subarachnoid hemorrhage (SAH) and are associated with high morbidity and mortality. Current IA rodent models often exhibit low rupture rates and limited imaging capabilities, restricting their translational utility. This study introduces a modified elastase-based rat model that incorporates angiographic imaging to overcome these challenges. IAs were induced in 7-week-old female Sprague-Dawley rats using a combination of surgical and pharmacological interventions, including carotid artery and renal artery ligation, bilateral ovariectomy, high-salt diet, and two elastase injections into the basal cistern. Digital subtraction angiography (DSA) was employed to assess aneurysm formation and rupture rate. Histological and immunohistochemical analyses were conducted to characterize aneurysm morphology and the inflammatory response. The modified model achieved a high rate of IA formation (85%) and rupture (60%) within 28 days. DSA enabled visualization of vessel tortuosity and flow dynamics, features relevant to human IA development, which often occurs in areas subjected to hemodynamic stress, and the tortuosity of intracranial vessels affects their rupture [1]. Histological analysis indicated structural degradation of the aneurysm wall, while immunohistochemistry showed neutrophil infiltration, potentially implicating inflammation in IA rupture. This improved IA model offers a reliable method for inducing and visualizing IAs with a high rupture rate, making it a valuable tool for studying the pathophysiology and therapeutic interventions of IAs. Enhanced by DSA, this model has the potential to advance therapeutic research by enabling the real-time monitoring of aneurysm development and rupture.

颅内动脉瘤（IAs）是自发性蛛网膜下腔出血（SAH）的主要原因，且与高发病率和高死亡率相关。目前的IA啮齿动物模型往往破裂率低且成像能力有限，限制了其转化应用价值。本研究引入了一种基于弹性蛋白酶改良的大鼠模型，该模型结合了血管造影成像技术以克服这些挑战。研究人员通过手术和药物干预相结合的方式，在7周龄雌性Sprague - Dawley大鼠身上诱导出IA，干预措施包括颈动脉和肾动脉结扎、双侧卵巢切除术、高盐饮食，以及向基底池注射两次弹性蛋白酶。采用数字减影血管造影（DSA）评估动脉瘤的形成和破裂率。进行组织学和免疫组织化学分析以表征动脉瘤的形态和炎症反应。改良模型在28天内实现了较高的IA形成率（85%）和破裂率（60%）。DSA能够观察到血管迂曲和血流动力学情况，这些特征与人类IA的发生发展相关，人类IA常发生在承受血流动力学压力的区域，且颅内血管的迂曲会影响其破裂情况[1]。组织学分析显示动脉瘤壁出现结构退化，而免疫组织化学分析显示有中性粒细胞浸润，这可能表明炎症与IA破裂有关。这种改良的IA模型为诱导和可视化具有高破裂率的IA提供了一种可靠的方法，使其成为研究IA病理生理学和治疗干预措施的有价值工具。借助DSA技术，该模型有望通过实现对动脉瘤发展和破裂的实时监测来推动治疗研究的进展。

REF: Pan WW, Itani M, Karagiozov K, et al. Modified Intracranial Aneurysm Rupture Rat Model with Angiographic Imaging. Transl Stroke Res. Published online July 16, 2025. doi:10.1007/s12975-025-01366-w PMID: 40670870

Gamma-Benzylidene Digoxin Derivative Attenuates Neurotoxicity Response in a Murine Stroke Model

γ-亚苄基地高辛衍生物减轻小鼠中风模型中的神经毒性反应

Stroke is a prevalent age-related disease globally, contributing significantly to neurological dysfunction, disability, and mortality rates. Despite its substantial healthcare burden, effective therapies remain limited. Na/K-ATPase (NKA), beyond its canonical role in ion homeostasis, emerges as a pivotal player in oxidative stress induction, implicating its potential as a therapeutic target. Here, we investigate the efficacy of the semi-synthetic cardiotonic steroid gamma-benzylidene digoxin-15 (BD-15) in ameliorating brain ischemia-induced damage. A total of 44 male Wistar albino rats were randomly assigned to four groups (n = 11/group). The animals were subjected to experimental brain ischemia induction and treated with BD-15. Behavioral assessments revealed a significant improvement in mobility and exploration in BD-15-treated rats compared to brain ischemia alone (P < 0.05). Histological analysis suggested a reduction in brain damage in BD-15-treated rats. Moreover, BD-15 administration attenuated oxidative stress, evidenced by decreased thiobarbituric acid reactive substances levels (TBARS) in the hippocampus and sensory-motor cortex in brain ischemia rats (P < 0.05). Additionally, BD-15 treatment mitigated changes in lipid composition, possibly via modulation of membrane integrity. BD-15 also significantly restored ionic homeostasis in brain ischemia rats, improving the activities of NKA, Ca2+-ATPase, Sarcoendoplasmic Reticulum Calcium ATPase, and Mg2+-ATPase activities in the hippocampus and sensory-motor cortex (P < 0.05). Notably, acetylcholinesterase activity in brain ischemia rats was improved after BD-15 treatment (P < 0.05), suggesting additional benefits in maintaining neurotransmission following ischemic injury. These findings suggest a multifaceted neuroprotective mechanism of BD-15 in brain ischemia pathology. Our results propose BD-15 as a promising therapeutic strategy for mitigating ischemia-induced neurotoxicity. Further clinical studies are necessary to validate these findings and explore the translational potential of BD-15 in human stroke management.

中风是一种在全球范围内普遍存在的与年龄相关的疾病，对神经功能障碍、残疾和死亡率有显著影响。尽管其给医疗保健带来了沉重负担，但有效的治疗方法仍然有限。钠/钾 - 腺苷三磷酸酶（NKA）除了在离子稳态中发挥经典作用外，还在氧化应激诱导中扮演关键角色，这表明它有作为治疗靶点的潜力。在此，我们研究了半合成强心类固醇γ - 亚苄基地高辛 - 15（BD - 15）改善脑缺血损伤的效果。将44只雄性Wistar白化大鼠随机分为四组（每组n = 11）。对这些动物进行实验性脑缺血诱导，并给予BD - 15治疗。行为评估显示，与仅患脑缺血的大鼠相比，BD - 15治疗组大鼠的活动能力和探索能力有显著改善（P < 0.05）。组织学分析表明，BD - 15治疗组大鼠的脑损伤有所减轻。此外，BD - 15给药减轻了氧化应激，脑缺血大鼠海马和感觉运动皮层中的硫代巴比妥酸反应物质（TBARS）水平降低可证明这一点（P < 0.05）。此外，BD - 15治疗减轻了脂质组成的变化，可能是通过调节膜完整性实现的。BD - 15还显著恢复了脑缺血大鼠的离子稳态，提高了海马和感觉运动皮层中NKA、Ca²⁺ - 腺苷三磷酸酶、肌浆网钙腺苷三磷酸酶和Mg²⁺ - 腺苷三磷酸酶的活性（P < 0.05）。值得注意的是，BD - 15治疗后，脑缺血大鼠的乙酰胆碱酯酶活性得到改善（P < 0.05），这表明其在缺血性损伤后维持神经传递方面还有额外益处。这些发现表明BD - 15在脑缺血病理过程中具有多方面的神经保护机制。我们的研究结果表明BD - 15是减轻缺血性神经毒性的一种有前景的治疗策略。需要进一步的临床研究来验证这些发现，并探索BD - 15在人类中风治疗中的转化潜力。

REF: de Souza Gonçalves B, Dos Santos CP, Machado MV, et al. Gamma-Benzylidene Digoxin Derivative Attenuates Neurotoxicity Response in a Murine Stroke Model. Transl Stroke Res. Published online July 12, 2025. doi:10.1007/s12975-025-01365-x PMID: 40650840

Exploring Hypoxia-Induced Neuroprotection Mechanisms in Post-Stroke Recovery

探索缺氧诱导的中风后神经保护机制

Stroke recovery is a multifaceted process influenced by various neuroprotective mechanisms that support long-term rehabilitation. Recent studies on hypoxia-induced neuroprotection have shown promising potential in enhancing stroke recovery through adaptive cellular responses. Hypoxic conditioning in techniques of passive intermittent hypoxic exposures (IHE) or intermittent hypoxic-hyperoxic exposures (IHHE), which alternates between low and normal/high oxygen levels, is emerging as a novel complementary therapy that may improve post-stroke outcomes by promoting neuroprotection, neurogenesis, and vascular remodeling. This review aims to explore the therapeutic implications of IHE/IHHE as a novel complementary therapy to mitigate post-stroke exacerbations and enhance recovery through various physiological and molecular mechanisms. A comprehensive literature search was conducted using public databases such as PubMed, Scopus, Relemed, the National Library of Medicine, and Google Scholar. The search focused on studies related to hypoxia training, neuroprotection, stroke recovery, and IHE/IHHE. The review synthesizes current findings on the pathophysiological insights and therapeutic potential of intermittent hypoxic conditioning in stroke rehabilitation. The review highlights several key areas where IHE/IHHE shows adaptive responses involving hypoxia-inducible factor (HIF) signaling, reactive oxygen species (ROS) regulation, and mitochondrial energetics, contributing to enhanced neuroprotection and tissue recovery. Angiogenesis and vascular remodeling: IHE/IHHE promotes angiogenesis and improves cerebral blood flow, facilitating vascular remodeling and improved perfusion in damaged brain areas. Neurogenesis: IHE/IHHE enhances neurogenesis, aiding in brain repair and functional recovery by promoting neuronal survival and regeneration. Cognitive and motor function: IHE/IHHE has been shown to improve cognitive performance and motor function in post-stroke patients, as well as in elderly individuals with mild cognitive impairment. Cardioprotection: IHE/IHHE reduces cardiovascular risk factors, such as hypertension and inflammation, and has been shown to enhance cardiac function in patients with ischemic heart disease. Integrative rehabilitation: Incorporating IHE/IHHE into post-stroke rehabilitation programs may enhance physical and cognitive outcomes, supporting a holistic approach to recovery. Hypoxic conditioning in modes of IHE/IHHE represents a promising complementary therapy for stroke recovery, leveraging adaptive responses to hypoxia and hyperoxia to promote neuroprotection, neurogenesis, and vascular remodeling. Further research is needed to optimize IHHE protocols, understand their long-term effects, and integrate them effectively into clinical practice. This review benefits physicians, molecular biologists, and neurologists and describes the potential of IHE/IHHE in enhancing stroke rehabilitation outcomes, and highlights the need for well-controlled clinical trials to validate its efficacy and safety.

中风康复是一个多方面的过程，受多种神经保护机制的影响，这些机制支持长期康复。近期关于缺氧诱导神经保护的研究表明，通过适应性细胞反应，其在促进中风康复方面具有良好的潜力。被动间歇性低氧暴露（IHE）或间歇性低氧 - 高氧暴露（IHHE）技术中的低氧调节，即在低氧水平与正常/高氧水平之间交替，正逐渐成为一种新型的辅助疗法，可通过促进神经保护、神经发生和血管重塑来改善中风后的预后。本综述旨在探讨IHE/IHHE作为一种新型辅助疗法的治疗意义，通过多种生理和分子机制减轻中风后的病情加重并促进康复。我们使用PubMed、Scopus、Relemed、美国国立医学图书馆和谷歌学术等公共数据库进行了全面的文献检索。检索重点为与低氧训练、神经保护、中风康复以及IHE/IHHE相关的研究。本综述综合了当前关于间歇性低氧调节在中风康复中的病理生理学见解和治疗潜力的研究成果。综述强调了IHE/IHHE在几个关键领域显示出的适应性反应，涉及缺氧诱导因子（HIF）信号传导、活性氧（ROS）调节和线粒体能量代谢，有助于增强神经保护和组织恢复。血管生成和血管重塑：IHE/IHHE促进血管生成并改善脑血流量，促进受损脑区的血管重塑和灌注改善。神经发生：IHE/IHHE增强神经发生，通过促进神经元存活和再生来帮助大脑修复和功能恢复。认知和运动功能：研究表明，IHE/IHHE可改善中风后患者以及轻度认知障碍老年人的认知表现和运动功能。心脏保护：IHE/IHHE可降低心血管危险因素，如高血压和炎症，并已被证明能改善缺血性心脏病患者的心脏功能。综合康复：将IHE/IHHE纳入中风后康复计划可能会改善身体和认知预后，支持全面的康复方法。IHE/IHHE模式的低氧调节是一种有前景的中风康复辅助疗法，利用对低氧和高氧的适应性反应来促进神经保护、神经发生和血管重塑。需要进一步的研究来优化IHHE方案，了解其长期效果，并将其有效地整合到临床实践中。本综述对医生、分子生物学家和神经科医生有益，阐述了IHE/IHHE在改善中风康复预后方面的潜力，并强调了需要进行严格对照的临床试验来验证其有效性和安全性。

REF: Nyamukondiwa M, Koneva ES, Achkasov EE, et al. Exploring Hypoxia-Induced Neuroprotection Mechanisms in Post-Stroke Recovery. Transl Stroke Res. Published online July 5, 2025. doi:10.1007/s12975-025-01364-y PMID: 40615654