Abstract Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases. 

Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects

Cervical artery dissection is an important cause of stroke, particularly in young adults. Data conflict on the diagnostic evaluation and treatment of patients with suspected cervical artery dissection, leading to variability in practice. We aim to provide an overview of cervical artery dissection in the setting of minor or no reported mechanical trigger with a focus on summarizing the available evidence and providing suggestions on the diagnostic evaluation, treatment approaches, and outcomes. Writing group members drafted their sections using a literature search focused on publications between January 1, 1990, and December 31, 2022, and included randomized controlled trials, prospective and retrospective observational studies, meta-analyses, opinion papers, case series, and case reports. The writing group chair and vice chair compiled the manuscript and obtained writing group members’ approval. Cervical artery dissection occurs as a result of the interplay among risk factors, minor trauma, anatomic and congenital abnormalities, and genetic predisposition. The diagnosis can be challenging both clinically and radiologically. In patients with acute ischemic stroke attributable to cervical artery dissection, acute treatment strategies such as thrombolysis and mechanical thrombectomy are reasonable in otherwise eligible patients. We suggest that the antithrombotic therapy choice be individualized and continued for at least 3 to 6 months. The risk of recurrent dissection is low, and preventive measures may be considered early after the diagnosis and continued in high-risk patients. Ongoing longitudinal and population-based observational studies are needed to close the present gaps on preferred antithrombotic regimens considering clinical and radiographic prognosticators of cervical artery dissection.

Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association.

Stroke remains the main leading cause of death and disabilities worldwide, with diabetes mellitus being a significant independent risk factor for it. Metformin, as an efficient hypoglycemic drug in treating type 2 diabetes, has been reported to alleviate the risk of diabetes-related stroke. However, its underlying mechanisms remain unclear. This study aimed to investigate the role of mitophagy and its regulatory pathway in the neuroprotective mechanism of metformin against cerebral ischemia/reperfusion (I/R) injury aggravated by hyperglycemia. A hyperglycemic cerebral I/R animal model and a high glucose cultured oxygen-glucose deprivation/reperfusion (OGD/R) cell model were used in the experiment. The indexes of brain injury, cell activity, mitochondrial morphology and function, mitophagy, mitochondrial pathway apoptosis and the AMPK pathway were observed. In diabetic rats, metformin treatment decreased cerebral infarction volume and neuronal apoptosis, and improved neurological symptoms following I/R injury. Additionally, metformin induced activation of the AMPK/ULK1/PINK1/Parkin mitophagy pathway to have neuroprotective effects. In vitro, high glucose culture and OGD/R treatment impaired mitochondrial morphology and function, mitochondrial membrane potential, and induced apoptosis. However, metformin activated AMPK/ULK1/PINK1/Parkin mitophagy pathway, normalized mitochondrial injury. This protection was reversed by autophagy inhibitor 3-methyladenine (3MA) and AMPK inhibitor compound C. In conclusion, our present study validates the potential mechanism of metformin in alleviating hyperglycemia aggravated cerebral I/R injury by the activation of AMPK/ULK1/PINK1/Parkin mitophagy pathway. 

Metformin alleviates cerebral ischemia/reperfusion injury aggravated by hyperglycemia via regulating AMPK/ULK1/PINK1/Parkin pathway-mediated mitophagy and apoptosis

Abstract Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg 2+ /Mn 2+ dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke. 

PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons

Cerebrovascular diseases are known to cause significant morbidity and mortality to the general population. In patients with cerebrovascular disease, prompt clinical evaluation and radiographic interpretation are both essential in optimizing clinical management and in triaging patients for critical and potentially life-saving neurosurgical interventions. With recent advancements in the domains of artificial intelligence (AI) and machine learning (ML), many AI and ML algorithms have been developed to further optimize the diagnosis and subsequent management of cerebrovascular disease. Despite such advances, further studies are needed to substantively evaluate both the diagnostic accuracy and feasibility of these techniques for their application in clinical practice. This review aims to analyze the current use of AI and MI algorithms in the diagnosis of, and clinical decision making for cerebrovascular disease, and to discuss both the feasibility and future applications of utilizing such algorithms.We review the use of AI and ML algorithms to assist clinicians in the diagnosis and management of ischemic stroke, hemorrhagic stroke, intracranial aneurysms, and arteriovenous malformations (AVMs). After identifying the most widely used algorithms, we provide a detailed analysis of the accuracy and effectiveness of these algorithms in practice.The incorporation of AI and ML algorithms for cerebrovascular patients has demonstrated improvements in time to detection of intracranial pathologies such as intracerebral hemorrhage (ICH) and infarcts. For ischemic and hemorrhagic strokes, commercial AI software platforms such as RapidAI and Viz.AI have bene implemented into routine clinical practice at many stroke centers to expedite the detection of infarcts and ICH, respectively. Such algorithms and neural networks have also been analyzed for use in prognostication for such cerebrovascular pathologies. These include predicting outcomes for ischemic stroke patients, hematoma expansion, risk of aneurysm rupture, bleeding of AVMs, and in predicting outcomes following interventions such as risk of occlusion for various endovascular devices. Preliminary analyses have yielded promising sensitivities when AI and ML are used in concert with imaging modalities and a multidisciplinary team of health care providers.The implementation of AI and ML algorithms to supplement clinical practice has conferred a high degree of accuracy, efficiency, and expedited detection in the clinical and radiographic evaluation and management of ischemic and hemorrhagic strokes, AVMs, and aneurysms. Such algorithms have been explored for further purposes of prognostication for these conditions, with promising preliminary results. Further studies should evaluate the longitudinal implementation of such techniques into hospital networks and residency programs to supplement clinical practice, and the extent to which these techniques improve patient care and clinical outcomes in the long-term.

Role of artificial intelligence and machine learning in the diagnosis of cerebrovascular disease

The time window from stroke onset is critical for the treatment decision. However, in unknown onset stroke, it is often difficult to determine the exact onset time because of the lack of assessment methods, which can result in controversial and random treatment decisions. Previous studies have shown that serum biomarkers, in addition to imaging assessment, are useful for determining the stroke onset time. However, as yet there are no specific biomarkers or corresponding methodologies that are accurate and effective for determining the onset time of unknown onset stroke. Herein, we describe our novel advanced metabolites-based machine learning method (termed extreme gradient boost [XGBoost]) combined with recursive feature elimination, which accurately screened five metabolites from 1124 metabolites detected in serum. These metabolites were capable of both detecting acute ischemic stroke and backtracking the acute ischemic stroke onset time. To further investigate the pathological mechanisms of acute ischemic stroke, we also examined characteristic metabolites in different brain regions, and found two metabolites that could distinguish the core infarct area from the ischemic penumbra. Although this study is based on animal experiments, our machine learning framework and selected metabolites may provide a basis for clinical stroke evaluation and treatment. 

Detection of acute ischemic stroke and backtracking stroke onset time via machine learning analysis of metabolomics.

Metformin treatment and acute ischemic stroke outcomes in patients with type 2 diabetes: a retrospective cohort study

Objective Extracranial vertebral artery dissection (EVAD) is one of the main causes of stroke in young and middle-aged patients. However, the diagnosis is challenging. This study aimed to identify the characteristics of EVAD on color duplex ultrasonography (CDU) and high-resolution magnetic resonance imaging (hrMRI), hoping to improve the accuracy and determine the relative contribution of vessel findings and clinical factors to acute ischemic events. Methods Patients with unilateral EVAD were recruited and divided into ischemia and non-ischemia groups. Clinical features of patients and the lesion location; a variety of signs which indicate dissection, including the presence of an intimal flap, double lumen, intramural hematoma, dissecting aneurysm, intraluminal thrombus, and irregular lumen; and other quantitative parameters of each dissected segment on CDU and hrMRI were reviewed, respectively. Multiple logistic regression was performed to explore the association between clinical, imaging characteristics, and ischemic events in patients with unilateral EVAD. Results Ninety-six patients with unilateral EVAD who met the inclusion criteria were enrolled during a six-year period. Overall, 41 cases (42.7%) were confirmed as ischemic stroke (n = 40) or transient ischemic attack (n = 1) during the 48 h after the onset of symptoms. Men, infections during the last week, and smoking were more common in the ischemia group. Intraluminal thrombus and occlusion on CDU were more prevalent in patients with cerebral ischemia than in those without (36.6 vs. 5.5%; p < 0.001, and 39.0 vs. 9.1%; p = 0.001, respectively). On hrMRI, intraluminal thrombus and occlusion were also more frequent in the ischemia group than in the non-ischemia group (34.1 vs. 5.5%; p < 0.001, and 34.1 vs. 9.1%; p = 0.003, respectively). In addition, lesion length on hrMRI was significantly longer for patients with ischemia (81.5 ± 41.7 vs. 64.7 ± 30.8 mm; p = 0.025). In multivariable logistic regression analysis, male gender, infections during the last week, and the presence of intraluminal thrombus on CDU and hrMRI were independently associated with acute ischemic events. Conclusion Male sex, infections during the last week, and the presence of intraluminal thrombus due to dissection are associated with an increased risk of ischemic events in patients with unilateral EVAD.

Predictors of ischemic events in patients with unilateral extracranial vertebral artery dissection: A single-center exploratory study

Leukocyte Telomere Length and Lacunar Stroke: A Mendelian Randomization Study.

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