Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve ...achieving rapid reperfusion either pharmacologically or surgically, both of which are time‐sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.
Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment ...of post‐ischemic stroke remains a critical challenge. Recently, iron has emerged as a crucial factor in post‐reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely, ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development.
Ischemic stroke caused by arterial occlusion is the most common type of stroke, and it strongly associates with age‐related neurological deficits. Recently, iron has emerged as a crucial factor of neuronal pathology in ischemic stroke. Iron dyshomeostasis leads to brain iron accumulation, and together with the excessive production of free arachidonic acid, insufficient antioxidant supply, they collectively induce lipid peroxidation and ferroptosis during cerebral ischemia/reperfusion. Independently or co‐currently, peripheral iron deficiency also aggravates the cerebral ischemic injury. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development. ACSL4, acyl‐CoA synthetase long‐chain family member 4; GPx4, glutathione peroxidase 4; LOX, lipoxygenase.
Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the ...accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
Ferroptosis is a recently defined form of cell death with the involvement of iron and reactive oxygen species (ROS), which is distinct from apoptosis, autophagy and other forms of cell death. ...Emerging evidence suggested that iron accumulation and lipid peroxidation can be discovered in various neurological diseases, accompanied with reduction of glutathione (GSH) and glutathione peroxidase 4 (GPX4). In addition, ferroptotic inhibitors have been shown to protect neurons, and recover the cognitive function in disease animal models. This review summarizes the mechanisms underlying ferroptosis and reviews the contributions of ferroptosis in neurodegenerative diseases (i.e. Alzheimer’s disease and Parkinson’s disease), traumatic brain injury, as well as hemorrhagic and ischemic stroke, to provide the current understanding of this novel form of cell death in neurological disorders.
As a bottom-up approach, the effectiveness of the environmental information transparency policy hinges on a broad societal ecosystem, including elements such as the active mass media and the robust ...civil society. However, due to the lack of public participation and accountability mechanisms, it is still doubtful whether the Chinese environmental transparency program promoted corporate pollution mitigation efforts. In this study, we investigated the impacts of the Environmental Information Disclosure (EID) program, an important Chinese environmental transparency program, on corporate mitigation investments, by using the 2012 Chinese Private Enterprise Survey. Our Tobit-IV model provides robust evidence that transparency policy exerts significant influences only on non-politically connected polluters, while, by contrast, politically connected firms are less susceptible to the EID program. We suggest that the community should be empowered to deter the shelter effects of local governors to the connected firms, which deteriorate the effectiveness of the transparency program.
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•We investigated the impacts of the Chinese Environmental Information Disclosure (EID) program.•EID exerts significant influences only on non-politically connected polluters, while, by contrast.•Politically connected firms are less susceptible.•The community should be empowered to deter the pollution shelter effects.
Ferroptosis has been implicated in several neurological disorders and may be therapeutically targeted. However, the susceptibility to ferroptosis varies in different cells, and inconsistent results ...have been reported even using the same cell line. Understanding the effects of key variables of in vitro studies on ferroptosis susceptibility is of critical importance to facilitate drug discoveries targeting ferroptosis. Here, we showed that increased cell seeding density leads to enhanced resistance to ferroptosis by reducing intracellular iron levels. We further identified iron‐responsive protein 1 (IRP1) as the key protein affected by cell density, which affects the expression of ferroportin or transferrin receptor and results in altered iron levels. Such observations were consistent across different cell lines, indicating that cell density should be tightly controlled in studies of ferroptosis. Since cell densities vary in different brain regions, these results may also shed light on selective regional vulnerability observed in neurological disorders.
Ferroptosis is pivotal in neurodisorders, holding therapeutic promise. Understanding how in vitro variables affect ferroptosis susceptibility is crucial for drug discovery in this context. In this study, the authors pinpointed that increased cell seeding density leads to enhanced resistance to ferroptosis. Mechanistically, increased cell seeding density led to a decrease in iron‐responsive protein 1 levels, which leads to reduction in intracellular iron levels by affecting the level of ferroportin or transferrin receptor. As a result, the reduced iron levels markedly boosted resistance against ferroptosis.
Both elevated iron and α-synuclein (α-syn) aggregates are neuropathological hallmarks of Parkinson's disease (PD). It has been previously shown that iron promotes α-synuclein aggregation, and ...α-synuclein dysfunction impairs iron metabolism. In their latest work, Kim et al. have shown that the H63D variant of the homeostatic iron regulator (HFE) facilitates α-syn degradation via REDD1-mediated autophagy. Mice with the H63D variant of HFE were protected against α-syn toxicity. These results may shed light on recent clinical studies of PD using iron chelation therapy.
Circular RNAs, as hopeful diagnosis markers and therapeutic molecules, have been studied, probed and applied into several diseases, such as cardiovascular diseases, systemic lupus erythematosus, ...leukemia, pulmonary tuberculosis, and cancer especially. Recently, mounting evidence has supported that circRNAs play a key role in the tumorigenesis, progress, invasion and metastasis in lung cancer. Its special structure-3'-5' covalent loop-allow it to execute several special functions in both normal eukaryotic cells and cancer cells. Our review summaries the latest studies on characteristics and biogenesis of circRNAs, and highlight the regulatory functions about miRNA sponge of lung-cancer-related circRNAs. In addition, the interaction of the circRNA-miRNA-mRNA regulatory network will also be elaborated in detail in this review. Therefore, this review can provide a new idea or strategy for further development and application in clinical setting in terms of early-diagnosis and better treatment.
Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic ...stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.
Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. Here, we report that glycine, serine and threonine catabolic pathway is ...down-regulated in serum-resistant Escherichia coli, whereas exogenous glycine reverts the serum resistance and effectively potentiates serum to eliminate clinically-relevant bacterial pathogens in vitro and in vivo. We find that exogenous glycine increases the formation of membrane attack complex on bacterial membrane through two previously unrecognized regulations: 1) glycine negatively and positively regulates metabolic flux to purine biosynthesis and Krebs cycle, respectively. 2) α-Ketoglutarate inhibits adenosine triphosphate synthase, which in together promote the formation of cAMP/CRP regulon to increase the expression of complement-binding proteins HtrE, NfrA, and YhcD. The results could lead to effective strategies for managing the infection with serum-resistant bacteria, an especially valuable approach for treating individuals with weak acquired immunity but a normal complement system.
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