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The neurological diseases primarily include acute injuries, chronic neurodegeneration, and others (e.g., infectious diseases of the central nervous system). Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Recent studies have suggested that autophagy, particularly selective autophagy, such as mitophagy, pexophagy, ER-phagy, ribophagy, lipophagy, etc., is closely implicated in neurological diseases. These forms of selective autophagy are controlled by a group of important proteins, including PTEN-induced kinase 1 (PINK1), Parkin, p62, optineurin (OPTN), neighbor of BRCA1 gene 1 (NBR1), and nuclear fragile X mental retardation-interacting protein 1 (NUFIP1). This review highlights the characteristics and underlying mechanisms of different types of selective autophagy, and their implications in various forms of neurological diseases.

Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells.

Stroke is one of the leading causes of death and disability worldwide. Brain injury after ischemic stroke involves multiple pathophysiological mechanisms, such as oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium overload, neuroinflammation, neuronal apoptosis, and blood-brain barrier (BBB) disruption. All of these factors are associated with dysfunctional energy metabolism after stroke. Mitochondria are organelles that provide adenosine triphosphate (ATP) to the cell through oxidative phosphorylation. Mitochondrial dynamics means that the mitochondria are constantly changing and that they maintain the normal physiological functions of the cell through continuous division and fusion. Mitochondrial dynamics are closely associated with various pathophysiological mechanisms of post-stroke brain injury. In this review, we will discuss the role of the molecular mechanisms of mitochondrial dynamics in energy metabolism after ischemic stroke, as well as new strategies to restore energy homeostasis and neural function. Through this, we hope to uncover new therapeutic targets for the treatment of ischemic stroke.

Stroke is a leading cause of death and disability in humans. The excessive production of reactive oxygen species (ROS) is an important contributor to oxidative stress and secondary brain damage after stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme complex consisting of membrane subunits and cytoplasmic subunits, regulates neuronal maturation and cerebrovascular homeostasis. However, NADPH oxidase overproduction contributes to neurotoxicity and cerebrovascular disease. NADPH oxidase has been implicated as the principal source of ROS in the brain, and numerous studies have shown that the knockout of NADPH exerts a protective effect in the model of ischemic stroke. In this review, we summarize the mechanism of activation of the NADPH oxidase family members, the pathophysiological effects of NADPH oxidase isoforms in ischemic stroke, and the studies of NADPH oxidase inhibitors to explore potential clinical applications.

The discovery of long noncoding RNAs (lncRNAs) has improved the understanding of development and progression in various cancer subtypes. However, the role of lncRNAs in temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) remains largely undefined. In this present study, the differential expression of lncRNAs was identified between U87 and U87 TMZ‐resistant (TR) cells. lncRNA XLOC013218 (XLOC) was drastically upregulated in TR cells and was associated with poor prognosis in glioma. Overexpression of XLOC markedly increased TMZ resistance, promoted proliferation, and inhibited apoptosis in vitro and in vivo. In addition, RNA‐seq analysis and gain‐of‐function or loss‐of‐function studies revealed that PIK3R2 was the potential target of XLOC. Mechanistically, XLOC recruited specificity protein 1 (Sp1) transcription factor and promoted the binding of Sp1 to the promoters of PIK3R2, which elevated the expression of PIK3R2 in both mRNA and protein levels. Finally, PIK3R2‐mediated activation of the PI3K/AKT signaling pathway promoted TMZ resistance and cell proliferation, but inhibited cell apoptosis. In conclusion, these data highlight the vital role of the XLOC/Sp1/PIK3R2/PI3K/AKT axis in GBM TMZ resistance. lncRNA XLOC013218 (XLOC) confers temozolomide (TMZ) resistance of glioma by promoting cell proliferation and inhibiting cell apoptosis via activation of the PIK3R2‐mediated PI3K/AKT signaling pathway in an Sp1‐dependent manner.

Puerarin was shown to exert anti-oxidative and anti-ferroptosis effects in multiple diseases. The goal of this study was to explore the neuroprotective effect of puerarin on early brain injury (EBI) after subarachnoid hemorrhage (SAH) in rats. A total of 177 adult male Sprague Dawley rats were used. SAH was included via endovascular perforation. Intranasal puerarin or intracerebroventricular dorsomorphin (AMPK inhibitor) and SR18292 (PGC1α inhibitor) were administered. The protein levels of pAMPK, PGC1α, Nrf2, 4HNE, HO1, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere were significantly increased, whereas SOD, GPX4, and GSH were decreased at 24 h after SAH. Moreover, puerarin treatment significantly increased the protein levels of pAMPK, PGC1α, Nrf2, HO1, SOD, GPX4, and GSH, but decreased the levels of 4HNE, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere at 24 h after SAH. Dorsomorphin or SR18292 partially abolished the beneficial effects of puerarin exerted on neurological dysfunction, oxidative stress injury, and ferroptosis. In conclusion, puerarin improved neurobehavioral impairments and attenuated oxidative-stress-induced brain ferroptosis after SAH in rats. The neuroprotection acted through the activation of the AMPK/PGC1α/Nrf2-signaling pathway. Thus, puerarin may serve as new therapeutics against EBI in SAH patients.

Background Pyroptosis is a programmed cell death mediated by inflammasomes. Previous studies have reported that inhibition of neurokinin receptor 1 (NK1R) exerted neuroprotection in several neurological diseases. Herein, we have investigated the role of NK1R receptor inhibition using Aprepitant to attenuate NLRC4-dependent neuronal pyroptosis after intracerebral hemorrhage (ICH), as well as the underlying mechanism. Methods A total of 182 CD-1 mice were used. ICH was induced by injection of autologous blood into the right basal ganglia. Aprepitant, a selective antagonist of NK1R, was injected intraperitoneally at 1 h after ICH. To explore the underlying mechanism, NK1R agonist, GR73632, and protein kinase C delta (PKCδ) agonist, phorbol 12-myristate 13-acetate (PMA), were injected intracerebroventricularly at 1 h after ICH induction, and small interfering ribonucleic acid (siRNA) for NLRC4 was administered via intracerebroventricular injection at 48 h before ICH induction, respectively. Neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results The expression of endogenous NK1R and NLRC 4 were gradually increased after ICH. NK1R was expressed on neurons. Aprepitant significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased neuronal pyroptosis, as well as decreased expression of NLRC4, Cleaved-caspase-1, GSDMD (gasdermin D), IL-1β, and IL-18. Activation of NK1R or PKCδ abolished these neuroprotective effects of Aprepitant after ICH. Similarly, knocking down NLRC4 using siRNA produced similar neuroprotective effects. Conclusion Aprepitant suppressed NLRC4-dependent neuronal pyroptosis and improved neurological function, possibly mediated by inhibition of NK1R/PKCδ signaling pathways after ICH. The NK1R may be a promising therapeutic target for the treatment of ICH.

Nanobiotechnology plays an important role in drug delivery, and various kinds of nanoparticles have demonstrated new properties, which may provide opportunities in clinical treatment. Nanoparticle-mediated drug delivery systems have been used in anti-inflammatory therapies. Diseases, such as inflammatory bowel disease, rheumatoid arthritis, and osteoarthritis have been widely impacted by the pathogenesis of inflammation. Efficient delivery of anti-inflammatory drugs can reduce medical dosage and improve therapeutic effect. In this review, we discuss nanoparticles with potential anti-inflammatory activity, and we present a future perspective regarding the application of nanomedicine in inflammatory diseases.

Intracerebral hemorrhage (ICH) is the second-largest stroke subtype and has a high mortality and disability rate. Secondary brain injury (SBI) is delayed after ICH. The main contributors to SBI are inflammation, oxidative stress, and excitotoxicity. Harmful substances from blood and hemolysis, such as hemoglobin, thrombin, and iron, induce SBI. When cells suffer stress, a critical protective mechanism called “autophagy” help to maintain the homeostasis of damaged cells, remove harmful substances or damaged organelles, and recycle them. Autophagy plays a critical role in the pathology of ICH, and its function remains controversial. Several lines of evidence demonstrate a pro-survival role for autophagy in ICH by facilitating the removal of damaged proteins and organelles. However, many studies have found that heme and iron can aggravate SBI by enhancing autophagy. Autophagy and inflammation are essential culprits in the progression of brain injury. It is a fascinating hypothesis that autophagy regulates inflammation in ICH-induced SBI. Autophagy could degrade and clear pro-IL-1β and apoptosis-associated speck-like protein containing a CARD (ASC) to antagonize NLRP3-mediated inflammation. In addition, mitophagy can remove endogenous activators of inflammasomes, such as reactive oxygen species (ROS), inflammatory components, and cytokines, in damaged mitochondria. However, many studies support the idea that autophagy activates microglia and aggravates microglial inflammation via the toll-like receptor 4 (TLR4) pathway. In addition, autophagy can promote ICH-induced SBI through inflammasome-dependent NLRP6-mediated inflammation. Moreover, some resident cells in the brain are involved in autophagy in regulating inflammation after ICH. Some compounds or therapeutic targets that regulate inflammation by autophagy may represent promising candidates for the treatment of ICH-induced SBI. In conclusion, the mutual regulation of autophagy and inflammation in ICH is worth exploring. The control of inflammation by autophagy will hopefully prove to be an essential treatment target for ICH.

Hemorrhagic stroke is a life-threatening neurological disease characterized by high mortality and morbidity. Various pathophysiological responses are initiated after blood enters the interstitial space of the brain, compressing the brain tissue and thus causing cell death. Recently, three new programmed cell deaths (PCDs), necroptosis, pyroptosis, and ferroptosis, were also found to be important contributors in the pathophysiology of hemorrhagic stroke. Additionally, blood-brain barrier (BBB) dysfunction plays a crucial role in the pathophysiology of hemorrhagic stroke. The primary insult following BBB dysfunction may disrupt the tight junctions (TJs), transporters, transcytosis, and leukocyte adhesion molecule expression, which may lead to brain edema, ionic homeostasis disruption, altered signaling, and immune infiltration, consequently causing neuronal cell death. This review article summarizes recent advances in our knowledge of the mechanisms regarding these new PCDs and reviews their contributions in hemorrhagic stroke and potential crosstalk in BBB dysfunction. Numerous studies revealed that necroptosis, pyroptosis, and ferroptosis participate in cell death after subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Endothelial dysfunction caused by these three PCDs may be the critical factor during BBB damage. Also, several signaling pathways were involved in PCDs and BBB dysfunction. These new PCDs (necroptosis, pyroptosis, ferroptosis), as well as BBB dysfunction, each play a critical role after hemorrhagic stroke. A better understanding of the interrelationship among them might provide us with better therapeutic targets for the treatment of hemorrhagic stroke.