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Background: The coexistence of autoimmune encephalitis (AE) with multiple neural auto-antibodies is of great clinical significance because overlying antibodies may cause superposition or variation of clinical syndrome, which increases the difficulty of diagnosis and treatment of the disease. To the best of our knowledge, the coexistence of anti-N-methyl d-aspartate Receptor (NMDAR) and anti-IgLON5 antibodies in AE has not been published previously. Case presentation: A 38-year-old female patient presented to our hospital due to headache and abnormal psychiatric behavior. Based on her clinical manifestations (psychiatric and behavioral abnormalities, involuntary limb movements, and sleep disorders) and laboratory assessment results (positive human leukocyte antigen (HLA)-DQB1*05:01 haplotype, anti-NMDAR, and anti-IgLON5 antibodies), she was diagnosed as AE with coexisting anti-NMDAR and anti-IgLON5 antibodies. After treatment with intravenous methylprednisolone and immunoglobulin, as well as plasmapheresis, her symptoms gradually improved with exception for the sleep disorders. Although oral prednisone acetate and mycophenolate mofetil were continued after discharge, her symptoms of sleep disorders did not improve at 6-month follow-up. Conclusion: This is the first case of AE co-existing with anti-NMDAR and anti-IgLON5 antibodies. Co-existence of neural auto-antibodies should be considered when patients present with overlapping or atypical symptoms. Special attention should be paid to the treatment of these patients as some anti-IgLON5 encephalitis patients may not benefit from immunotherapy treatment.

Abstract N6-methylation of adenosine (m6A) is one of the most frequent chemical modifications in eukaryotic RNAs and plays a vital role in tumorigenesis and progression. Recently, emerging studies have shown that m6A modification by ALKBH5 was associated with immunotherapy response in various types of cancer. However, whether m6A demethylases ALKBH5 participate in regulating the tumor immune microenvironment and the efficacy of immunotherapy in glioblastoma remain unknown. Here, we found that deletion of ALKBH5 significantly inhibited the growth of glioma allografts, rescued the antitumoral immune response, and increased cytotoxic lymphocyte infiltration and proinflammatory cytokines in CSF while significantly suppressing PD-L1 protein expression. m6A-methylated RNA immunoprecipitation sequencing and RNA sequencing identify ZDDHC3 as the direct target of ALKBH5. Mechanically, ALKBH5 deficiency impairs the YTHDF2-mediated stability of ZDHHC3 mRNA, thereby suppressing PD-L1 expression by accelerating PD-L1 degradation in glioma. In addition, genetic deletion or pharmacological inhibition of ALKBH5 with IOX1 enhances the therapeutic efficacy of anti-PD-1 treatment in preclinical mice models. These data suggest that the combination of anti-PD-1 therapy and ALKBH5 inhibition may be a promising treatment strategy in glioma.

Abstract 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.

Abstract Background C–C chemokine receptor type 1 (CCR1) and its endogenous ligand, CCL5, participate in the pathogenesis of neuroinflammatory diseases. However, much remains unknown regarding CCL5/CCR1 signaling in blood–brain barrier (BBB) permeability after intracerebral hemorrhage (ICH). Methods A total of 250 CD1 male mice were used and ICH was induced via autologous whole blood injection. Either Met-RANTES, a selective CCR1 antagonist, or Met-RANTES combined with a Rac1 CRISPR activator was administered to the mice 1 h after ICH. Post-ICH assessments included neurobehavioral tests, brain water content, BBB integrity, hematoma volume, Western blot, and immunofluorescence staining. The CCR1 ligand, rCCL5, and SRC CRISPR knockout in naïve mice were used to further elucidate detrimental CCL5/CCR1/SRC signaling. Results Brain endogenous CCR1 and CCL5 were upregulated after ICH in mice with a peak at 24 h, and CCR1 was expressed in endothelial cells, astrocytes, and neurons. Met-R treatment reduced brain edema and neurobehavioral impairment, as well as preserved BBB integrity and tight junction protein expression in ICH mice. Met-R treatment decreased expression of p-SRC, Rac1, albumin, and MMP9, but increased claudin-5, occludin, and ZO-1 tight junction proteins after ICH. These effects were regressed using the Rac1 CRISPR activator. Administration of rCCL5 in naïve mice increased expression of p-SRC, Rac1, albumin, and MMP9, but decreased levels of claudin-5, occludin, and ZO-1 tight junction proteins. These effects in naïve mice were reversed with SRC CRISPR (KO). Conclusions Our findings demonstrate that CCR5 inhibition by Met-R improves neurological deficits after ICH by preserving BBB integrity through inhibiting CCR1/SRC/Rac1 signaling pathway in mice. Thus, Met-R has therapeutic potential in the management of ICH patients.

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.

Subarachnoid hemorrhage (SAH) is an important public health concern with high morbidity and mortality worldwide. SAH induces cell death, blood−brain barrier (BBB) damage, brain edema and oxidative stress. As the most abundant cell type in the central nervous system, astrocytes play an essential role in brain damage and recovery following SAH. This review describes astrocyte activation and polarization after SAH. Astrocytes mediate BBB disruption, glymphatic–lymphatic system dysfunction, oxidative stress, and cell death after SAH. Furthermore, astrocytes engage in abundant crosstalk with other brain cells, such as endothelial cells, neurons, pericytes, microglia and monocytes, after SAH. In addition, astrocytes also exert protective functions in SAH. Finally, we summarize evidence regarding therapeutic approaches aimed at modulating astrocyte function following SAH, which could provide some new leads for future translational therapy to alleviate damage after SAH.

Adiponectin (APN), a fat-derived plasma hormone, is a classic anti-inflammatory agent. Multiple studies have demonstrated the beneficial role of APN in acute brain injury, but the effect of APN in germinal matrix hemorrhage (GMH) is unclear, and the underlying molecular mechanisms remain largely undefined. In the current study, we used a GMH rat model with rh-APN treatment, and we observed that APN demonstrated a protective effect on neurological function and an inhibitory effect on neuroinflammation after GMH. To further explore the underlying mechanisms of these effects, we found that the expression of Adiponectin receptor 1 (AdipoR1) primarily colocalized with microglia and neurons in the brain. Moreover, AdiopR1, but not AdipoR2, was largely increased in GMH rats. Meanwhile, further investigation showed that APN treatment promoted AdipoR1/APPL1-mediated AMPK phosphorylation, further increased peroxisome proliferator-activated receptor gamma (PPARγ) expression, and induced microglial M2 polarization to reduce the neuroinflammation and enhance hematoma resolution in GMH rats. Importantly, either knockdown of AdipoR1, APPL1, or LKB1, or specific inhibition of AMPK/PPARγ signaling in microglia abrogated the protective effect of APN after GMH in rats. In all, we propose that APN works as a potential therapeutic agent to ameliorate the inflammatory response following GMH by enhancing the M2 polarization of microglia via AdipoR1/APPL1/AMPK/PPARγ signaling pathway, ultimately attenuating inflammatory brain injury induced by hemorrhage.

Abstract Background Rupture of intracranial aneurysm (IA) is the main cause of devastating subarachnoid hemorrhage, which urges our understanding of the pathogenesis and regulatory mechanisms of IA. However, the regulatory roles of long non-coding RNAs (lncRNAs) in IA is less known. Results We processed the raw SRR files of 12 superficial temporal artery (STA) samples and 6 IA samples to count files. Then the differentially expressed (DE) mRNAs, miRNAs, and lncRNAs between STAs and IAs were identified. The enrichment analyses were performed using DEmRNAs. Next, a lncRNA-miRNA-mRNA regulatory network was constructed using integrated bioinformatics analysis. In summary, 341 DElncRNAs, 234 DEmiRNAs, and 2914 DEmRNAs between the STA and IA. The lncRNA-miRNA-mRNA regulatory network of IA contains 91 nodes and 146 edges. The subnetwork of hub lncRNA PVT1 was extracted. The expression level of PVT1 was positively correlated with a majority of the mRNAs in its subnetwork. Moreover, we found that several mRNAs (CCND1, HIF1A, E2F1, CDKN1A, VEGFA, COL1A1 and COL5A2) in the PVT1 subnetwork served as essential components in the PI3K-Akt signaling pathway, and that some of the non-coding RNAs (ncRNAs) (PVT1, HOTAIR, hsa-miR-17, hsa-miR-142, hsa-miR-383 and hsa-miR-193b) interacted with these mRNAs. Conclusion Our annotations noting ncRNA’s role in the pathway may uncover novel regulatory mechanisms of ncRNAs and mRNAs in IA. These findings provide significant insights into the lncRNA regulatory network in IA.

Abstract Background Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of hypoxic-ischemic (HI)-induced brain injury. Activation of melanocortin-1 receptor (MC1R) has been shown to exert anti-inflammatory and neuroprotective effects in several neurological diseases. In the present study, we have explored the role of MC1R activation on neuroinflammation and the potential underlying mechanisms after neonatal hypoxic-ischemic brain injury in rats. Methods A total of 169 post-natal day 10 unsexed rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. BMS-470539, a specific selective MC1R agonist, was administered intranasally at 1 h after HI induction. To elucidate the potential underlying mechanism, MC1R CRISPR KO plasmid or Nurr1 CRISPR KO plasmid was administered via intracerebroventricular injection at 48 h before HI induction. Percent brain infarct area, short- and long-term neurobehavioral tests, Nissl staining, immunofluorescence staining, and Western blot were conducted. Results The expression levels of MC1R and Nurr1 increased over time post-HI. MC1R and Nurr1 were expressed on microglia at 48 h post-HI. Activation of MC1R with BMS-470539 significantly reduced the percent infarct area, brain atrophy, and inflammation, and improved short- and long-term neurological deficits at 48 h and 28 days post-HI. MC1R activation increased the expression of CD206 (a microglial M2 marker) and reduced the expression of MPO. Moreover, activation of MC1R with BMS-470539 significantly increased the expression levels of MC1R, cAMP, p-PKA, and Nurr1, while downregulating the expression of pro-inflammatory cytokines (TNFα, IL-6, and IL-1β) at 48 h post-HI. However, knockout of MC1R or Nurr1 by specific CRISPR reversed the neuroprotective effects of MC1R activation post-HI. Conclusions Our study demonstrated that activation of MC1R with BMS-470539 attenuated neuroinflammation, and improved neurological deficits after neonatal hypoxic-ischemic brain injury in rats. Such anti-inflammatory and neuroprotective effects were mediated, at least in part, via the cAMP/PKA/Nurr1 signaling pathway. Therefore, MC1R activation might be a promising therapeutic target for infants with hypoxic-ischemic encephalopathy (HIE).

The ketogenic diet (KD) is a low-carbohydrate, high-fat diet regarded as a potential intervention for cancers owing to its effects on tumor metabolism and behavior. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, and its management is worth investigating because of the high fatality rate. Additionally, as the liver is the glucose and lipid metabolism center where ketone bodies are produced, the application of KD to combat HCC is promising. Prior studies have reported that KD could reduce the energy supply and affect the proliferation and differentiation of cancer cells by lowering the blood glucose and insulin levels. Furthermore, KD can increase the expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in hepatocytes and regulate lipid metabolism to inhibit the progression of HCC. In addition, β-hydroxybutyrate can induce histone hyperacetylation and reduce the expression of inflammatory factors to alleviate damage to hepatocytes. However, there are few relevant studies at present, and the specific effects and safety of KD on HCC warrant further research. Optimizing the composition of KD and combining it with other therapies to enhance its anti-cancer effects warrant further exploration.

Abstract Background Orexins are two neuropeptides (orexin A, OXA; orexin B, OXB) secreted mainly from the lateral hypothalamus, which exert a wide range of physiological effects by activating two types of receptors (orexin receptor 1, OXR1; orexin receptor 2, OXR2). OXA has equal affinity for OXR1 and OXR2, whereas OXB binds preferentially to OXR2. OXA rapidly crosses the blood-brain barrier by simple diffusion. Many studies have reported OXA’s protective effect on neurological diseases via regulating inflammatory response which is also a fundamental pathological process in intracerebral hemorrhage (ICH). However, neuroprotective mechanisms of OXA have not been explored in ICH. Methods ICH models were established using stereotactic injection of autologous arterial blood into the right basal ganglia of male CD-1 mice. Exogenous OXA was administered intranasally; CaMKKβ inhibitor (STO-609), OXR1 antagonist (SB-334867), and OXR2 antagonist (JNJ-10397049) were administered intraperitoneally. Neurobehavioral tests, hematoma volume, and brain water content were evaluated after ICH. Western blot and ELISA were utilized to evaluate downstream mechanisms. Results OXA, OXR1, and OXR2 were expressed moderately in microglia and astrocytes and abundantly in neurons. Expression of OXA decreased whereas OXR1 and OXR2 increased after ICH. OXA treatment significantly improved not only short-term but also long-term neurofunctional outcomes and reduced brain edema in ipsilateral hemisphere. OXA administration upregulated p-CaMKKβ, p-AMPK, and anti-inflammatory cytokines while downregulated p-NFκB and pro-inflammatory cytokines after ICH; this effect was reversed by STO-609 or JNJ-10397049 but not SB-334867. Conclusions OXA improved neurofunctional outcomes and mitigated brain edema after ICH, possibly through alleviating neuroinflammation via OXR2/CaMKKβ/AMPK pathway.

Billions of cells undergo turnover and die via apoptosis throughout our lifetime. A prompt clearance of these apoptotic cells and debris by phagocytic cells, a process known as efferocytosis, is important in maintaining tissue homeostasis. Accordingly, impaired efferocytosis due to the defective clearance and disrupted stages can lead to a growing number of inflammation- and immune-related diseases. Although numerous studies have shown the mechanisms of efferocytosis, its role in disorders, such as non-tumor and tumor diseases, remains poorly understood. This review summarizes the processes and signal molecules in efferocytosis, and efferocytosis-related functions in non-tumor (e.g., atherosclerosis, lung diseases) and tumor diseases (e.g., breast cancer, prostate cancer), as well as describes the role of involved cytokines. Of note, there is a dual role of efferocytosis in the abovementioned disorders, and a paradoxical effect among non-tumor and tumor diseases in terms of inflammation resolution, immune response, and disease progression. Briefly, intact efferocytosis and cytokines promote tissue repair, while they contribute to tumor progression via the tumor microenvironment and macrophage politzerization. Additionally, this review provides potential targets associated with TAM (TYRO3, AXL, MERTK) receptors and cytokines, such as tumor necrosis factor α and CXCL5, suggesting potential novel therapeutic ways in treating diseases.

Abstract Background Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted anti-inflammatory effects in a variety of nervous system diseases. This study aimed to investigate the anti-inflammatory effects of recombinant human CSF1 (rh-CSF1) and the underlying mechanisms in a rat model of HIE. Methods A total of 202 10-day old Sprague Dawley rat pups were used. HI was induced by the right common carotid artery ligation with subsequent exposure of 2.5-h hypoxia. At 1 h and 24 h after HI induction, exogenous rh-CSF1 was administered intranasally. To explore the underlying mechanism, CSF1R inhibitor, BLZ945, and phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, were injected intraperitoneally at 1 h before HI induction, respectively. Brain infarct area, brain water content, neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results The expressions of endogenous CSF1, CSF1R, PLCG2, protein kinase C epsilon type (PKCε), and cAMP response element-binding protein (CREB) were gradually increased after HIE. Rh-CSF1 significantly improved the neurological deficits at 48 h and 4 weeks after HI, which was accompanied by a reduction in the brain infarct area, brain edema, brain atrophy, and neuroinflammation. Moreover, activation of CSF1R by rh-CSF1 significantly increased the expressions of p-PLCG2, p-PKCε, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1β and TNF-α. Inhibition of CSF1R and PLCG2 abolished these neuroprotective effects of rh-CSF1 after HI. Conclusions Our findings demonstrated that the activation of CSF1R by rh-CSF1 attenuated neuroinflammation and improved neurological deficits after HI. The anti-inflammatory effects of rh-CSF1 partially acted through activating the CSF1R/PLCG2/PKCε/CREB signaling pathway after HI. These results suggest that rh-CSF1 may serve as a potential therapeutic approach to ameliorate injury in HIE patients.

Summary: Background: Neuroinflammation and blood coagulation responses in cerebrospinal fluid (CSF) contribute to the poor outcome associated with subarachnoid haemorrhage (SAH). We explored the role of caspase-1-mediated inflammasome activation on extrinsic blood coagulation in CSF after SAH. Methods: Post-SAH proteomic changes and correlation between caspase-1 with extrinsic coagulation factors in human CSF after SAH were analysed. Time course and cell localisation of brain inflammasome and extrinsic coagulation proteins after SAH were explored in a rat SAH model. Pharmacological inhibition of caspase-1 via VX-765 was used to explore the role of caspase-1 in blood clearance and CSF circulation after SAH in rats. Primary astrocytes were used to evaluate the role of caspase-1 in haemoglobin-induced pyroptosis and tissue factor (TF) production/release. Findings: Neuroinflammation and blood coagulation activated after SAH in human CSF. The caspase-1 levels significantly correlated with the extrinsic coagulation factors. The activated caspase-1 and extrinsic coagulation initiator TF was increased on astrocytes after SAH in rats. VX-765 attenuated neurological deficits by accelerating CSF circulation and blood clearance through inhibiting pyroptotic neuroinflammation and TF-induced fibrin deposition in the short-term, and improved learning and memory capacity by preventing hippocampal neuronal loss and hydrocephalus in the long-term after SAH in rats. VX-765 reduced haemoglobin-induced pyroptosis and TF production/release in primary astrocytes. Interpretation: Inhibition of caspase-1 by VX-765 appears to be a potential treatment against neuroinflammation and blood coagulation in CSF after SAH. Funding: This study was supported by National Institutes of Health of United States of America, and National Natural Science Foundation of China.

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.

Abstract Stroke is a devastating disease that occurs when a blood vessel in the brain is either blocked or ruptured, consequently leading to deficits in neurological function. Stroke consistently ranked as one of the top causes of mortality, and with the mean age of incidence decreasing, there is renewed interest to seek novel therapeutic treatments. The Scavenger Receptor Class B type 1 (SR-B1) is a multifunctional protein found on the surface of a variety of cells. Research has found that that SR-B1 primarily functions in an anti-inflammatory and anti-atherosclerotic capacity. In this review, we discuss the characteristics of SR-B1 and focus on its potential correlation with the modifiable risk factors of stroke. SR-B1 likely has an impact on stroke through its interaction with smoking, diabetes mellitus, diet, physical inactivity, obesity, hypercholesterolemia, atherosclerosis, coronary heart disease, hypertension, and sickle cell disease, all of which are critical risk factors in the pathogenesis of stroke.

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 the destruction of brain function and structure, and is caused by either cerebrovascular obstruction or rupture. It is a disease associated with high mortality and disability worldwide. Brain edema after stroke is an important factor affecting neurologic function recovery. The glymphatic system is a recently discovered cerebrospinal fluid (CSF) transport system. Through the perivascular space and aquaporin 4 (AQP4) on astrocytes, it promotes the exchange of CSF and interstitial fluid (ISF), clears brain metabolic waste, and maintains the stability of the internal environment within the brain. Excessive accumulation of fluid in the brain tissue causes cerebral edema, but the glymphatic system plays an important role in the process of both intake and removal of fluid within the brain. The changes in the glymphatic system after stroke may be an important contributor to brain edema. Understanding and targeting the molecular mechanisms and the role of the glymphatic system in the formation and regression of brain edema after stroke could promote the exclusion of fluids in the brain tissue and promote the recovery of neurological function in stroke patients. In this review, we will discuss the physiology of the glymphatic system, as well as the related mechanisms and therapeutic targets involved in the formation of brain edema after stroke, which could provide a new direction for research against brain edema after stroke.

The recently discovered ferroptosis is a new kind of iron-regulated cell death that differs from apoptosis and necrosis. Ferroptosis can be induced by an oxidative stress response, a crucial pathological process implicated in cardiovascular diseases (CVDs). Accordingly, mounting evidence shows that oxidative stress-induced ferroptosis plays a pivotal role in angio-cardiopathy. To date, the inhibitors and activators of ferroptosis, as well as the many involved signaling pathways, have been widely explored. Among which, epigenetic regulators, molecules that modify the package of DNA without altering the genome, emerge as a highly targeted, effective option to modify the signaling pathway of ferroptosis and oxidative stress, representing a novel and promising therapeutic potential target for CVDs. In this review, we will briefly summarize the mechanisms of ferroptosis, as well as the role that ferroptosis plays in various CVDs. We will also expound the epigenetic regulators of oxidative stress-induced ferroptosis, and the promise that these molecules hold for treating the intractable CVDs.

DNA methylation at the gene promoter region is reportedly involved in the development of intracranial aneurysm (IA). This study aims to investigate the methylation levels of polypyrimidine tract-binding protein 1 (PTBP1) in IA, as well as its potential to predict IA. Forty-eight patients with IA and 48 age- and sex-matched healthy controls were recruited into this study. Methylation levels of CpG sites were determined via bisulfite pyrosequencing. The PTBP1 levels in the blood were determined using a real-time quantitative reverse transcription-polymerase chain reaction test. Significant differences were found between IAs and controls in CpG1 (p = 0.001), CpG2 (p < 0.001), CpG3 (p = 0.037), CpG4 (p = 0.003), CpG5 (p = 0.006), CpG6 (p = 0.02), and mean methylation (p < 0.001). The mRNA level of PTBP1 in the blood was much lower in IAs compared with controls (p = 0.002), and the PTBP1 expression was significantly associated with DNA methylation promoter levels in individuals (r = −0.73, p < 0.0001). In addition, stratification analysis comparing smokers and non-smokers revealed that tobacco smokers had significantly higher levels of DNA methylation in PTBP1 than non-smokers (p = 0.002). However, no statistical difference in PTBP1 methylation was found between ruptured and unruptured IA groups (p > 0.05). The ROC analyses of curves revealed that PTBP1 methylation may be a predictor of IA regardless of sex (both sexes, area under curve (AUC) = 0.78, p < 0.0001; male, AUC = 0.76, p = 0.002; female, AUC = 0.79, p < 0.0001). These findings suggest that long-term tobacco smoke exposure led to DNA methylation in the promoter region of the PTBP1 gene, which further decreased PTBP1 gene expression and participated in the pathogenesis of IA. The methylation of PTBP1 may be a potential predictive marker for the occurrence of IA.

Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.

Stroke is a neurological disease responsible for significant morbidity and disability worldwide. However, there remains a dearth of effective therapies. The failure of many therapies for stroke in clinical trials has promoted the development of human cell-based models, such as brain organoids. Brain organoids differ from pluripotent stem cells in that they recapitulate various key features of the human central nervous system (CNS) in three-dimensional (3D) space. Recent studies have demonstrated that brain organoids could serve as a new platform to study various neurological diseases. However, there are several limitations, such as the scarcity of glia and vasculature in organoids, which are important for studying stroke. Herein, we have summarized the application of brain organoid technology in stroke research, such as for modeling and transplantation purposes. We also discuss methods to overcome the limitations of brain organoid technology, as well as future prospects for its application in stroke research. Although there are many difficulties and challenges associated with brain organoid technology, it is clear that this approach will play a critical role in the future exploration of stroke treatment.

Introduction: The melanoma-associated antigen D2 (MAGED2) is one of the melanoma-associated antigen family members. It is commonly overexpressed in a variety of malignancies. However, the mechanism and function of MAGED2 in glioma remain unknown. Methods: The MAGED2 expression level and the correlations between clinical characteristics were analyzed with the data from the CGGA and TCGA datasets. MAGED2 expression in 98 glioma tissues was measured using RT-qPCR, Western blot, and immunohistochemistry. CCK-8, colony formation, and EdU assays were used to assess the effect of MAGED2 on U251-MG cell proliferation. Flow cytometry was used to track changes in the cell cycle and cell apoptosis following plasmid transfection with CRISPRi. Results: MAGED2 was shown to be highly expressed in glioma tissues, and high MAGED2 expression predicted poor prognosis. Furthermore, MAGED2 knockdown significantly inhibited the proliferation of U251-MG cells by preventing cell cycle arrest at the G0/G1 phase and triggering apoptosis. In line with in vitro findings, the results of the xenograft experiment and immunohistochemistry also showed that MAGED2 suppression inhibited tumor development and decreased Ki-67 expression levels. Conclusions: MAGED2 may be a possible biomarker for glioma and an important prognostic factor for glioma patients.

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: Cosmetic treatment was closely associated with beauty seekers' psychological well-being. Patients who seek cosmetic surgery often show anxiety. Nevertheless, not much is known regarding how personality traits relate to the selection of body parts that receive cosmetic treatment.Aims: This study aims to investigate the correlation between personality traits and various selection sites for cosmetic treatment via Eysenck Personality Questionnaire (EPQ).Methods: A cross-sectional approach was adopted to randomly recruited patients from a general hospital planning to undergo cosmetic treatments. All respondents completed the EPQ and provided their demographic information. The EPQ involves four scales: the extraversion (E), neuroticism (N), psychoticism (P), and lying scales (L). Psychological scales were evaluated to verify that people who selected different body sites for cosmetic intervention possessed different personality portraits.Results: A total of 426 patients with an average age of 32.14 ± 8.06 were enrolled. Among them, 384 were females, accounting for more than 90% of patients. Five treatment sites were analyzed, including the body, eye, face contour, nose, and skin. Comparatively, patients with neuroticism were more likely to undergo and demand rhinoplasty (OR 1.15, 95% CI 1.07–1.24, P < 0.001). Face contour treatment was commonly associated with extraversion (OR 1.05, 95% CI 1.00–1.11, P = 0.044), psychoticism (OR 1.13, CI 1.03–1.25, P = 0.013), and neuroticism (OR 1.05, CI 1.01–1.10, P = 0.019).Conclusions: This novel study attempted to determine the personality profiles of beauty seekers. The corresponding assessments may provide references for clinical treatment options and enhance postoperative satisfaction for both practitioners and patients.

Facial fat grafting techniques often offer impressive surgical results. However, fatal complications, such as irreversible cerebral ischemia, blindness, and hemiplegia are associated with them. We have presented a case report of a patient who presented with a massive cerebral infarction, a serious complication of facial autologous fat injection. The patient was a 28-year-old female who experienced motor dysfunction of the left extremities, which was accompanied with loss of consciousness immediately following fat grafting for facial augmentation. Imaging studies suggested that the patient had a large cerebral infarction on the right frontal, temporal, and parietal lobes due to complete occlusion of her right external carotid artery. Emergency decompressive craniectomy was completed in addition to multiple follow-up medical treatments. The patient recovered after 4 months with reduced motor function in her left upper extremity. This report further summarizes published cases of massive cerebral ischemia after facial injection of autologous fat, as well as lists high-risk facial areas and critical warnings.

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.

Strokes are the most common types of cerebrovascular disease and remain a major cause of death and disability worldwide. Cerebral ischemic stroke is caused by a reduction in blood flow to the brain. In this disease, two major zones of injury are identified: the lesion core, in which cells rapidly progress toward death, and the ischemic penumbra (surrounding the lesion core), which is defined as hypoperfusion tissue where cells may remain viable and can be repaired. Two methods that are approved by the Food and Drug Administration (FDA) include intravenous thrombolytic therapy and endovascular thrombectomy, however, the narrow therapeutic window poses a limitation, and therefore a low percentage of stroke patients actually receive these treatments. Developments in stem cell therapy have introduced renewed hope to patients with ischemic stroke due to its potential effect for reversing the neurological sequelae. Over the last few decades, animal tests and clinical trials have been used to treat ischemic stroke experimentally with various types of stem cells. However, several technical and ethical challenges must be overcome before stem cells can become a choice for the treatment of stroke. In this review, we summarize the mechanisms, processes, and challenges of using stem cells in stroke treatment. We also discuss new developing trends in this field.

Background: Major depressive disorder (MDD) is a serious mental disorder that represents a substantial public health problem. Several trials have been undertaken to investigate the role of botulinum toxin type A (BTX-A) in the treatment of MDD, but the conclusions were controversial. To examine the efficacy and safety of BTX-A vs. placebo on patients with a clinical diagnosis of MDD, we conducted this systematic review and meta-analysis.Methods: A systematic search was conducted for all relevant randomized controlled trials (RCTs) in PubMed and Web of Science from inception to June 17, 2020. All published studies that investigated the efficacy and safety of BTX-A injections on patients with a clinical diagnosis of MDD were included. The overall effect size was summarized using a random-effects meta-analysis model. The primary outcomes of the present meta-analysis were the changes in depressive rating scale at week 6 after BTX-A injection compared with placebo. The safety of BTX-A injections also was assessed.Results: Five RCTs with a total of 417 participants (189 patients in the BTX-A group, 228 patients in placebo group) were eligible in this meta-analysis. The results indicated an overall positive effect of BTX-A injections for reducing the depressive symptoms of patients with MDD (Hedges' g, −0.82; 95% CI, −1.38 to −0.27) with large effect size. Differences are likely explained by the dose of BTX-As and the gender of the participants. Our findings also highlighted that BTX-A injections were generally well-tolerated, with only mild and temporary adverse events reported.Conclusions: The present meta-analysis provides evidence that BTX-A injections are associated with a statistically significant improvement in depressive symptoms. BTX-A injections are generally safe and may provide a new, alternative option for the treatment of depression.

The extracellular matrix is composed of a variety of macromolecular substances secreted by cells, which form a complex network that supports and connects tissue structures, regulates the morphogenesis of tissues, and maintains the physiological activities of cells. Tenascin-C, a secreted extracellular matrix glycoprotein, is abundantly expressed after exposure to pathological stimuli. It plays an important regulatory role in brain tumors, vascular diseases, and neurodegenerative diseases by mediating inflammatory responses, inducing brain damage, and promoting cell proliferation, migration, and angiogenesis through multiple signaling pathways. Therefore, tenascin-C may become a potential therapeutic target for intracranial diseases. Here, we review and discuss the latest literature regarding tenascin-C, and we comprehensively explain the role and clinical significance of tenascin-C in intracranial diseases.

Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI.Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1α inhibitor 2ME and agonist DMOG were used to study the role of HIF-1α in TRAIL-induced neuronal death. Meanwhile, HIF-1α siRNA was used to investigate the role of HIF-1α in TRAIL-induced neuronal death in vitro.Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1α siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro.Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1α mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.

Apoptosis is a vital pathological factor that accounts for the poor prognosis of traumatic spinal cord injury (t-SCI). The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is a critical regulator for energy metabolism and proven to have antiapoptotic effects. This study aimed to investigate the neuroprotective role of PFKFB3 in t-SCI. A compressive clip was introduced to establish the t-SCI model. Herein, we identified that PFKFB3 was extensively distributed in neurons, and PFKFB3 levels significantly increased and peaked 24 h after t-SCI. Additionally, knockdown of PFKFB3 inhibited glycolysis, accompanied by aggravated neuronal apoptosis and white matter injury, while pharmacological activation of PFKFB3 with meclizine significantly enhanced glycolysis, attenuated t-SCI-induced spinal cord injury, and alleviated neurological impairment. The PFKFB3 agonist, meclizine, activated cyclin-dependent kinase 1 (CDK1) and promoted the phosphorylation of p27, ultimately suppressing neuronal apoptosis. However, the neuroprotective effects of meclizine against t-SCI were abolished by the CDK1 antagonist, RO3306. In summary, our data demonstrated that PFKFB3 contributes robust neuroprotection against t-SCI by enhancing glycolysis and modulating CDK1-related antiapoptotic signals. Moreover, targeting PFKFB3 may be a novel and promising therapeutic strategy for t-SCI.

Acute central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) present a grave health care challenge worldwide due to high morbidity and mortality, as well as limited clinical therapeutic strategies. Established literature has shown that oxidative stress (OS), inflammation, excitotoxicity, and apoptosis play important roles in the pathophysiological processes of acute CNS injuries. Recently, there have been many studies on the topic of ferroptosis, a form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxidation. Some studies have revealed an emerging connection between acute CNS injuries and ferroptosis. Ferroptosis, induced by the abnormal metabolism of lipids, glutathione (GSH), and iron, can accelerate acute CNS injuries. However, pharmaceutical agents, such as iron chelators, ferrostatin-1 (Fer-1), and liproxstatin-1 (Lip-1), can inhibit ferroptosis and may have neuroprotective effects after acute CNS injuries. However, the specific mechanisms underlying this connection has not yet been clearly elucidated. In this paper, we discuss the general mechanisms of ferroptosis and its role in stroke, TBI, and SCI. We also summarize ferroptosis-related drugs and highlight the potential therapeutic strategies in treating various acute CNS injuries. Additionally, this paper suggests a testable hypothesis that ferroptosis may be a novel direction for further research of acute CNS injuries by providing corresponding evidence.

Retinal alterations have recently been associated with numerous neurodegenerative diseases. Rhodopsin is a G-protein coupled receptor found in the rod cells of the retina. As a biomarker associated with retinal thinning and degeneration, it bears potential in the early detection and monitoring of several neurodegenerative diseases. In this review article, we summarize the findings of correlations between rhodopsin and several neurodegenerative disorders as well as the potential of a novel technique, cSLO, in the quantification of rhodopsin.

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.

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. The aim of this study was to explore whether Sodium Benzoate (NaB) could reduce neural cell apoptosis and alleviate neurological deficits after ICH. To assess the therapeutic effects of NaB, first, we measured brain water content, neurobehavior, and blood-brain barrier (BBB) integrity at 24 h after ICH in different groups. Then western blot and immunofluorescence staining (IF) were applied to test the levels of different proteins. Transmission electron microscope (TEM) was used to observe ultra-structures within the cells in different groups. The results showed that levels of DJ-1, p-Akt and p-IκB kinase (IKK) increased after ICH and peaked at 24 h. Besides, NaB significantly upregulated DJ-1 in both cytoplasm and mitochondria, and also increased the levels of p-Akt, p-IKK and Bcl-2/Bax ratio, but decreased the levels of caspase-3 and caspase-9. Additionally, NaB decreased reactive oxygen species (ROS) while increased adenosine triphosphate (ATP), which then improving the neurological functions at 24 h and long-term (21 days) memory and spatial learning ability after ICH. However, the results mentioned above could be greatly reversed by MK2206 and rotenone. Therefore, we concluded that NaB could attenuate secondary brain injury via inhibiting neuronal apoptosis and reducing mitochondria-mediated oxidative stress via DJ-1/Akt/IKK/NFκB pathway.

Neuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT/enhancer-binding protein homologous protein (CHOP) siRNAs were applied in this study. Brain edema, neurological functions, blood-brain barrier (BBB) integrity were evaluated at 24 h after ICH. Western blot analysis was used to evaluate the protein level of target proteins (ATF6, CHOP, Bip, Bcl-2, Bax, and cleaved caspase-3). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA level of ATF6, CHOP and cleaved caspase-3. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 immunofluorescence staining were applied to evaluate the neuronal cell death. The results suggested that the levels of ATF6 and its downstream protein, CHOP, were upregulated and reached the peak at 24 h after ICH. ATF6 was highly expressed in neurons. The administration of melatonin significantly decreased the mRNA and protein levels of ATF6, and its downstream targets, CHOP and cleaved caspase-3, but increased the Bcl-2/Bax ratio, which ameliorated the neurological functions. The CHOP siRNA significantly reversed the pro-apoptotic effect induced by the increased ATF6 level after ICH. Melatonin could protect against neuronal apoptosis via suppression of ATF6/CHOP arm of ER-stress-response pathway.

Background and purpose C-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model.Methods SAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed.Results The expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2.Conclusion CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.