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Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life. Many stroke victims are left with long-term neurological dysfunction, which adversely affects the well-being of the individual and the broader socioeconomic impact. Currently, post-stroke brain dysfunction is a major and difficult area of treatment. Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autism, refractory depression, epilepsy, and Alzheimer's disease. It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as altering neurotransmitters and the plasticity of central neurons. In animal models of acute ischemic stroke, vagus nerve stimulation has been shown to reduce infarct size, reduce post-stroke neurological damage, and improve learning and memory capacity in rats with stroke by reducing the inflammatory response, regulating blood-brain barrier permeability, and promoting angiogenesis and neurogenesis. At present, vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation. Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in improving upper limb motor and cognitive abilities in stroke patients. Further clinical studies have shown that non-invasive vagus nerve stimulation, including ear/cervical vagus nerve stimulation, can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect. In this paper, we first describe the multiple effects of vagus nerve stimulation in stroke, and then discuss in depth its neuroprotective mechanisms in ischemic stroke. We go on to outline the results of the current major clinical applications of invasive and non-invasive vagus nerve stimulation. Finally, we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends. We believe that vagus nerve stimulation, as an effective treatment for stroke, will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis., Methods: Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting BAP1 mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH., Results: First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH., Conclusions: Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH., Competing Interests: None.

Background: Research in the areas of inflammation and mitochondrial stress in ischemic stroke is rapidly expanding, but a comprehensive overview that integrates bibliometric trends with an in-depth review of molecular mechanisms is lacking., Objective: To map the evolving landscape of research using bibliometric analysis and to detail the molecular mechanisms that underpin these trends, emphasizing their implications in ischemic stroke., Methods: We conducted a bibliometric analysis to identify key trends, top contributors, and focal research themes. In addition, we review recent research advances in mitochondrial stress and inflammation in ischemic stroke to gain a detailed understanding of the pathophysiological processes involved., Conclusion: Our integrative approach not only highlights the growing research interest and collaborations but also provides a detailed exploration of the molecular mechanisms that are central to the pathology of ischemic stroke. This synthesis offers valuable insights for researchers and paves the way for targeted therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Targeting Ca 2+ /calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.

Aim: This study aimed to explore the mechanisms of transient receptor potential (TRP) channels on the immune microenvironment and develop a TRP-related signature for predicting prognosis, immunotherapy response, and drug sensitivity in gliomas., Methods: Based on the unsupervised clustering algorithm, we identified novel TRP channel clusters and investigated their biological function, immune microenvironment, and genomic heterogeneity. In vitro and in vivo experiments revealed the association between TRPV2 and macrophages. Subsequently, based on 96 machine learning algorithms and six independent glioma cohorts, we constructed a machine learning-based TRP channel signature (MLTS). The performance of the MLTS in predicting prognosis, immunotherapy response, and drug sensitivity was evaluated., Results: Patients with high expression levels of TRP channel genes had worse prognoses, higher tumor mutation burden, and more activated immunosuppressive microenvironment. Meanwhile, TRPV2 was identified as the most essential regulator in TRP channels. TRPV2 activation could promote macrophages migration toward malignant cells and alleviate glioma prognosis. Furthermore, MLTS could work independently of common clinical features and present stable and superior prediction performance., Conclusion: This study investigated the comprehensive effect of TRP channel genes in gliomas and provided a promising tool for designing effective, precise treatment strategies., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Cell division cycle-associated (CDCA) gene family members are essential cell proliferation regulators and play critical roles in various cancers. However, the function of the CDCA family genes in gliomas remains unclear. This study aims to elucidate the role of CDCA family members in gliomas using in vitro and in vivo experiments and bioinformatic analyses. We included eight glioma cohorts in this study. An unsupervised clustering algorithm was used to identify novel CDCA gene family clusters. Then, we utilized multi-omics data to elucidate the prognostic disparities, biological functionalities, genomic alterations, and immune microenvironment among glioma patients. Subsequently, the scRNA-seq analysis and spatial transcriptomic sequencing analysis were carried out to explore the expression distribution of CDCA2 in glioma samples. In vivo and in vitro experiments were used to investigate the effects of CDCA2 on the viability, migration, and invasion of glioma cells. Finally, based on ten machine-learning algorithms, we constructed an artificial intelligence-driven CDCA gene family signature called the machine learning-based CDCA gene family score (MLCS). Our results suggested that patients with the higher expression levels of CDCA family genes had a worse prognosis, more activated RAS signaling pathways, and more activated immunosuppressive microenvironments. CDCA2 knockdown inhibited the proliferation, migration, and invasion of glioma cells. In addition, the MLCS had robust and favorable prognostic predictive ability and could predict the response to immunotherapy and chemotherapy drug sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study conducts a systematic investigation into the causal relationships between plasma uric acid levels and subtypes of ischemic stroke (IS), as well as the extent to which Type 2 diabetes mellitus (T2DM) mediates this relationship., Background: There is a known association between Uric acid and IS but whether they have a causal relationship remains unclear. This study aims to determine whether a genetic predisposition to uric acid is causally linked to IS, including three subtypes, and to determine the mediating role of T2DM., Methods: Bidirectional Mendelian randomization (MR) analyses was initially used to explore the causal relationship between uric acid and three subtypes of IS. Two-step MR methods were then used to investigate the role of T2DM in mediating the effect of uric acid and IS with its subtypes., Results: A primary analysis showed uric acid had a markedly causal association with IS (IVW, OR 1.23; 95 % CI, 1.13 - 1.34; p = 6.39 × 10 -9 ), and two subtypes of IS, Large-vessel atherosclerotic stroke LAS (IVW, OR 1.25; 95 % CI, 1.03 - 1.53; p = 0.026) and small vessel stroke (SVS) (IVW, OR 1.20; 95 % CI, 1.00 - 1.43; p = 0.049), but not with cardioembolic stroke (CES)(IVW, OR 1.00; 95 % CI, 0.87 - 1.15; p = 0.993). Two-step MR results showed that T2DM mediated the association between uric acid and LAS and SVS, accounting for 13.85 % (p = 0.025) and 13.57 % (p = 0.028), respectively., Conclusions: The study suggests that genetic predisposition to uric acid is linked to a greater risk of IS, especially LAS and SVS. T2DM might mediate a significant proportion of the associations between uric acid and LAS as well as SVS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioma, the most prevalent primary brain tumor in adults, is characterized by significant invasiveness and resistance. Current glioma treatments include surgery, radiation, chemotherapy, and targeted therapy, but these methods often fail to eliminate the tumor completely, leading to recurrence and poor prognosis. Immune checkpoint inhibitors, a class of commonly used immunotherapeutic drugs, have demonstrated excellent efficacy in treating various solid malignancies. Recent research has indicated that unconventional levels of expression of the MAP2K3 gene closely correlates with glioma malignancy, hinting it could be a potential immunotherapy target. Our study unveiled substantial involvement of MAP2K3 in gliomas, indicating the potential of the enzyme to serve as a prognostic biomarker related to immunity. Through the regulation of the infiltration of immune cells, MAP2K3 can affect the prognosis of patients with glioma. These discoveries establish a theoretical foundation for exploring the biological mechanisms underlying MAP2K3 and its potential applications in glioma treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pu, Feng, Gu, Smerin, Jian, Xiong and Wei.)

Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is the fifth leading cause of death worldwide, and the functional status of the gut plays a key role in patients' prognosis. Recent publications have explored the gut association with stroke, but few articles have been published that specifically address a comprehensive bibliometric analysis of the gut microbiota and its association with stroke. To address this gap, we used bibliometric methods to examine the landscape of research concerning the gut and stroke over approximately two decades, utilizing the Web of Science Core Collection (WoSCC). On November 1, 2022, a search was conducted for English-language articles published between 2002 and 2022, with only including original articles. Visual and statistical analyses were performed using CiteSpace, VOSviewer, and Bibliometrix 4.1.0 Package. After screening relevant articles, the results revealed that the number of articles published in this field has progressively increased during the last two decades. In particular, the total number of publications rapidly increased year by year from 2014. Among them, China ranked first in the world with a total of 227 publications. Authorship analysis highlighted Wang Z as the most prolific author, with 18 publications and an H-index of 14, highlighting significant contributions to this field. Meanwhile, the Southern Medical University of China was identified as the most productive institution. Moreover, analysis of keywords revealed that 'cerebral ischemia', 'intestinal microbiota', 'gut microbiota', and 'trimethylamine N-oxide' were popular topics searched, and research on the relationship between stroke and the gut continues to be a research hotspot. In summary, this study presents an overview of the progress and emerging trends in research on the relationship between stroke and gut health over the past two decades, providing a valuable resource for researchers aiming to understand the current state of the field and identify potential directions for future studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

A smart and heavy-atom-free photoinactive nano-photosensitizer capable of being activated by cysteine at the tumor site to generate highly photoactive nano-photosensitizers that show strong NIR absorption and fluorescence with a good singlet oxygen quantum yield (16.8%) for photodynamic therapy is reported.

Background: Association between depression and aneurysm has been implicated but the specific role of depression in aneurysm remains unclear. We aimed to comprehensively characterize the relation of major depressive disorder (MDD) with aneurysm by subtype., Methods: Harnessing summary statistics from genome-wide association studies (N case /N control  = 7603/317,899 for aortic aneurysm; 7321/317,899 for thoracic aortic aneurysm; 3201/317,899 for abdominal aortic aneurysm; 1788/317,899 for cerebral aneurysm; and 246,363/561,190 for major depressive disorder), we estimated the genetic correlation between MDD and each of four aneurysm subtypes via LD Score Regression and tested the causality via various estimators under the bi-directional Mendelian randomization (MR) framework., Results: Positive genetic correlation of statistical significance, ranging between 0.15 (with thoracic aortic aneurysm, P = 0.005) and 0.25 (with abdominal aortic aneurysm, P = 0.001), was consistently observed for MDD with each aneurysm subtype. In the MR analysis of MDD as an exposure, genetic liability to MDD causally increased the risk of cerebral (odds ratio: 1.71; 95 % confidence interval: 1.26-2.34) but not aortic aneurysm. Replication analysis of an independent dataset (N case /N control  = 6242/59,418) corroborated this signal. In contrast, causal effect was not evident for any neurysm subtype on susceptibility to MDD., Limitations: Aneurysm could have been underdiagnosed if asymptomatic, leading to an underestimated causal impact on MDD. Non-linearity of the causal effect was not tested due to the lack of individual-level data., Conclusions: Depression and aneurysm may share common pathomechanisms. Screening depressed population and improving the clinical management for depression may benefit the primary prevention of cerebral aneurysm., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle-associated membrane protein-associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB-PTPIP51 in experimental cerebral ischemia., Methods: We simulated cerebral ischemia-reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model., Results: We observed a decrease in VAPB-PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria-ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator., Conclusions: Our findings suggest that the downregulation of VAPB-PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: The crosstalk between ferroptosis and neuroinflammation considerably impacts the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Neutral polysaccharide from Gastrodia elata (NPGE) has shown significant effects against oxidative stress and inflammation. This study investigated the potential effects of NPGE on CIRI neuropathology., Methods: The effects of NPGE were studied in a mouse model of ischemic stroke (IS) and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells., Results: NPGE treatment decreased neurological deficits, reduced infarct volume, and alleviated cerebral edema in IS mice, and promoted the survival of OGD/R-induced HT22 cells. Mechanistically, NPGE treatment alleviated neuronal ferroptosis by upregulating GPX4 levels, lowering reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ excessive hoarding, and meliorating GSH levels and SOD activity. Additionally, it inhibited neuroinflammation by down-regulating the level of IL-1β, IL-6, TNF-α, NLRP3, and HMGB1. Meanwhile, NPGE treatment alleviated ferroptosis and inflammation in erastin-stimulated HT22 cells. Furthermore, NPGE up-regulated the expression of NRF2 and HO-1 and promoted the translocation of NRF2 into the nucleus. Using the NRF2 inhibitor brusatol, we verified that NRF2/HO-1 signaling mediated the anti-ferroptotic and anti-inflammatory properties of NPGE., Conclusion: Collectively, our results demonstrate the protective effects of NPGE and highlight its therapeutic potential as a drug component for CIRI treatment., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Ferroptosis is a form of non-apoptotic programmed cell death, and its mechanisms mainly involve the accumulation of lipid peroxides, imbalance in the amino acid antioxidant system, and disordered iron metabolism. The primary organelle responsible for coordinating external challenges and internal cell demands is the endoplasmic reticulum, and the progression of inflammatory diseases can trigger endoplasmic reticulum stress. Evidence has suggested that ferroptosis may share pathways or interact with endoplasmic reticulum stress in many diseases and plays a role in cell survival. Ferroptosis and endoplasmic reticulum stress may occur after ischemic stroke. However, there are few reports on the interactions of ferroptosis and endoplasmic reticulum stress with ischemic stroke. This review summarized the recent research on the relationships between ferroptosis and endoplasmic reticulum stress and ischemic stroke, aiming to provide a reference for developing treatments for ischemic stroke.

Aims: Cell death, except for cuproptosis, in gliomas has been extensively studied, providing novel targets for immunotherapy by reshaping the tumor immune microenvironment through multiple mechanisms. This study aimed to explore the effect of cuproptosis on the immune microenvironment and its predictive power in prognosis and immunotherapy response., Methods: Eight glioma cohorts were included in this study. We employed the unsupervised clustering algorithm to identify novel cuproptosis clusters and described their immune microenvironmental characteristics, mutation landscape, and altered signaling pathways. We verified the correlation among FDX1, SLC31A1, and macrophage infiltration in 56 glioma tissues. Next, based on multicenter cohorts and 10 machine learning algorithms, we constructed an artificial intelligence-driven cuproptosis-related signature named CuproScore., Results: Our findings suggested that glioma patients with high levels of cuproptosis had a worse prognosis owing to immunosuppression caused by unique immune escape mechanisms. Meanwhile, we experimentally validated the positive association between cuproptosis and macrophages and its tumor-promoting mechanism in vitro. Furthermore, our CuproScore exhibited powerful and robust prognostic predictive ability. It was also capable of predicting response to immunotherapy and chemotherapy drug sensitivity., Conclusions: Cuproptosis facilitates immune activation but promotes immune escape. The CuproScore could predict prognosis and immunotherapy response in gliomas., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Autophagy has been described to be both protective and pathogenic in cerebral ischemia/reperfusion (I/R) injury. The underlying association between autophagy and ferroptosis in ischemic stroke has not yet been clearly investigated. The purpose of this study was to explore the role of autophagy-related gene 5 (ATG5) in experimental ischemic stroke. After injection of ATG5 shRNA lentivirus, mice underwent surgery for transient middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. The infarct volume, neurological function, apoptosis, reactive oxygen species (ROS), autophagy, and ferroptosis levels were evaluated. After MCAO, ATG5-knockdown mice had a smaller infarct size and fewer neurological deficits than wild-type mice. The levels of apoptosis and ROS in ischemic mouse brains were alleviated through ATG5 knockdown. The expression of LC3 I/II was reduced through ATG5 knockdown after MCAO. Additionally, the expression of beclin1 and LC3 II was increased after I/R, but the increase was counteracted by preconditioning with ATG5 knockdown. After ischemic stroke, the levels of Fe 2+ and malondialdehyde (MDA) were increased, but they were reduced by ATG5 knockdown. Similarly, the expression of glutathione peroxidase 4 (GPX4) and glutathione (GSH) was decreased by I/R but elevated by ATG5 knockdown. The present study shows that ATG5 knockdown attenuates autophagy-induced ferroptosis, which may offer a novel potential approach for ischemic stroke treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Venous thromboembolism is a sudden cardiovascular disease that can lead to death, and its pathologic development is closely related to vascular viscosity and inflammation. However, direct evidence from in vivo is really scarce. The key limitation is that the combined probes cannot detect multiple markers simultaneously, which may lead to unreliable results. Therefore, to develop a single probe that can simultaneously monitor the variations of viscosity in the vascular microenvironment as well as inflammation level during venous thrombosis., Results: A dual-responsive two-photon fluorescent probe, Cou-ONOO, was designed and synthesized. Cou-ONOO provides a visualization tool for monitoring the viscosity of the vascular as well as the inflammatory marker ONOO‾ during thromboembolism via dual-channel simultaneous imaging. As a single probe that can recognize dual targets, Cou-ONOO effectively avoids the problems from unreliable results caused by complex synthesis and differences in intracellular localization, diffusion, and metabolism of different dyes as using combinatorial probes. Using Cou-ONOO, simultaneous imaging the variations of viscosity and ONOO‾at the cellular and tissue levels was successfully performed. In addition, Cou-ONOO also successfully visualized and tracked the viscosity of the vascular microenvironment and ONOO‾ during venous embolism in mice., Significance: Experimental results show that both viscosity and inflammation are abnormally overexpressed in the microenvironment at the thrombus site during venous thrombosis. An intuitive visualization tool to elucidate the variations of viscosity as well as inflammation level in the vascular microenvironment during thrombosis was provided, which will facilitate a better clinical understanding of the pathological process of thrombosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The incidence of adolescent depressive disorder is globally skyrocketing in recent decades, albeit the causes and the decision deficits depression incurs has yet to be well-examined. With an instrumental learning task, the aim of the current study is to investigate the extent to which learning behavior deviates from that observed in healthy adolescent controls and track the underlying mechanistic channel for such a deviation., Methods: We recruited a group of adolescents with major depression and age-matched healthy control subjects to carry out the learning task with either gain or loss outcome and applied a reinforcement learning model that dissociates valence (positive v . negative) of reward prediction error and selection (chosen v. unchosen)., Results: The results demonstrated that adolescent depressive patients performed significantly less well than the control group. Learning rates suggested that the optimistic bias that overall characterizes healthy adolescent subjects was absent for the depressive adolescent patients. Moreover, depressed adolescents exhibited an increased pessimistic bias for the counterfactual outcome. Lastly, individual difference analysis suggested that these observed biases, which significantly deviated from that observed in normal controls, were linked with the severity of depressive symoptoms as measured by HAMD scores., Conclusions: By leveraging an incentivized instrumental learning task with computational modeling within a reinforcement learning framework, the current study reveals a mechanistic decision-making deficit in adolescent depressive disorder. These findings, which have implications for the identification of behavioral markers in depression, could support the clinical evaluation, including both diagnosis and prognosis of this disorder.

Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms., Competing Interests: None

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Chen, Wang, Zhu, Gu, Li, Xiong, Chen and Jian.)

Postoperative cognitive dysfunction (POCD) is a cluster of cognitive problems that may arise after surgery. POCD symptoms include memory loss, focus inattention, and communication difficulties. Inflammasomes, intracellular multiprotein complexes that control inflammation, may have a significant role in the development of POCD. It has been postulated that the NLRP3 inflammasome promotes cognitive impairment by triggering the inflammatory response in the brain. Nevertheless, there are many gaps in the current literature to understand the underlying pathophysiological mechanisms and develop future therapy. This review article underlines the limits of our current knowledge about the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome and POCD. We first discuss inflammasomes and their types, structures, and functions, then summarize recent evidence of the NLRP3 inflammasome's involvement in POCD. Next, we propose a hypothesis that suggests the involvement of inflammasomes in multiple organs, including local surgical sites, blood circulation, and other peripheral organs, leading to systemic inflammation and subsequent neuronal dysfunction in the brain, resulting in POCD. Research directions are then discussed, including analyses of inflammasomes in more clinical POCD animal models and clinical trials, studies of inflammasome types that are involved in POCD, and investigations into whether inflammasomes occur at the surgical site, in circulating blood, and in peripheral organs. Finally, we discuss the potential benefits of using new technologies and approaches to study inflammasomes in POCD. A thorough investigation of inflammasomes in POCD might substantially affect clinical practice.

Background and Aims: The immune-inflammatory cascade and pyroptosis play an important role in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). The maintenance of immune homeostasis is inextricably linked to the Notch signaling pathway, but whether myeloid Notch1 affects microglia polarization as well as neuronal pyroptosis in CIRI is not fully understood. This study was designed to clarify the role of myeloid Notch1 in CIRI, providing new therapeutic strategies for ischemic stroke., Methods and Results: Myeloid-specific Notch1 knockout (Notch1 M-KO ) mice and the floxed Notch1 (Notch1 FL/FL ) mice were subjected to middle cerebral artery occlusion (MCAO). After 3 days of CIRI, we evaluated the neurological deficit score and cerebral infarction volume. Immunofluorescence staining was used to detect the expression of Notch1 and microglial subtype markers. Cerebral infiltrating macrophages were detected by flow cytometry. RT-qPCR was used to detect pro-inflammatory cytokines. Western blot was used to detect the expression of pyroptosis related proteins. The Notch1-siRNA transfected BV2 cells were co-cultured with HT22 cells to investigate the potential mechanisms by which microglial Notch1 affects neuronal pyroptosis induced by anoxia/reoxygenation in vitro. We found that Notch1 was activated in cerebral microglia/macrophages after CIRI. Myeloid Notch1 deficiency decreased the cerebral infarct volume (24.17 ± 3.29 vs. 36.17 ± 2.27, p < 0.001), neurological function scores (2.33 ± 0.47 vs. 3.17 ± 0.37, p < 0.001) and the infiltration of peripheral monocytes/macrophages (3.26 ± 0.53 vs. 5.67 ± 0.57, p < 0.01). Strikingly, myeloid-specific Notch1 knockout alleviated pyroptosis. Compared with microglia M1, increased microglia M2 were detected in the ischemic penumbra. In parallel in vitro co-culture experiments, we found that Notch1 knockdown in microglial BV2 cells inhibited anoxia/reoxygenation-induced JAK2/STAT3 activation and pyroptosis in hippocampal neuron HT22 cells., Conclusions: Our findings elucidate the underlying mechanism of the myeloid Notch1 signaling pathway in regulating neuronal pyroptosis in CIRI, suggesting that targeting myeloid-specific Notch1 is an effective strategy for the treatment of ischemic stroke.

Background: Ischemic stroke is a leading cause of permanent disability and death globally. The nucleotide-biding oligomaerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that plays a role in ischemic stroke. Recently, research on the role of NLRP3 in ischemic stroke has developed rapidly worldwide. However, there is no bibliometric analysis of NLRP3 in ischemic stroke to date., Aim: Through bibliometric analysis, the aim of this study was to assess the current state of research on NLRP3 in the field of ischemic stroke research worldwide over the past 12 years and to identify important results, major research areas, and emerging trends., Methods: Publications related to NLRP3 in ischemic stroke from January 1, 2011 to December 31, 2022 were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSviewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. The Total Global Citation Score (TGCS) was employed to assess the impact of publications., Results: We found that research of NLRP3 in ischemic stroke developed rapidly starting in 2011. 601 relevant studies have been published in 245 journals over the past 12 years. Journal of Neuroinflammation and International Immunopharmacology were the most productive journals and Journal of Neuroinflammation was the most cited journal. Additionally, Stroke and Journal of Cerebral Blood Flow & Metabolism were the most co-cited journal. The most productive country was China (records = 430) and the most productive university was the Zhejiang University (records = 24). Arumugam TV (TGCS = 949) was the most cited author in this field. NLRP3 inflammasome activation, nf-κb, oxidative stress, and inflammation were the knowledge bases for the research in this field., Conclusion: This study is a scientometric study utilizing quantitative and qualitative methods to comprehensively review the publications on NLRP3 in ischemic stroke. This information provides a reference for scholars to further study NLRP3 in ischemic stroke., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide, with late detection, ineffective treatment and poor overall survival. Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, holds great potential for treatment of HCC. Although some patients respond well to ICIs, many fail to obtain a significant benefit. It is therefore of great interest to find appropriate markers to stratify patient responses to immunotherapy and to explore suitable targets for modulating the TME and immune cell infiltration. ATP6V1F encodes a constituent of vacuolar ATPase (V-ATPase). V-ATPase-mediated acidification of organelles is required for intracellular processes such as zymogen activation, receptor-mediated endocytosis, protein sorting and synaptic vesicle proton gradient generation. In this study, we confirmed for the first time that ATP6V1F is overexpressed in HCC and related to poor prognosis in these patients. We identified that overexpression of ATP6V1F is associated with infiltration of some immune cells and expression of several immune checkpoints. Furthermore, we explored the possible mechanisms of action of ATP6V1F. Finally, we conducted in vitro experiments, including wound healing, Transwell invasion, and apoptosis assays, to verify that ATP6V1F promotes development of HCC by promoting migration and invasion and inhibiting apoptosis of HCC cells. Our findings will contribute to providing precise immunotherapy to patients with HCC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: The mechanisms underpinning Moyamoya disease (MMD) remain unclear, and effective biomarkers remain unknown. The purpose of this study was to identify novel serum biomarkers of MMD., Methods: Serum samples were collected from 23 patients with MMD and 30 healthy controls (HCs). Serum proteins were identified using tandem tandem-mass-tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins (DEPs) in the serum samples were identified using the SwissProt database. The DEPs were assessed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, Gene Ontology (GO), and protein-protein interaction (PPI) networks, and hub genes were identified and visualized using Cytoscape software. Microarray datasets GSE157628, GSE189993, and GSE100488 from the Gene Expression Omnibus (GEO) database were collected. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DE-miRNAs) were identified, and miRNA targets of DEGs were predicted using the miRWalk3.0 database. Serum apolipoprotein E (APOE) levels were compared in 33 MMD patients and 28 Moyamoya syndrome (MMS) patients to investigate the potential of APOE to be as an MMD biomarker., Results: We identified 85 DEPs, of which 34 were up- and 51 down-regulated. Bioinformatics analysis showed that some DEPs were significantly enriched in cholesterol metabolism. A total of 1105 DEGs were identified in the GSE157628 dataset (842 up- and 263 down-regulated), whereas 1290 were identified in the GSE189993 dataset (200 up- and 1,090 down-regulated). The APOE only overlaps with the upregulated gene expression in Proteomic Profiling and in GEO databases. Functional enrichment analysis demonstrated that APOE was associated with cholesterol metabolism. Moreover, 149 miRNAs of APOE were predicted in the miRWalk3.0 database, and hsa-miR-718 was the only DE-miRNA overlap identified in MMD samples. Serum APOE levels were significantly higher in patients with MMD than in those without. The performance of APOE as an individual biomarker to diagnose MMD was remarkable., Conclusions: We present the first description of the protein profile of patients with MMD. APOE was identified as a potential biomarker for MMD. Cholesterol metabolism was found to potentially be related to MMD, which may provide helpful diagnostic and therapeutic insights for MMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Xu, Sun, Duan, Xiao, Ren, Zhou, Yan, Li, Xiong and Zeng.)

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis following conventional therapeutic interventions. Moreover, the blood-brain barrier (BBB) severely impedes the permeation of chemotherapy drugs, thereby reducing their efficacy. Consequently, it is essential to develop novel GBM treatment methods. A novel kind of pericyte immunotherapy known as chimeric antigen receptor T (CAR-T) cell treatment uses CAR-T cells to target and destroy tumor cells without the aid of the antigen with great specificity and in a manner that is not major histocompatibility complex (MHC)-restricted. It has emerged as one of the most promising therapy techniques with positive clinical outcomes in hematological cancers, particularly leukemia. Due to its efficacy in hematologic cancers, CAR-T cell therapy could potentially treat solid tumors, including GBM. On the other hand, CAR-T cell treatment has not been as therapeutically effective in treating GBM as it has in treating other hematologic malignancies. CAR-T cell treatments for GBM have several challenges. This paper reviewed the use of CAR-T cell therapy in hematologic tumors and the selection of targets, difficulties, and challenges in GBM.

The gene expression profile of abdominal aortic aneurysm (AAA) neck is not fully understood. The etiology of AAA is considered to be related to atherosclerosis and the inflammatory response, involving congenital, genetic, metabolic, and other factors. The level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to those of cholesterol, oxidized low-density lipoprotein, and triglycerides. PCSK9 inhibitors have significant effects on lowering LDL-cholesterol, reversing atherosclerotic plaques, and reducing the risk of cardiovascular events and have been approved by several lipid-lowering guidelines. This work was aimed to investigate the potential role of PCSK9 in the neck of AAA. We extracted the expression dataset (GSE47472) containing 14 AAA patients and 8 donors and single-cell RNAseq (scRNA-seq) data (GSE164678) of CaCl 2 -induced (AAA) samples from the Gene Expression Omnibus dataset. Through bioinformatics methods, we found that PCSK9 was up-regulated in the proximal neck of human AAA. In AAA, PCSK9 was mainly expressed in fibroblasts. Additionally, immune check-point PDCD1LG2 was also expressed higher in AAA neck than donor, while CTLA4, PDCD1, and SIGLEC15 were down-regulated in AAA neck. The expression of PCSK was correlated with PDCD1LG2, LAG3, and CTLA4 in AAA neck. Additionally, some ferroptosis-related genes were also down-regulated in AAA neck. PCSK9 was also correlated with ferroptosis-related genes in AAA neck. In conclusion, PCSK9 was highly expressed in AAA neck, and may exert its role through interacting with immune check-points and ferroptosis-related genes., (© 2023. The Author(s).)

Recently, newly developed carbon-based nanomaterials known as carbon dots (CDs) have generated significant interest in nanomedicine. However, current knowledge regarding CD research in the biomedical field is still lacking. An overview of the most recent development of CDs in biomedical research is given in this review article. Several crucial CD applications, such as biosensing, bioimaging, cancer therapy, and antibacterial applications, are highlighted. Finally, CD-based biomedicine's challenges and future potential are also highlighted to enrich biomedical researchers' knowledge about the potential of CDs and the need for overcoming various technical obstacles.

Although metallacycle-based supramolecular photosensitizers (PSs) have attracted increasing attention in biomedicine, their clinical translation is still hindered by their inherent dark toxicity. Herein, we report what to our knowledge is the first example of a molecular engineering approach to building blocks of metallacycles for constructing a series of supramolecular PSs (RuA-RuD), with the aim of simultaneously reducing dark toxicity and enhancing phototoxicity, and consequently obtaining high phototoxicity indexes (PI). Detailed in vitro investigations demonstrate that RuA-RuD display high cancer cellular uptake and remarkable antitumor activity even under hypoxic conditions. Notably, RuD exhibited no dark toxicity and displayed the highest PI value (≈406). Theoretical calculations verified that RuD has the largest steric hindrance and the lowest singlet-triplet energy gap (ΔE ST , 0.61 eV). Further in vivo studies confirmed that RuD allows safe and effective phototherapy against A549 tumors., (© 2023 Wiley-VCH GmbH.)

Abstract: Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective treatment. Mild cognitive impairment (MCI) is an early disease that may progress to AD. The effective diagnosis of AD and MCI in the early stage has important clinical significance., Methods: To this end, this paper proposed a hypergraph-based netNMF (HG-netNMF) algorithm for integrating structural magnetic resonance imaging (sMRI) of AD and MCI with corresponding gene expression profiles., Results: Hypergraph regularization assumes that regions of interest (ROIs) and genes were located on a non-linear low-dimensional manifold and can capture the inherent prevalence of two modalities of data and mined high-order correlation features of the two data. Further, this paper used the HG-netNMF algorithm to construct a brain structure connection network and a protein interaction network (PPI) with potential role relationships, mine the risk (ROI) and key genes of both, and conduct a series of bioinformatics analyses., Conclusion: Finally, this paper used the risk ROI and key genes of the AD and MCI groups to construct diagnostic models. The AUC of the AD group and MCI group were 0.8 and 0.797, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhuang, Tian, Xiong, Li, Chen, Chen, Chen and Li.)

Introduction: This article aimed to investigate the effects of the endoscopic-assisted microsurgery technique on the resection of large (Koos grade IV) vestibular schwannoma (VS) and provide a prognosis analysis of the patients., Methods: A retrospective analysis of the use of the endoscopic-assisted microsurgery technique in 16 cases of large vestibular schwannoma surgery was carried out. Intraoperative nerve electrophysiological monitoring was conducted to explore the effect of neuroendoscopy on the resection of internal auditory canal tumors, protection of the facial nerve, and minimizing postoperative complications., Results: Tumors were completely removed in all 16 cases, and the facial nerve was anatomically preserved in 14 cases (87.5%). There was no postoperative cerebrospinal fluid leakage and no intracranial infection complications occurred.Following the House-Brackmann (H-B) grading system, post-operative facial nerve function was grade I in 5 cases, grade II in 6 cases, grade III in 3 cases, and grade V in 2 cases. As a result, the preservation rate of facial nerve function (H-B grade I-II) was 68.8%. All 16 patients were followed up for 3 to 24 months, and no tumor recurrence was found on enhanced MRI., Discussion: Using the endoscopic-assisted microsurgery technique in the retrosigmoid approach has many advantages over the microscopic-only approach. When compared to the microscopy-only approach, the endoscope can provide a wide-angle surgical field superior to that of a microscope in areas such as the internal auditory canal in the resection of large VS, minimize iatrogenic injuries, ensure complete removal of internal auditory canal tumors, and well as reducing postoperative complications such as cerebrospinal fluid leakage and the loss of facial and auditory nerve functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Xiong, Jian and Du.)

Cerebral ischemic stroke is characterized by acute ischemia in a certain part of the brain, which leads to brain cells necrosis, apoptosis, ferroptosis, pyroptosis, etc. At present, there are limited effective clinical treatments for cerebral ischemic stroke, and the recovery of cerebral blood circulation will lead to cerebral ischemia-reperfusion injury (CIRI). Cerebral ischemic stroke involves many pathological processes such as oxidative stress, inflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), as one of the most critical antioxidant transcription factors in cells, can coordinate various cytoprotective factors to inhibit oxidative stress. Targeting Nrf2 is considered as a potential strategy to prevent and treat cerebral ischemia injury. During cerebral ischemia, Nrf2 participates in signaling pathways such as Keap1, PI3K/AKT, MAPK, NF-κB, and HO-1, and then alleviates cerebral ischemia injury or CIRI by inhibiting oxidative stress, anti-inflammation, maintaining mitochondrial homeostasis, protecting the blood-brain barrier, and inhibiting ferroptosis. In this review, we have discussed the structure of Nrf2, the mechanisms of Nrf2 in cerebral ischemic stroke, the related research on the treatment of cerebral ischemia through the Nrf2 signaling pathway in recent years, and expounded the important role and future potential of the Nrf2 pathway in cerebral ischemic stroke.

The past decade has witnessed unprecedented medical progress, which has translated into cardiac surgery being increasingly common and safe. However, complications such as postoperative delirium remain a major concern. Although the pathophysiological changes of delirium after cardiac surgery remain poorly understood, it is widely thought that inflammation and oxidative stress may be potential triggers of delirium. The development of delirium following cardiac surgery is associated with perioperative risk factors. Multiple interventions are being explored to prevent and treat delirium. Therefore, research on the potential role of biomarkers in delirium as well as identification of perioperative risk factors and pharmacological interventions are necessary to mitigate the development of delirium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pang, Li, Zhang, Wang, Lang, Han, Liu, Xiong, Gu and Wu.)

High-fat diet (HFD) consumption is known to be associated with ovulatory disorders among women of reproductive age. Previous studies in animal models suggest that HFD-induced microglia activation contributes to hypothalamic inflammation. This causes the dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis, leading to subfertility. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of lipid-soluble antidiabetic drugs that target primarily the early proximal tubules in kidney. Recent evidence revealed an additional expression site of SGLT2 in the central nervous system (CNS), indicating a promising role of SGLT2 inhibitors in the CNS. In type 2 diabetes patients and rodent models, SGLT2 inhibitors exhibit neuroprotective properties through reduction of oxidative stress, alleviation of cerebral atherosclerosis and suppression of microglia-induced neuroinflammation. Furthermore, clinical observations in patients with polycystic ovary syndrome (PCOS) demonstrated that SGLT2 inhibitors ameliorated patient anthropometric parameters, body composition and insulin resistance. Therefore, it is of importance to explore the central mechanism of SGLT2 inhibitors in the recovery of reproductive function in patients with PCOS and obesity. Here, we review the hypothalamic inflammatory mechanisms of HFD-induced microglial activation, with a focus on the clinical utility and possible mechanism of SGLT2 inhibitors in promoting reproductive fitness., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background and Purpose: Stroke is associated with high disability and mortality rates and increases the incidence of organ-related complications. Research has revealed that the outcomes and prognosis of stroke are regulated by the state of the intestinal microbiota. However, the possibility that the manipulation of the intestinal microbiota can alter sex-related stroke outcomes remain unknown., Methods: To verify the different effects of microbiota from different sexes on stroke outcomes, we performed mouse fecal microbiota transplantation (FMT) and established a model of ischemic stroke. Male and female mice received either male or female microbiota through FMT. Ischemic stroke was triggered by MCAO (middle cerebral artery occlusion), and sham surgery served as a control. Over the next few weeks, the mice underwent neurological evaluation and metabolite and inflammatory level detection, and we collected fecal samples for 16S ribosomal RNA analysis., Results: We found that when the female mice were not treated with FMT, the microbiota (especially the Firmicutes-to-Bacteroidetes ratio) and the levels of three main metabolites tended to resemble those of male mice after experimental stroke, indicating that stroke can induce an ecological imbalance in the biological community. Through intragastric administration, the gut microbiota of male and female mice was altered to resemble that of the other sex. In general, in female mice after MCAO, the survival rate was increased, the infarct area was reduced, behavioral test performance was improved, the release of beneficial metabolites was promoted and the level of inflammation was mitigated. In contrast, mice that received male microbiota were much more hampered in terms of protection against brain damage and the recovery of neurological function., Conclusion: A female-like biological community reduces the level of systemic proinflammatory cytokines after ischemic stroke. Poor stroke outcomes can be positively modulated following supplementation with female gut microbiota., (© 2022. The Author(s).)

Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein L4 (APOL4) in glioma. We downloaded the expression data of APOL4 and clinical information from several databases and used R software for preprocessing. The clinical significance of APOL4 in a glioma outcome was explored by the Cox regression analysis and Kaplan-Meier survival analysis. In addition, immune infiltrates and microenvironmental indicators were assessed by CIBERSORT and TIMER. GO and KEGG analyses were used to analyze the potential functions of APOL4 in gliomas. APOL4 expression was increased in glioma specimens compared to normal tissues and correlated dramatically with the WHO grade. A survival analysis showed a shorter overall survival (OS) in glioma patients with APOL4 overexpression, and a Cox regression analysis showed that APOL4 was an independent prognostic factor for the OS of glioma patients. GSEA, GO, and KEGG enrichment analyses showed remarkable enrichment in immune-related pathways. APOL4 expression was positively correlated with immune infiltration (including DC cells, neutrophils, CD8+ T cells, B cells, macrophages, CD4+ T cells, etc.) and microenvironmental parameters (including immune, stromal, and ESTIMATE scores) in gliomas. Glioma patients with a higher expression of APOL4 may be more sensitive to immune checkpoint inhibitors (ICI). In conclusion, these findings suggest that APOL4 is associated with the tumor grade and immune infiltrates; APOL4 may be a new and potential biomarker for therapeutic and prognostic evaluations that may further suggest the therapeutic efficacy of immunotherapy.

Liver hepatocellular carcinoma (LIHC) is a malignancy with a high mortality and morbidity rate worldwide. However, the pathogenesis of LIHC has still not been thoroughly studied. Transmembrane and coiled-coil domains 3 (TMCO3) encodes a monovalent cation, a member of the proton transducer 2 (CPA2) family of transporter proteins. In the present study, TMCO3 expression and its relationship with cancer prognosis, as well as its immunological role in LIHC were studied by bioinformatic analysis. We found the significant overexpression of TMCO3 in LIHC in the TCGA, HCCDB, and GEO databases. In LIHC patients, high TMCO3 expression was related to poorer overall survival (OS) and TMCO3 had good predictive accuracy for prognosis. Moreover, TMCO3 was linked to the infiltrates of certain immune cells in LIHC. The correlation of TMCO3 with immune checkpoints was also revealed. Moreover, patients with LIHC with low TMCO3 expression showed a better response to immune checkpoint blockade (ICB) than those with LIHC with high TMCO3 expression. GO and KEGG enrichment analyses indicated that TMCO3 was probably involved in the microtubule cytoskeleton organization involved in mitosis, small GTPase mediated signal transduction, and TGF-β pathway. In conclusion, TMCO3 may be a potential biomarker for LIHC prognosis and immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Zhu, Feng, Wang, Ye and Xiong.)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders of the central nervous system (CNS). Increasing evidence supports the view that dysfunction of innate immune cells initiated by accumulated and misfolded proteins plays essential roles in the pathogenesis and progression of these diseases. The TLR family was found to be involved in the regulation of microglial function in the pathogenesis and progression of AD or PD, making it as double-edged sword in these diseases. Altered function of peripheral innate immune cells was found in AD and PD and thus contributed to the development and progression of AD and PD. Alteration of different subsets of T cells was found in the peripheral blood and CNS in AD and PD. The CNS-infiltrating T cells can exert both neuroprotective and neurotoxic effects in the pathogenesis and progression. Here, we review recent evidences for the roles of innate and adaptive immune cells in the pathogenesis and progression of AD and PD., Competing Interests: There are no conflicts of interest to disclose relevant to this paper., (Copyright © 2022 Boyuan Huang et al.)

Ischemic stroke is a leading cause of disability and death. It imposes a heavy economic burden on individuals, families and society. The mortality rate of ischemic stroke has decreased with the help of thrombolytic drug therapy and intravascular intervention. However, the nerve damage caused by ischemia-reperfusion is long-lasting and followed by multiple organ dysfunction. In this process, the immune responses manifested by systemic inflammatory responses play an important role. It begins with neuroinflammation following ischemic stroke. The large number of inflammatory cells released after activation of immune cells in the lesion area, along with the deactivated neuroendocrine and autonomic nervous systems, link the center with the periphery. With the activation of systemic immunity and the emergence of immunosuppression, peripheral organs become the second "battlefield" of the immune response after ischemic stroke and gradually become dysfunctional and lead to an adverse prognosis. The purpose of this review was to describe the systemic immune responses after ischemic stroke. We hope to provide new ideas for future research and clinical treatments to improve patient outcomes and quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Liu, Zhou, Ye, Zhu, Huang, Weng, Xiong, Zhan and Shen.)

Stroke is a neurological disease that causes significant disability and death worldwide. Ischemic stroke accounts for 75% of all strokes. The pathophysiological processes underlying ischemic stroke include oxidative stress, the toxicity of excitatory amino acids, ion disorder, enhanced apoptosis, and inflammation. Noncoding RNAs (ncRNAs) may have a vital role in regulating the pathophysiological processes of ischemic stroke, as confirmed by the altered expression of ncRNAs in blood samples from acute ischemic stroke patients, animal models, and oxygen-glucose-deprived (OGD) cell models. Due to specific changes in expression, ncRNAs can potentially be biomarkers for the diagnosis, treatment, and prognosis of ischemic stroke. As an important brain cell component, glial cells mediate the occurrence and progression of oxidative stress after ischemic stroke, and ncRNAs are an irreplaceable part of this mechanism. This review highlights the impact of ncRNAs in the oxidative stress process of ischemic stroke. It focuses on specific ncRNAs that underlie the pathophysiology of ischemic stroke and have potential as diagnostic biomarkers and therapeutic targets., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Zhongzhou Su et al.)

WHO 2/3 glioma is a common intracranial tumor that seriously affects the quality of life and survival time of patients. Previous studies have shown that the tricarboxylic acid (TCA) cycle is closely related to the occurrence and development of glioma, while recent studies have shown that cuproptosis, a novel programmed death pathway, is closely related to the inhibition of the TCA cycle. In our study, eight of ten cuproptosis-related genes (CRGs) were found to be differentially expressed between normal and WHO 2/3 glioma tissues. Through the LASSO algorithm, the cuproptosis-associated risk signatures (CARSs) were constructed, which can effectively predict the prognosis of WHO 2/3 glioma patients and are closely related to clinicopathological features. We analyzed the relationship between risk score and immune cell infiltration through Xcell, ssGSEA, TIMER database, and immune checkpoint molecules. In addition, the relationship between risk score and chemotherapeutic drug sensitivity was also investigated. The prognosis-related independent risk factors FDX1 and CDKN2A identified from CARSs are considered potential prognostic biomarkers for WHO 2/3 glioma. The clinical prognosis model based on cuproptosis is expected to provide an effective reference for the diagnosis and treatment of clinical WHO 2/3 glioma patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ye, Zhang, Cai, Ye, Gao, Wang, Tong, Sun, Wu, Xiong and Chen.)

Herein, we construct a series of Ru(II) metallacycles with multimodal chemo-phototherapeutic properties, which exhibited much higher anticancer activity and better cancer-cell selectivity than cisplatin. The antitumor mechanism could be ascribed to the activation of caspase 3/7 and the resulting apoptosis. These results open new possibilities for Ru(II) metallacycles in biomedicine.

Background: Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear., Methods: This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3 f/f and STAT3 f/f LysM cre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization., Results: For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro, and decreased p-STAT3/STAT3 ratio in STAT3 f/f LysM cre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1β, IL-6, TNF-α with STAT3 deletion, as well as increased CD68 + /iNOS + cell numbers., Conclusion: Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Glioma is the most common primary brain tumor in the human brain. The present study was designed to explore the expression of PIMREG in glioma and its relevance to the clinicopathological features and prognosis of glioma patients. The correlations of PIMREG with the infiltrating levels of immune cells and its relevance to the response to immunotherapy were also investigated. PIMREG expression in glioma was analyzed based on the GEO, TCGA, and HPA databases. Kaplan-Meier survival analysis was used to examine the predictive value of PIMREG for the prognosis of patients with glioma. The correlation between the infiltrating levels of immune cells in glioma and PIMREG was analyzed using the CIBERSORT algorithm and TIMRE database. The correlation between PIMREG and immune checkpoints and its correlation with the patients' responses to immunotherapy were analyzed using R software and the GEPIA dataset. Cell experiments were conducted to verify the action of PIMREG in glioma cell migration and invasion. We found that PIMREG expression was upregulated in gliomas and positively associated with WHO grade. High PIMREG expression was correlated with poor prognosis of LGG, prognosis of all WHO grade gliomas, and prognosis of recurrent gliomas. PIMREG was related to the infiltration of several immune cell types, such as M1 and M2 macrophages, monocytes and CD8+ T cells. Moreover, PIMREG was correlated with immune checkpoints in glioma and correlated with patients' responses to immunotherapy. KEGG pathway enrichment and GO functional analysis illustrated that PIMREG was related to multiple tumor- and immune-related pathways. In conclusion, PIMREG overexpression in gliomas is associated with poor prognosis of patients with glioma and is related to immune cell infiltrates and the responses to immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhu, Hu, Feng, Gu, Jian, Zou and Xiong.)

Redox regulation is an inherent feature of nature and plays a crucial role in the transport of ions/small molecules. However, whether redox status affects the biomolecule transport remains largely unknown. To explore the effects of redox status on biomolecule transport, herein, we constructed a glutathione/glutathione disulfide (GSH/GSSG)-driven and pillar[5]arene (P5)-modified artificial nanochannel for protein transport. The results indicate that hemoglobin (Hb) protein is selectively and effectively transported across the GSH-driven P5-modified nanochannel, which suggests that the redox status of the nanochannel could affect the process of protein transport. Therefore, this redox-driven nanochannel could provide a potential application for biomolecule detection and redox-controllable biomolecular drug release.

Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by small emboli on the inner wall of the blood vessels supplying the brain, which can lead to arterial embolism, and can also be caused by cerebrovascular or thrombotic bleeding. With the exception of recombinant tissue plasminogen activator (rt-PA), which is a thrombolytic drug used to recanalize the occluded artery, most treatments have been demonstrated to be ineffective. Stroke can also induce peripheral organ damage. Most stroke patients have different degrees of injury to one or more organs, including the lung, heart, kidney, spleen, gastrointestinal tract and so on. In the acute phase of stroke, severe inflammation occurs in the brain, but there is strong immunosuppression in the peripheral organs, which greatly increases the risk of peripheral organ infection and aggravates organ damage. Nonneurological complications of stroke can affect treatment and prognosis, may cause serious short-term and long-term consequences and are associated with prolonged hospitalization and increased mortality. Many of these complications are preventable, and their adverse effects can be effectively mitigated by early detection and appropriate treatment with various medical measures. This article reviews the pathophysiological mechanism, clinical manifestations and treatment of peripheral organ injury after stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhang, Ye, Xu, Li, Feng, Xiong, Jian and Gu.)

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a potential prognostic marker and is overexpressed in various cancers. This study analyzed sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, with external validation using the Chinese Glioma Genome Atlas (CGGA) data. CKS2 expression in the normal brain and tumor tissue was compared. cBioPortal and MethSurv were utilized to scrutinize the prognostic value of CKS2 methylation. Gene set enrichment examination and single-sample gene set enrichment analysis were employed to explore the potential biological functions of CKS2. Cell viability, colony formation, and transwell assays were conducted to evaluate the influence of CKS2 on glioma cell proliferation and invasion. Compared with normal brain tissue, the expression of CKS2 was upregulated in glioma samples ( p  < 0.001). Multivariate data analysis from TCGA and CGGA indicated that increased expression of CKS2 was an independent risk factor for the prognosis of overall survival in glioma patients. CKS2 methylation was negatively associated with CKS2 expression. Patients with CKS2 hypomethylation had worse overall survival compared with patients with CKS2 methylation, as suggested by the analysis of both TCGA and CGGA datasets. The expression level of CKS2 is closely related to tumor immunity, including the correlation of tumor immune cell infiltration, immune score, and co-expression of multiple immune-related genes. In addition, CKS2 is associated with several immune checkpoints and responses to the chemotherapy drug cisplatin. CKS2 knockdown impeded the expansion and aggression of glioma cell lines. The changes in CKS2 expression may provide a novel prognostic biomarker that can be used to improve patient overall survival rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Ji, Liu, Shen, Xiong, Gu, Lu, Ye, Feng and He.)

Ischemic stroke is an acute cerebrovascular disease characterized by sudden interruption of blood flow in a certain part of the brain, leading to serious disability and death. At present, treatment methods for ischemic stroke are limited to thrombolysis or thrombus removal, but the treatment window is very narrow. However, recovery of cerebral blood circulation further causes cerebral ischemia/reperfusion injury (CIRI). The endoplasmic reticulum (ER) plays an important role in protein secretion, membrane protein folding, transportation, and maintenance of intracellular calcium homeostasis. Endoplasmic reticulum stress (ERS) plays a crucial role in cerebral ischemia pathophysiology. Mild ERS helps improve cell tolerance and restore cell homeostasis; however, excessive or long-term ERS causes apoptotic pathway activation. Specifically, the protein kinase R-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways are significantly activated following initiation of the unfolded protein response (UPR). CIRI-induced apoptosis leads to nerve cell death, which ultimately aggravates neurological deficits in patients. Therefore, it is necessary and important to comprehensively explore the mechanism of ERS in CIRI to identify methods for preserving brain cells and neuronal function after ischemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Zhang, Ye, Xiong, Zhang, Gu, Jian and Wang.)