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Abstract The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.

Abstract Differences in prognostic outcomes are prevalent in patients with colorectal cancer liver metastases. Comparative analysis of tissue samples, particularly applying single-cell transcriptome sequencing technology, can provide a deeper understanding of potential impacting factors. However, long-term monitoring for prognosis determination necessitates extended preservation of tissue samples using formalin-fixed and paraffin-embedded (FFPE) treatments, which can cause substantial RNA degradation, presenting challenges to single-cell or single-nucleus sequencing. In this study, employing snRandom-seq, a single-nucleus RNA sequencing (snRNA-seq) technology specifically for FFPE samples, we tested multiple lesion samples from 18 distinctive colorectal cancer liver metastasis cases with diverse prognostic outcomes that have been preserved for at least three years (mostly over five years). The process yielded expression data from 82,285 cells. The high-quality snRNA-seq data demonstrate the feasibility of single-nucleus sequencing in long-term preserved FFPE samples, offering potential insights into the heterogeneity between different prognoses of colorectal cancer liver metastases, and the relationship between the heterogeneity within different lesions of the same patient and prognosis.

Context Cephaeline is a natural product isolated from ipecac (Cephaelis ipecacuanha [Brot.] A. Rich. [Rubiaceae]). It exhibits promising anti-lung cancer activity and ferroptosis induction may be a key mechanism for its anti-lung cancer effect.Objectives This study investigates the anti-lung cancer activity and mechanisms of cephaeline both in vitro and in vivo.Materials and methods H460 and A549 lung cancer cells were used. The cephaeline inhibition rate on lung cancer cells was detected via a Cell Counting Kit-8 assay after treatment with cephaeline for 24 h. Subsequently, the concentrations of 25, 50 and 100 nM were used for in vitro experiments. In addition, the antitumour effects of cephaeline (5, 10 mg/kg) in vivo were evaluated after 12 d of cephaeline treatment.Results Cephaeline showed significant inhibitory effects on lung cancer cells, and the IC50 of cephaeline on H460 and A549 at 24, 48 and 72 h were 88, 58 and 35 nM, respectively, for H460 cells and 89, 65 and 43 nM, respectively, for A549 cells. Meanwhile, we demonstrated that ferroptosis is the key mechanism of cephaeline against lung cancer. Finally, we found that cephaeline induced ferroptosis in lung cancer cells by targeting NRF2.Discussion and conclusion We demonstrated for the first time that cephaeline inhibits NRF2, leading to ferroptosis in lung cancer cells. These findings may contribute to the development of innovative therapeutics for lung cancer.

Abstract Puncture biopsy, especially those preserved by formalin fixed paraffin embedding (FFPE) samples, play an important role in various research purposes. Diverse single‐nucleus RNA sequencing (snRNA‐seq) techniques have been developed for FFPE samples, however, how to perform high‐throughput snRNA‐seq on small FFPE puncture samples is still a challenge. Here, the previously developed snRNA‐seq technique (snRandom‐seq) is optimized by implementing a pre‐indexing procedure for the minimal puncture FFPE samples. In analyzing 20 samples from various solid tumors, optimized snRandom‐seq still detected ≈17 000 genes and 12 000 long non‐coding RNAs (lncRNAs), achieving precise clustering based on tissue origin. A head‐to‐head comparison with 10× Genomics on fresh biopsy samples showed a similar gene detection rate, with significantly enhanced lncRNA detection, indicating that the optimized snRandom‐seq technique maintains its established gene detection advantages even when applied to small samples. Utilizing 7 puncture FFPE samples of liver metastases from 3 colorectal cancer patients pre‐ and post‐immunotherapy, the cellular developmental trajectories are reconstructed and revealed dynamic spatiotemporal heterogeneity during treatment, including insights into pseudoprogression of immunotherapy. Therefore, the optimized snRandom‐seq offers a solution for high‐throughput single‐cell RNA and non‐coding RNA analysis in minimal puncture FFPE sample.

Golgi Protein 73 (GP73) is a Golgi-resident protein that is highly expressed in primary tumor tissues. Initially identified as an oncoprotein, GP73 has been shown to promote tumor development, particularly by mediating the transport of proteins related to epithelial-mesenchymal transition (EMT), thus facilitating tumor cell EMT. Though our previous review has summarized the functional roles of GP73 in intracellular signal transduction and its various mechanisms in promoting EMT, recent studies have revealed that GP73 plays a crucial role in regulating the tumor and immune microenvironment. GP73 can modulate intracellular signaling pathways to influence cytokine and chemokine networks, resulting in inflammation caused by viral and bacterial infection or immune diseases, and leading tumor microenvironment deteriorated. Additionally, extracellular GP73 can also regulate signaling pathways of target cells by binding to their cell-surface receptors or entering the acceptor cells, thereby facilitating inflammation or promoting tumor development. In this review, we aim to summarize the findings, providing insights for future investigations on GP73 and its potential as a therapeutic target in ameliorating chronic inflammation in the immune and tumor microenvironment.

Abstract Herpes simplex virus (HSV), an epidemic human pathogen threatening global public health, gains notoriety for its complex pathogenesis that encompasses lytic infection of mucosal cells, latent infection within neurons, and periodic reactivation. This intricate interplay, coupled with HSV's sophisticated immune evasion strategies, gives rise to various diseases, including genital lesions, neonatal encephalitis, and cancer. Despite more than 70 years of relentless research, an effective preventive or therapeutic vaccine against HSV has yet to emerge, primarily due to the limited understanding of virus-host interactions, which in turn impedes the identification of effective vaccine targets. However, HSV's unique pathological features, including its substantial genetic load capacity, high replicability, transmissibility, and neurotropism, render it a promising candidate for various applications, spanning oncolytic virotherapy, gene and immune therapies, and even as an imaging tracer in neuroscience. In this review, we comprehensively update recent breakthroughs in HSV pathogenesis and immune evasion, critically summarize the progress made in vaccine candidate development, and discuss the multifaceted applications of HSV as a biological tool. Importantly, we highlight both success and challenges, emphasizing the critical need for intensified research into HSV, with the aim of providing deeper insights that can not only advance HSV treatment strategies but also broaden its application horizons.

Abstract Background Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Abstract Cigarette smoke (CS) exposure is known to cause injury to respiratory tract epithelial cells and is a contributing factor in the development of chronic obstructive pulmonary disease and lung cancer. Electronic cigarettes (e-cigarettes) are gaining popularity as a potential substitute for conventional cigarettes due to their potential for aiding smoking cessation. However, the safety of e-cigarettes remains uncertain, and scientific evidence on this topic is still limited. In this study, we aimed to investigate the effects of CS and e-cigarette smoke (ECS) of different flavors on human lung bronchial epithelial cells. Real-time smoke exposure was carried out using an air–liquid interface system, and cell viability was assessed. RNA-Seq transcriptome analysis was performed to compare the differences between CS and ECS. The transcriptome analysis revealed a significantly higher number of differentially expressed genes in CS than in ECS. Moreover, the impact of mint-flavored e-cigarettes on cells was found to be greater than that of tobacco-flavored e-cigarettes, as evidenced by the greater number of differentially expressed genes. These findings provide a reference for future safety research on traditional cigarettes and e-cigarettes, particularly those of different flavors. The use of omics-scale methodologies has improved our ability to understand the biological effects of CS and ECS on human respiratory tract epithelial cells, which can aid in the development of novel approaches for smoking cessation and lung disease prevention.

The study of non-axisymmetric fuel dispersal and detonation can provide reference for the prevention of industrial cloud explosion accidents and the design of fuel air explosive (FAE). The concentration and detonation fields of 85 kg cylindrical and fan-shaped fuel are investigated by experiments and numerical simulations. A dynamic model of the whole process for fuel dispersal and detonation is built. The concentration distribution of fuel is used as the initial condition to calculate the detonation stage, thus solving the initial value problem of detonation field. The phase and component changes of fuel cloud at different locations are compared. The fuel cloud is divided into directions of 0°, 90°, 135° and 180°. The results show that the maximum cloud radius is 20.94 m in 135° and the minimum is 12.04 m in 0°. The diameter of the detonation fireball is 53.6 m, and the peak temperature is 3455 K. The highest peak overpressure is 3.44 MPa in 0° and the lowest is 2.97 MPa in 135°. The proportion of liquid phase in 0° is 22.90%, and the fuel loss is 11.8% and 9% higher than that in 135° and cylindrical charge, respectively. The stable propagation distance of blast wave in 135° is 42.50% longer than 0° and 28.37% longer than cylindrical charge.

Abstract Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.

Golgi protein 73 (GP73), a resident protein of the Golgi apparatus, is notably elevated in hepatocellular carcinoma (HCC). While its critical role in remodeling the tumor microenvironment (TME) is recognized, the intricate mechanisms are not fully understood. This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2 (PHD-2) in a competitive manner, thereby impeding the hydroxylation of hypoxia-induced factor-1α (HIF-1α). The effect above promotes the production and secretion of vascular endothelial growth factor A (VEGFA). Moreover, exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells (HUVECs) and competitively interact with HECTD1, an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2 (GRB2). This interaction stabilizes GRB2, thereby activating the Ras–mitogen-activated protein kinase (MAPK) signaling pathway. Consequently, escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells, fostering angiogenesis in the TME. Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.

Abstract Two-dimensional (2D) nanomaterials, such as graphene, black phosphorus and transition metal dichalcogenides, have attracted increasing attention in biology and biomedicine. Their high mechanical stiffness, excellent electrical conductivity, optical transparency, and biocompatibility have led to rapid advances. Neuroscience is a complex field with many challenges, such as nervous system is difficult to repair and regenerate, as well as the early diagnosis and treatment of neurological diseases are also challenged. This review mainly focuses on the application of 2D nanomaterials in neuroscience. Firstly, we introduced various types of 2D nanomaterials. Secondly, due to the repairment and regeneration of nerve is an important problem in the field of neuroscience, we summarized the studies of 2D nanomaterials applied in neural repairment and regeneration based on their unique physicochemical properties and excellent biocompatibility. We also discussed the potential of 2D nanomaterial-based synaptic devices to mimic connections among neurons in the human brain due to their low-power switching capabilities and high mobility of charge carriers. In addition, we also reviewed the potential clinical application of various 2D nanomaterials in diagnosing and treating neurodegenerative diseases, neurological system disorders, as well as glioma. Finally, we discussed the challenge and future directions of 2D nanomaterials in neuroscience. Graphical Abstract

Disclosed herein is a novel Rh/Ag co-catalyzed SNH directed C–H activation and C–H/N–H bond functionalization protocol of free NH-sulfoximines with hypervalent iodonium ylides. With the aid of AgOTf, these C–H functionalization/cyclization sequences could be achieved at room temperature conditions. The reaction employed EtOH as a “green” solvent and low catalyst loading was required under an oxygen/water-insensitive condition. Under this mild protocol, a wide range of polyheterocyclic sulfoximines bearing fused saturated carbo(hetero)cycles are readily prepared, even toward a complex pharmaceutical Folliculin analog.

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.

Abstract Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3–C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 μg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice. Graphical Abstract

Objective: This study describes the state of the art in the field of cancer-related cognitive impairment (CRCI) to facilitate research opportunities in future CRCI research. Methods: Five databases were searched: PubMed, Web of Science, Cochrane Library, Cumulative Index to Nursing and Allied Health (CINAHL), and PsycINFO, from inception to August 20, 2022. Python, VOSviewer, and CiteSpace software were used for data preprocessing and analysis. Results: The published articles were predominantly from the United States, followed by China and Canada. Breast cancer and brain tumors were the dominant cancer types. The study population consisted mainly of adult cancer survivors. Prospective and multicenter studies were the most frequently used study designs. Keyword co-occurrence and mutation analysis indicated major themes: drug therapy was the most common treatment cluster, and adverse effects were another major cluster. The etiology of CRCI was a research hotspot and included the exploration of chemotherapy-associated and psychosocial factors by using measurement tools, such as neuropsychological tests and treatment outcomes. Conclusions: This study’s findings highlight CRCI as a major research area, on the basis of the significantly increasing number of annual publications. Keyword co-occurrence analysis provided a quantitative visualization of the current research status for CRCI, but this method cannot provide in-depth qualitative insights explaining the potential emerging trends in this field.

Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. Finally, we conclude with our perspectives on the future development in this field.

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

ObjectiveAltered expression patterns of Na+-K+-2Cl– (NKCC1) and K+-Cl– (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD).Materials and methodsWe sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting.ResultsResults revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group.ConclusionOur results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs).

Abstract Microbes with complex functions have been found to be a potential component in tumor microenvironments. Due to their low biomass and other obstacles, intratumor microbiota is poorly understood. Mucosal sites and normal adjacent tissues are important sources of intratumor microbiota, while hematogenous spread also leads to the invasion of microbes. Intratumor microbiota affects the progression of tumors through several mechanisms, such as DNA damage, activation of oncogenic pathways, induction of immunosuppression, and metabolization of drugs. Notably, in different types of tumors, the composition and abundance of intratumor microbiota are highly heterogeneous and may play different roles in the progression of tumors. Because of the concern in this field, several techniques such as omics and immunological methods have been used to study intratumor microbiota. Here, recent progress in this field is reviewed, including the potential sources of intratumor microbiota, their functions and related mechanisms, and their heterogeneity. Techniques that can be used to study intratumor microbiota are also discussed. Moreover, research is summarized into the development of strategies that can be used in antitumor treatment and prospects for possible future research in this field.

Abstract SUMOylation is a ubiquitination‐like post‐translational modification that plays an essential role in the regulation of protein function. Recent studies have shown that proteins from both RNA and DNA virus families can be modified by SUMO conjugation, which facilitates viral replication. Viruses can manipulate the entire process of SUMOylation through interplay with the SUMO pathway. By contrast, SUMOylation can eliminate viral infection by regulating host antiviral immune components. A deeper understanding of how SUMOylation regulates viral proteins and cellular antiviral components is necessary for the development of effective antiviral therapies. In the present review, the regulatory mechanism of SUMOylation in viral replication and infection and the antiviral immune response, and the consequences of this regulation for viral replication and engagement with antiviral innate immunity are summarized. The potential therapeutic applications of SUMOylation in diseases caused by viruses are also discussed.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is characterized by demyelination, axonal injury and neurological deterioration. Few medications are available for progressive MS, which is associated with neuroinflammation confined to the CNS compartment. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in a wide range of neuroinflammatory diseases; however, the underlying molecular mechanisms of TRPM2 remain elusive. Here, we established a cuprizone model that presents hallmark MS pathologies to investigate the role of TRPM2 in progressive MS. We demonstrated that genetic deletion of TRPM2 yields protection from the cuprizone-induced demyelination, synapse loss, microglial activation, NLRP3 inflammasome activation and proinflammatory cytokines production and ultimately leads to an improvement in cognitive decline. Furthermore, we showed that the pharmacological inhibition of NLRP3 ameliorated the demyelination, neuroinflammation and cognitive impairment in the model with no additive effects on the TRPM2 KO mice. Taken together, these results indicated that TRPM2 plays important roles in regulating neuroinflammation in progressive MS via NLRP3 inflammasome, and the results shed light on TRPM2's potential role as a therapeutic target for MS.

Abstract In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti‐tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor‐infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti‐tumor immune response to certain groups of patients. Herein, the recent research progress on tumor‐infiltrating B cells and T cells, including CD8+ T cells, CD4+ T cells, and exhausted T cells and their role in anti‐tumor immunity, is summarized. Moreover, several anti‐tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment.

The interferon-stimulating gene 15 (ISG15) protein is a ubiquitin-like protein induced by interferons or pathogens. ISG15 can exist in free form or covalently bind to the target protein through an enzymatic cascade reaction, which is called ISGylation. ISGylation has been found to play an important role in the innate immune responses induced by type I interferon, and is, thus, critical for the defense of host cells against RNA, DNA, and retroviruses. Through covalent binding with the host and viral target proteins, ISG15 inhibits the release of viral particles, hinder viral replication, and regulates the incubation period of viruses, thereby exerting strong antiviral effects. The SARS-CoV-2 papain-like protease, a virus-encoded deubiquitinating enzyme, has demonstrated activity on both ubiquitin and ISG15 chain conjugations, thus playing a suppressive role against the host antiviral innate immune response. Here we review the recent research progress in understanding ISG15-type ubiquitin-like modifications, with an emphasis on the underlying molecular mechanisms. We provide comprehensive references for further studies on the role of ISG15 in antiviral immunity, which may enable development of new antiviral drugs.

This document provides brief biographies of three researchers in the field of epilepsy. Zhe Hu is a postgraduate student at the National Clinical Research Center for Child Health, Children¿s Hospital, Zhejiang University, School of Medicine, with research interests in neurocircuitry alterations in epilepsy. Shangbin Chen is an associate professor at Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, specializing in quantitative physiology and computational neuroscience. Yicheng Xie is a principal investigator at the National Clinical Research Center for Child Health, Children¿s Hospital, Zhejiang University, School of Medicine, focusing on the immunoinflammatory and neuron-circuit mechanisms of epilepsy. The biographies of the other authors are not provided. [Extracted from the article]

Nischarin is a cytoplasmic protein expressed in various organs that plays an inhibitory role in cell migration and invasion and the carcinogenesis of breast cancer cells. We previously reported that Nischarin is highly expressed in neuronal cell lines and is differentially expressed in the brain tissue of adult rats. However, the physiological function of Nischarin in neural cells remains unknown. Here, we show that Nischarin is expressed in rat primary cortical neurons but not in astrocytes. Nischarin is localized around the nucleus and dendrites. Using shRNA to knockdown the expression of endogenous Nischarin significantly increases the percentage of neurite-bearing cells, remarkably increases neurite length, and accelerates neurite extension in neuronal cells. Silencing Nischarin expression also promotes dendrite elongation in rat cortical neurons where Nischarin interacts with p21-activated kinase 1/2 (PAK1/2) and negatively regulates phosphorylation of both PAK1 and PAK2. The stimulation of neurite growth observed in cells with decreased levels of Nischarin is partially abolished by IPA3-mediated inhibition of PAK1 activity. Our findings indicate that endogenous Nischarin inhibits neurite outgrowth by blocking PAK1 activation in neurons.

Objective: Altered expression patterns of NaC-KC-2Cl􀀀 (NKCC1) and KC- Cl􀀀 (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on g- aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). Materials and methods: We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the nonseizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. Results: Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non- SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. Conclusion: Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs). [ABSTRACT FROM AUTHOR]

Posttraumatic epilepsy is a major source of disability following traumatic brain injury (TBI) and a common cause of medically-intractable epilepsy. Previous attempts to prevent the development of posttraumatic epilepsy with treatments administered immediately following TBI have failed. Recently, the mammalian target of rapamycin complex 1 (mTORC1) pathway has been implicated in mechanisms of epileptogenesis and the mTORC1 inhibitor, rapamycin, has been proposed to have antiepileptogenic effects in preventing some types of epilepsy. In this study, we have tested the hypothesis that rapamycin has antiepileptogenic actions in preventing the development of posttraumatic epilepsy in an animal model of TBI. A detailed characterization of posttraumatic epilepsy in the mouse controlled cortical impact model was first performed using continuous video-EEG monitoring for 16 weeks following TBI. Controlled cortical impact injury caused immediate hyperactivation of the mTORC1 pathway lasting at least one week, which was reversed by rapamycin treatment. Rapamycin decreased neuronal degeneration and mossy fiber sprouting, although the effect on mossy fiber sprouting was reversible after stopping rapamycin and did not directly correlate with inhibition of epileptogenesis. Most posttraumatic seizures occurred greater than 10 weeks after TBI, and rapamycin treatment for one month after TBI decreased the seizure frequency and rate of developing posttraumatic epilepsy during the entire 16 week monitoring session. These results suggest that rapamycin may represent a rational treatment for preventing posttraumatic epilepsy in patients with TBI.