Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice.

BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.

Interspecific barrier effect driven by heavy metals makes soil bacterial functional assembly more stochastic.

Residual heavy metals in soils will destroy microbial community stability and influence its aggregation. However, exploring microbial ecology under heavy-metal stress still requires a conjoint analysis of bacterial interspecies communication and the community diversity maintenance mechanism. In this study, soil samples were collected from a heavy-metal-contaminated site in China to investigate the ecological response of indigenous microbial communities through high-throughput sequencing. Results showed that bacterial taxa and functions generated unusual decoupling phenomena. There were no significant differences in the diversity of species with the increase in concentration of heavy metals (Hg, Se, and Cr), but the functional diversity was lost. Also, the average niche breadth of bacterial species increased from 1.70 to 2.28, but community stability declined and the species assembly was always a deterministic process (NST <0.5). After the bacterial functional assembly changed from a stochastic process to a deterministic process (NST <0.5), it was transformed into a stochastic process (NST >0.5) again under the stress of high-concentration heavy metals, indicating that the collective stress resistance of bacterial communities changed from positive mutation into passive functional propagation. The research results can provide new insight into understanding the adaptive evolution of communities and ecosystem restoration under the stress of soil heavy metals.

Effects of Bone Marrow Mesenchymal Stem Cell-Derived Exosomes in Central Nervous System Diseases.

Central nervous system (CNS) diseases are one of the diseases that threaten human health. The delivery of drugs targeting the CNS has always been a significant challenge; the blood-brain barrier (BBB) is the main obstacle that must be overcome. The rise of bone marrow mesenchymal stem cell (BMSC) therapy has brought hope for the treatment of CNS diseases. However, the problems of low homing rate, susceptibility differentiation into astrocytes, immune rejection, and formation of iatrogenic tumors of transplanted BMSCs limit their clinical application. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have become a hot research topic in the treatment of CNS diseases in recent years because of their excellent histocompatibility, low immunogenicity, ease of crossing the BBB, and their ability to serve as natural carriers for treatment. This article reviews the mechanisms of BMSC-Exos in CNS diseases and provides direction for further research.

Tumor-derived extracellular vesicles: how they mediate glioma immunosuppression.

Gliomas, the most common malignant brain tumor, present a grim prognosis despite available treatments such as surgical resection, temozolomide (TMZ) therapy, and radiation therapy. This is due to their aggressive growth, high level of immunosuppression, and the blood-brain barrier (BBB), which obstruct the effective exchange of therapeutic drugs. Gliomas can significantly affect differentiation and function of immune cells by releasing extracellular vesicles (EVs), resulting in a systemic immunosuppressive state and a highly immunosuppressive microenvironment. In the tumor immune microenvironment (TIME), the primary immune cells are regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). In particular, glioma-associated TAMs are chiefly composed of monocyte-derived macrophages and brain-resident microglia. These cells partially exhibit characteristics of a pro-tumorigenic, anti-inflammatory M2-type. Glioma-derived EVs can hijack TAMs to differentiate into tumor-supporting phenotypes or directly affect the maturation of peripheral blood monocytes (PBMCs) and promote the activation of MDSCs. In addition, EVs impair the ability of dendritic cells (DCs) to process antigens, subsequently hindering the activation of lymphocytes. EVs also impact the proliferation, differentiation, and activation of lymphocytes. This is primarily evident in the overall reduction of CD4 + helper T cells and CD8 + T cells, coupled with a relative increase in Tregs, which possess immunosuppressive characteristics. This study investigates thoroughly how tumor-derived EVs impair the function of immune cells and enhance immunosuppression in gliomas, shedding light on their potential implications for immunotherapy strategies in glioma treatment.

Research progress on mechanisms of ischemic stroke: Regulatory pathways involving Microglia.

Microglia, as the intrinsic immune cells in the brain, are activated following ischemic stroke. Activated microglia participate in the pathological processes after stroke through polarization, autophagy, phagocytosis, pyroptosis, ferroptosis, apoptosis, and necrosis, thereby influencing the injury and repair following stroke. It has been established that polarized M1 and M2 microglia exhibit pro-inflammatory and anti-inflammatory effects, respectively. Autophagy and phagocytosis in microglia following ischemia are dynamic processes, where moderate levels promote cell survival, while excessive responses may exacerbate neurofunctional deficits following stroke. Additionally, pyroptosis and ferroptosis in microglia after ischemic stroke contribute to the release of harmful cytokines, further aggravating the damage to brain tissue due to ischemia. This article discusses the different functional states of microglia in ischemic stroke research, highlighting current research trends and gaps, and provides insights and guidance for further study of ischemic stroke.

Multilayer Semantic Features Adaptive Distillation for Object Detectors.

Knowledge distillation (KD) is a well-established technique for compressing neural networks and has gained increasing attention in object detection tasks. However, typical object detection distillation methods use fixed-level semantic features for distillation, which might not be best for all training stages and samples. In this paper, a multilayer semantic feature adaptive distillation (MSFAD) method is proposed that uses a routing network composed of a teacher and a student detector, along with an agent network for decision making. Specifically, the inputs to the proxy network consist of the features output by the neck structures of the teacher and student detectors, and the output is a decision on which features to choose for distillation. The MSFAD method improves the distillation training process by enabling the student detector to automatically select valuable semantic-level features from the teacher detector. Experimental results demonstrated that the proposed method increased the mAP50 of YOLOv5s by 3.4% and the mAP50-90 by 3.3%. Additionally, YOLOv5n with only 1.9 M parameters achieved detection performance comparable to that of YOLOv5s.

Mechanism of ligusticum cycloprolactam against neuroinflammation based on network pharmacology and experimental verification.

Ligustilide, a natural phthalide mainly derived from chuanxiong rhizomes and Angelica Sinensis roots, possesses anti-inflammatory activity, particularly in the context of the nervous system. However, its application is limited because of its unstable chemical properties. To overcome this limitation, ligusticum cycloprolactam (LIGc) was synthesized through structural modification of ligustilide. In this study, we combined network pharmacological methods with experimental verification to investigate the anti-neuroinflammatory effects and mechanisms of ligustilide and LIGc. Based on our network pharmacology analysis, we identified four key targets of ligustilide involved in exerting an anti-inflammatory effect, with the nuclear factor (NF)-κB signal pathway suggested as the main signalling pathway. To verify these results, we examined the expression of inflammatory cytokines and inflammation-related proteins, analysed the phosphorylation level of NF-κB, inhibitor of κBα (IκBα) and inhibitor of κB kinase α and ß (IKKα+ß), and evaluated the effect of BV2 cell-conditioned medium on HT22 cells in vitro. Our results, demonstrate for the first time that LIGc can downregulate the activation of the NF-κB signal pathway in BV2 cells induced by lipopolysaccharide, suppress the production of inflammatory cytokines and reduce nerve injury in HT22 cells mediated by BV2 cells. These findings suggest that LIGc inhibits the neuroinflammatory response mediated by BV2 cells, providing strong scientific support for the development of anti-inflammatory drugs based on natural ligustilide or its derivatives. However, there are some limitations to our current study. In the future, further experiments using in vivo models may provide additional evidence to support our findings.

Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke.

Ischemic stroke (IS) is characterized by high incidence, high recurrence, and high mortality and places a heavy burden on society and families. The pathological mechanisms of IS are complex, among which secondary neurological impairment mediated by neuroinflammation is considered to be the main factor in cerebral ischemic injury. At present, there is still a lack of specific therapies to treat neuroinflammation. The tumor suppressor protein p53 has long been regarded as a key substance in the regulation of the cell cycle and apoptosis in the past. Recently, studies have found that p53 also plays an important role in neuroinflammatory diseases, such as IS. Therefore, p53 may be a crucial target for the regulation of the neuroinflammatory response. Here, we provide a comprehensive review of the potential of targeting p53 in the treatment of neuroinflammation after IS. We describe the function of p53, the major immune cells involved in neuroinflammation, and the role of p53 in inflammatory responses mediated by these cells. Finally, we summarize the therapeutic strategies of targeting p53 in regulating the neuroinflammatory response after IS to provide new directions and ideas for the treatment of ischemic brain injury.

Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppression Mediated Through the PI3K/Akt/mTOR Axis.

Irisin is a muscle-derived hormone that promotes the survival of motor neurons and enhances muscle size following injury. In this study, we investigated the beneficial effects and mechanism(s) of action of irisin in response to cerebral ischemia-reperfusion injury (CIRI). Right-middle cerebral artery occlusion (MCAO) and hypoxia/reoxygenation (H/R) models were generated in C57BL/6 J mice. Mouse neuronal cell lines (NSC-34) were used to confirm the molecular mechanisms of the protection afforded by irisin in response to CIRI. We found that irisin (250 µg/kg) improved cerebral function and reduced the cerebral infarct volume following CIRI. Irisin also protected neuronal cells against ischemia-reperfusion (I/R) induced apoptosis, assessed via TUNEL, and cleaved Caspase-3 staining. Western blotting of neuronal tissue from irisin treated I/R mice showed lower expression of pro-apoptotic Bax and caspase-9 (P < 0.001 and P < 0.01) and increased levels of the pro-survival protein Bcl-2 (P < 0.01 & P < 0.001 vs. I/R). Irisin also reduced the levels of reactive oxygen species (ROS) characterized through malondialdehyde (MDA) assays. Irisin was found to maintain mitochondrial homeostasis through the suppression of mitochondrial fission-linked dynamin-related protein 1 in CIRI mice (P < 0.01 and P < 0.05 v. I/R cohort). Moreover, mitochondrial fusion-related protein (Mfn2) and Opa1 expression were rescued following irisin treatment (P < 0.001 and P < 0.01 v. I/R cohort). Cell-based assays showed that irisin activates PI3K/AKT/mTOR signaling in the neurons of CIRI mice. Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor. Collectively, these data highlight the ability of irisin to alleviate CIRI in vivo and in vitro. The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI.

Graph-Based Self-Training for Semi-Supervised Deep Similarity Learning.

Semi-supervised learning is a learning pattern that can utilize labeled data and unlabeled data to train deep neural networks. In semi-supervised learning methods, self-training-based methods do not depend on a data augmentation strategy and have better generalization ability. However, their performance is limited by the accuracy of predicted pseudo-labels. In this paper, we propose to reduce the noise in the pseudo-labels from two aspects: the accuracy of predictions and the confidence of the predictions. For the first aspect, we propose a similarity graph structure learning (SGSL) model that considers the correlation between unlabeled and labeled samples, which facilitates the learning of more discriminative features and, thus, obtains more accurate predictions. For the second aspect, we propose an uncertainty-based graph convolutional network (UGCN), which can aggregate similar features based on the learned graph structure in the training phase, making the features more discriminative. It can also output the uncertainty of predictions in the pseudo-label generation phase, generating pseudo-labels only for unlabeled samples with low uncertainty; thus, reducing the noise in the pseudo-labels. Further, a positive and negative self-training framework is proposed, which combines the proposed SGSL model and UGCN into the self-training framework for end-to-end training. In addition, in order to introduce more supervised signals in the self-training process, negative pseudo-labels are generated for unlabeled samples with low prediction confidence, and then the positive and negative pseudo-labeled samples are trained together with a small number of labeled samples to improve the performance of semi-supervised learning. The code is available upon request.

A Critical Review on Artificial Intelligence-Based Microplastics Imaging Technology: Recent Advances, Hot-Spots and Challenges.

Due to the rapid artificial intelligence technology progress and innovation in various fields, this research aims to use science mapping tools to comprehensively and objectively analyze recent advances, hot-spots, and challenges in artificial intelligence-based microplastic-imaging field from the Web of Science (2019-2022). By text mining and visualization in the scientific literature we emphasized some opportunities to bring forward further explication and analysis by (i) exploring efficient and low-cost automatic quantification methods in the appearance properties of microplastics, such as shape, size, volume, and topology, (ii) investigating microplastics water-soluble synthetic polymers and interaction with other soil and water ecology environments via artificial intelligence technologies, (iii) advancing efficient artificial intelligence algorithms and models, even including intelligent robot technology, (iv) seeking to create and share robust data sets, such as spectral libraries and toxicity database and co-operation mechanism, (v) optimizing the existing deep learning models based on the readily available data set to balance the related algorithm performance and interpretability, (vi) facilitating Unmanned Aerial Vehicle technology coupled with artificial intelligence technologies and data sets in the mass quantities of microplastics. Our major findings were that the research of artificial intelligence methods to revolutionize environmental science was progressing toward multiple cross-cutting areas, dramatically increasing aspects of the ecology of plastisphere, microplastics toxicity, rapid identification, and volume assessment of microplastics. The above findings can not only determine the characteristics and track of scientific development, but also help to find suitable research opportunities to carry out more in-depth research with many problems remaining.

Molecular Mechanism of the Protective Effects of M2 Microglia on Neurons: A Review Focused on Exosomes and Secretory Proteins.

Microglia, as innate immune cells in the brain, closely monitor changes in the internal environment and participate in the maintenance of homeostasis in the central nervous system (CNS). Microglia can be polarized to the M1 or M2 phenotype in response to various stimuli in vivo or in vitro, affecting the functions of peripheral neurons. M2 microglia have attracted increasing attention in recent years owing to their beneficial effects on various diseases and injuries of the CNS, such as traumatic brain injury, stroke, Alzheimer's disease and multiple sclerosis. They exert neuroprotective effects by various mechanisms, e.g., suppressing inflammation, promoting the degradation of misfolded and aggregated proteins, promoting neurite growth, enhancing neurogenesis, inhibiting autophagy and apoptosis, promoting myelination, maintaining blood-brain barrier integrity, and enhancing phagocytic activity.This review summarizes the molecular mechanisms by which M2 microglia exert protective effects on neurons and provides a reference for the selection of therapeutic targets for CNS diseases.

Rab11-mediated recycling endosome role in nervous system development and neurodegenerative diseases.

STUDY: Membrane trafficking process is significant for the complex and precise regulatory of the nervous system. Rab11, as a small GTPase of the Rab superfamily, controls endocytic vesicular trafficking to the cell surface after sorting in recycling endosome (RE), coordinating with its receptors to maintain neurological function. MATERIALS AND METHODS: This article reviewed the literature of Rab11 in nervous system. RESULTS: Rab11-positive vesicles targeted transport growth-related molecules, such as integrins, protrudin, tropomyosin receptor kinase (Trk) A/B receptor and AMPA receptor (AMPAR) to membrane surface to promote the regeneration capacity of axon and dendrites and maintain synaptic plasticity. In addition, many studies have shown that the expression of Rab11 is decreased in multiple neurodegenerative diseases, which is highly correlated with the process of production, transport and clearance of disease-related pathological proteins. And overexpression or increased activity of Rab11 can greatly improve the defect of membrane trafficking and slow down the disease process. CONCLUSION: With increasing research efforts on Rab11-dependent membrane trafficking mechanisms, a potential target for nerve regeneration and neurodegenerative diseases will be provided.

Effect of AnnexinA Group Translocated in Extracellular Vesicles on Tumorigenesis.

Annexin, a calcium-dependent phospholipid-binding protein, can affect tumor cell adhesion, proliferation, apoptosis, invasion and metastasis, as well as tumor neovascularization in different ways. Recent studies have shown that annexin exists not only as an intracellular protein in tumor cells, but also in different ways to be secret outside the cell as a "cross-talk" tool for tumor cells and tumor microenvironment, thus playing an important role in the development of tumors, such as participating in epithelial-mesenchymal transition, regulating immune cell behavior, promoting neovascularization and so on. The mechanism of annexin secretion in the form of extracellular vesicles and its specific role is still unclear. This paper summarizes the main role of annexin secreted into the extracellular space in the form of extracellular vesicles in tumorigenesis and drug resistance and analyzes its possible mechanism.

Scalp-acupuncture for patients with hemiplegic paralysis of acute ischaemic stroke: a randomized controlled clinical trial.

OBJECTIVE: To evaluate the efficacy of scalp-acupuncture on subjects with hemiplegic paralysis of acute ischaemic stroke (AIS). METHODS: One hundred and twenty patients with hemiplegic paralysis of 1 to 7 d post stroke, aged 40 to 75 years, were randomly allocated to receive either standard care (control group) or standard care plus 30 min of scalp-acupuncture applied to the bilateral anterior oblique line of the vertex-temporal (MS6) for 14 d (6 d/week) (trial group). The outcome measures included the National Institutes of Health Stroke scale (NIHSS) for neurological deficits, the Fugl-Meyer assessment (FMA) for limb impairment, and Barthel index (BI) for activities of daily living before and after intervention. The manual muscle test (MMT) was assessed at pre-intervention, at the first post-intervention immediately, and at the 14th day after intervention commencement. Measurements were recorded by a blinded investigator at different time points after initiating the intervention. RESULTS: The trial group had a greater increase in MMT (P < 0.05), FMA, and BI scores (P < 0.01), and a greater decrease in NIHSS scores (P < 0.01) from pre-intervention to post-intervention, and the control group had a greater increase in MMT scores (P < 0.05), and a greater decrease in NIHSS scores(P < 0.01) from pre-intervention to post-intervention. The improvement in MMT (P < 0.01), FMA, BI (P < 0.05), and NIHSS (P < 0.01) scores in the trial group was superior to that of the control group. Meanwhile, scalp-acupuncture intervention had an immediate effect on myodynamia of patients with hemiplegic paralysis after acute ischaemic stroke in this randomized controlled trial. CONCLUSION: The early scalp-acupuncture intervention after stroke effectively increased myodynamia of the affected limbs, improved neurological deficit degrees, and daily living ability.

Rodent models for intravascular ischemic cerebral infarction: a review of influencing factors and method optimization.

Rodent models for cerebral infarction are useful for studying human focal ischemic cerebral infarction, by simulating etiological and pathophysiological mechanisms. However, differences in the selection of anesthetic drugs, surgical methods and other factors may affect the extent to which preclinical models reflect the human condition. This review summarizes these factors. We searched pertinent literature from the MEDLINE and Web of Science databases, and reviewed differences in rodent strain, anesthesia method, sex, surgical method, timing of surgery, and factors influencing postoperative evaluation. In particular, circadian rhythm was found to have a significant impact on the outcome of cerebral infarction in rodent models. This information will enable researchers to quickly and clearly select appropriate modeling methods, acquire reliable quantitative experimental results, and obtain basic data for fundamental mechanism research.

Inhibition of microRNA-9-5p and microRNA-128-3p can inhibit ischemic stroke-related cell death in vitro and in vivo.

Ischemic stroke is the major form of stroke and is accentuated by multiple comorbidities. It has been previously shown that different microRNAs (miRNAs) regulate separate aspects of ischemic stroke. Differential miRNA expression analysis in cerebrospinal fluid of stroke patients had revealed upregulation of miR-124-3p, miR-9-3p, miR-9-5p, and miR-128-3p. However, whether the overexpression is correlative or causative was not known. Here, using an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal cell model, we saw OGD/R-induced injury was associated with significant upregulation of the aforementioned four miRNAs. Target gene prediction using in situ algorithms and gene set enrichment analysis revealed significant enrichment of FOXO and Relaxin signaling pathways and regulatory processes associated with endothelial cell migration, which are all known to associate with apoptotic pathways. In situ protein-protein interaction network analysis confirmed the findings of gene set enrichment analysis. TUNEL analysis showed that OGD/R-induced injury resulted in significant apoptosis, which was significantly inhibited in neuronal cells pretransfected with inhibitors of either miR-9-5p or miR-128-3p. Further testing in an in vivo middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke showed that inhibiting miR-9-5p or miR-128-3p significantly decreases MCAO-induced infraction volume and inhibited apoptotic response as revealed by decreased cleaved Caspase-3 protein expression in immunohistochemical analysis. Combined inhibition of miR-9-5p and miR-128-3p resulted in a synergistic decrease in cell death and infraction volume in vitro and in vivo, respectively. Cumulatively, our results provide critical knowledge about the mechanism by which elevated miR-9-5p and miR-128-3p causes brain damage in ischemic stroke and provides evidence of them being attractive therapeutic targets.

Mechanisms of Inhibition of Excessive Microglial Activation by Melatonin.

As the innate immune cells that permanently reside in the central nervous system (CNS), microglia play an increasingly important role in maintaining brain function. Normally, microglia act as resting phenotype, which can be activated by various types of stimuli and release a variety of inflammatory mediators. Melatonin is an endogenous rhythmic hormone secreted principally by the pineal gland. Increasing evidence suggests that melatonin can detoxify reactive oxygen species (ROS) and prevent microglia from over-activation. This review summarizes the mechanisms of melatonin in inhibiting excessive activation of microglia and demonstrates the feasibility of melatonin in the treatment of diseases related to microglial over-activation.

Effects of Peroxiredoxin 2 in Neurological Disorders: A Review of its Molecular Mechanisms.

Oxidative stress and neuroinflammation are closely related to the pathological processes of neurological disorders. Peroxiredoxin 2 (Prdx2) is an abundant antioxidant enzyme in the central nervous system. Prdx2 reduces the production of reactive oxygen species and participates in regulating various signaling pathways in neurons by catalyzing hydrogen peroxide (H2O2), thereby protecting neurons against oxidative stress and an inflammatory injury. However, the spillage of Prdx2, as damage-associated molecular patterns, accelerates brain damage after stroke by activating an inflammatory response. The post-translational modifications of Prdx2 also affect its enzyme activity. This review focuses on the effects of Prdx2 and its molecular mechanisms in various neurological disorders.