Reduction of excitatory synapses in the medial prefrontal cortex (mPFC) is closely associated with depression and can be mitigated by running exercise. However, precise quantitative studies focusing on subregion-specific excitatory synaptic changes under depression remain limited, and the potential involvement of microglia and astrocytes in exercise-mediated synaptic protection remains unclear. In this study, Sprague-Dawley (SD) rats were subjected to chronic unpredictable stress (CUS) followed by a 6-week treadmill running program. Behavioral assessments included the sucrose preference test and the elevated plus maze test. Nissl staining, immunogold staining, and stereological methods were employed to evaluate the volume of mPFC subregions and the number of dendritic spines in each subregion. Immunofluorescence combined with three-dimensional confocal imaging was used to evaluate microglial and astrocytic density, morphology, and synaptic contacts. Our results demonstrated that running exercise exerted significant antidepressant effects in CUS rats, as evidenced by improved anhedonia-related behaviors. Concurrently, running exercise increased the volume of the mPFC in CUS model rats, particularly in the anterior cingulate cortex (ACC) subregion, and restored the number of dendritic spines across all mPFC subregions. Additionally, running exercise reversed the CUS-induced alterations in microglial and astrocytic morphology and reduced excitatory synapse contacts on glial cells in a subregion-specific manner in the mPFC. These findings provide novel morphological evidence that running exercise protects excitatory synapses in the mPFC, potentially via modulation of glial-synapse interactions, offering insights into the cellular mechanisms underlying exercise-based antidepressant effects.

Amygdala dysfunction is implicated in stress-related affective disorders, and astrocytes are key regulators of amygdalar neuroplasticity. Here, we examined whether running exercise modulates astrocyte number, morphology, proliferation, and excitatory synaptic contacts in the basolateral amygdala (BLA) and central amygdala (CeA) in rats exposed to chronic unpredictable stress (CUS). Anhedonia-like behaviors were evaluated using the sucrose preference test, while anxiety-related behaviors were assessed using the elevated plus maze and open field tests. Unbiased stereological three-dimensional quantification was used to assess amygdalar volume and estimate astrocyte numbers in BLA and CeA, and immunofluorescence with morphological reconstruction was performed to quantify astrocytic complexity, proliferation, and astrocyte-associated PSD95+ puncta. Running exercise significantly increased sucrose preference in CUS rats, whereas elevated plus maze and open field measures were not significantly changed. CUS reduced astrocyte number and proliferation, and induced astrocytic morphological atrophy in both subregions. These alterations were reversed by running. Moreover, running increased the number of excitatory synapses contacted by astrocytes in the BLA and CeA of CUS rats. These findings suggest that running promotes astrocyte-mediated structural remodeling in amygdalar subregions, which may contribute to the regulation of anhedonia-like behavioral alterations associated with chronic stress.

Decreased hemoglobin (Hb) levels in peripheral blood may be a risk factor for Alzheimer's disease (AD). Hb-α is a monomeric form of Hb that exists in the central nervous system. Our previous RNA sequencing results revealed a decrease in the expression of the Hb-α gene in the hippocampus of AD model mice. However, the effects of Hb-α deficiency in the hippocampus on cognitive function and the underlying mechanism are unclear. Running exercise has been shown to improve cognition, but whether it can reverse the damage caused by Hb-α deficiency in the hippocampus needs to be further researched. In the present study, Mendelian randomization (MR) analyses revealed that lower levels of mean corpuscular Hb and Hemoglobin alpha 1 (HBA1) increased the risk of developing AD. When an adeno-associated virus (AAV) was used to knock down hippocampal Hb-α, the learning and memory ability of the resulting model mice decreased, similar to that of AD model mice. Moreover, the expression levels of advanced glycation end products (AGE) and their receptor (RAGE) were upregulated, microglia were activated, and the number of engulfed synapses increased, which damaged the number and structure of hippocampal synapses in the model mice. However, four weeks of voluntary wheel exercise effectively improved these conditions. In addition, we found that voluntary wheel exercise may compensate for Hb-α protein deficiency in the hippocampus by increasing the expression levels of Hb-α protein in plasma, cerebrospinal fluid, and other brain regions without altering Hb-α mRNA in the hippocampus of model mice. These results highlight the key role of Hb-α in hippocampal synaptic damage, elucidate the mechanism by which running exercise improves cognition by connecting the peripheral circulation and central nervous system through Hb-α, and provide new ideas for the diagnosis and treatment of AD.

Although the antidepressant effects of running exercise have been widely reported, further research is still needed to determine the structural bases for these effects. Astrocyte processes physically contact many synapses and directly regulate the numbers of synapses, but it remains unclear whether running exercise can modulate astrocyte morphological complexity and astrocyte-contacted synapses in the hippocampus of the mice with depressive -like behavior. Male C57BL/6 J mice underwent four weeks of running exercise after four weeks of chronic unpredictable stress (CUS). The sucrose preference test (SPT), tail suspension test (TST) and forced swim test (FST) were used to assess anhedonia in mice. Western blotting was used to measure the expression of astrocyte- and synapse -related proteins. Immunofluorescence and 3D reconstruction were used to quantify the density and morphology of astrocytes, and astrocyte-contacted synapses in each hippocampal subregion. Four weeks of running exercise alleviated depressive -like symptoms in mice. The expression of astrocyte- and synapserelated proteins in the hippocampus; astrocyte process lengths, process numbers, and dendritic arborization; and the number of astrocyte-contacted PSD95 positive synapses in the CA2 -3 and DG regions were significantly decreased in the mice with depressive -like behavior, and running exercise successfully reserved these changes. Running exercise improved the decreases in astrocyte morphological complexity and astrocyte-contacted PSD95 positive synapses in the CA2 -3 and DG regions of the mice with depressive -like behavior, suggesting that the physical interactions between astrocytes and synapses can be increased by running exercise, which might be an important structural basis for the antidepressant effects of running exercise.

In this study, the zeolitic imidazolate framework (ZIF-8) and glutathione silver nanoclusters (GSH-AgNCs) were assembled by the in situ synthesis method to form nanomaterials (GSH-AgNCs-ZIF-8). Meanwhile, a luminescent functional assembly of nanocomposites with adjustable potentials and luminescence enhancement was gained through innovative mixing of the luminophores tetracarboxyphenyl zinc porphyrin (TCPP-Zn) and GSH-AgNCs-ZIF-8. Composition and morphology of the materials were studied by electrochemistry and spectroscopy techniques. The blended material was used as high-efficiency luminophore to build the electrochemiluminescence (ECL) sensing system for iodide ion (I-) detection whose ECL mechanism has also been studied in depth. Under optimization conditions, ECL sensors showed excellent responses to I- in the linear range from 10 pM to 10 mu M. This detection method showed selectivity, stability, and sensitivity. Moreover, it achieved relatively satisfying results to iodide ion detection in cola, milk, nori, and urine samples. This research not only develops and applies functional nanomaterials, but also establishes an ECL sensor system and provides ideas for the detection of micromolecules in food and clinical testing.

Background Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy. Methods Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models. Results The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases. Conclusion PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.

Previous postmortem and animal studies have shown decreases in the prefrontal cortex (PFC) volume and the number of glial cells in the PFC of depression. Running exercise has been shown to alleviate depressive symptoms. However, the effects of running exercise on the medial prefrontal cortex (mPFC) volume and oligodendrocytes in the mPFC of depressed patients and animals have not been investigated. To address these issues, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks, followed by treadmill running for 6 weeks. Then, the mPFC volume and the mPFC oligodendrocytes were investigated using stereology, immunohistochemistry, immunofluorescence and western blotting. Using a CUS paradigm that allowed for the analysis of anhedonia, we found that running exercise alleviated the deficits in sucrose preference, as well as the decrease in the mPFC volume. Meanwhile, we found that running exercise significantly increased the number of CNPase + oligodendrocytes and Olig2 + oligodendrocytes, reduced the ratio between Olig2 + /NG2 + oligodendrocytes and Olig2 + oligodendrocytes and increased myelin basic protein (MBP), CNPase and Olig2 protein expression in the mPFC of the CUS rat model. However, running exercise did not change NG2 + oligodendrocyte number in the mPFC in these rats. These results indicated that running exercise promoted the differentiation of oligodendrocytes and myelin-forming ability in the mPFC in the context of depression. These findings suggest that the beneficial effects of running exercise on mPFC volume and oligodendrocytes in mPFC might be an important structural basis for the antidepressant effects of running exercise.

BACKGROUND:N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear.METHODS:Firstly, expression of GluN3A was examined in a mouse model of depression induced by chronic restraint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting.RESULTS:GluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression.LIMITATIONS:The mechanism underlying GluN3A involvement in depression is not fully determined.CONCLUSIONS:Our data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs.

M2-like tumor-associated macrophages (TAMs) typically exhibit numerous tumor-promoting properties. Reducing the abundance of M2-like TAMs would shed light on the relief of immunosuppressive tumor microenvironment (TME), activation of the host immune system, infiltration of CD8+ T cells into the TME and restoring the function of the infiltrating T cells, which collectively inhibits tumor growth. Therefore, targeted depletion of M2-like TAMs can be a promising immunotherapy approach. In this study, we ra-tionally constructed an M2-like TAMs-targeted nanoliposome, which encapsulates zoledronic acid (ZA) in the core, loads hematoporphyrin monomethyl ether (HMME, a typical sonosensitizer) in the lipid bi-layer, and modifies M2pep peptide (the targeting unit) on the surface (designated as M-H@lip-ZA). Our aim is to validate the effectiveness of M-H@lip-ZA nanoliposomes to remodel TME via targeted depletion of M2-like TAMs for cancer immunotherapy. Through the M2pep peptide, M-H@lip-ZA can be efficiently delivered to M2-like TAMs. In the meantime, reactive oxygen species (ROS) resulting from sonodynamic therapy (SDT), together with inner ZA that shows high affinity and cytotoxicity to TAMs, can effectively deplete M2-like TAMs and remodel TME (normalize tumor vasculatures, strengthen intertumoral perfu-sion, ease tumor hypoxia, increase immune-promoting cytokines and decrease immunosuppressive cy-tokines). The tumor growth can be effectively inhibited. This work proposed a new paradigm for cancer immunotherapy via targeted depletion of M2-like TAMs.Statement of Significance center dot M2-like TAMs-targeted nanoliposome (M-H@lip-ZA) was designed and prepared.center dot Sonodynamic therapy (SDT), together with zoledronic acid (ZA) that shows high affinity and cy-totoxicity to tumor-associated macrophages (TAMs), can effectively deplete M2-like TAMs. Subsequently, immune-promoting tumor microenvironment (TME) can be formed, which includes normalized tumor vasculatures, enhanced intertumoral perfusion, relieved tumor hypoxia, increased immune-promoting cy-tokines, and decreased immunosuppressive cytokines.center dot The targeted depletion of M2-like TAMs is a promising cancer immunotherapy approach.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Running exercise has been shown to alleviate depressive symptoms, but the mechanism of its antidepressant effect is still unclear. Astrocytes are the predominant cell type in the brain and perform key functions vital to central nervous system (CNS) physiology. Mounting evidence suggests that changes in astrocyte number in the hippocampus are closely associated with depression. However, the effects of running exercise on astrocytes in the hippocampus of depression have not been investigated. Here, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks followed by treadmill running for 6 weeks. The sucrose preference test (SPT) was used to assess anhedonia of rats. Then, immunohistochemistry and modern stereological methods were used to precisely quantify the total number of glial fibrillary acidic protein (GFAP)+ astrocytes in each hippocampal subregion, and immunofluorescence was used to quantify the density of bromodeoxyuridine (BrdU)+ and GFAP+ cells in each hippocampal subregion. We found that running exercise alleviated CUS-induced deficit in sucrose preference and hippocampal volume decline, and that CUS intervention significantly reduced the number of GFAP+ cells and the density of BrdU+/GFAP+ cells in the hippocampal CA1 region and dentate gyrus (DG), while 6 weeks of running exercise reversed these decreases. These results further confirmed that running exercise alleviates depressive symptoms and protects hippocampal astrocytes in depressed rats. These findings suggested that the positive effects of running exercise on astrocytes and the generation of new astrocytes in the hippocampus might be important structural bases for the antidepressant effects of running exercise.

Depression, a common and important cause of morbidity and mortality worldwide, is commonly treated with antidepressants, electric shock and psychotherapy. Recently, increasing evidence has shown that exercise can effectively alleviate depression. To determine the difference in efficacy between exercise and the classic antidepressant fluoxetine in treating depression, we established four groups: the Control, chronic unpredictable stress (CUS/STD), running (CUS/RUN) and fluoxetine (CUS/FLX) groups. The sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), immunohistochemistry, immunofluorescence and stereological analyses were used to clarify the difference in therapeutic efficacy and mechanism between exercise and fluoxetine in the treatment of depression. In the seventh week, the sucrose preference of the CUS/RUN group was significantly higher than that of the CUS/STD group, while the sucrose preference of the CUS/FLX group did not differ from that of the CUS/STD group until the eighth week. Exercise reduced the immobility time in the FST and TST, while fluoxetine only reduced immobility time in the TST. Hippocampal structure analysis showed that the CUS/STD group exhibited an increase in immature neurons and a decrease in mature neurons. Exercise reduced the number of immature neurons and increased the number of mature neurons, but no increase in the number of mature neurons was observed after fluoxetine treatment. In addition, both running and fluoxetine reversed the decrease in the number of MAP2+ dendrites in depressed mice. Exercise increased the number of spinophilin-positive (Sp+) dendritic spines in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, whereas fluoxetine only increased the number of SP+ spines in the DG. In summary, exercise promoted newborn neuron maturation in the DG and regulated neuronal plasticity in three hippocampal subregions, which might explain why running exerts earlier and more comprehensive antidepressant effects than fluoxetine.

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.

Neuroinflammation can cause cognitive deficits, and preexisting neuroinflammation is observed frequently in the clinic after trauma, surgery, and infection. Patients with preexisting neuroinflammation often need further medical treatment under general anesthesia. However, the effects of postconditioning with general anesthetics on preexisting neuroinflammation have not been determined. In this study, adult rats were posttreated with sevoflurane or propofol after intracerebroventricular administration of lipopolysaccharide. The effects of sevoflurane or propofol postconditioning on neuroinflammation-induced recognition memory deficits were detected. Our results found that postconditioning with sevoflurane but not propofol reversed the selective spatial recognition memory impairment induced by neuroinflammation, and these differential effects did not appear to be associated with the similar anti-neuroinflammatory responses of general anesthetics. However, postconditioning with propofol induced a selective long-lasting upregulation of extrasynaptic NR2B-containing N-methyl-D-aspartate receptors in the dorsal hippocampus, which downregulated the cAMP response element-binding signaling pathway and impaired spatial recognition memory. Additionally, the NR2B antagonists memantine and Ro25-6981 reversed this neurotoxicity induced by propofol postconditioning. Taken together, these results indicate that under preexisting neuroinflammation, postconditioning with sevoflurane can provide reliable neuroprotection by attenuating lipopolysaccharide-induced neuroinflammation, apoptosis, and neuronal loss and eventually improving spatial recognition deficits. However, although posttreatment with propofol also has the same anti-neuroinflammatory effects, the neurotoxicity caused by propofol postconditioning following neuroinflammation warrants further consideration.

Although selective serotonin reuptake inhibitor (SSRI) systems have been meaningfully linked to the clinical phenomena of mood disorders, 15–35% of patients do not respond to multiple SSRI interventions or even experience an exacerbation of their condition. As we previously showed, both running exercise and fluoxetine reversed depression-like behavior. However, whether exercise reverses depression-like behavior more quickly than fluoxetine treatment and whether this rapid effect is achieved via the promotion of oligodendrocyte differentiation and/or myelination in the hippocampus was previously unknown. Sixty male C57BL/6 J mice were used in the present study. We subjected mice with unpredictable chronic stress (UCS) to a 4-week running exercise trial (UCS + RN) or intraperitoneally injected them with fluoxetine (UCS + FLX) to address these uncertainties. At the behavioral level, mice in the UCS + RN group consumed significantly more sugar water in the sucrose preference test (SPT) at the end of the 7th week than those in the UCS group, while those in the UCS + FLX group consumed significantly more sugar water than mice in the UCS group at the end of the 8th week. The unbiased stereological results and immunofluorescence analyses revealed that running exercise, and not fluoxetine treatment, increased the numbers of CC1 + and CC1 + /Olig2 + /BrdU + oligodendrocytes in the CA1 subfield in depressed mice exposed to UCS. Moreover, running exercise rather than fluoxetine increased the level of myelin basic protein (MBP) and the G-ratio of myelinated nerve fibers in the CA1 subfield in the UCS mouse model. Unlike fluoxetine, exercise promoted hippocampal myelination and oligodendrocyte differentiation and thus has potential as a therapeutic strategy to reduce depression-like behaviors induced by UCS.

关节软骨是最常见且研究最多的一种透明软骨;其软骨细胞的物质输运主要由扩散和对流2种方式完成.在关节软骨的胞外基质内,生物活性分子的扩散和对流输运在组织生理调节和细胞生物学响应中起到极为重要的作用.近年来,关节软骨与软骨下骨的交互作用备受关注;其交互作用在骨关节炎的发生发展中不容忽视.本文主要对关节软骨内、关节软骨与软骨下骨间物质输运的实验研究进展进行综述,旨在为研究关节软骨微环境的生理病理作用提供一定参考,并为临床治疗骨关节炎提供一定的新思路.

目的:探讨髓鞘形成相关N-甲基-D-天冬氨酸受体(NMDA-R)亚基在MK-801诱导的精神分裂症小鼠模型大脑中的变化.方法:35只雄性C57BL//6J小鼠,随机分为:对照组(control)和地卓西平马来酸盐处理组(MK-801),利用旷场实验、探孔实验及高架十字迷宫检测小鼠行为学改变,免疫荧光染色观察小鼠大脑NMDA-R亚基NR1的表达,real time RT-PCR检测髓鞘形成相关NMDA-R亚基NR1、NR2C和NR3A mRNA的表达.结果:与对照组小鼠相比,MK-801处理组在旷场内10 min总运动路程较对照组显著增加;3 min及5 min内探孔次数较对照组显著降低;模型组小鼠在开臂内停留总时间较对照组显著降低.NR1在小鼠神经细胞胞膜、轴突周围和髓鞘部位均有表达.大脑皮层、海马内的NMDA-R亚基NR1,NR2C及NR3A mRNA的表达在两组间均无显著差异;胼胝体区域NR1和NR2C mRNA表达在两组间同样无显著差异;但相较于对照组,MK-801慢性给药组小鼠胼胝体区域NMDA-R亚基NR3A mRNA表达显著上调.结论:NMDA-R在少突胶质细胞、髓鞘等部位确有表达;胼胝体部位NR3A亚基上调可能在MK-801诱导的精神分裂症中发挥作用.

Interferon stimulated gene 15 (ISG15) is one of the most robustly upregulated interferon stimulated genes (ISGs) and also a ubiquitin-like modifier which has been reported to play an important role in host defense against pathogens. Cytosolic nucleic acids detected by DNA sensors induce type Ⅰ interferons (IFN-Ⅰs) and ISGs in host cells. Streptococcus pneumoniae (S. pn) autolysin LytA triggers bacterial lysis and then S. pn-derived genomic DNA (hereafter referred to as S. pn-DNA) can be released and accumulates in the cytoplasm of host cells. However, it remains elusive whether LytA-mediated S. pn-DNA release is involved in ISG15 induction. Here we verified that ISG15 conjugation system can be widely activated by S. pn and cytosolic S. pn-DNA in host cells. Moreover, the phagocytosis of macrophages to the mutant strain S. pn D39 ΔlytA was enhanced when compared to S. pn D39, which in turn increased S. pn-DNA uptake into macrophages and augmented ISG15 expression. ISG15 might upregulate proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) in macrophages and further promoted the clearance of S. pn in the absence of LytA. These results indicate that S. pn autolysis blunts ISG15 induction through preventing bacteria internalization and reducing cytosolic S. pn-DNA accumulation in macrophages, revealing a new strategy of S. pn for avoiding elimination. This study will help us to further understand the role of ISG15 during S. pn infection as well as the regulatory mechanisms of immune responses mediated by bacterial autolysis and bacterial DNA.

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase) + and newborn CNPase + oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10) + cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR + oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model.

该文旨在探讨干扰素-β(interferon-β,IFN-β)在肺炎链球菌(Streptococcus pneumoniae,S.pn)感染早期对宿主炎症免疫的影响.使用外源重组IFN-β蛋白(recombinant IFN-β,rIFN-β)预处理WT小鼠及其腹腔渗出巨噬细胞(peritoneal exudate macrophages,PEMs),以培养基处理组作为对照.同时应用内源干扰素α/β受体(interferon α/β receptor,IFNAR)缺陷的小鼠以及PEMs,以WT组为对照.各组分别暴露于D39菌株后,通过RT-PCR和ELISA检测白细胞介素-1β(interleukin-1β,IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)的表达水平,并通过小鼠肺切片HE染色和肺干/湿重比评估其肺部炎症浸润和组织损伤,以分析IFN-β对宿主炎症反应的影响;为分析细菌清除率,对小鼠巨噬细胞系RAW264.7行吞噬实验、计数小鼠肺部细菌载量,最后通过小鼠生存率分析确认IFN-β对宿主抵抗S.pn的影响.结果表明,IFN-β抑制D39诱导的IL-1β和TNF-α的过度表达.与NC组比,rIFN-β预处理提高RAW264.7细胞对S.pn的吞噬能力(P＜0.001),降低感染小鼠的肺部细菌负荷(P＜0.01)和肺损伤评分(P＜0.05).而IFNAR-/-感染小鼠肺部菌载量相较于WT小鼠显著升高(P＜0.001),持续更高水平的局部炎症反应导致其肺组织损伤加重且在9天内死亡率明显增加(P＜0.05).但各组小鼠体质量、肺干/湿重比和脾指数值差异无显著性(P＞0.05).可见,在S.pn感染早期,IFN-β通过调节巨噬细胞中促炎细胞因子的表达而维持适度的局部炎症反应,有助于宿主清除细菌,防止局部感染进展为致死性感染.

Background In the central nervous system, the myelin sheath and the cells that form it—oligodendrocytes—are associated with cognitive function. Oligodendrocyte abnormalities is an important early pathogenic factor of Alzheimer’s disease (AD). However, it is unclear how the hippocampal oligodendrocytes change during early AD and whether early hippocampal oligodendrocyte pathology in AD can be regarded as a novel therapeutic target.Methods To address these questions, we subjected APP/PS1 transgenic mice and nontransgenic littermates to fluoxetine interventions for 2 months. After intervention, the behaviors were assessed with open field test and Morris water maze test, the changes in hippocampal oligodendrocytes were studied using immunohistochemistry, immunofluorescence, unbiased stereological techniques, laser scanning confocal microscope and molecular biotechnology.Results AD mice had an abnormally high number of oligodendrocyte lineage cells (Olig2 + cells) but lower expressions of CNPase and MBP and fewer mature oligodendrocytes (CNPase + cells) in the hippocampus than nontransgenic littermates. Among the oligodendrocyte lineage cells in the hippocampus of AD mice, fewer were mature oligodendrocytes and more were immature oligodendrocytes. Furthermore, decreased expression of SOX10, increased expression of LINGO1 and its ligands, and increased expression and activity of GSK3β might work together to induce oligodendrocyte maturation disorder in the hippocampus of AD mice. Fluoxetine treatment not only delayed the deficiencies in spatial learning and memory ability but also rescued the decrease in mature oligodendrocytes and reversed the abnormal increase in oligodendrocyte lineage cells in the hippocampus of AD mice, potentially by inhibiting the expression of LINGO1 and its ligands, inhibiting the expression and activity of GSK3β, reducing the levels of soluble Aβ40 and Aβ42, reducing β-amyloid plaques, reducing the ratio of oligodendrocytes expressing p16, promoting the expression of SOX10 in oligodendrocytes and promoting the maturation of newborn oligodendrocytes, and then increasing the number of mature oligodendrocytes in the hippocampus of AD mice.Conclusion There is oligodendrocyte maturation disorder in the hippocampus during early AD mice. Fluoxetine exposure during early AD may delay cognitive dysfunction by affecting hippocampal oligodendrocyte generation and maturation. Early hippocampal oligodendrocyte generation and maturation in AD might be regarded as a novel therapeutic target.