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Depletion of the paternal gut microbiome alters sperm small RNAs and impacts offspring physiology and behavior in mice 消耗父代肠道微生物群会改变精子的小核糖核酸,并影响小鼠后代的生理和行为。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.bbi.2024.09.020
The paternal environment prior to conception has been demonstrated to influence offspring physiology and behavior, with the sperm epigenome (including noncoding RNAs) proposed as a potential facilitator of non-genetic inheritance. Whilst the maternal gut microbiome has been established as an important influence on offspring development, the impact of the paternal gut microbiome on offspring development, health and behavior is largely unknown. Gut microbiota have major influences on immunity, and thus we hypothesized that they may be relevant to paternal immune activation (PIA) modulating epigenetic inheritance in mice. Therefore, male C57BL/6J mice (F0) were orally administered non-absorbable antibiotics via drinking water in order to substantially deplete their gut microbiome. Four weeks after administration of the antibiotics (gut microbiome depletion), F0 male mice were then mated with naïve female mice. The F1 offspring of the microbiome-depleted males had reduced body weight as well as altered gut morphology (shortened colon length). F1 females showed significant alterations in affective behaviors, including measures of anxiety and depressive-like behaviors, indicating altered development. Analysis of small noncoding RNAs in the sperm of F0 mice revealed that gut microbiome depletion is associated with differential expression of 8 different PIWI-interacting RNAs (piRNAs), each of which has the potential to modulate the expression of multiple downstream gene targets, and thus influence epigenetic inheritance and offspring development. This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors. These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans.
受孕前的父方环境已被证明会影响后代的生理和行为,精子表观基因组(包括非编码 RNA)被认为是非遗传的潜在促进因素。母体肠道微生物群对后代发育的重要影响已被证实,但父体肠道微生物群对后代发育、健康和行为的影响在很大程度上还不为人所知。肠道微生物群对免疫有重大影响,因此我们假设它可能与父系免疫激活调节小鼠表观遗传有关。因此,我们通过饮用水给雄性 C57BL/6J 小鼠(F0)口服非吸收性抗生素,以大量消耗其肠道微生物群。在服用抗生素(肠道微生物群耗竭)四周后,F0 雄性小鼠再与天真雌性小鼠交配。微生物群耗竭的雄性小鼠的 F1 后代体重减轻,肠道形态也发生了改变(结肠长度缩短)。F1雌性小鼠的情感行为(包括焦虑和抑郁样行为)发生了显著变化,这表明它们的发育发生了改变。对F0小鼠精子中的小非编码RNA分析表明,肠道微生物组的耗竭与8种不同的PIWI-interacting RNA(πRNA)的差异表达有关,每种RNA都有可能调节多个下游基因靶标的表达,从而影响表观遗传和后代发育。这项研究表明,肠道-生殖系轴影响精子小 RNA 图谱和后代生理,并对后代的情感和/或应对行为产生具体影响。这些发现可能会对其他具有相似肠道微生物群、代际表观遗传学和发育生物学的动物物种(包括人类)产生更广泛的影响。
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引用次数: 0
Differential effects of social versus monetary incentives on inhibitory control under acute inflammation. 在急性炎症情况下,社会激励与金钱激励对抑制控制的不同影响。
IF 15.1 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.bbi.2024.09.010
Gabriella M Alvarez,Tatum A Jolink,Taylor N West,Megan N Cardenas,Mallory J Feldman,Jessica R Cohen,Keely A Muscatell
While the impact of chronic, low-grade inflammation on cognitive functioning is documented in the context of neurodegenerative disease, less is known about the association between acute increases in inflammation and cognitive functioning in daily life. This study investigated how changes in interleukin-6 (IL-6) levels were associated with performance on an inhibitory control task, the go/no-go task. We further examined whether the opportunity to earn different incentive types (social or monetary) and magnitudes (high or low) was associated with differential performance on the task, depending on IL-6 levels. Using a within-participant design, individuals completed an incentivized go/no-go task before and after receiving the annual influenza vaccine. Multilevel logistic regressions were performed on the trial-level data (Nobs = 30,528). For no-go trials, we did not find significant associations between IL and 6 reactivity between the sessions and changes in trial accuracy. For go trials, we found significant differences in the associations between IL and 6 reactivity and changes in accuracy from session 1 to session 2 as a function of the incentive condition. Notably, greater IL-6 reactivity was consistently associated with fewer omission errors (i.e., greater accuracy on go trials) on high-magnitude social incentives (i.e., viewing a picture of a close-other picture) when compared to both low-magnitude social and high-magnitude monetary incentives. Together, these results suggest that mild fluctuations in inflammation might alter the valuation of an incentive, and possibly a shift toward devoting greater attentional resources when a large social incentive is on the line. Overall, this study sheds light on how everyday, low-grade fluctuations in inflammation may influence cognitive abilities essential for daily life and effective inhibitory control.
在神经退行性疾病中,慢性、低度炎症对认知功能的影响已被证实,但人们对炎症的急性增加与日常生活中认知功能之间的关系却知之甚少。本研究调查了白细胞介素-6(IL-6)水平的变化与抑制性控制任务(去/不去任务)的表现之间的关系。我们还进一步研究了获得不同激励类型(社会或金钱)和激励程度(高或低)的机会是否会因白细胞介素-6水平的不同而与任务中的不同表现有关。在接种年度流感疫苗之前和之后,受试者完成了 "去/不去 "任务。我们对试验水平数据(Nobs = 30,528)进行了多层次逻辑回归。对于 "不去 "试验,我们没有发现 IL 和 6 反应性与试验准确性变化之间存在显著关联。而对于 "开始 "试验,我们发现 IL 和 6 反应性与准确率的变化之间存在显著差异,这与激励条件有关。值得注意的是,与低强度的社交激励和高强度的金钱激励相比,在高强度的社交激励条件下(即观看一张近距离的图片),IL-6反应性越高,遗漏错误越少(即围棋试验的准确性越高)。总之,这些结果表明,炎症的轻微波动可能会改变对激励的评价,并可能在有大量社会激励时转向投入更多的注意力资源。总之,这项研究揭示了炎症的日常低级波动如何影响日常生活和有效抑制控制所必需的认知能力。
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引用次数: 0
Skull bone marrow-derived immune cells infiltrate the injured cerebral cortex and exhibit anti-inflammatory properties 颅骨骨髓免疫细胞渗入受伤的大脑皮层并表现出抗炎特性
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-16 DOI: 10.1016/j.bbi.2024.09.023

Identifying the origins and contributions of peripheral-derived immune cell populations following brain injury is crucial for understanding their roles in neuroinflammation and tissue repair. This study investigated the infiltration and phenotypic characteristics of skull bone marrow-derived immune cells in the murine brain after traumatic brain injury (TBI). We performed calvarium transplantation from GFP donor mice and subjected the recipients to controlled cortical impact (CCI) injury 14 days post-transplant. Confocal imaging at 3 days post-CCI revealed GFP+ calvarium-derived cells were present in the ipsilateral injured cortex, expressing CD45 and CD11b immune markers. These cells included Ly6G-positive neutrophil or Ccr2-positive monocyte identities. Calvarium-derived GFP+/Iba1+ monocyte/macrophages expressed the efferocytosis receptor MERTK and displayed engulfment of NeuN+ and cleaved caspase 3+ apoptotic cells. Phenotypic analysis showed that greater calvarium-derived monocytes/macrophages disproportionately express the anti-inflammatory arginase-1 marker than pro-inflammatory CD86. To differentiate the responses of blood- and calvarium-derived macrophages, we transplanted GFP calvarium skull bone into tdTomato bone marrow chimeric mice, then performed CCI injury 14 days post-transplant. Calvarium-derived GFP+cells predominantly infiltrated the lesion boundary, while blood-derived tdTomato+ cells dispersed throughout the lesion and peri-lesion. Compared to calvarium-derived cells, more blood-derived cells expressed pro-inflammatory CD86 and displayed altered 3D morphologic traits. These findings uniquely demonstrate that skull bone marrow-derived immune cells infiltrate the brain after injury and contribute to the neuroinflammatory milieu, representing a novel immune cell source that may be further investigated for their causal role in functional outcomes.

确定脑损伤后外周源性免疫细胞群的起源和贡献对于了解它们在神经炎症和组织修复中的作用至关重要。本研究调查了创伤性脑损伤(TBI)后颅骨骨髓衍生免疫细胞在小鼠大脑中的浸润和表型特征。我们从 GFP 供体小鼠进行了颅骨移植,并在移植后 14 天对受体进行了受控皮质冲击(CCI)损伤。CCI后3天的共聚焦成像显示,同侧损伤皮层中存在GFP+钙灶衍生细胞,表达CD45和CD11b免疫标记。这些细胞包括Ly6G阳性的中性粒细胞或Ccr2阳性的单核细胞。钙源GFP+/Iba1+单核细胞/巨噬细胞表达出细胞吞噬受体MERTK,并吞噬NeuN+和裂解卡巴酶3+凋亡细胞。表型分析表明,与促炎性 CD86 相比,更多的钙源单核细胞/巨噬细胞不成比例地表达抗炎性精氨酸酶-1 标记。为了区分血液和钙颅源性巨噬细胞的反应,我们将 GFP 钙颅骨移植到tdTomato 骨髓嵌合小鼠体内,然后在移植后 14 天进行 CCI 损伤。颅骨来源的 GFP+ 细胞主要浸润病变边界,而血液来源的 tdTomato+ 细胞则分散在整个病变和病变周围。与钙源细胞相比,更多的血源细胞表达促炎性 CD86,并显示出改变的三维形态特征。这些研究结果独特地证明了颅骨骨髓来源的免疫细胞在损伤后浸润大脑并导致神经炎症环境,是一种新的免疫细胞来源,可进一步研究其在功能结果中的因果作用。
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引用次数: 0
Biobehavioral mechanisms underlying symptoms in cancer patients with chronic graft-versus-host disease 慢性移植物抗宿主疾病癌症患者症状的生物行为机制
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-15 DOI: 10.1016/j.bbi.2024.09.017

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and high symptom burden. This study evaluated two biobehavioral mechanisms, inflammation and circadian rest-activity rhythms, that may underly commonly reported psychological and physical symptoms in cGVHD patients. Adults with cGVHD (N=57) wore a wrist actigraph for 7 days, provided a blood sample, and completed patient-reported outcome (PRO) measures. 24-hour rest-activity indices were derived from actigraphy. Cytokines and chemokines relevant to cGVHD were measured in peripheral blood plasma using multi-analyte immunoassays. Multiple regression evaluated the extent to which rest-activity indices and inflammatory biomarkers predicted PROs. Higher levels of circulating IL-8 and MIP-1α were associated with worse depression (β = 0.35, p = 0.01; β = 0.33, p = 0.02) and sexual function (β = -0.41, p = 0.01; β = -0.32, p = 0.03). MIP-1α was associated with more severe insomnia (β = 0.36, p = 0.01). Higher circulating MIF was associated with more severe anxiety (β = 0.28, p = 0.048) and fatigue (β = 0.35, p = 0.02). Il-6, TNFα, and MCP-1 showed few associations with PROs. There were few associations between actigraphy indices and PROs; however, participants with a later daily activity peak (acrophase) reported poorer sexual function (β = -0.31, p = 0.04). Models covarying for age, cGVHD severity, and time since HCT yielded a similar pattern of results. Results suggest that pro-inflammatory cytokines and chemokines associated with cGVHD may contribute to PROs, identifying a biobehavioral mechanism that may be a useful target for future interventions.

慢性移植物抗宿主疾病(cGVHD)是异基因造血细胞移植(HCT)的一种并发症,与发病率和高症状负担有关。本研究评估了炎症和昼夜节律-休息-活动节律这两种生物行为机制,它们可能是 cGVHD 患者常见的心理和生理症状的基础。成人 cGVHD 患者(57 人)佩戴腕式活动仪 7 天,提供血液样本,并完成患者报告结果 (PRO) 测量。24小时静息活动指数由腕动图得出。外周血血浆中与 cGVHD 相关的细胞因子和趋化因子是通过多分析免疫测定法测定的。多元回归评估了静息活动指数和炎症生物标志物对PROs的预测程度。较高水平的循环 IL-8 和 MIP-1α 与抑郁(β = 0.35,p = 0.01;β = 0.33,p = 0.02)和性功能(β = -0.41,p = 0.01;β = -0.32,p = 0.03)恶化相关。MIP-1α 与更严重的失眠有关(β = 0.36,p = 0.01)。较高的循环 MIF 与较严重的焦虑(β = 0.28,p = 0.048)和疲劳(β = 0.35,p = 0.02)有关。Il-6、TNFα和MCP-1与PROs几乎没有关联。活动量指数与PROs之间几乎没有关联;但是,每日活动量峰值(acrophase)较晚的参与者的性功能较差(β = -0.31,p = 0.04)。与年龄、cGVHD严重程度和接受造血干细胞移植后的时间相关的模型也得出了类似的结果。结果表明,与 cGVHD 相关的促炎细胞因子和趋化因子可能会导致 PROs,从而确定了一种生物行为机制,该机制可能成为未来干预的有用目标。
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引用次数: 0
Astrocyte-neuron communication through the complement C3-C3aR pathway in Parkinson’s disease 帕金森病中通过补体 C3-C3aR 通路进行的星形胶质细胞-神经元交流。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-15 DOI: 10.1016/j.bbi.2024.09.022

Neuroinflammation and autoimmunity are pivotal in the pathogenesis of neurodegenerative diseases. Complement activation and involvement of astrocyte-neuron C3/C3aR pathway have been observed, yet the mechanisms influencing α-synuclein (α-syn) pathology and neurodegeneration remain unclear. In this study, elevated levels of complement C3 were detected in the plasma of α-syn PFF-induced mice and the substantia nigra of A53T transgenic mice. Colocalization of complement C3 with astrocytes was also observed. Overexpression of complement C3 exacerbated motor dysfunction, dopaminergic neuron loss, and phosphorylated α-syn expression in mice injected with α-syn preformed fibrils (α-syn PFFs). Conversely, downregulation of complement C3 protected α-syn PFF-induced mice. Molecular investigations revealed that inhibition of Toll-like receptor 2 (TLR2) or NF-κB reduced complement C3 expression in primary astrocytes following α-syn PFF treatment. Astrocyte-neuron communication via the C3/C3aR pathway influenced α-syn PFF-induced neuronal apoptosis and α-syn pathology, potentially through modulation of GSK3β. These findings underscore the critical role of astrocyte-neuron communication via the C3/C3aR pathway in PD pathogenesis, highlighting its potential as a therapeutic target.

神经炎症和自身免疫是神经退行性疾病发病机制中的关键因素。补体激活和星形胶质细胞-神经元 C3/C3aR 通路的参与已被观察到,但影响α-突触核蛋白(α-syn)病理和神经退行性变的机制仍不清楚。本研究在α-syn PFF诱导的小鼠血浆和A53T转基因小鼠黑质中检测到补体C3水平升高。还观察到补体 C3 与星形胶质细胞共定位。在注射了α-syn预成纤维(α-syn PFFs)的小鼠中,补体C3的过表达加剧了运动功能障碍、多巴胺能神经元的缺失和磷酸化α-syn的表达。相反,下调补体 C3 能保护α-syn PFF 诱导的小鼠。分子研究发现,抑制 Toll 样受体 2 (TLR2) 或 NF-κB 可减少原代星形胶质细胞在α-syn PFF 处理后的补体 C3 表达。通过 C3/C3aR 途径进行的星形胶质细胞-神经元交流影响了α-syn PFF 诱导的神经元凋亡和α-syn 病理学,可能是通过调节 GSK3β。这些发现强调了星形胶质细胞通过 C3/C3aR 通路与神经元交流在帕金森病发病机制中的关键作用,突出了其作为治疗靶点的潜力。
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引用次数: 0
Depression-like behavior is associated with deficits in cognition and hippocampal neurogenesis in a subset of spinally contused male, but not female, rats 在一部分脊髓挫伤的雄性大鼠(而非雌性大鼠)中,抑郁样行为与认知缺陷和海马神经发生有关。
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-15 DOI: 10.1016/j.bbi.2024.09.015
Depression and cognitive deficits present at higher rates among people with spinal cord injury (SCI) compared to the general population, yet these SCI comorbidities are poorly addressed. Sex and age appear to play roles in depression incidence, but consensus on the direction of their effects is limited. Systemic and cortical inflammation and disruptions in hippocampal neurogenesis have been identified as potential treatment targets, but a comprehensive understanding of these mechanisms remains elusive.
We used a rodent SCI model to interrogate these gaps in knowledge. We examined post-injury depression-like behavior and cognitive deficits, as well as the association between affect, cognition, chronic hippocampal inflammation and hippocampal neurogenesis, in young and middle-aged male and female Sprague-Dawley rats. Depression-like behavior manifested in male and female subsets of SCI rats irrespective of age, at rates commensurate with the incidence of clinical depression. Changes in components of behavior were driven by sex and age, and affective outcomes were independent of common post-injury pathophysiological outcomes including locomotor functional deficits and spinal lesion severity. Interestingly, however, only male depression-like SCI rats exhibited deficits in hippocampal-associated spatial cognition. Neurogenesis was also disrupted in only SCI males in regions of the hippocampus responsible for affective outcomes. Decreased neurogenesis among middle-aged male subjects coincided with increases in numbers of the pro-inflammatory markers CD86 and iNOS, while middle-aged females had increased numbers of cells expressing Iba-1 and anti-inflammatory marker CD206.
Overall, the present data suggest that post-SCI depression and cognition may be affected, in part, by sex- and age-dependent changes in hippocampal neurogenesis and inflammation. Hippocampal neurogenesis is a potential target to address psychological wellbeing after SCI, but therapeutic strategies must carefully consider sex and age as biological variables.
与普通人群相比,脊髓损伤(SCI)患者出现抑郁和认知障碍的比例更高,但这些 SCI 并发症却很少得到关注。性别和年龄似乎对抑郁症的发病率有影响,但对其影响方向的共识却很有限。系统性和皮层炎症以及海马神经发生的破坏已被确定为潜在的治疗目标,但对这些机制的全面了解仍然遥遥无期。我们利用啮齿动物 SCI 模型来探究这些知识空白。我们研究了中青年雄性和雌性 Sprague-Dawley 大鼠受伤后的抑郁样行为和认知障碍,以及情感、认知、慢性海马炎症和海马神经发生之间的关联。在雌雄SCI大鼠亚群中,抑郁样行为的表现与年龄无关,其发生率与临床抑郁症的发生率相当。行为成分的变化受性别和年龄的影响,情感结果与常见的损伤后病理生理结果(包括运动功能障碍和脊柱损伤严重程度)无关。但有趣的是,只有雄性抑郁样损伤大鼠表现出与海马相关的空间认知障碍。只有雄性 SCI 大鼠负责情感结果的海马区域的神经发生也受到破坏。中年男性受试者神经发生减少的同时,促炎症标记物 CD86 和 iNOS 的数量增加,而中年女性受试者表达 Iba-1 和抗炎症标记物 CD206 的细胞数量增加。总之,本研究数据表明,SCI 后抑郁症和认知能力可能部分受到海马神经发生和炎症的性别和年龄变化的影响。海马神经发生是解决损伤后心理健康问题的潜在目标,但治疗策略必须仔细考虑性别和年龄这些生物变量。
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引用次数: 0
Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model 在突触核蛋白病小鼠模型中抑制 CSF-1R 后的小胶质细胞和神经元命运
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-14 DOI: 10.1016/j.bbi.2024.09.016

Synucleinopathies are age-related neurological disorders characterized by the abnormal accumulation of α-synuclein (α-syn) in neuronal and non-neuronal cells. It has been proposed that microglial cells play an important role in synucleinopathy neuroinflammation, as well as homeostatically, such as in the clearance of α-syn aggregates in the brain. Here, we examined the effects of microglia on the pathogenesis of synucleinopathies by cell depletion in a mouse model of synucleinopathies. For this purpose, we treated non-transgenic (Non-tg) and α-synuclein transgenic (α-syn-tg) mice with pexidartinib (PLX3397), a tyrosine kinase inhibitor of colony-stimulating factor 1 receptor (CSF-1R). Neuropathological and immunoblot analysis confirmed that Iba-1 immunoreactive microglial cells were decreased by 95% following PLX3397 treatment in Non-tg and α-syn-tg mice. The level of total α-syn in the Triton X-insoluble fraction of brain homogenate was significantly decreased by microglial depletion in the α-syn-tg mice, while the level of Triton X-soluble human α-syn was not affected. Furthermore, the number of p-α-syn immunoreactive inclusions was reduced in α-syn-tg mice treated with PLX3397. Microglial depletion also ameliorated neuronal and synaptic degeneration in α-syn-tg mice, thereby resulted partially improving the motor behavioral deficit in α-syn-tg mice. Moreover, we demonstrated that microglia that survived post-PLX3397 treatment (PLX-resistant microglia) have lower expressions of CSF-1R, and microglial transcriptome analysis further elucidated that PLX-resistant microglia have unique morphology and transcriptomic signatures relative to vehicle-treated microglia of both genotypes; these include differences in definitive microglial functions such as their immune response, cell mobility, cell–cell communications, and regulation of neural homeostasis. Therefore, we suggest that microglia play a critical role in the pathogenesis of synucleinopathies, and that modulation of microglial status might be an effective therapeutic strategy for synucleinopathies.

突触核蛋白病是一种与年龄有关的神经系统疾病,其特征是α-突触核蛋白(α-syn)在神经元和非神经元细胞中异常聚集。有研究认为,小胶质细胞在突触核蛋白病的神经炎症中发挥着重要作用,在清除大脑中的α-syn聚集物等体内平衡方面也发挥着重要作用。在此,我们在突触核蛋白病小鼠模型中通过细胞耗竭研究了小胶质细胞对突触核蛋白病发病机制的影响。为此,我们用集落刺激因子1受体(CSF-1R)的酪氨酸激酶抑制剂pexidartinib(PLX3397)处理了非转基因(Non-tg)和α-突触核蛋白转基因(α-synuclein-tg)小鼠。神经病理学和免疫印迹分析证实,PLX3397治疗后,Non-tg和α-syn-tg小鼠的Iba-1免疫活性小胶质细胞减少了95%。α-syn-tg小鼠脑匀浆中Triton X-不溶性部分的总α-syn水平因小胶质细胞耗竭而显著下降,而Triton X-可溶性人α-syn水平不受影响。此外,α-syn-tg 小鼠经 PLX3397 处理后,p-α-syn 免疫活性包涵体的数量减少。小胶质细胞消耗也改善了α-syn-tg小鼠的神经元和突触退化,从而部分改善了α-syn-tg小鼠的运动行为缺陷。此外,我们还证明,PLX3397 治疗后存活的小胶质细胞(PLX 抗性小胶质细胞)的 CSF-1R 表达量较低,小胶质细胞转录组分析进一步阐明,相对于两种基因型的车辆治疗小胶质细胞,PLX 抗性小胶质细胞具有独特的形态和转录组特征;这些特征包括小胶质细胞在免疫反应、细胞移动性、细胞间通讯和神经稳态调节等明确功能方面的差异。因此,我们认为小胶质细胞在突触核蛋白病的发病机制中起着关键作用,调节小胶质细胞的状态可能是治疗突触核蛋白病的有效策略。
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引用次数: 0
PNIRS Society Announcements PNIRS 协会公告
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-13 DOI: 10.1016/S0889-1591(24)00611-1
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引用次数: 0
Phlorizin ameliorates cognitive and behavioral impairments via the microbiota-gut-brain axis in high-fat and high-fructose diet-induced obese male mice 通过微生物群-肠-脑轴改善高脂和高果糖饮食诱导的肥胖雄性小鼠的认知和行为损伤
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.bbi.2024.09.008

The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. Phlorizin, a well-studied natural compound found in apples and other plants, is recognized for its bioactive properties, including modulation of glucose and lipid metabolism. Despite its established role in mitigating metabolic disorders, the neuroprotective effects of phlorizin, particularly against diabetes-related cognitive dysfunction, have not been fully elucidated. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. We found that dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5′-monophosphate (IMP), and D (−)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Therefore, phlorizin shows promise as a potential nutritional therapy for addressing cognitive impairment associated with metabolic disorders. Further research is needed to explore its effectiveness in preventing and alleviating neurodegenerative diseases.

长期高脂肪、高糖饮食会加剧与 2 型糖尿病(T2DM)相关的认知障碍。氯嗪是一种在苹果和其他植物中发现的天然化合物,其生物活性特性已得到公认,包括调节葡萄糖和脂质代谢。尽管叶绿素在缓解代谢紊乱方面的作用已得到证实,但它对神经的保护作用,尤其是对糖尿病相关认知功能障碍的保护作用,尚未得到充分阐明。因此,本研究旨在探讨膳食补充氯苯甘醚对高脂高果糖饮食(HFFD)诱导的认知功能障碍的影响,并评估微生物群-肠-脑轴的关键作用。我们发现,连续 14 周通过膳食补充氯苯甘醚能有效预防高脂高果饮食小鼠的糖脂代谢紊乱、空间学习障碍和记忆损伤。此外,叶枯素还能改善 HFFD 引起的海马突触可塑性下降、神经炎症和小胶质细胞过度激活。转录组学分析表明,氯嗪对认知障碍的保护作用与海马中神经递质和突触相关基因表达的增加有关。氯嗪治疗缓解了结肠微生物群紊乱,主要表现为肠道微生物群多样性和短链脂肪酸(SCFA)产生菌丰度的增加。经氯雷他定处理后,SCFA、5′-单磷酸肌苷(IMP)和D(-)-beta-羟丁酸(BHB)等微生物代谢物的含量也显著增加。综合多组学分析观察到了氯嗪调节基因、微生物群和代谢物之间的紧密联系。此外,通过抗生素治疗去除肠道微生物群会降低氯嗪对 HFFD 引起的认知障碍的保护作用,这突出了肠道微生物群在介导认知行为中的关键作用。重要的是,仅补充 SCFA 和 BHB 就能模拟氯苯甘醚对认知功能的调节作用。因此,氯苯甘醚有望成为一种潜在的营养疗法,用于治疗与代谢紊乱相关的认知障碍。还需要进一步的研究来探索它在预防和缓解神经退行性疾病方面的有效性。
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引用次数: 0
High level of immunoglobulin G targeting mycoplasma or cytomegalovirus in the newborn increases risk of ADHD 新生儿体内针对支原体或巨细胞病毒的免疫球蛋白 G 含量高会增加患多动症的风险
IF 8.8 2区 医学 Q1 IMMUNOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.bbi.2024.09.009

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder typically detected in childhood. Although ADHD has been demonstrated to have a strong genetic component, environmental risk factors, such as maternal infections during pregnancy, may also play a role. We therefore measured the immunological response to 5 abundant microorganisms (Toxoplasmosis Gondii, cytomegalovirus (CMV), Herpes Simplex Virus 1, Epstein Barr Virus and mycoplasma pneumoniae) in newborn heel prick samples of 1679 ADHD cases and 2948 matching controls as part of the iPSYCH Danish case-cohort study. We found an association between high anti-CMV (OR 1.30, 95 % CI [1.09,1.55], p = 0.015) and anti-mycoplasma (OR 1.30, 95 % CI [1.07,1.59], p = 0.037) signal and those newborns later being diagnosed with ADHD. The risk estimate remained increased when controlling for ADHD polygenic risk score as well as penicillin prescriptions. We saw a dose–response association with the amount of positive anti-microorganism titers increasing the risk of being diagnosed with ADHD later in life (p = 0.01 for the trend), suggesting that the more activated the immune system is prior to or at birth, the higher the risk is for a later diagnosis with ADHD. If the associations are causal, they emphasize the importance of a healthy life style during pregnancy to reduce the risk of infections when pregnant and the associated risks for the child.

注意缺陷多动障碍(ADHD)是一种神经发育障碍,通常在儿童时期就会被发现。虽然 ADHD 已被证实有很强的遗传因素,但环境风险因素(如孕妇在怀孕期间的感染)也可能起一定作用。因此,作为丹麦 iPSYCH 病例队列研究的一部分,我们测量了 1679 例多动症病例和 2948 例匹配对照的新生儿足跟点刺样本对 5 种大量微生物(弓形虫、巨细胞病毒(CMV)、单纯疱疹病毒 1、爱泼斯坦巴氏病毒和肺炎支原体)的免疫反应。我们发现,高抗 CMV(OR 1.30,95 % CI [1.09,1.55],p = 0.015)和抗支原体(OR 1.30,95 % CI [1.07,1.59],p = 0.037)信号与后来被诊断为多动症的新生儿之间存在关联。在控制了多动症多基因风险评分和青霉素处方后,风险估计值仍然增加。我们发现,抗微生物滴度呈阳性的数量与日后被诊断为多动症的风险呈剂量反应关系(趋势 p = 0.01),这表明出生前或出生时免疫系统越活跃,日后被诊断为多动症的风险就越高。如果这些关联是因果关系,那么它们强调了在怀孕期间保持健康生活方式的重要性,以降低怀孕时感染的风险和对孩子的相关风险。
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引用次数: 0
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Brain, Behavior, and Immunity
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