Brain, Behavior, and Immunity最新文献_第3页

Gut microbiota transfer from the preclinical maternal immune activation model of autism is sufficient to induce sex-specific alterations in immune response and behavioural outcomes 自闭症临床前母体免疫激活模型的肠道微生物群转移足以诱导免疫反应和行为结果的性别特异性改变。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-28 DOI: 10.1016/j.bbi.2024.10.030

The gut microbiome plays a vital role in health and disease, including neurodevelopmental disorders like autism spectrum disorder (ASD). ASD affects 4:1 males-to-females, and sex differences are apparent in gut microbiota composition among ASD individuals and in animal models of this condition, such as the maternal immune activation (MIA) mouse model. However, few studies have included sex as a biological variable when assessing the role of gut microbiota in mediating ASD symptoms. Using the MIA model of ASD, we assessed whether gut microbiota contributes to the sex differences in the presentation of ASD-like behaviors. Gut microbiota transplantation from MIA or vehicle/control male and female mice into healthy, otherwise unmanipulated, 4-week-old C57Bl/6 mice was performed for 6 treatments over 12 days. Colonization with male, but not female, MIA microbiota was sufficient to reduce sociability, decrease microbiota diversity and increase neuroinflammation with more pronounced deficits in male recipients. Colonization with both male and female donor microbiota altered juvenile ultrasonic vocalizations and anxiety-like behavior in recipients of both sexes, and there was an accompanied change in the gut microbiota and serum cytokine IL-4 and IL-7 levels of all recipients of MIA gut microbiota. In addition to the increases in gut microbes associated with pathological states, the female donor microbiota profile also had increases in gut microbes with known neural protective effects (e.g., Lactobacillus and Rikenella). These results suggest that gut reactivity to environmental insults, such as in the MIA model, may play a role in shaping the sex disparity in ASD development.

肠道微生物群在健康和疾病（包括自闭症谱系障碍（ASD）等神经发育障碍）中发挥着至关重要的作用。自闭症谱系障碍的男女患病比例为 4:1，自闭症谱系障碍患者的肠道微生物群组成以及该疾病的动物模型（如母体免疫激活（MIA）小鼠模型）中都存在明显的性别差异。然而，在评估肠道微生物群在介导 ASD 症状中的作用时，很少有研究将性别作为一个生物变量。我们利用 MIA ASD 模型评估了肠道微生物群是否会导致 ASD 类行为表现的性别差异。我们将来自 MIA 或载体/对照组的雄性和雌性小鼠的肠道微生物群移植到健康、未受其他操纵的 4 周大 C57Bl/6 小鼠体内，共进行了 6 次处理，历时 12 天。雄性（而非雌性）MIA 微生物群的定植足以降低小鼠的交际能力、减少微生物群的多样性并增加神经炎症，雄性受体的缺陷更为明显。雄性和雌性供体微生物群的定植改变了两性受体的幼年超声波发声和焦虑样行为，所有MIA肠道微生物群受体的肠道微生物群和血清细胞因子IL-4和IL-7水平也随之发生了变化。除了与病理状态相关的肠道微生物增加外，女性供体微生物群谱中具有已知神经保护作用的肠道微生物（如乳酸杆菌和利肯菌）也增加了。这些结果表明，肠道对环境损伤的反应性（如在 MIA 模型中）可能在形成 ASD 发展过程中的性别差异方面起了作用。

{"title":"Gut microbiota transfer from the preclinical maternal immune activation model of autism is sufficient to induce sex-specific alterations in immune response and behavioural outcomes","authors":"","doi":"10.1016/j.bbi.2024.10.030","DOIUrl":"10.1016/j.bbi.2024.10.030","url":null,"abstract":"<div><div>The gut microbiome plays a vital role in health and disease, including neurodevelopmental disorders like autism spectrum disorder (ASD). ASD affects 4:1 males-to-females, and sex differences are apparent in gut microbiota composition among ASD individuals and in animal models of this condition, such as the maternal immune activation (MIA) mouse model. However, few studies have included sex as a biological variable when assessing the role of gut microbiota in mediating ASD symptoms. Using the MIA model of ASD, we assessed whether gut microbiota contributes to the sex differences in the presentation of ASD-like behaviors. Gut microbiota transplantation from MIA or vehicle/control male and female mice into healthy, otherwise unmanipulated, 4-week-old C57Bl/6 mice was performed for 6 treatments over 12 days. Colonization with male, but not female, MIA microbiota was sufficient to reduce sociability, decrease microbiota diversity and increase neuroinflammation with more pronounced deficits in male recipients. Colonization with both male and female donor microbiota altered juvenile ultrasonic vocalizations and anxiety-like behavior in recipients of both sexes, and there was an accompanied change in the gut microbiota and serum cytokine IL-4 and IL-7 levels of all recipients of MIA gut microbiota. In addition to the increases in gut microbes associated with pathological states, the female donor microbiota profile also had increases in gut microbes with known neural protective effects (e.g., <em>Lactobacillus</em> and <em>Rikenella</em>). These results suggest that gut reactivity to environmental insults, such as in the MIA model, may play a role in shaping the sex disparity in ASD development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson's disease. 帕金森病发病机制中 IL 和 17A/IL-17RA 通路失调与 α-突触核蛋白之间的双向相互作用

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-24 DOI: 10.1016/j.bbi.2024.10.025

Yu-Chen Yan, Lu Su, Wan-Bing Zhao, Yun Fan, James B Koprich, Bao-Guo Xiao, Bin Song, Jian Wang, Wen-Bo Yu

Parkinson's disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.

帕金森病（PD）的发病机制以α-突触核蛋白（α-syn）病理学为特征，而α-突触核蛋白病理学又受到神经炎症和衰老等多种因素的影响。越来越多的证据表明，白细胞介素-17A（IL-17A）和白细胞介素-17受体A（IL-17RA）在帕金森病中起着关键作用，但IL-17A/IL-17RA激活在帕金森病中的诱因和影响仍未确定。本研究观察到人类中枢神经系统中 IL-17A 和 IL-17RA 的增加与年龄有关，同时伴随着 α-syn 和衰老生物标志物的增加。有趣的是，与年龄匹配的对照组相比，帕金森病患者体内的IL-17A和IL-17RA水平均显著升高，其中IL-17A主要存在于神经元中。在α-syn小鼠模型中，帕金森病大脑神经元IL-17A的这种异常激活也得到了重现。相应地，服用重组 IL-17A 会加剧神经元和小鼠模型中的病理 α-syn。此外，通过阻断抗体或 shRNA 介导的基因敲除干预 IL-17A/IL-17RA 通路可以减轻病理性 α-syn 的影响。这项研究揭示了IL-17A/IL-17RA通路失调与α-syn之间的相互作用，表明调节IL-17A/IL-17RA通路可以通过破坏有害循环来改变帕金森病的进展。

{"title":"Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson's disease.","authors":"Yu-Chen Yan, Lu Su, Wan-Bing Zhao, Yun Fan, James B Koprich, Bao-Guo Xiao, Bin Song, Jian Wang, Wen-Bo Yu","doi":"10.1016/j.bbi.2024.10.025","DOIUrl":"https://doi.org/10.1016/j.bbi.2024.10.025","url":null,"abstract":"<p><p>Parkinson's disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemogenetic targeting TRPV1 in obesity-induced depression: Unveiling therapeutic potential of eicosapentaenoic acid and acupuncture 在肥胖诱发的抑郁症中针对 TRPV1 的化学遗传学：揭示二十碳五烯酸和针灸的治疗潜力

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-23 DOI: 10.1016/j.bbi.2024.10.028

The comorbidity of obesity and depression has major public health impacts, highlighting the need to understand their shared mechanisms. This study explored the connection between obesity and depression through the transient receptor potential V1 (TRPV1) signaling pathway, using obese/depressed murine models and clinical data. Mice fed a high-fat diet showed altered TRPV1 pathway expression in brain regions of the mice: downregulated in the medial prefrontal cortex (mPFC) and hippocampus, and upregulated in the hypothalamus and amygdala, influencing depression-like behaviors and inflammation. Treatments like eicosapentaenoic acid (EPA) and acupoint catgut embedding (ACE) reversed these effects, similar to observations in Trpv1^−/− mice. Furthermore, chemogenetic activation in the ventral mPFC also alleviated depression via TRPV1. In our clinical validation, single nucleotide polymorphisms (SNPs) in TRPV1-related genes (PIK3C2A and PRKCA) were linked to interferon-induced depression. These findings underscore the potential of targeting TRPV1 as a therapeutic approach for obesity-related depression.

肥胖症和抑郁症的并发症对公众健康产生了重大影响，因此需要了解它们的共同机制。这项研究利用肥胖/抑郁小鼠模型和临床数据，通过瞬时受体电位V1（TRPV1）信号通路探索肥胖与抑郁之间的联系。以高脂肪饮食喂养的小鼠脑区的TRPV1通路表达发生了改变：内侧前额叶皮层（mPFC）和海马下调，下丘脑和杏仁核上调，从而影响了抑郁样行为和炎症。二十碳五烯酸（EPA）和穴位埋线（ACE）等治疗方法可逆转这些影响，这与在Trpv1-/-小鼠身上观察到的结果相似。此外，腹侧 mPFC 的化学激活也能通过 TRPV1 缓解抑郁。在我们的临床验证中，TRPV1相关基因（PIK3C2A和PRKCA）中的单核苷酸多态性（SNPs）与干扰素诱导的抑郁有关。这些发现强调了靶向 TRPV1 作为肥胖相关抑郁症治疗方法的潜力。

引用次数: 0

Peptidoglycan accumulates in distinct brain regions and cell types over lifetime but is absent in newborns 在人的一生中，肽聚糖会在不同的大脑区域和细胞类型中积累，但在新生儿中却不存在。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-22 DOI: 10.1016/j.bbi.2024.10.024

Peptidoglycan (PGN) is a large complex polymer critical to structure and function of all bacterial species. Intact PGN and its fragments are inflammatory, contributing to infectious and autoimmune disease. Recent studies show that PGN physiologically contributes to immune setpoints, and importantly also to mouse brain development and behavior. However, for the human brain, it remains unknown whether PGN and its fragments differentially gain access to distinct brain regions, which cell types accumulate it, and whether PGN brain load varies with age. Therefore, we investigated human postmortem brain samples of donors with an extensive age range, from newborns to nonagenarians. We examined two monoclonal antibodies against PGN which were validated using dot blot analysis, competition assays and immunofluorescence experiments on bacteria sacculi, which jointly showed specific detection of Gram-positive PGN. As positive reference tissue, brain tissue from sepsis patients, and human liver were used, both showing the expected high PGN levels. In adult brain tissue of different age (34- to 94-year-old) and sex, we detected PGN signals in seven different brain regions, with highest loads in the occipital cortex, hippocampal formation, frontal cortex, the periventricular region and the olfactory bulb. Age-dependent increase of signals was not evident by microscopic observations and only weak correlation was found by statistical analysis in this cohort. PGN was found intracellularly in the cytoplasm surrounding the cell nucleus in astrocytes, oligodendrocytes, neurons, and endothelial cells, but not in macrophages like microglia. PGN was absent in brain tissues of three human newborns (stillbirth to four weeks old). For comparison, three brain regions from non-human primates of varying age (newborn to 21 years) were immunohistochemically stained. The highest PGN-load was observed in brain tissue from 18- to 21-year-old macaques.

This first systematic evaluation of PGN in human postmortem brain suggests that PGN accumulates during lifetime until it reaches a plateau by homeostatic turnover and highlights the ubiquitous presence of PGN in human brain tissues, and their ability to participate in physiological as well as pathological processes throughout life.

肽聚糖（PGN）是一种大型复杂聚合物，对所有细菌物种的结构和功能至关重要。完整的 PGN 及其片段具有炎症性，可导致感染性和自身免疫性疾病。最近的研究表明，PGN 在生理上有助于免疫设置点，而且对小鼠的大脑发育和行为也有重要影响。然而，对于人脑而言，PGN 及其片段是否会以不同方式进入不同的脑区、哪些细胞类型会积聚 PGN 以及 PGN 的脑负荷是否会随年龄而变化，这些问题仍然不得而知。因此，我们研究了从新生儿到高龄老人等不同年龄段供体的人脑死后样本。我们检测了两种针对 PGN 的单克隆抗体，并通过点印迹分析、竞争分析和细菌囊免疫荧光实验对其进行了验证，结果显示这两种抗体都能特异性地检测到革兰氏阳性 PGN。作为阳性参考组织，脓毒症患者的脑组织和人体肝脏都显示出预期的高 PGN 水平。在不同年龄（34 至 94 岁）和性别的成人脑组织中，我们在七个不同的脑区检测到了 PGN 信号，其中枕叶皮层、海马形成、额叶皮层、脑室周围和嗅球的 PGN 信号量最高。通过显微镜观察，信号的增加与年龄的关系并不明显，而且通过统计分析，在该组人群中也只发现了微弱的相关性。在星形胶质细胞、少突胶质细胞、神经元和内皮细胞中，PGN 存在于细胞核周围的细胞质中，但不存在于巨噬细胞（如小胶质细胞）中。三例人类新生儿（死产至四周大）的脑组织中没有 PGN。为了进行比较，对不同年龄（从新生儿到 21 岁）的非人灵长类动物的三个脑区进行了免疫组化染色。在 18 至 21 岁猕猴的脑组织中观察到最高的 PGN 含量。这是对人类死后大脑中 PGN 的首次系统性评估，表明 PGN 在人的一生中会不断积累，直到通过同源性周转达到一个平衡点，并强调了 PGN 在人类脑组织中的普遍存在，以及它们在人的一生中参与生理和病理过程的能力。

{"title":"Peptidoglycan accumulates in distinct brain regions and cell types over lifetime but is absent in newborns","authors":"","doi":"10.1016/j.bbi.2024.10.024","DOIUrl":"10.1016/j.bbi.2024.10.024","url":null,"abstract":"<div><div>Peptidoglycan (PGN) is a large complex polymer critical to structure and function of all bacterial species. Intact PGN and its fragments are inflammatory, contributing to infectious and autoimmune disease. Recent studies show that PGN physiologically contributes to immune setpoints, and importantly also to mouse brain development and behavior. However, for the human brain, it remains unknown whether PGN and its fragments differentially gain access to distinct brain regions, which cell types accumulate it, and whether PGN brain load varies with age. Therefore, we investigated human postmortem brain samples of donors with an extensive age range, from newborns to nonagenarians. We examined two monoclonal antibodies against PGN which were validated using dot blot analysis, competition assays and immunofluorescence experiments on bacteria sacculi, which jointly showed specific detection of Gram-positive PGN. As positive reference tissue, brain tissue from sepsis patients, and human liver were used, both showing the expected high PGN levels. In adult brain tissue of different age (34- to 94-year-old) and sex, we detected PGN signals in seven different brain regions, with highest loads in the occipital cortex, hippocampal formation, frontal cortex, the periventricular region and the olfactory bulb. Age-dependent increase of signals was not evident by microscopic observations and only weak correlation was found by statistical analysis in this cohort. PGN was found intracellularly in the cytoplasm surrounding the cell nucleus in astrocytes, oligodendrocytes, neurons, and endothelial cells, but not in macrophages like microglia. PGN was absent in brain tissues of three human newborns (stillbirth to four weeks old). For comparison, three brain regions from non-human primates of varying age (newborn to 21 years) were immunohistochemically stained. The highest PGN-load was observed in brain tissue from 18- to 21-year-old macaques.</div><div>This first systematic evaluation of PGN in human postmortem brain suggests that PGN accumulates during lifetime until it reaches a plateau by homeostatic turnover and highlights the ubiquitous presence of PGN in human brain tissues, and their ability to participate in physiological as well as pathological processes throughout life.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

C-section and systemic inflammation synergize to disrupt the neonatal gut microbiota and brain development in a model of prematurity 在早产儿模型中，剖腹产和全身炎症会协同破坏新生儿肠道微生物群和大脑发育。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-22 DOI: 10.1016/j.bbi.2024.10.023

Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis. In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery. We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation. This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.

早产儿（妊娠 28 周以下）患神经发育障碍（如智力缺陷、自闭症谱系障碍和注意力缺陷）的风险很高。早产往往是在绒毛膜羊膜炎和产后败血症导致围产期全身炎症的情况下发生的。此外，为了避免阴道分娩过程中的缺氧，通常会对极早产新生儿实施剖腹产。我们开发了一种小鼠模型，并对其进行了表征，该模型基于在出生后第 1 天和第 5 天之间腹腔注射 IL-1β，以再现围产期全身炎症。该模型复制了在早产儿身上观察到的几种神经病理学、脑成像和行为缺陷。我们假设剖腹产会与全身炎症协同诱发更严重的大脑异常。我们观察到，与阴道分娩加腹腔注射生理盐水相比，剖腹产明显加剧了IL-1β对肠道微生物多样性减少、循环肽聚糖水平升高、小胶质细胞/巨噬细胞反应异常、髓鞘化受损和大脑功能连接性降低的有害影响。这些数据证明了剖腹产和新生儿全身炎症对大脑发育不良和功能失调的有害协同作用，而这两种情况在极早产儿中经常出现，他们患神经发育障碍的风险很高。

{"title":"C-section and systemic inflammation synergize to disrupt the neonatal gut microbiota and brain development in a model of prematurity","authors":"","doi":"10.1016/j.bbi.2024.10.023","DOIUrl":"10.1016/j.bbi.2024.10.023","url":null,"abstract":"<div><div>Infants born very preterm (below 28 weeks of gestation) are at high risk of developing neurodevelopmental disorders, such as intellectual deficiency, autism spectrum disorders, and attention deficit. Preterm birth often occurs in the context of perinatal systemic inflammation due to chorioamnionitis and postnatal sepsis. In addition, C-section is often performed for very preterm neonates to avoid hypoxia during a vaginal delivery. We have developed and characterized a mouse model based on intraperitoneal injections of IL-1β between postnatal days one and five to reproduce perinatal systemic inflammation. This model replicates several neuropathological, brain imaging, and behavioral deficits observed in preterm infants. We hypothesized that C-sections could synergize with systemic inflammation to induce more severe brain abnormalities. We observed that C-sections significantly exacerbated the deleterious effects of IL-1β on reduced gut microbial diversity, increased levels of circulating peptidoglycans, abnormal microglia/macrophage reactivity, impaired myelination, and reduced functional connectivity in the brain relative to vaginal delivery plus intraperitoneal saline. These data demonstrate the deleterious synergistic effects of C-section and neonatal systemic inflammation on brain maldevelopment and malfunction, two conditions frequently observed in very preterm infants, who are at high risk of developing neurodevelopmental disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prophylactic use of probiotics as an adjunctive treatment for ischemic stroke via the gut-spleen-brain axis 通过肠道-脾脏-大脑轴预防性使用益生菌作为缺血性中风的辅助治疗。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-22 DOI: 10.1016/j.bbi.2024.10.026

A growing body of research has focused on the role of spleen in orchestrating brain injury through the peripheral immune system following stroke, highlighting the brain-spleen axis as a potential target for mitigating neuronal damage during stroke. The gut microbiota plays a pivotal role in the bidirectional communication between the gut and the brain. Several studies have suggested that probiotic supplements hold promise as a strategic approach to maintaining a balanced intestinal microecology, reducing the apoptosis of intestinal epithelial cells, protecting the intestinal mucosal and blood–brain barrier (BBB), enhancing both intestinal and systemic immune functions, and thereby potentially affecting the pathogenesis and progression of ischemic stroke. In this study, we aimed to clarify the neuroprotective effects of supplementation with Lactobacillus, specifically Limosilactobacillus reuteri GMNL-89 (G89) and Lacticaseibacillus paracasei GMNL-133 (G133) on ischemic stroke and investigate how G89 and G133 modulate the communication mechanisms between the gut, brain, and spleen following ischemic stroke. We explored the neuroprotection and the underlying mechanisms of Lactobacillus supplementation in C57BL/6 mice subjected to permanent middle cerebral artery occlusion. Our results revealed that oral treatment with G89 or G133 alone, as well as oral administration combining G89 and G133, significantly decreased the infarct volume and improved the neurological function in mice with ischemic stroke. Moreover, G89 treatment alone preserved the tight junction integrity of gut barrier, while G133 alone and the combined treatment of G89 and G133 would significantly decreased the BBB permeability, and thereby significantly attenuated stroke-induced local and systemic inflammatory responses. Both G89 and G133 regulated cytotoxic T cells, and the balance between T helper 1 cells and T helper 2 cells in the spleen following ischemic stroke. Additionally, the combined administration of G89 and G133 improved the gut dysbiosis and significantly increased the concentration of short‐chain fatty acids. In conclusion, our findings suggest that G89 and G133 may be used as nutrient supplements, holding promise as a prospective approach to combat ischemic stroke by modulating the gut-spleen-brain axis.

越来越多的研究关注中风后脾脏通过外周免疫系统协调脑损伤的作用，强调脑-脾轴是减轻中风期间神经元损伤的潜在靶点。肠道微生物群在肠道与大脑之间的双向交流中发挥着关键作用。多项研究表明，益生菌补充剂有望成为维持肠道微生态平衡的战略方法，减少肠道上皮细胞凋亡，保护肠道粘膜和血脑屏障（BBB），增强肠道和全身免疫功能，从而可能影响缺血性脑卒中的发病机制和进展。本研究旨在阐明补充乳酸杆菌，特别是Limosilactobacillus reuteri GMNL-89（G89）和Lacticaseibacillus paracasei GMNL-133（G133）对缺血性脑卒中的神经保护作用，并研究G89和G133如何调节缺血性脑卒中后肠道、大脑和脾脏之间的沟通机制。我们对C57BL/6小鼠永久性大脑中动脉闭塞后补充乳酸菌的神经保护作用及其内在机制进行了探讨。我们的研究结果表明，单独口服 G89 或 G133 以及同时口服 G89 和 G133 能显著减少缺血性脑卒中小鼠的梗死体积并改善其神经功能。此外，G89单独治疗可保持肠道屏障紧密连接的完整性，而G133单独治疗以及G89和G133联合治疗可显著降低BBB的通透性，从而显著减轻中风引起的局部和全身炎症反应。G89和G133都能调节缺血性中风后脾脏中的细胞毒性T细胞以及T辅助1细胞和T辅助2细胞之间的平衡。此外，联合服用 G89 和 G133 还能改善肠道菌群失调，并显著提高短链脂肪酸的浓度。总之，我们的研究结果表明，G89 和 G133 可用作营养补充剂，有望成为通过调节肠道-脾脏-大脑轴来防治缺血性中风的一种前瞻性方法。

{"title":"Prophylactic use of probiotics as an adjunctive treatment for ischemic stroke via the gut-spleen-brain axis","authors":"","doi":"10.1016/j.bbi.2024.10.026","DOIUrl":"10.1016/j.bbi.2024.10.026","url":null,"abstract":"<div><div>A growing body of research has focused on the role of spleen in orchestrating brain injury through the peripheral immune system following stroke, highlighting the brain-spleen axis as a potential target for mitigating neuronal damage during stroke. The gut microbiota plays a pivotal role in the bidirectional communication between the gut and the brain. Several studies have suggested that probiotic supplements hold promise as a strategic approach to maintaining a balanced intestinal microecology, reducing the apoptosis of intestinal epithelial cells, protecting the intestinal mucosal and blood–brain barrier (BBB), enhancing both intestinal and systemic immune functions, and thereby potentially affecting the pathogenesis and progression of ischemic stroke. In this study, we aimed to clarify the neuroprotective effects of supplementation with <em>Lactobacillus</em>, specifically <em>Limosilactobacillus</em> reuteri GMNL-89 (G89) and Lacticaseibacillus <em>paracasei</em> GMNL-133 (G133) on ischemic stroke and investigate how G89 and G133 modulate the communication mechanisms between the gut, brain, and spleen following ischemic stroke. We explored the neuroprotection and the underlying mechanisms of <em>Lactobacillus</em> supplementation in C57BL/6 mice subjected to permanent middle cerebral artery occlusion. Our results revealed that oral treatment with G89 or G133 alone, as well as oral administration combining G89 and G133<em>,</em> significantly decreased the infarct volume and improved the neurological function in mice with ischemic stroke. Moreover, G89 treatment alone preserved the tight junction integrity of gut barrier, while G133 alone and the combined treatment of G89 and G133 would significantly decreased the BBB permeability, and thereby significantly attenuated stroke-induced local and systemic inflammatory responses. Both G89 and G133 regulated cytotoxic T cells, and the balance between T helper 1 cells and T helper 2 cells in the spleen following ischemic stroke. Additionally, the combined administration of G89 and G133 improved the gut dysbiosis and significantly increased the concentration of short‐chain fatty acids. In conclusion, our findings suggest that G89 and G133 may be used as nutrient supplements, holding promise as a prospective approach to combat ischemic stroke by modulating the gut-spleen-brain axis.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A systematic approach to identify gaps in neuroimmunology: TNF-α and fear learning deficits, a worked example 找出神经免疫学空白的系统方法：以 TNF-α 和恐惧学习障碍为例

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-21 DOI: 10.1016/j.bbi.2024.10.027

Background

The pathophysiology of several neurodegenerative and neuropsychiatric disorders is linked to an altered immune system. However, it is often unclear how the immune system specifically affects these disorders since neuroimmune interactions are very complex. In this paper, we introduce an adjusted version of the adverse outcome pathway (AOP) approach from toxicology to the field of neuroimmunology. A review of the effect of TNF-α on fear learning deficits is used as a worked example to demonstrate how an AOP approach can help identify gaps of knowledge and crucial steps in the pathophysiology of neuroimmunological disorders.

Methods

The AOP was constructed in five steps. First, the adverse outcome was formulated clearly and specifically. Second, the link between the molecular initiating event and the adverse outcome was established with a preliminary literature search in the Medline database. Third, a systematic literature search was performed in which we identified 95 relevant articles. Fourth, the main biological processes and relevant key events were identified. Fifth, the links between key events were determined and an AOP network was constructed.

Results

We identified three pathways through which TNF-α may affect fear learning. First, TNF-α receptor activation increases NF-κB levels which increases oxidative stress levels and reduces the activity of glutamate transporters. This alters the synaptic plasticity which is associated with impaired fear acquisition, consolidation, and fear extinction. Second, activation of TNF-α receptors increases the expression and capacity of the serotonin transporter which is linked to impaired fear acquisition, expression, and extinction. Third, TNF-α receptor 1 activation can induce necroptosis, leading to neuroinflammation which is linked to fear learning deficits.

Conclusion

To successfully apply the AOP approach in neuroimmunology we recommend defining adverse outcomes more precisely, establishing stronger connections between key events from various biological processes, incorporating feedforward and feedback loops, and identifying more mechanistic knowledge in later key events. These adjustments are needed to map the complex processes within the field of neuroimmunology and to identify gaps of knowledge.

背景：一些神经退行性疾病和神经精神疾病的病理生理学与免疫系统的改变有关。然而，由于神经免疫相互作用非常复杂，人们往往不清楚免疫系统是如何具体影响这些疾病的。在本文中，我们将毒理学中的不良后果途径（AOP）方法调整后引入神经免疫学领域。本文以 TNF-α 对恐惧学习障碍的影响为例，展示了 AOP 方法如何帮助识别神经免疫疾病病理生理学中的知识空白和关键步骤：AOP 的构建分为五个步骤。首先，明确而具体地提出不良后果。其次，在 Medline 数据库中进行初步文献检索，确定分子起始事件与不良后果之间的联系。第三，进行系统的文献检索，我们发现了 95 篇相关文章。第四，确定了主要的生物学过程和相关的关键事件。第五，确定了关键事件之间的联系，并构建了 AOP 网络：结果：我们发现了 TNF-α 影响恐惧学习的三个途径。首先，TNF-α受体激活会增加NF-κB水平，从而增加氧化应激水平并降低谷氨酸转运体的活性。这就改变了突触的可塑性，而突触的可塑性与恐惧的获得、巩固和消除有关。其次，TNF-α受体的激活会增加血清素转运体的表达和能力，而血清素转运体与恐惧的获得、表达和消除受损有关。第三，TNF-α受体1激活可诱导坏死，导致神经炎症，而神经炎症与恐惧学习障碍有关：为了在神经免疫学中成功应用 AOP 方法，我们建议更精确地定义不良后果，在各种生物过程的关键事件之间建立更强的联系，纳入前馈和反馈回路，并在后面的关键事件中确定更多的机理知识。需要进行这些调整，以绘制神经免疫学领域的复杂过程图，并找出知识差距。

{"title":"A systematic approach to identify gaps in neuroimmunology: TNF-α and fear learning deficits, a worked example","authors":"","doi":"10.1016/j.bbi.2024.10.027","DOIUrl":"10.1016/j.bbi.2024.10.027","url":null,"abstract":"<div><h3>Background</h3><div>The pathophysiology of several neurodegenerative and neuropsychiatric disorders is linked to an altered immune system. However, it is often unclear how the immune system specifically affects these disorders since neuroimmune interactions are very complex. In this paper, we introduce an adjusted version of the adverse outcome pathway (AOP) approach from toxicology to the field of neuroimmunology. A review of the effect of TNF-α on fear learning deficits is used as a worked example to demonstrate how an AOP approach can help identify gaps of knowledge and crucial steps in the pathophysiology of neuroimmunological disorders.</div></div><div><h3>Methods</h3><div>The AOP was constructed in five steps. First, the adverse outcome was formulated clearly and specifically. Second, the link between the molecular initiating event and the adverse outcome was established with a preliminary literature search in the Medline database. Third, a systematic literature search was performed in which we identified 95 relevant articles. Fourth, the main biological processes and relevant key events were identified. Fifth, the links between key events were determined and an AOP network was constructed.</div></div><div><h3>Results</h3><div>We identified three pathways through which TNF-α may affect fear learning. First, TNF-α receptor activation increases NF-κB levels which increases oxidative stress levels and reduces the activity of glutamate transporters. This alters the synaptic plasticity which is associated with impaired fear acquisition, consolidation, and fear extinction. Second, activation of TNF-α receptors increases the expression and capacity of the serotonin transporter which is linked to impaired fear acquisition, expression, and extinction. Third, TNF-α receptor 1 activation can induce necroptosis, leading to neuroinflammation which is linked to fear learning deficits.</div></div><div><h3>Conclusion</h3><div>To successfully apply the AOP approach in neuroimmunology we recommend defining adverse outcomes more precisely, establishing stronger connections between key events from various biological processes, incorporating feedforward and feedback loops, and identifying more mechanistic knowledge in later key events. These adjustments are needed to map the complex processes within the field of neuroimmunology and to identify gaps of knowledge.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lifetime chronic stress Exposures, stress Hormones, and biological Aging: Results from the midlife in the United States (MIDUS) study. 终生慢性压力暴露、压力荷尔蒙和生物衰老：美国中年（MIDUS）研究结果。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-21 DOI: 10.1016/j.bbi.2024.10.022

Jenna L Hansen, Judith E Carroll, Teresa E Seeman, Steve W Cole, Kelly E Rentscher

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (M_age = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16^INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life.

社会心理压力和逆境与加速衰老和增加罹患老年相关疾病的风险有关。动物和体外研究表明，暴露于应激激素（儿茶酚胺、糖皮质激素）会影响 DNA 损伤和细胞衰老等生物衰老过程，这表明它们在应激和衰老之间的联系中起着关键作用；然而，这些联系在人类中还没有得到很好的研究。我们研究了中年成人长期压力暴露、压力荷尔蒙和生物衰老标志物之间的横断面关联，以及压力荷尔蒙是否介导了压力和衰老之间的关联。研究对象是具有全国代表性的美国中年进修队列中的 531 名 26-78 岁成年人（年龄 = 53.9，女性占 50.1%）。他们报告了童年和成年时所遭受的慢性压力（生活压力事件量表），并提供了用于评估去甲肾上腺素、肾上腺素和皮质醇的 12 小时尿样。外周血单核细胞的 RNA 测序得出了衰老生物标志物：DNA 损伤反应（DDR；30 个基因合成）、细胞衰老信号 p16INK4a (CDKN2A) 和促炎症衰老相关分泌表型（SASP；57 个基因合成）。对年龄、性别、种族/民族、体重指数、吸烟状况、饮酒和药物进行调整后的回归模型显示，童年时期接触较多的去甲肾上腺素较高（β = 0.09，p = 0.04），这与成人接触无关。较高的去甲肾上腺素与 DDR 表达的升高有关（β = 0.17，p = 0.04）。

{"title":"Lifetime chronic stress Exposures, stress Hormones, and biological Aging: Results from the midlife in the United States (MIDUS) study.","authors":"Jenna L Hansen, Judith E Carroll, Teresa E Seeman, Steve W Cole, Kelly E Rentscher","doi":"10.1016/j.bbi.2024.10.022","DOIUrl":"10.1016/j.bbi.2024.10.022","url":null,"abstract":"<p><p>Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (M<sub>age</sub> = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16<sup>INK4a</sup> (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

No association of posttraumatic stress disorder with epigenetic aging in women at mid-life: A longitudinal cohort study 创伤后应激障碍与中年女性的表观遗传衰老无关：纵向队列研究

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-17 DOI: 10.1016/j.bbi.2024.10.003

Posttraumatic stress disorder (PTSD) is associated with mortality and increased risk of diseases of aging, but underlying mechanisms remain unclear. We examine associations of PTSD with one potential pathway, accelerated epigenetic aging. In a longitudinal cohort of trauma-exposed middle-aged women (n = 831, n observations = 1,516), we examined cross-sectional and longitudinal associations between PTSD, with and without comorbid depression, and epigenetic aging measured by six clocks at two time points approximately 13.5 years apart: Hannum, Horvath, PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE. We further examined associations of 3 well-established predictors of aging and mortality also linked with PTSD, namely, body mass index (BMI), diet quality, and physical activity, with epigenetic aging. Cross-sectionally, across all six clocks, epigenetic aging in women with PTSD alone, depression alone, and co-occurring depression and PTSD did not differ from the reference group of women without PTSD or depression in analyses adjusted for age, self-reported race, cell proportions, and ancestry principal components. In longitudinal analyses, we similarly did not find any difference in change in epigenetic age over time by PTSD and depression status at baseline. Among the health factors, in cross-sectional analyses, higher BMI was significantly and consistently associated with greater epigenetic aging measured by the PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE clocks, but not measured by the Hannum or Horvath clocks. Physical activity was not consistently associated with epigenetic aging measured by Hannum, Horvath, PhenoAge, or GrimAge. In analyses with the DunedinPoAm and DunedinPACE clocks, women who reported exercise equivalent to 1 or more hours/week walking had slower epigenetic aging than women with less exercise. Diet quality was not consistently associated with epigenetic aging measured by any of the clocks. Our data do not provide evidence that biological aging, as measured by any of the six epigenetic clocks, is a pathway linking PTSD with mortality and diseases of aging.

创伤后应激障碍（PTSD）与死亡率和衰老疾病风险的增加有关，但其潜在机制仍不清楚。我们研究了创伤后应激障碍与加速表观遗传衰老这一潜在途径之间的关系。在一个受过创伤的中年女性纵向队列（n = 831，n 观察 = 1,516）中，我们研究了创伤后应激障碍（伴有或不伴有抑郁症）与表观遗传老化之间的横向和纵向联系，这些联系是在相隔约 13.5 年的两个时间点通过六个时钟测量的：Hannum、Horvath、PhenoAge、GrimAge、DunedinPoAM 和 DunedinPACE。我们还进一步研究了与创伤后应激障碍有关的三个成熟的衰老和死亡率预测因素，即体重指数（BMI）、饮食质量和体育锻炼与表观遗传衰老的关系。横向分析显示，在所有六个时钟中，单独患有创伤后应激障碍的女性、单独患有抑郁症的女性、同时患有抑郁症和创伤后应激障碍的女性的表观遗传学衰老与无创伤后应激障碍或抑郁症的参照组女性的表观遗传学衰老在年龄、自我报告的种族、细胞比例和祖先主成分调整后的分析中没有差异。同样，在纵向分析中，我们也没有发现创伤后应激障碍和抑郁状态基线表观遗传年龄随时间变化的差异。在健康因素中，在横断面分析中，较高的体重指数（BMI）与 PhenoAge、GrimAge、DunedinPoAM 和 DunedinPACE 时钟测量的更大的表观遗传衰老有显著且一致的关联，但与 Hannum 或 Horvath 时钟测量的关联不大。体育锻炼与用 Hannum、Horvath、PhenoAge 或 GrimAge 测量的表观遗传衰老并不一致。在使用达尼丁时间钟（DunedinPoAm）和达尼丁时间钟（DunedinPACE）进行的分析中，与运动量较少的女性相比，运动量相当于每周步行 1 小时或以上的女性的表观遗传衰老速度较慢。饮食质量与任何时钟测量的表观遗传衰老都没有一致的关联。我们的数据没有提供证据表明，用六种表观遗传时钟中的任何一种测量的生物衰老是创伤后应激障碍与死亡率和衰老疾病相关的途径。

{"title":"No association of posttraumatic stress disorder with epigenetic aging in women at mid-life: A longitudinal cohort study","authors":"","doi":"10.1016/j.bbi.2024.10.003","DOIUrl":"10.1016/j.bbi.2024.10.003","url":null,"abstract":"<div><div>Posttraumatic stress disorder (PTSD) is associated with mortality and increased risk of diseases of aging, but underlying mechanisms remain unclear. We examine associations of PTSD with one potential pathway, accelerated epigenetic aging. In a longitudinal cohort of trauma-exposed middle-aged women (n = 831, n observations = 1,516), we examined cross-sectional and longitudinal associations between PTSD, with and without comorbid depression, and epigenetic aging measured by six clocks at two time points approximately 13.5 years apart: Hannum, Horvath, PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE. We further examined associations of 3 well-established predictors of aging and mortality also linked with PTSD, namely, body mass index (BMI), diet quality, and physical activity, with epigenetic aging. Cross-sectionally, across all six clocks, epigenetic aging in women with PTSD alone, depression alone, and co-occurring depression and PTSD did not differ from the reference group of women without PTSD or depression in analyses adjusted for age, self-reported race, cell proportions, and ancestry principal components. In longitudinal analyses, we similarly did not find any difference in change in epigenetic age over time by PTSD and depression status at baseline. Among the health factors, in cross-sectional analyses, higher BMI was significantly and consistently associated with greater epigenetic aging measured by the PhenoAge, GrimAge, DunedinPoAM, and DunedinPACE clocks, but not measured by the Hannum or Horvath clocks. Physical activity was not consistently associated with epigenetic aging measured by Hannum, Horvath, PhenoAge, or GrimAge. In analyses with the DunedinPoAm and DunedinPACE clocks, women who reported exercise equivalent to 1 or more hours/week walking had slower epigenetic aging than women with less exercise. Diet quality was not consistently associated with epigenetic aging measured by any of the clocks. Our data do not provide evidence that biological aging, as measured by any of the six epigenetic clocks, is a pathway linking PTSD with mortality and diseases of aging.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute effects of interferon-alpha on cellular anabolic and catabolic processes are associated with the development of fatigue during Interferon-alpha-based therapy for Hepatitis-C: A preliminary study 干扰素-α对细胞合成代谢和分解代谢过程的急性影响与干扰素-α治疗丙型肝炎期间疲劳的产生有关：一项初步研究。

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity

Pub Date : 2024-10-15 DOI: 10.1016/j.bbi.2024.09.038

Introduction

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue.

Methods

In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein–protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment.

Results

IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078).

Conclusion

Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations.

导言：干扰素-α（IFN-α）是抗病毒免疫反应的关键介质，用于治疗丙型肝炎病毒（HCV）感染。虽然 IFN-α 在临床上很有效，但它经常会诱发功能性的情绪和动力受损症状，尤其是疲劳。与通常在治疗数周后出现的情绪损害不同，疲劳往往出现和发展迅速，通常在首次注射 IFN-α 后数小时内出现。尽管疲劳是 IFN-α 和其他免疫疗法过程中功能损害的一个主要来源，但人们对其背后的生物机制仍然知之甚少。在此，我们旨在确定可预测日后疲劳发展的 IFN-α 急性免疫反应特征：在这项探索性研究中，我们对开始接受 IFN-α 和利巴韦林治疗的 27 名 HCV 患者的纵向样本进行了全血转录组学分析。我们在基线和首次服用 IFN-α 后 4½ 小时采集了血样，并使用 Affymetrix 人类基因 1.1 ST 阵列条采集了转录组数据。使用 Partek Genomics Suite V6.6 对基因表达数据的可视化和质量控制进行了评估，并使用 STRING 和 Ingenuity Pathway Analysis (IPA) 对蛋白质-蛋白质相互作用网络进行了评估。采用疲劳视觉模拟量表（fVAS）记录基线、治疗开始后4个半小时和4周的疲劳症状：结果：IFN-α 与 526 个转录本的上调和 228 个基因的下调相关，表明在注射后 4 个半小时内，全血中的转录本组反应迅速。93个基因与疲劳度的变化呈明显的正相关，基因表达的变化是从基线到4.5小时的测量，疲劳度的增加是从基线到第4周的fVAS评估。我们发现了一个主要由细胞质核糖体单位和泛素蛋白组成的新型网络，它们与调节 mTOR 信号转导有关，该网络与开始 IFN-α 治疗 4 周后疲劳的发生有关（p = 0.0078）：我们的研究结果表明，IFN-α对这种合成代谢/代谢网络的急性激活可能会导致疲劳，这与癌症相关疲劳中发现的证据相似。为了证实这些观察结果的探索性质，有必要进行进一步调查。

{"title":"Acute effects of interferon-alpha on cellular anabolic and catabolic processes are associated with the development of fatigue during Interferon-alpha-based therapy for Hepatitis-C: A preliminary study","authors":"","doi":"10.1016/j.bbi.2024.09.038","DOIUrl":"10.1016/j.bbi.2024.09.038","url":null,"abstract":"<div><h3>Introduction</h3><div>Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue.</div></div><div><h3>Methods</h3><div>In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein–protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment.</div></div><div><h3>Results</h3><div>IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078).</div></div><div><h3>Conclusion</h3><div>Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0