Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome

经皮耳迷走神经刺激对便秘型肠易激综合征小鼠模型的改善作用

Limited treatment options have been shown to alter the natural course of constipation-predominant irritable bowel syndrome (IBS-C). Therefore, safer and more effective approaches are urgently needed. We investigated the effects of transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of IBS-C. In the current study, C57BL/6 mice were randomly divided into normal control, IBS-C model control, sham-electrostimulation (sham-ES), taVNS, and drug treatment groups. The effects of taVNS on fecal pellet number, fecal water content, and gastrointestinal transit were evaluated in IBS-C model mice. We assessed the effect of taVNS on visceral hypersensitivity using the colorectal distention test. 16S rRNA sequencing was used to analyze the fecal microbiota of the experimental groups. First, we found that taVNS increased fecal pellet number, fecal water content, and gastrointestinal transit in IBS-C model mice compared with the sham-ES group. Second, taVNS significantly decreased the abdominal withdrawal reflex (AWR) score compared with the sham-ES group, thus relieving visceral hyperalgesia. Third, the gut microbiota outcomes showed that taVNS restored Lactobacillus abundance while increasing Bifidobacterium probiotic abundance at the genus level. Notably, taVNS increased the number of c-kit-positive interstitial cells of Cajal (ICC) in the myenteric plexus region in IBS-C mice compared with the sham-ES group. Therefore, our study indicated that taVNS effectively ameliorated IBS-C in the gut microbiota and ICC.

有限的治疗选择已被证明可以改变便秘型肠易激综合征 (ibs-c) 的自然病程。因此，迫切需要更安全和更有效的方法。我们在ibs-c小鼠模型中研究了经皮耳迷走神经刺激 (taVNS) 的作用。在目前的研究中，将C57BL/6小鼠随机分为正常对照组，ibs-c模型对照组，假电刺激 (sham-es)，taVNS和药物治疗组。在ibs-c模型小鼠中评估了taVNS对粪便颗粒数，粪便含水量和胃肠道运输的影响。我们使用结直肠扩张试验评估了taVNS对内脏高敏感性的影响。16srrna测序用于分析实验组的粪便微生物群。首先，我们发现与假手术组相比，taVNS增加了ibs-c模型小鼠的粪便颗粒数量，粪便含水量和胃肠道运输。其次，与sham-es组相比，taVNS显着降低了腹部撤回反射 (AWR) 评分，从而减轻了内脏痛觉过敏。第三，肠道微生物群结果表明，taVNS恢复了乳杆菌丰度，同时在属水平上增加了双歧杆菌益生菌丰度。值得注意的是，与假手术组相比，taVNS增加了ibs-c小鼠肌间神经丛区域Cajal (ICC) 的c-kit阳性间质细胞的数量。因此，我们的研究表明，taVNS有效改善肠道微生物群和ICC中的ibs-c。

REF: Liu J, Dai Q, Qu T, et al. Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome. Neurobiol Dis. 2024;193:106440. doi:10.1016/j.nbd.2024.106440 PMID: 38369213

Role of soluble epoxide hydrolase in pain and depression comorbidity

可溶性环氧化物水解酶在疼痛和抑郁共病中的作用

The coexistence of chronic pain and depression in clinical practice places a substantial social burden and profoundly impacts in patients. Although a clear correlation exists, the underlying mechanism of comorbidity between chronic pain and depression remains elusive. Research conducted in recent decades has uncovered that soluble epoxide hydrolase, a pivotal enzyme in the metabolism of polyunsaturated fatty acids, plays a crucial role in inflammation. Interestingly, this enzyme is intricately linked to the development of both pain and depression. With this understanding, this review aims to summarize the roles of soluble epoxide hydrolase in pain, depression, and their comorbidity. Simultaneously, we will also explore the underlying mechanisms, providing guidance for future research and drug development.

临床实践中慢性疼痛和抑郁症的共存给患者带来了巨大的社会负担和深远的影响。尽管存在明显的相关性，但慢性疼痛和抑郁症之间合并症的潜在机制仍然难以捉摸。近几十年来进行的研究发现，可溶性环氧化物水解酶是多不饱和脂肪酸代谢的关键酶，在炎症中起着至关重要的作用。有趣的是，这种酶与疼痛和抑郁的发展密切相关。基于这种认识，本文旨在总结可溶性环氧化物水解酶在疼痛，抑郁症及其合并症中的作用。同时，我们还将探讨潜在的机制，为未来的研究和药物开发提供指导。

REF: Bu Y, Yang S, Wang D, et al. Role of soluble epoxide hydrolase in pain and depression comorbidity. Neurobiol Dis. 2024;193:106443. doi:10.1016/j.nbd.2024.106443 PMID: 38395315

Alteration of gut microbiota in post-stroke depression patients with Helicobacter pylori infection

幽门螺杆菌感染的卒中后抑郁患者肠道菌群的变化

Several studies have identified an association between the gut microbiome and post-stroke depression(PSD), and Helicobacter pylori(H. pylori) infection cause significant alterations in the composition of the gastrointestinal microbiome. However, evidence regarding the role of the H. pylori infection in promoting PSD is still lacking. Here, we conducted a retrospective study to explore risk factors associated with PSD. DWMLs and H. pylori infection may play important roles in the development of PSD. H. pylori infection is likely to be involved in the pathogenesis of PSD by altering the intestinal flora.

几项研究已经确定了肠道微生物组与中风后抑郁症 (PSD) 之间的关联，并且幽门螺杆菌 (H. pylori) 感染会导致胃肠道微生物组的组成发生重大变化。然而，关于幽门螺杆菌感染在促进PSD中的作用的证据仍然缺乏。在这里，我们进行了一项回顾性研究，以探讨与PSD相关的危险因素。DWMLs和幽门螺杆菌感染可能在PSD的发生发展中起重要作用。幽门螺杆菌感染可能通过改变肠道菌群参与PSD的发病。

REF: Sun M, Chen H, Dong S, Zhang G, Zhou X, Cheng H. Alteration of gut microbiota in post-stroke depression patients with Helicobacter pylori infection. Neurobiol Dis. 2024;193:106458. doi:10.1016/j.nbd.2024.106458 PMID: 38423194

Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa

肠道菌群对下丘脑食欲调节神经肽的影响: 来自神经性厌食症的常规，抗生素治疗和无菌小鼠模型的见解

Recent research highlights the profound impact of the gut microbiome on neuropsychiatric disorders, shedding light on its potential role in shaping human behavior. In this study, we investigate the role of the gut microbiome in appetite regulation using activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) - a severe eating disorder with significant health consequences. ABA was induced in conventional, antibiotic-treated, and germ-free mice. Our results show the clear influence of the gut microbiome on the expression of four orexigenic (neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, and orexin) and four anorexigenic peptides (cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, thyrotropin-releasing hormone, and pro-opiomelanocortin) in the hypothalamus. Additionally, we assessed alterations in gut barrier permeability. While variations were noted in germ-free mice based on feeding and activity, they were not directly attributable to the gut microbiome. This research emphasizes that the gut microbiome is a pivotal factor in AN's appetite regulation beyond just dietary habits or physical activity.

最近的研究强调了肠道微生物组对神经精神疾病的深远影响，揭示了其在塑造人类行为中的潜在作用。在这项研究中，我们使用神经性厌食症 (AN) 的基于活动的厌食症 (ABA) 小鼠模型来研究肠道微生物组在食欲调节中的作用，这是一种严重的进食障碍，对健康有重大影响。在常规、抗生素处理和无菌小鼠中诱导ABA。我们的研究结果表明，肠道微生物组对四种致食欲肽 (神经肽Y，刺鼠相关肽，黑色素浓缩激素和食欲素) 和四种致食欲肽 (可卡因和苯丙胺调节的转录本，促肾上腺皮质激素释放激素，促甲状腺激素释放激素，和前阿黑皮素) 在下丘脑。此外，我们评估了肠道屏障通透性的变化。虽然在无菌小鼠中发现了基于喂养和活动的变化，但它们并不直接归因于肠道微生物组。这项研究强调，肠道微生物组是AN食欲调节的关键因素，而不仅仅是饮食习惯或身体活动。

REF: Roubalová R, Procházková P, Kovářová T, et al. Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa. Neurobiol Dis. 2024;193:106460. doi:10.1016/j.nbd.2024.106460 PMID: 38432539

Free water in gray matter linked to gut microbiota changes with decreased butyrate producers in Alzheimer's disease and mild cognitive impairment

灰质中的自由水与阿尔茨海默氏病和轻度认知障碍中丁酸产生减少的肠道菌群变化有关

Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes, Lachnospiraceae UCG-004, and [Ruminococcus] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis.

神经炎症有助于阿尔茨海默氏病 (AD) 的病理和进展，并且即使在AD的前驱期轻度认知障碍 (MCI) 中也可以观察到。自由水 (FW) 成像估计细胞外水含量，并已用于研究包括AD在内的几种神经系统疾病中的神经炎症。最近，肠道微生物群的作用与AD的发病机理有关。在AD和MCI患者中检查FW成像与肠道菌群之间的关系。56名参与者接受了针对细菌16s rRNA基因的神经心理学评估，FW成像和肠道菌群分析。根据神经心理学评估，将他们分为认知正常对照组 (NC) (n = 19)，MCI (n = 19) 和AD (n = 18) 组。分析FW值、神经心理学评估得分与肠道菌群相对丰度的相关性。AD/MCI组的几个白质束和灰质区域的FW高于NC组，主要是额叶，颞叶，边缘和边缘区域。在AD/MCI组中，颞叶 (上颞和颞极)，边缘和边缘 (岛叶，海马和杏仁核) 区域较高的FW值与较差的神经心理学评估得分最相关。在AD/MCI组中，这些区域的FW值与产生丁酸的anaerastipes，Lachnospiraceae UCG-004和 [Ruminococcus] gnavus组的相对丰度呈负相关，它们显示出按NC，MCI和AD组的顺序显着下降的趋势。本研究表明，与认知障碍相关的灰质区域的FW增加与AD/MCI组中丁酸产生物的丰度低有关。这些发现表明，神经炎症与短链脂肪酸丁酸水平降低之间存在关联，而短链脂肪酸丁酸是主要的肠道微生物代谢产物之一，在大脑稳态中具有潜在的有益作用。

REF: Yamashiro K, Takabayashi K, Kamagata K, et al. Free water in gray matter linked to gut microbiota changes with decreased butyrate producers in Alzheimer's disease and mild cognitive impairment. Neurobiol Dis. 2024;193:106464. doi:10.1016/j.nbd.2024.106464 PMID: 38452948

Navigating the future of retinitis pigmentosa treatments: A comprehensive analysis of therapeutic approaches in rd10 mice

导航视网膜色素变性治疗的未来: rd10小鼠治疗方法的综合分析

Retinitis pigmentosa (RP) is a degenerative disease, caused by genetic mutations that lead to a loss in photoreceptors. For research on RP, rd10 mice, which carry mutations in the phosphodiesterase (PDE) gene, exhibit degenerative patterns comparable to those of patients with RP, making them an ideal model for investigating potential treatments. Although numerous studies have reported the potential of biochemical drugs, gene correction, and stem cell transplantation in decelerating rd10 retinal degeneration, a comprehensive review of these studies has yet to be conducted. Therefore, here, a comparative analysis of rd10 mouse treatment research over the past decade was performed. Our findings suggest that biochemical drugs capable of inhibiting the inflammatory response may be promising therapeutics. Additionally, significant progress has been made in the field of gene therapy; nevertheless, challenges such as strict delivery requirements, bystander editing, and off-target effects still need to be resolved. Nevertheless, secretory function is the only unequivocal protective effect of stem cell transplantation. In summary, this review presents a comprehensive analysis and synthesis of the treatment approaches employing rd10 mice as experimental subjects, describing a clear pathway for future RP treatment research and identifies potential clinical interventions.

色素性视网膜炎 (RP) 是一种退行性疾病，由导致光感受器丧失的基因突变引起。对于RP的研究，携带磷酸二酯酶 (PDE) 基因突变的rd10小鼠表现出与RP患者相当的退行性模式，使其成为研究潜在治疗方法的理想模型。尽管许多研究已经报道了生化药物，基因校正和干细胞移植在减缓rd10视网膜变性中的潜力，但尚未对这些研究进行全面审查。因此，在这里，对过去十年的rd10小鼠治疗研究进行了比较分析。我们的发现表明，能够抑制炎症反应的生化药物可能是有希望的治疗方法。此外，基因治疗领域取得了重大进展; 然而，诸如严格的递送要求、旁观者编辑和脱靶效应等挑战仍然需要解决。然而，分泌功能是干细胞移植唯一明确的保护作用。总之，这篇综述对以rd10小鼠为实验对象的治疗方法进行了全面的分析和综合，描述了未来RP治疗研究的明确途径，并确定了潜在的临床干预措施。

REF: Yang H, Zhang H, Li X. Navigating the future of retinitis pigmentosa treatments: A comprehensive analysis of therapeutic approaches in rd10 mice. Neurobiol Dis. 2024;193:106436. doi:10.1016/j.nbd.2024.106436 PMID: 38341159

The potential roles of salivary biomarkers in neurodegenerative diseases

唾液生物标志物在神经退行性疾病中的潜在作用

Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, β-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.

目前对神经退行性疾病的研究工作集中在鉴定新的和可靠的生物标志物，以用于早期诊断和洞察疾病进展。唾液分析作为用于测量神经退行性疾病的生物标志物和基质的有希望的来源正获得越来越多的兴趣。唾液收集与目前检测到的生物流体相比具有多种优势，因为它易于获取，无创且可重复，从而可以早期诊断和及时治疗疾病。在这里，我们回顾了有关唾液生物标志物的现有发现，并探讨了其在诊断神经退行性疾病中的潜在价值，例如阿尔茨海默氏病，帕金森氏病，亨廷顿氏病和肌萎缩性侧索硬化症。根据现有的研究，唾液中的 β-淀粉样蛋白，tau蛋白，α-突触核蛋白，DJ-1，亨廷顿蛋白作为神经退行性疾病的生物标志物显示出可靠性和有效性。

REF: Jiao LL, Dong HL, Liu MM, et al. The potential roles of salivary biomarkers in neurodegenerative diseases. Neurobiol Dis. 2024;193:106442. doi:10.1016/j.nbd.2024.106442 PMID: 38382884

T cell infiltration mediates neurodegeneration and cognitive decline in Alzheimer's disease

T细胞浸润介导阿尔茨海默病的神经变性和认知下降

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with pathological features of β-amyloid (Aβ) and hyperphosphorylated tau protein accumulation in the brain, often accompanied by cognitive decline. So far, our understanding of the extent and role of adaptive immune responses in AD has been quite limited. T cells, as essential members of the adaptive immune system, exhibit quantitative and functional abnormalities in the brains of AD patients. Dysfunction of the blood-brain barrier (BBB) in AD is considered one of the factors leading to T cell infiltration. Moreover, the degree of neuronal loss in AD is correlated with the quantity of T cells. We first describe the differentiation and subset functions of peripheral T cells in AD patients and provide an overview of the key findings related to BBB dysfunction and how T cells infiltrate the brain parenchyma through the BBB. Furthermore, we emphasize the risk factors associated with AD, including Aβ, Tau protein, microglial cells, apolipoprotein E (ApoE), and neuroinflammation. We discuss their regulation of T cell activation and proliferation, as well as the connection between T cells, neurodegeneration, and cognitive decline. Understanding the innate immune response is crucial for providing comprehensive personalized therapeutic strategies for AD.

阿尔茨海默病 (AD) 是一种常见的神经退行性疾病，其病理特征为 β-淀粉样蛋白 (a β) 和过度磷酸化的tau蛋白在大脑中积累，通常伴有认知能力下降。到目前为止，我们对AD中适应性免疫反应的程度和作用的理解非常有限。T细胞作为适应性免疫系统的重要成员，在AD患者的大脑中表现出数量和功能异常。AD中的血脑屏障 (BBB) 功能障碍被认为是导致T细胞浸润的因素之一。此外，AD中神经元损失的程度与T细胞的数量相关。我们首先描述了AD患者外周T细胞的分化和亚群功能，并概述了与BBB功能障碍相关的关键发现以及T细胞如何通过BBB浸润脑实质。此外，我们强调与AD相关的危险因素，包括a β，Tau蛋白，小胶质细胞，载脂蛋白E (ApoE) 和神经炎症。我们讨论了它们对T细胞活化和增殖的调节，以及T细胞，神经变性和认知能力下降之间的联系。了解先天免疫反应对于提供全面的个性化AD治疗策略至关重要。

REF: Zeng J, Liao Z, Yang H, et al. T cell infiltration mediates neurodegeneration and cognitive decline in Alzheimer's disease. Neurobiol Dis. 2024;193:106461. doi:10.1016/j.nbd.2024.106461 PMID: 38437992

Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives

2A型charcot-marie-tooth病: 发病机制和治疗观点的更新

Mutations in the gene encoding MFN2 have been identified as associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a neurological disorder characterized by a broad clinical phenotype involving the entire nervous system. MFN2, a dynamin-like GTPase protein located on the outer mitochondrial membrane, is well-known for its involvement in mitochondrial fusion. Numerous studies have demonstrated its participation in a network crucial for various other mitochondrial functions, including mitophagy, axonal transport, and its controversial role in endoplasmic reticulum (ER)-mitochondria contacts. Considerable progress has been made in the last three decades in elucidating the disease pathogenesis, aided by the generation of animal and cellular models that have been instrumental in studying disease physiology. A review of the literature reveals that, up to now, no definitive pharmacological treatment for any CMT2A variant has been established; nonetheless, recent years have witnessed substantial progress. Many treatment approaches, especially concerning molecular therapy, such as histone deacetylase inhibitors, peptide therapy to increase mitochondrial fusion, the new therapeutic strategies based on MF1/MF2 balance, and SARM1 inhibitors, are currently in preclinical testing. The literature on gene silencing and gene replacement therapies is still limited, except for a recent study by Rizzo et al.(Rizzo et al., 2023), which recently first achieved encouraging results in in vitro and in vivo models of the disease. The near-future goal for these promising therapies is to progress to the stage of clinical translation.

编码MFN2的基因中的突变已被鉴定为与2A型charcot-marie-tooth疾病 (CMT2A) 相关，该疾病是一种神经系统疾病，其特征在于涉及整个神经系统的广泛临床表型。MFN2是一种位于线粒体外膜上的动力蛋白样GTPase蛋白，因其参与线粒体融合而闻名。大量研究表明，它参与了对其他各种线粒体功能至关重要的网络，包括线粒体自噬，轴突运输及其在内质网 (ER)-线粒体接触中的有争议的作用。在过去的三十年中，在阐明疾病发病机理方面取得了相当大的进展，这得益于动物和细胞模型的产生，这些模型有助于研究疾病生理学。文献综述显示，到目前为止，尚未建立针对任何CMT2A变体的明确药理学治疗; 尽管如此，近年来已经取得了实质性进展。许多治疗方法，特别是涉及分子治疗，如组蛋白去乙酰化酶抑制剂，增加线粒体融合的肽治疗，基于MF1/MF2平衡的新治疗策略和SARM1抑制剂，目前正在临床前测试中。关于基因沉默和基因替代疗法的文献仍然有限，除了Rizzo等人最近的研究 (Rizzo等人，2023)，该研究最近首次在疾病的体外和体内模型中取得了令人鼓舞的结果。这些有希望的疗法的近期目标是进展到临床转化阶段。

REF: Alberti C, Rizzo F, Anastasia A, Comi G, Corti S, Abati E. Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives. Neurobiol Dis. 2024;193:106467. doi:10.1016/j.nbd.2024.106467 PMID: 38452947