Life sciences最新文献_第4页

Epitalon-activated telomerase enhance bovine oocyte maturation rate and post-thawed embryo development 表italon活化的端粒酶促进牛卵母细胞成熟率和解冻后胚胎发育。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2025.123381

Safeer Ullah , Zaheer Haider , Chalani Dilshani Perera , Su Hyeon Lee , Muhammad Idrees , Song Park , Il-Keun Kong

Telomerase is highly expressed in oocyte cumulus cells and plays a significant role in follicular development and oocyte maturation. In this study, we hypothesized that in vitro culture conditions may affect telomerase activity during in vitro embryo production (IVP) and that its activation may improve embryo quality. We first examined telomerase protein levels and localization in bovine cumulus-oocyte complexes via immunofluorescence assays. The results showed that healthy cumulus-oocyte complexes have the nuclear localization of the telomerase while the degraded cumulus-oocyte complex had reduced telomerase levels and that telomerase was localized in the cytoplasm. We activated telomerase via Epitalon, a tetrapeptide with the amino acid sequence Ala-Glut-Asp-Gly. We observed a significant improvement in the oocyte maturation rate compared with the control group (p < 0.05). Furthermore, telomerase activity was significantly compromised in post-thawed embryos, and Epitalon treatment significantly improved blastocyst hatching rate and implantation potential (p < 0.05). Moreover, we performed qPCR, reactive oxygen species, and JC-1 (ΔΨm) assays to evaluate the effect of Epitalon on the health of in vitro mature oocytes, cumulus cells, and post-thawed blastocysts, and the result showed that Epitalon highly enhances the quality and health of the oocyte, cumulus cell, and post-thawed blastocyst. Our results suggest that telomerase activation via Epitalon improves bovine in vitro embryo production.

端粒酶在卵母细胞卵丘细胞中高表达，在卵泡发育和卵母细胞成熟过程中起重要作用。在本研究中，我们假设体外培养条件可能影响体外胚胎生产（IVP）过程中端粒酶的活性，其激活可能提高胚胎质量。我们首先通过免疫荧光法检测了端粒酶蛋白水平和牛卵母细胞复合物的定位。结果表明，健康的卵丘-卵母细胞复合物具有端粒酶的核定位，而降解的卵丘-卵母细胞复合物的端粒酶水平降低，端粒酶定位于细胞质中。我们通过Epitalon激活端粒酶，Epitalon是一种氨基酸序列为Ala-Glut-Asp-Gly的四肽。与对照组相比，我们观察到卵母细胞成熟率有显著提高(p

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引用次数: 0

Roflumilast attenuates doxorubicin and cyclophosphamide combination-induced chemobrain in rats through modulation of NLRP3/ASC/caspase-1/GSDMD axis 罗氟司特通过调节NLRP3/ASC/caspase-1/GSDMD轴减弱阿霉素和环磷酰胺联合诱导的大鼠化学脑。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2025.123378

Georgette Eskander , Sherihan G. Abdelhamid , Sara A. Wahdan , Sara M. Radwan

Aim

The aim of this study is to investigate the neuroprotective effect of roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor on cognitive impairment induced by doxorubicin (DOX)/cyclophosphamide (CP) combination therapy and to elucidate its modulatory effect on the pyroptosis pathway.

Materials and methods

Rats were allocated into five groups: a control group, a DOX/CP-intoxicated group, two groups receiving DOX/CP plus low-dose (0.5 mg/kg/day) or high-dose (1 mg/kg/day) roflumilast, and a roflumilast-only group. Behavioral assessments and brain tissue analyses were conducted, including histopathological staining and the measurement of inflammatory and oxidative stress markers.

Findings

DOX/CP treatment resulted in cognitive impairment, abnormal brain histology. It significantly elevated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and malondialdehyde (MDA). Concurrently, superoxide dismutase (SOD) activity was reduced. Pyroptosis-associated markers, including nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, gasdermin-D (GSDMD), and interleukin-18 (IL-18) were upregulated. Apoptotic marker caspase-3 also exhibited increased expression. Conversely, administration of roflumilast (1 mg/kg/day) for four weeks ameliorated these pathological changes. Roflumilast improved cognitive function, reduced oxidative stress, and modulated inflammatory signaling. Additionally, it suppressed pyroptotic and apoptotic pathways within hippocampal tissue.

Significance

These results suggest that roflumilast exerts neuroprotective effects against chemotherapy-induced cognitive dysfunction and neurodegeneration through inhibition of the NLRP3/ASC/caspase-1/GSDMD pyroptosis pathway.

目的：探讨磷酸二酯酶-4 （PDE-4）抑制剂罗氟米司特对阿霉素(DOX)/环磷酰胺（CP）联合治疗所致认知功能障碍的神经保护作用，并阐明其对焦死通路的调节作用。材料和方法：将大鼠分为5组：对照组、DOX/CP中毒组、DOX/CP加低剂量（0.5 mg/kg/day）或高剂量（1 mg/kg/day）罗氟司特组和单剂量罗氟司特组。进行行为评估和脑组织分析，包括组织病理学染色和炎症和氧化应激标志物的测量。结果：DOX/CP治疗导致认知功能障碍，脑组织异常。显著提高肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)和丙二醛（MDA）水平。同时，超氧化物歧化酶（SOD）活性降低。凋亡相关标志物，包括核苷酸结合寡聚化结构域样受体家族pyrin结构域- 3 （NLRP3）、凋亡相关斑点样蛋白（ASC）、caspase-1、gasdermind （GSDMD）和白细胞介素-18 （IL-18）上调。凋亡标志物caspase-3的表达也增加。相反，连续4周给予罗氟司特（1 mg/kg/天）可改善这些病理改变。罗氟司特改善认知功能，减少氧化应激，调节炎症信号。此外，它还能抑制海马组织内的焦亡和凋亡途径。意义：这些结果提示罗氟司特通过抑制NLRP3/caspase-1/GSDMD焦亡通路对化疗诱导的认知功能障碍和神经退行性变具有神经保护作用。

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引用次数: 0

Insight into a multifunctional potassium channel Kv1.3 and its novel implication in chronic kidney disease 多功能钾通道Kv1.3及其在慢性肾脏疾病中的新意义

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123338

Zac Dragan, Carol A. Pollock, Chunling Huang

Chronic kidney disease (CKD), a global public health problem, causes substantial morbidity and mortality worldwide. Innovative therapeutic strategies to mitigate the progression of CKD are needed due to the limitations of existing treatments. Kv1.3, a voltage-gated potassium ion channel, plays a crucial role in multiple biological processes, including cell proliferation, apoptosis, energy homeostasis, and migration. Inhibition of the Kv1.3 channels has shown beneficial effects in the therapy of a wide range of human diseases such as cancer, autoimmune and neuroinflammatory diseases. Increasing evidence reveals a close link between Kv1.3 and CKD. This review summarises the most recent insights into the physiological functions of the Kv1.3 channel and its pharmacological modulators. Furthermore, the therapeutic potential of targeting Kv1.3 for CKD is also discussed. Collectively, these studies suggested that Kv1.3 channels may serve as a novel target for CKD therapy.

慢性肾脏疾病（CKD）是一个全球性的公共卫生问题，在世界范围内造成大量的发病率和死亡率。由于现有治疗方法的局限性，需要创新的治疗策略来缓解CKD的进展。Kv1.3是一种电压门控钾离子通道，在细胞增殖、凋亡、能量稳态和迁移等多种生物过程中起着至关重要的作用。抑制Kv1.3通道在治疗多种人类疾病（如癌症、自身免疫性疾病和神经炎性疾病）中显示出有益的效果。越来越多的证据表明Kv1.3与CKD之间存在密切联系。本文综述了最近对Kv1.3通道及其药理调节剂的生理功能的研究进展。此外，还讨论了靶向Kv1.3治疗CKD的治疗潜力。总的来说，这些研究表明Kv1.3通道可能作为CKD治疗的新靶点。

引用次数: 0

Combined analysis of bulk, single-cell RNA sequencing, and spatial transcriptomics reveals the expression patterns of lipid metabolism and ferroptosis in the immune microenvironment of metabolic-associated fatty liver disease 大体积、单细胞RNA测序和空间转录组学的联合分析揭示了代谢相关脂肪肝免疫微环境中脂质代谢和铁下垂的表达模式。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2025.123377

Zhihao Fang , Changxu Liu , Yue Cheng , Yanchao Ji , Chang Liu

Aims

This study aims to identify key biomarkers associated with ferroptosis and lipid metabolism and investigate their roles in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD). It further explores interactions between these biomarkers and the immune-infiltration environment, shedding light on how ferroptosis and lipid metabolism influence immune dynamics in MAFLD.

Main methods

Single-cell RNA sequencing data from liver samples were analyzed to evaluate expression variations related to ferroptosis and lipid metabolism in MAFLD patients. Gene scores were assessed to explore their impact on the immune microenvironment, particularly hepatocyte-macrophage communication. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to Bulk-RNA-Seq data to identify gene clusters associated with ferroptosis and lipid metabolism. The analyses were integrated into a risk assessment system and predictive model, with validation conducted through in vivo experiments.

Key findings

Integration of single-cell and WGCNA data identified 11 key genes linked to ferroptosis and lipid metabolism (e.g., IER5L, SOCS2, KLF9), significantly influencing the liver's immune microenvironment. The risk assessment system and predictive model achieved an AUC of 0.92 and revealed distinct immune and biological characteristics in MAFLD patients across risk levels. The expression patterns and biological roles of these genes were confirmed in in vivo studies.

Significance

This study establishes a strong link between ferroptosis- and lipid metabolism-related gene expression and MAFLD's complexity. It provides novel insights into disease mechanisms, supporting personalized prognosis and targeted therapeutic strategies for MAFLD patients.

目的：本研究旨在确定与铁下垂和脂质代谢相关的关键生物标志物，并探讨它们在代谢功能障碍相关脂肪性肝病（MAFLD）进展中的作用。它进一步探讨了这些生物标志物与免疫浸润环境之间的相互作用，揭示了铁下垂和脂质代谢如何影响MAFLD的免疫动力学。主要方法：分析肝脏单细胞RNA测序数据，评估MAFLD患者中与铁下垂和脂质代谢相关的表达变化。评估基因评分以探索其对免疫微环境，特别是肝细胞-巨噬细胞通讯的影响。加权基因共表达网络分析（WGCNA）应用于Bulk-RNA-Seq数据，以确定与铁下垂和脂质代谢相关的基因簇。这些分析被整合到一个风险评估系统和预测模型中，并通过体内实验进行验证。主要发现：整合单细胞和WGCNA数据，鉴定出11个与铁死亡和脂质代谢相关的关键基因（如IER5L、SOCS2、KLF9），显著影响肝脏的免疫微环境。风险评估系统和预测模型的AUC为0.92，揭示了不同风险水平下MAFLD患者不同的免疫和生物学特征。这些基因的表达模式和生物学作用在体内研究中得到证实。意义：本研究建立了铁下垂和脂质代谢相关基因表达与MAFLD复杂性之间的紧密联系。它提供了对疾病机制的新见解，支持mald患者的个性化预后和靶向治疗策略。

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引用次数: 0

The many faces of DGAT1 DGAT1的许多面。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123322

Ewa Oleszycka , Kamila Kwiecień , Beata Grygier , Joanna Cichy , Patrycja Kwiecińska

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.

酰基辅酶a：二酰基甘油酰基转移酶1 （DGAT1）是一种多面酶，具有广泛的底物，从脂质到蜡质再到类维生素a，这使其成为一个有趣的治疗靶点。DGAT1抑制剂目前处于临床前和临床试验的各个阶段，主要与代谢性疾病有关。有趣的是，近年来越来越多的研究表明DGAT1对免疫细胞代谢和功能的影响，突出了其在感染和肿瘤发生中的重要作用。在这篇综述中，我们旨在阐明DGAT1在生理和病理条件下的潜在免疫调节作用。

引用次数: 0

Probing the familial ties between serpin members Kallistatin and PEDF: A comparative analysis review 探索serpin成员Kallistatin与PEDF的家族关系：比较分析综述。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123333

Jingnan Chen , Zihan Wang , Simin Wang , Jiayi Lyu , Zhenzhen Fang , Weiwei Qi , Xia Yang , Guoquan Gao , Ti Zhou

The serine protease inhibitors (Serpins) represent a diverse protein superfamily that holds paramount significance in governing vital pathophysiological processes. Their influence on critical biological pathways renders serpins highly coveted targets for drug discovery endeavors. Among the numerous members of this family, two distinct proteins, Kallistatin (encoded by the SERPINA4 gene) and Pigment Epithelium-Derived Factor (PEDF, encoded by the SERPINF1 gene), stand out as secreted proteins that are abundantly present in peripheral blood. Kallistatin is a serine protease inhibitor that specifically inhibits human tissue kallikrein, while PEDF is a non-inhibitory member of the serine protease inhibitors superfamily (Lin et al., 2015a; Chao and Chao, 1995 [1,2]). Instead, they exhibit notable anti-angiogenic effects and play pivotal roles in the pathogenesis of metabolic disorders. Extensive research, including our own investigations, has revealed intriguing similarities as well as noteworthy differences between these two proteins. Despite their shared characteristics, the distinctive features of Kallistatin and PEDF render them unique in their respective functions and mechanisms of action. However, a comprehensive literature review comparing their similarities and differences remains elusive. Therefore, the present review aims to systematically delve into and summarize the comparable and contrasting aspects of Kallistatin and PEDF. We will delve into their expression patterns, structural features, and mechanisms of expression regulation. Furthermore, this review will delve into their physiological functions and roles in diseases, the signaling pathways they influence, and their potential clinical applications. By comparing and contrasting these two proteins, we hope to provide a comprehensive understanding of their functions and potential in biomedical research and clinical practice.

丝氨酸蛋白酶抑制剂（Serpins）代表了一个多样化的蛋白质超家族，在控制重要的病理生理过程中具有至关重要的意义。它们对关键生物学途径的影响使蛇蛋白成为药物发现努力的高度垂涎的目标。在这个家族的众多成员中，有两种不同的蛋白，Kallistatin（由SERPINA4基因编码）和色素上皮衍生因子（PEDF，由serpin1基因编码），作为分泌蛋白在外周血中大量存在。Kallistatin是一种丝氨酸蛋白酶抑制剂，特异性抑制人组织kallikrein，而PEDF是丝氨酸蛋白酶抑制剂超家族的非抑制性成员(Lin et al., 2015a；Chao and Chao, 1995[1,2])。相反，它们表现出显著的抗血管生成作用，并在代谢紊乱的发病机制中发挥关键作用。广泛的研究，包括我们自己的调查，揭示了这两种蛋白质之间有趣的相似之处以及值得注意的差异。尽管它们具有共同的特征，但卡利司他汀和PEDF的独特特征使它们在各自的功能和作用机制上是独一无二的。然而，一个全面的文献综述比较他们的异同仍然是难以实现的。因此，本综述旨在系统地探讨和总结卡利司他汀与PEDF的可比性和对比性。深入研究其表达模式、结构特征和表达调控机制。本文将对其在疾病中的生理功能、作用、影响的信号通路及其潜在的临床应用进行综述。通过对这两种蛋白的比较和对比，我们希望对它们在生物医学研究和临床实践中的功能和潜力提供全面的了解。

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引用次数: 0

Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia 改变肌营养不良蛋白S3059的磷酸化以减轻癌症恶病质。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123343

Kristy Swiderski , Jennifer Trieu , Annabel Chee , Timur Naim , Christopher J. Brock , Dale M. Baum , Audrey S. Chan , Justin P. Hardee , Wenlan Li , Andrew J. Kueh , Marco J. Herold , Kate T. Murphy , Paul Gregorevic , Gordon S. Lynch

Aims

Cancer cachexia affects up to 80 % of patients with advanced cancer and accounts for >20 % of all cancer-related deaths. Sarcolemmal localization of dystrophin, a key protein within the dystrophin-glycoprotein complex (DGC), is perturbed in multiple muscle wasting conditions, including cancer cachexia, indicating a potential role for dystrophin in the maintenance of muscle mass. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan and attenuates atrophy of mouse muscle myotubes in vitro when cultured in the presence of colon-26 (C-26) cancer cells. Whether dystrophin S3059 phosphorylation can attenuate cachexia in tumor-bearing mice has not been determined.

Materials and methods

Mice with systemic mutations of serine 3059 to alanine (DmdS3059A; phospho-null) or glutamate (DmdS3059E; phosphomimetic) were generated to investigate the impact of S3059 phosphorylation on survival and skeletal muscle health in the C-26 tumor-bearing mouse model of cancer cachexia using measures of skeletal muscle function in situ combined with biochemical and histological assessments.

Key findings

In a model of mild cachexia, loss of skeletal muscle mass and function was greater in DmdS3059A mice. Conversely, in a model of severe cachexia, overall survival was prolonged, and markers of protein degradation were decreased in skeletal muscles of DmdS3059E mice. Thus, manipulating dystrophin S3059 phosphorylation can alter the progression of cachexia in tumor-bearing mice.

Significance

Strategies to increase phosphorylation of this site, and/or increase dystrophin protein expression, have therapeutic potential for cancer cachexia.

目的：癌症恶病质影响高达80% %的晚期癌症患者，占所有癌症相关死亡的20% %。肌营养不良蛋白是肌营养不良蛋白-糖蛋白复合物（DGC）中的一个关键蛋白，在多种肌肉萎缩情况下，包括癌症恶病质，肌营养不良蛋白的肌上皮定位受到干扰，这表明肌营养不良蛋白在维持肌肉质量方面具有潜在作用。因此，保持肌膜上肌营养不良蛋白表达的策略可能会对抗肌肉萎缩。抗肌营养不良蛋白丝氨酸3059 （S3059）的磷酸化增强了抗肌营养不良蛋白与β-肌营养不良聚糖的相互作用，并在体外培养结肠癌-26 （C-26）癌细胞时减轻了小鼠肌管的萎缩。抗营养不良蛋白S3059磷酸化是否能减轻荷瘤小鼠的恶病质尚未确定。材料和方法：丝氨酸3059到丙氨酸（DmdS3059A）系统性突变小鼠；phospho-null)或谷氨酸(DmdS3059E；通过骨骼肌原位功能测量，结合生化和组织学评估，研究S3059磷酸化对C-26癌恶病质小鼠模型存活和骨骼肌健康的影响。关键发现：在轻度恶病质模型中，DmdS3059A小鼠骨骼肌质量和功能的损失更大。相反，在严重恶病质模型中，DmdS3059E小鼠的总生存期延长，骨骼肌中蛋白质降解标志物减少。因此，调控肌营养不良蛋白S3059的磷酸化可以改变荷瘤小鼠恶病质的进展。意义：增加该位点磷酸化和/或增加肌营养不良蛋白表达的策略对癌症恶病质具有治疗潜力。

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引用次数: 0

Transcranial alternating current stimulation inhibits ferroptosis and promotes functional recovery in spinal cord injury via the cGMP-PKG signalling pathway 经颅交流电刺激通过cGMP-PKG信号通路抑制铁下垂并促进脊髓损伤的功能恢复。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123341

Ke Huang , Jing Fang , Shining Xiao , Wansong Wang , Guodong Zhang , Weiming Sun , Lang Shuai , Haidi Bi

Aims

This study explores the potential of neuromodulation, specifically transcranial alternating current stimulation (tACS), as a promising rehabilitative therapy in spinal cord injury (SCI).

Main methods

By meticulously optimizing treatment parameters and durations, our objective was to enhance nerve regeneration and facilitate functional recovery. To assess the efficacy of tACS, our experiments used the rat T10 SCI model. Motor function outcomes were measured using the Basso-Beattie-Bresnahan (BBB) scoring scale and footprint analysis. To thoroughly understand the impact of tACS, we conducted a series of histological evaluations two weeks post-injury. These included q-PCR, enzyme-linked immunosorbent assays (ELISA), transmission electron microscopy (TEM), immunofluorescence staining, and Western blotting. The mechanisms underlying the role of tACS will be elucidated through comprehensive analyses.

Key findings

Simultaneously, tACS reduced the levels of reactive oxygen species (ROS), Fe, and malondialdehyde (MDH), and increased the levels of glutathione (GSH) after SCI. Additionally, tACS significantly enhanced motor function, reduced fibrotic scar tissue formation, and provided substantial neuroprotection. It also contributed to the restoration of the blood-spinal cord barrier and supported the regeneration of essential neural components, including axons, myelin, and synapses. The cGMP-PKG signalling pathway was identified as playing a crucial role in these processes.

Significance

Our findings suggest that tACS inhibits ferroptosis and necrotic degeneration by modulating the cGMP-PKG signalling pathway. This highlights the importance of tACS in promoting neural repair and functional recovery in SCI patients. Overall, tACS emerges as a highly effective and cost-efficient rehabilitative approach for SCI, offering new hope for improving patient outcomes.

目的：本研究探讨神经调节，特别是经颅交流电刺激（tACS）作为脊髓损伤（SCI）康复治疗的潜力。主要方法：通过精心优化治疗参数和持续时间，我们的目标是增强神经再生和促进功能恢复。为了评估tACS的疗效，我们的实验采用大鼠T10脊髓损伤模型。运动功能结果采用Basso-Beattie-Bresnahan （BBB）评分量表和足迹分析进行测量。为了彻底了解tACS的影响，我们在损伤后两周进行了一系列组织学评估。其中包括q-PCR，酶联免疫吸附测定（ELISA），透射电子显微镜（TEM），免疫荧光染色和Western blotting。本文将通过综合分析阐明tACS作用的机制。主要发现：同时，tACS降低了脊髓损伤后的活性氧（ROS）、铁（Fe）和丙二醛（MDH）水平，并增加了谷胱甘肽（GSH）水平。此外，tACS显著增强运动功能，减少纤维化瘢痕组织的形成，并提供大量的神经保护。它还有助于血脊髓屏障的恢复，并支持必要神经成分的再生，包括轴突、髓磷脂和突触。cGMP-PKG信号通路在这些过程中起着至关重要的作用。意义：我们的研究结果表明，tACS通过调节cGMP-PKG信号通路抑制铁下垂和坏死性变性。这凸显了tACS在促进脊髓损伤患者神经修复和功能恢复中的重要性。综上所述，tACS是一种高效、经济的脊髓损伤康复方法，为改善患者预后带来了新的希望。

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引用次数: 0

Inhibition of peptidyl arginine deiminase-4 ameliorated pulmonary fibrosis via modulating M1/M2 polarisation of macrophages 抑制肽基精氨酸脱亚胺酶-4通过调节巨噬细胞的M1/M2极化改善肺纤维化。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123354

Biswajit Panda, Shrilekha Chilvery, Priyanka Devi, Radha Kalmegh, Chandraiah Godugu

Pulmonary fibrosis (PF) arises from dysregulated wound healing, leading to excessive extracellular matrix (ECM) deposition and impaired lung function. Macrophages exhibit high plasticity, polarizing to pro-inflammatory M1 during early inflammation and anti-inflammatory, fibrosis-inducing M2 during later stages of PF. Additionally, neutrophils and neutrophil extracellular traps (NETs) release mediated by peptidyl arginine deiminase (PAD-4), also play a key role in PF progression. PAD-4 inhibitor chloro-amidine (CLA) has shown anti-fibrotic effects in bleomycin (BLM) induced PF mouse model in our earlier study. Here, we have demonstrated that CLA also exhibited inhibition of macrophage polarisation in in-vitro in THP-1 monocytes and in-vivo in BLM induced PF. THP-1 monocytes were exposed to NETs isolated from phorbol 12-myristate-13-acetate (PMA) stimulated and PMA plus CLA treated differentiated HL-60 (dHL-60) cells. Monocytes exposed to stimulated NETs resulted in increased oxidative stress, disrupted mitochondrial membrane potential and increased M1 and M2 macrophage markers. These alterations were abrogated in THP-1 cells upon exposure to CLA treated NETs. Further, CLA treatment in BLM induced mice improved abnormal BALF, biochemical, and histological parameters in line with our previous findings. Additionally, CLA also reduced M1 and M2 markers time-dependently, as shown by immunofluorescence (IF), western blot, and RT-PCR analysis. CLA treatment led to decreased expression of PAD-4, M1-related pro-inflammatory cytokines and M2-related pro-fibrotic cytokines and mediators, as confirmed by western blot and ELISA analysis. Thus, it is established that inhibition of PAD-4 lead to mitigation of macrophage polarisation and a combined anti-fibrotic effect is achieved which can be explored further.

肺纤维化（PF）源于伤口愈合失调，导致过度的细胞外基质（ECM）沉积和肺功能受损。巨噬细胞表现出高度的可塑性，在炎症早期和抗炎期间极化为促炎M1，在PF晚期极化为纤维化诱导M2。此外，中性粒细胞和由肽基精氨酸脱亚胺酶（PAD-4）介导的中性粒细胞胞外陷阱（NETs）释放也在PF进展中发挥关键作用。我们前期研究发现，PAD-4抑制剂氯脒（CLA）在博来霉素（BLM）诱导的PF小鼠模型中显示出抗纤维化作用。在此，我们证明了CLA在体外对THP-1单核细胞和体内对BLM诱导的PF的巨噬细胞极化也有抑制作用。THP-1单核细胞暴露于从phorbol 12-肉豆酸酯-13-乙酸酯（PMA）刺激和PMA加CLA处理分化的HL-60 （dHL-60）细胞中分离的NETs中。单核细胞暴露于受刺激的NETs导致氧化应激增加，线粒体膜电位破坏，M1和M2巨噬细胞标志物增加。暴露于CLA处理的NETs后，THP-1细胞中的这些改变被消除。此外，CLA治疗BLM诱导的小鼠改善了异常的BALF、生化和组织学参数，这与我们之前的研究结果一致。此外，免疫荧光（IF）、western blot和RT-PCR分析显示，CLA还能以时间依赖性降低M1和M2标记物。western blot和ELISA分析证实，CLA治疗导致PAD-4、m1相关的促炎细胞因子和m2相关的促纤维化细胞因子和介质的表达降低。因此，可以确定，抑制PAD-4导致巨噬细胞极化的缓解，并实现了联合抗纤维化作用，这可以进一步探索。

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引用次数: 0

Pediococcus acidilactici CECT 9879 (pA1c®) and heat inactivated pA1c® (pA1c® HI) ameliorate gestational diabetes mellitus in mice 酸化Pediococcus acilacactii CECT 9879 （pA1c®）和热灭活pA1c®（pA1c®HI）改善小鼠妊娠期糖尿病。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2025-02-01 DOI: 10.1016/j.lfs.2024.123359

Deyan Yavorov-Dayliev , Fermín I. Milagro , Josune Ayo , María Oneca , Ignacio Goyache , Miguel López-Yoldi , Jamie A. FitzGerald , Fiona Crispie , Paul D. Cotter , Paula Aranaz

Aims

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy and is known to be associated with an increased risk of postpartum metabolic disease. Based on the important role that the intestinal microbiota plays in blood glucose regulation and insulin sensitivity, supplementation of probiotic and postbiotic strains could improve glucose metabolism and tolerance in GDM.

Main methods

56 4-week-old female C57BL/6J-mice were divided into 4 groups (n = 14 animals/group): control (CNT), high-fat/high-sucrose (HFS), pA1c® alive (pA1c®) and heat-inactivated pA1c® (pA1c®HI). Serum biochemical parameters were analyzed, gene expression analyses were conducted, and fecal microbiota composition was evaluated by shot-gun sequencing.

Key findings

pA1c®- and pA1c® HI-supplemented groups presented reduced fasting blood glucose levels and reduced insulin resistance during gestation and exhibited lower visceral adiposity and increased muscle tissue, together with an improvement in intrahepatic TGs content and ALT levels. Liver gene expression analyses demonstrated that pA1c® and pA1c® HI activities were mediated by modulation of the insulin receptor, but also by an overexpression of beta-oxidation genes, and downregulation of fatty acid biosynthesis genes. Shot-gun metagenomics demonstrated that Pediococcus acidilactici was detected in the feces of all the pA1c® and pA1c® HI-group after the supplementation period (75 % of the microbial profile was Pediococcus acidilactici) in only nine weeks of supplementation, and modulated gut microbiota composition.

Significance

These results may be considered as future perspectives for the development of preventive, even therapeutic options for GDM based on hyperglycemia reduction, blood glucose regulation, hepatic steatosis attenuation and insulin resistance alleviation.

目的：妊娠期糖尿病（GDM）是妊娠最常见的并发症，已知与产后代谢疾病的风险增加有关。鉴于肠道菌群在血糖调节和胰岛素敏感性中的重要作用，补充益生菌和益生菌后菌株可改善GDM患者的糖代谢和耐受性。主要方法：将56只4周龄雌性C57BL/ 6j小鼠分为4组（n = 14只/组）：对照组（CNT）、高脂高糖组（HFS）、活pA1c组（pA1c®）和热灭活pA1c组（pA1c®HI）。进行血清生化指标分析，基因表达分析，并采用散弹枪测序法评估粪便微生物群组成。主要发现：pA1c®-和pA1c®hi补充组在妊娠期间空腹血糖水平降低，胰岛素抵抗降低，内脏脂肪降低，肌肉组织增加，肝内tg含量和ALT水平改善。肝脏基因表达分析表明，pA1c®和pA1c®HI活性是由胰岛素受体的调节介导的，但也由β -氧化基因的过度表达和脂肪酸生物合成基因的下调介导。霰弹枪宏基因组学显示，在补充期后的9周内，所有pA1c®和pA1c®hi组的粪便中都检测到酸乳酸球球菌（75%的微生物谱是酸乳酸球球菌），并调节了肠道微生物群组成。意义：这些结果可能被认为是未来基于高血糖降低、血糖调节、肝脂肪变性衰减和胰岛素抵抗缓解的GDM预防甚至治疗选择的发展前景。

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