Life sciences最新文献_第8页

Sinomenine ameliorates myocardial ischemia/reperfusion injury by inhibiting mitochondrial oxidative stress-mediated PANoptosis and ferroptosis via α7nAChR 青藤碱通过α7nAChR抑制线粒体氧化应激介导的PANoptosis和ferroptosis，改善心肌缺血/再灌注损伤。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-09 DOI: 10.1016/j.lfs.2026.124199

Jia-Rong Yang , Fu-Qin Tan , Chen-Jie Cheng, Meng-Wan Zhang, Jian-Guang Yu

Aims

To elucidate the cardioprotective effect of sinomenine (SIN) against myocardial ischemia/reperfusion injury (MIRI) and to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) and its downstream mechanisms.

Materials and methods

A murine MIRI model and cardiomyocyte hypoxia/reoxygenation (H/R) models were employed. Key parameters measured included myocardial infarct size, cardiac function, lactate dehydrogenase (LDH) activity, cell viability, adenosine triphosphate (ATP) content, 4-hydroxynonenal (4-HNE) level, α7nAChR expression, mitochondrial reactive oxygen species (ROS), and markers of PANoptosis and ferroptosis. The role of α7nAChR was verified using its antagonist methyllycaconitine and specific siRNA. The mitochondrial antioxidant mito-TEMPO served as a positive control in key cellular assays.

Key findings

SIN reduced myocardial infarct size, serum LDH, and cardiomyocyte apoptosis, while improving cardiac function and increasing myocardial ATP and α7nAChR expression in MIRI mice, with concordant reductions in oxidative stress marker 4-HNE. In H/R-injured cardiomyocytes, SIN restored cell viability, decreased LDH release, preserved ATP, attenuated oxidative stress (4-HNE, mitochondrial ROS), and upregulated α7nAChR. SIN concurrently suppressed PANoptosis (apoptosis, necroptosis, pyroptosis) and ferroptosis. The efficacy of SIN in reducing mitochondrial ROS and cell death was comparable to mito-TEMPO. All protective effects of SIN were abolished by inhibition of α7nAChR.

Significance

This study provides the first evidence linking SIN's cardioprotection to the concurrent inhibition of PANoptosis and ferroptosis via α7nAChR activation. We demonstrate that SIN protects against MIRI by activating α7nAChR, thereby improving mitochondrial function, reducing oxidative stress, and suppressing integrated cell death pathways, identifying α7nAChR as a promising target for MIRI.

目的：阐明青叶碱（SIN）对心肌缺血再灌注损伤（MIRI）的保护作用，探讨α7烟碱乙酰胆碱受体（α7nAChR）的作用及其下游机制。材料和方法：采用小鼠MIRI模型和心肌细胞缺氧/再氧化（H/R）模型。主要指标包括心肌梗死面积、心功能、乳酸脱氢酶（LDH）活性、细胞活力、三磷酸腺苷（ATP）含量、4-羟基烯醛（4-HNE）水平、α7nAChR表达、线粒体活性氧（ROS）、PANoptosis和ferroptosis标志物。α7nAChR的作用通过其拮抗剂甲基莱卡乌碱和特异性siRNA得到验证。线粒体抗氧化剂mito-TEMPO在关键细胞检测中作为阳性对照。主要发现：在MIRI小鼠中，SIN降低心肌梗死面积、血清LDH和心肌细胞凋亡，同时改善心功能，增加心肌ATP和α7nAChR表达，同时氧化应激标志物4-HNE也相应降低。在H/ r损伤的心肌细胞中，SIN恢复细胞活力，降低LDH释放，保存ATP，减轻氧化应激（4-HNE，线粒体ROS），上调α7nAChR。SIN同时抑制PANoptosis（凋亡、坏死、焦亡）和铁下垂。SIN在减少线粒体ROS和细胞死亡方面的效果与mito-TEMPO相当。α7nAChR的抑制消除了SIN的所有保护作用。意义：本研究首次提供了通过α7nAChR激活将SIN的心脏保护作用与PANoptosis和ferroptosis同时抑制联系起来的证据。我们证明了SIN通过激活α7nAChR来预防MIRI，从而改善线粒体功能，减少氧化应激，抑制综合细胞死亡途径，确定α7nAChR是MIRI的一个有希望的靶点。

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引用次数: 0

Retraction notice to “Effectiveness of mesenchymal stem cell-seeded onto the 3D polylactic acid/polycaprolactone/hydroxyapatite scaffold on the radius bone defect in rat” [Life Sci. 257 (2020) 118038] 引用本文：“聚乳酸/聚己内酯/羟基磷灰石三维支架植入间充质干细胞修复大鼠桡骨缺损的效果”[生命科学，257(2020):118038]。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-09 DOI: 10.1016/j.lfs.2025.124146

A. Oryan , S. Hassanajili , S. Sahvieh , N. Azarpira

引用次数: 0

Minocycline-induced microglial remodeling restores hippocampal NMDA-dependent synaptic plasticity and reduces anxiety-like behavior in juvenile rats with temporal lobe epileptogenesis 二甲胺四环素诱导的小胶质细胞重塑恢复海马nmda依赖的突触可塑性并减少颞叶癫痫发生的幼年大鼠的焦虑样行为。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-07 DOI: 10.1016/j.lfs.2026.124193

Tatiana Y. Postnikova, Georgy P. Diespirov, Alexandra V. Griflyuk, Aleksey V. Zaitsev

Microglial activation and neuroinflammation are recognized as key drivers of synaptic dysfunction in temporal lobe epilepsy (TLE), yet the causal mechanisms linking specific microglial phenotypes to neuronal hyperexcitability remain poorly understood, and clinically viable therapeutic strategies to modulate these processes are urgently needed. Using the lithium-pilocarpine model in young male rats (P21-P28), we demonstrate that a 7-day minocycline treatment (100 → 50 mg/kg, i.p.), initiated immediately following status epilepticus, induces robust and selective microglial morphological remodeling. Quantitative morphometric analysis of Iba1⁺ cells revealed a significant shift from activated amoeboid morphology to surveillant ramified phenotypes, without altering microglial density in hippocampal CA1 regions. This structural reorganization correlated with complete functional recovery: electrophysiological recordings showed full restoration of NMDA receptor-dependent long-term potentiation and rescue of NMDAR-mediated currents during high-frequency stimulation. Importantly, these synaptic improvements occurred independently of neuroprotection, as Nissl staining confirmed unchanged neuronal survival in CA1/CA3 subfields. Behavioral assessments at P27 demonstrated significant attenuation of epilepsy-associated anxiety-like behaviors, including reduced self-grooming and normalized exploratory activity in the open field test. Notably, minocycline treatment also attenuated reactive astrogliosis, suggesting coordinated modulation of neuroinflammatory cascades. Our findings demonstrate that short-term minocycline administration induces a structural and functional reprogramming of microglia, which is sufficient to restore hippocampal synaptic plasticity and reduce anxiety in a rat model of TLE. This highlights microglial morphological plasticity as a critical therapeutic target for counteracting epileptogenesis.

小胶质细胞激活和神经炎症被认为是颞叶癫痫（TLE）突触功能障碍的关键驱动因素，但将特定小胶质细胞表型与神经元高兴奋性联系起来的因果机制仍然知之甚少，迫切需要临床可行的治疗策略来调节这些过程。在年轻雄性大鼠（P21-P28）的锂-匹罗卡品模型中，我们证明了在癫痫持续状态后立即开始的7天二甲胺四环素治疗（100 → 50 mg/kg, i.p）可诱导强而选择性的小胶质细胞形态重塑。Iba1+细胞的定量形态学分析显示，从活化的变形虫形态到监视分支表型的显著转变，没有改变海马CA1区域的小胶质细胞密度。这种结构重组与完全的功能恢复相关：电生理记录显示，在高频刺激期间，NMDA受体依赖的长期增强和NMDA介导的电流的恢复完全恢复。重要的是，这些突触改善独立于神经保护发生，因为尼氏染色证实CA1/CA3亚区神经元存活不变。P27的行为评估显示，癫痫相关的焦虑样行为显著减弱，包括在野外测试中自我梳理的减少和正常的探索活动。值得注意的是，二甲胺四环素治疗也减轻了反应性星形胶质细胞增生，提示神经炎症级联反应的协调调节。我们的研究结果表明，短期给药二甲胺四环素可诱导小胶质细胞的结构和功能重编程，这足以恢复海马突触可塑性并减少TLE大鼠模型的焦虑。这突出了小胶质细胞形态可塑性作为对抗癫痫发生的关键治疗靶点。

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引用次数: 0

Compressive stress induces cartilage endplate degeneration through the Piezo1/YAP-TEAD/NLRP3 axis 压应力通过Piezo1/YAP-TEAD/NLRP3轴诱导软骨终板退变。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-06 DOI: 10.1016/j.lfs.2026.124195

Tong Cao , Fushuai Peng , Wei Wang , Xingzhi Jing , Fei Chen , Mingtong Sun , Jiaju Ma , Wei Yang , Zhihao Xu , Zhenghao Xie , Jun Dong , Tao Li

Aims

To investigate the potential mechanisms by which compressive stress induces degeneration of cartilage endplate, and to elucidate the specific roles of mechanosensitive protein Piezo1, YAP, and NLRP3 in this process. A pressure-inflammation model of chondrocytes is proposed.

Materials and methods

Firstly, a bipedal standing mouse model was established to investigate the effect of mechanical stress on cartilage endplate degeneration and calcification. Next, cells were subjected to compression stress and western blot analysis as well as Bulk RNAseq were employed to detect the expression changes of Piezo1, YAP, NLRP3, ASC, and IL-1β. Additionally, intracellular Ca²⁺ levels, cytoskeleton and mitochondrial membrane potential were assessed. At last, Piezo1 chondrocyte conditional knockout mice were established to illustrate the role of Piezo1 in mechanical stress induced cartilage endplate degeneration.

Key findings

The bipedal standing mouse model demonstrated that compressive stress promotes cartilage endplate degeneration. The in vitro experiments demonstrated that compressive stress promoted degeneration of cartilage endplate via Piezo1-induced NLRP3 activation. Compressive stress activate Piezo1, triggering Ca²⁺ influx and promoting cytoskeletal polymerization, which facilitated nuclear translocation of YAP. Subsequently, YAP-TEAD complex formation activated the NLRP3 inflammasome, leading to enhanced expression of IL-1β, MMP13, MMP3, RUNX2, and COL10, while suppressing expression of COL2 and SOX9.

Significance

Our study reveals the role of Piezo1/YAP-TEAD/NLRP3 axis in pressure stress-induced cartilage endplate degeneration. This signaling axis not only regulates inflammation, ossification, and oxidative stress responses in chondrocytes but also promotes chondrocyte apoptosis through mitochondrial dysfunction. These findings provide novel molecular mechanisms for understanding the role of mechanical stress in cartilage degeneration.

目的：探讨压应力诱导软骨终板退变的可能机制，并阐明力学敏感蛋白Piezo1、YAP和NLRP3在这一过程中的具体作用。提出了一种软骨细胞压力炎症模型。材料与方法：首先，建立小鼠两足直立模型，研究机械应力对软骨终板退变和钙化的影响。接下来，对细胞进行压缩应力和western blot分析，并采用Bulk RNAseq检测Piezo1、YAP、NLRP3、ASC和IL-1β的表达变化。此外，评估细胞内Ca2+水平，细胞骨架和线粒体膜电位。最后，建立Piezo1软骨细胞条件敲除小鼠，以说明Piezo1在机械应力诱导的软骨终板退变中的作用。主要发现：双足站立小鼠模型表明，压缩应力促进软骨终板退变。体外实验表明，压缩应力通过piezo1诱导的NLRP3激活促进软骨终板退变。压缩应力激活Piezo1，触发Ca2+内流，促进细胞骨架聚合，促进YAP核易位。随后，YAP-TEAD复合物的形成激活了NLRP3炎症小体，导致IL-1β、MMP13、MMP3、RUNX2和COL10的表达增强，同时抑制COL2和SOX9的表达。意义：我们的研究揭示了Piezo1/YAP-TEAD/NLRP3轴在压力应力诱导的软骨终板退变中的作用。该信号轴不仅调节软骨细胞的炎症、骨化和氧化应激反应，还通过线粒体功能障碍促进软骨细胞凋亡。这些发现为理解机械应力在软骨退变中的作用提供了新的分子机制。

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引用次数: 0

Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia 对香豆酸脂质体对间歇性缺氧认知功能障碍和线粒体损伤的改善作用及机制

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-06 DOI: 10.1016/j.lfs.2026.124197

Yan-Zi Liang , Meng-Zhen Jiang , Xue-Ting Xu , Ting Zhu , Hui Guo , Li Ding , Hao Zhong , Jian Bao , Li-Qiang Qin , Yun-Hong Li

Aims

Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

Materials and methods

APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

Results

Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

Conclusions

CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.

阿尔茨海默病（AD）已成为一个全球性的公共卫生问题。线粒体功能障碍与阿尔茨海默病的发病有关，充足的氧气供应对于维持线粒体稳态至关重要。对香豆酸（CA）是一种具有抗缺氧和抗ad特性的多酚。本研究将CA配制成一种仿生脂质体（CA- lip）以提高其治疗效果，并对其机制进行了研究。材料与方法将sapp /PS1小鼠分为4组：AD组、缺氧治疗组（AD- hy组）、缺氧+ CA治疗组（CA组）、缺氧+ CA- lip治疗组（CA- lip组）。年龄匹配的野生型幼崽作为对照。缺氧处理组小鼠每天缺氧舱6小时，连续8周。随后评估认知能力和线粒体功能，以确定CA-Lip的改善作用和机制。结果AD- hy组认知功能障碍和线粒体功能障碍明显高于AD组。CA- lip比CA具有更强的神经保护作用。机制分析表明，CA- lip减少了淀粉样蛋白-β (Aβ)积累，增强了线粒体生物发生（上调PGC-1α表达），维持了线粒体动力学（上调MFN2表达，下调DRP1表达），抑制了过度的线粒体自噬（下调PINK1和Parkin表达）。增强细胞自噬（上调ATG7和LC3B表达，下调mTOR和P62表达），减少神经元凋亡。结论ca - lip可通过减少Aβ的生成和改善线粒体功能，有效改善缺氧性认知障碍。

{"title":"Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia","authors":"Yan-Zi Liang , Meng-Zhen Jiang , Xue-Ting Xu , Ting Zhu , Hui Guo , Li Ding , Hao Zhong , Jian Bao , Li-Qiang Qin , Yun-Hong Li","doi":"10.1016/j.lfs.2026.124197","DOIUrl":"10.1016/j.lfs.2026.124197","url":null,"abstract":"<div><h3>Aims</h3><div>Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. <em>P</em>-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.</div></div><div><h3>Materials and methods</h3><div>APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.</div></div><div><h3>Results</h3><div>Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.</div></div><div><h3>Conclusions</h3><div>CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"387 ","pages":"Article 124197"},"PeriodicalIF":5.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927799","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

Risk stratification using inflammatory and metabolic biomarkers: A multi-cohort predictive study of mortality in atherosclerotic cardiovascular disease 使用炎症和代谢生物标志物进行风险分层：动脉粥样硬化性心血管疾病死亡率的多队列预测研究

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-05 DOI: 10.1016/j.lfs.2025.124182

Xiao Li , Qingyue Zeng , Xiaoyu Zhang , Shuangqiu Wang , Tong Jiang , Liangzheng You , Hongcai Shang

Background

The pathological process of atherosclerotic cardiovascular disease (ASCVD) involves complex interactions between metabolic dysregulation and inflammatory responses. The stress hyperglycemia ratio (SHR) and neutrophil-to-lymphocyte ratio (NLR), as biomarkers reflecting metabolic stress and systemic inflammation respectively, have demonstrated significant value in ASCVD prognosis assessment. This study aims to investigate the predictive role of combined SHR and NLR indicators for all-cause mortality in ASCVD patients and their clinical applicability.

Methods

ASCVD patients were identified from the Medical Information Mart for Intensive Care IV (MIMIC-IV) and National Health and Nutrition Examination Survey (NHANES) databases, stratified by SHR/NLR tertiles. Multivariable Cox regression, restricted cubic splines, time-dependent ROC, and machine learning models assessed mortality associations.

Results

Among 6159 patients, the highest SHR tertile showed increased mortality (NHANES: HR = 1.20, 95 % CI 1.08–1.34; MIMIC-IV: HR = 2.27, 95 % CI 1.44–3.57). The highest NLR tertile showed elevated risk (NHANES: HR = 1.56, 95 % CI 1.39–1.74; MIMIC-IV: HR = 1.61, 95 % CI 1.03–2.52). The combined high SHR/NLR group exhibited the most pronounced risk (NHANES: HR = 1.54, 95 % CI 1.35–1.77; MIMIC-IV: HR = 2.90, 95 % CI 1.70–4.93), with significantly improved predictive accuracy.

Conclusion

The combined SHR-NLR assessment effectively quantifies combined metabolic-inflammatory injury and provides superior prognostic stratification for ASCVD patients compared to individual biomarker evaluation. These findings highlight the clinical potential of this dual-biomarker approach for enhancing risk prediction, though further prospective validation is warranted to establish its predictive utility across various patient populations.

背景：动脉粥样硬化性心血管疾病（ASCVD）的病理过程涉及代谢失调和炎症反应之间复杂的相互作用。应激性高血糖比（SHR）和中性粒细胞与淋巴细胞比（NLR）分别作为反映代谢应激和全身性炎症的生物标志物，在ASCVD预后评估中具有重要价值。本研究旨在探讨SHR和NLR联合指标对ASCVD患者全因死亡率的预测作用及其临床适用性。方法：从重症监护医学信息市场IV （MIMIC-IV）和国家健康与营养检查调查（NHANES）数据库中识别ASCVD患者，按SHR/NLR分类。多变量Cox回归、受限三次样条、随时间变化的ROC和机器学习模型评估了死亡率的相关性。结果：在6159例患者中，最高SHR指标显示死亡率增加（NHANES: HR = 1.20,95 % CI 1.08-1.34; MIMIC-IV: HR = 2.27,95 % CI 1.44-3.57）。NHANES: HR = 1.56,95 % CI 1.39-1.74; MIMIC-IV: HR = 1.61,95 % CI 1.03-2.52)。联合高SHR/NLR组表现出最显著的风险（NHANES: HR = 1.54,95 % CI 1.35-1.77; MIMIC-IV: HR = 2.90,95 % CI 1.70-4.93），预测准确性显著提高。结论：与单独的生物标志物评估相比，shrr - nlr联合评估有效地量化了代谢-炎症联合损伤，并为ASCVD患者提供了更好的预后分层。这些发现强调了这种双生物标志物方法在增强风险预测方面的临床潜力，尽管需要进一步的前瞻性验证来确定其在不同患者群体中的预测效用。

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引用次数: 0

Mitochondrial function of peripheral lymphocytes: role on multiple sclerosis clinical subtypes 外周淋巴细胞线粒体功能：在多发性硬化临床亚型中的作用。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-05 DOI: 10.1016/j.lfs.2026.124196

Adela González-Jiménez , Paloma de Heras-Pino , Alba Moreno-Jerez , Estela Mena-Plaza , Yolanda Aladro , Belén Pilo , Celia Oreja-Guevara , Irene Gómez-Estévez , Andrea R. López-Pastor , Irene Gómez-Delgado , Elena Urcelay

Aims

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of unknown etiology, resulting in unmet therapeutic needs. Symptoms heterogeneity and incomplete mechanistic understanding hinder effective patient stratification. We aimed to evaluate the integrated peripheral immune response in established MS clinical subtypes, focusing on differences in mitochondrial function that might validate this stratification and further clarify MS etiology.

Materials and methods

Mitochondrial activity of peripheral blood mononuclear cells (PBMCs) upon PHA-stimulation was analysed in MS patients (58 relapsing-remitting (RRMS), 21 secondary progressive (SPMS), and 35 primary progressive (PPMS)) and 35 healthy controls (HC).

Key findings

In unstimulated conditions, MS patients presented higher mitochondrial ROS (reactive oxygen species) and decreased coupling than HC. Compared with other progressive MS (PMS) subtypes, PBMCs from RRMS presented significantly higher early/late activation and proliferation after PHA stimulation (P = 0.013/P = 0.002, and P = 0.04, respectively), with increased mitochondrial depolarization (P = 0.017). Compared to HC, PHA-stimulated PBMCs from PMS exhibited marked decreases in basal (P = 0.017), maximal, and ATP-linked respiration, increased coupling (P = 0.009), and lower spare respiratory and glycolytic capacities (basal: P = 0.015, maximal: P = 0.064), with parallel decreased GLUT1 expression (P = 0.025). These changes appeared independent of some treatments.

Significance

Upon PHA-stimulation, PMS patients displayed decreased basal, maximal, ATP-linked respiration, and reduced spare respiratory and glycolytic capacities, compared to RRMS and HC, mirroring opposed trends in unstimulated conditions. These findings suggest a severity gradient across MS clinical forms, supporting a disease continuum rather than strictly defined subtypes. The central role of unresolved mitochondrial dysfunction in MS warrants further investigation and may guide novel therapeutic strategies.

目的：多发性硬化症（MS）是一种病因不明的免疫介导的神经退行性疾病，导致治疗需求未得到满足。症状异质性和不完整的机制理解阻碍了有效的患者分层。我们旨在评估已建立的MS临床亚型的综合外周免疫反应，重点关注线粒体功能的差异，这可能验证这种分层并进一步阐明MS病因。材料与方法：对58例复发缓解型（RRMS）、21例继发性进展型（SPMS）、35例原发性进展型（PPMS）和35例健康对照（HC）患者外周血单个核细胞（PBMCs）在pha刺激下的线粒体活性进行了分析。主要发现：在非刺激条件下，MS患者比HC患者线粒体ROS（活性氧）更高，偶联减少。与其他进行性MS （PMS）亚型相比，来自RRMS的PBMCs在PHA刺激后表现出明显更高的早期/晚期激活和增殖（P = 0.013/P = 0.002,P = 0.04），线粒体去极化增加（P = 0.017）。HC相比,PHA-stimulated PBMCs从经前综合症表现出显著降低基底(P = 0.017),最大,ATP-linked呼吸,增加耦合(P = 0.009),并降低备用呼吸和糖酵解能力(基底:P = 0.015,最大:P = 0.064),与平行GLUT1表达下降(P = 0.025)。这些变化似乎与某些治疗无关。意义：在pha刺激下，与RRMS和HC相比，PMS患者表现出基础呼吸、最大呼吸和atp相关呼吸减少，备用呼吸和糖酵解能力减少，这与未刺激条件下的趋势相反。这些发现表明MS临床形式的严重程度梯度，支持疾病连续体而不是严格定义的亚型。未解决的线粒体功能障碍在MS中的核心作用值得进一步研究，并可能指导新的治疗策略。

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引用次数: 0

Estrogen receptor–autophagy axis protects the heart, aorta and kidneys during perimenopausal aging: Evidence from human cohort and mouse experiments 雌激素受体自噬轴在围绝经期衰老过程中保护心脏、主动脉和肾脏：来自人类队列和小鼠实验的证据。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-03 DOI: 10.1016/j.lfs.2025.124183

Xiuting Xiang , Weizhou Jiang , Praneetha Palasuberniama , M. Tanveer Hossain Parash , Rahmawati Pare , Yunjun Ruan

Aim

The gradual decline in estrogen levels during perimenopause is strongly associated with an increased risk of metabolic and cardiovascular diseases. However, the specific relationship and underlying mechanisms remain incompletely understood. This study combines population data, network pharmacology, and mouse models to explore the detailed mechanisms underlying estrogen's organ-protective effects.

Materials and methods

We utilized data from the National Health and Nutrition Examination Survey (NHANES) to analyze the correlation between estradiol levels and conditions such as hypertension, kidney disease, diabetes, and hypercholesterolemia. A perimenopausal mouse model was established to assess the impact of estrogen replacement therapy on various organs, including the heart, aorta, and kidneys. Network pharmacology was used to identify molecular targets, and receptor-specific inhibitors along with autophagy inhibitors were applied for functional validation in estrogen-treated mice.

Key findings

Lower estradiol levels were significantly associated with an increased risk of hypertension, kidney disease, diabetes, and hypercholesterolemia. Estrogen treatment markedly reduced fibrosis in the heart, aorta, and kidneys, and promoted weight gain in mice, which mirrored BMI trends observed in human cohorts. Network pharmacology identified key molecular targets involved in estradiol-mediated pathways and mTOR-regulated autophagy. Functional validation confirmed that estrogen's protective effects depend on receptor activation and downstream autophagy signaling.

Significance

This study underscores the crucial role of the estrogen receptor-autophagy axis in metabolic regulation and organ protection during perimenopause. It provides new mechanistic insights that could inform precision hormone therapy strategies aimed at preventing aging-related diseases in women.

目的：围绝经期雌激素水平的逐渐下降与代谢和心血管疾病的风险增加密切相关。然而，具体的关系和潜在的机制仍然不完全清楚。本研究结合人群数据、网络药理学和小鼠模型，探讨雌激素器官保护作用的详细机制。材料和方法：我们利用国家健康和营养调查（NHANES）的数据分析雌二醇水平与高血压、肾病、糖尿病和高胆固醇血症等疾病的相关性。建立围绝经期小鼠模型，评估雌激素替代疗法对不同器官的影响，包括心脏、主动脉和肾脏。网络药理学用于鉴定分子靶点，受体特异性抑制剂和自噬抑制剂应用于雌激素处理小鼠的功能验证。主要发现：较低的雌二醇水平与高血压、肾病、糖尿病和高胆固醇血症的风险增加显著相关。雌激素治疗显著减少了心脏、主动脉和肾脏的纤维化，并促进了小鼠的体重增加，这反映了在人类队列中观察到的BMI趋势。网络药理学确定了参与雌二醇介导途径和mtor调节的自噬的关键分子靶点。功能验证证实雌激素的保护作用依赖于受体激活和下游自噬信号。意义：本研究强调了雌激素受体-自噬轴在围绝经期代谢调节和器官保护中的重要作用。它提供了新的机制见解，可以为旨在预防女性衰老相关疾病的精确激素治疗策略提供信息。

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引用次数: 0

GABA induces myokine irisin release from skeletal muscle GABA诱导骨骼肌释放肌因子鸢尾素。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-03 DOI: 10.1016/j.lfs.2025.124181

Linling Fan , Yijing Liao , Zhihong Wang , Yunzhi Ni , Qiaoli Cui , Yahao Wang , Li Zhang , Hongying Ye , Xiaodong Sun , Yiming Li , Qinghua Wang

Introduction

γ-Aminobutyric acid (GABA), a classical neurotransmitter, also regulates skeletal muscle-an endocrine organ secreting irisin. This FNDC5-derived myokine induces white adipose tissue browning, augmenting thermogenesis and metabolic function.

Objectives

This study investigated the effects of GABA on irisin secretion and its molecular mechanisms.

Methods

In L6 myotubes, GABA activated GABA_AR, causing membrane depolarization and calcium influx, which upregulated CREB phosphorylation and increased PGC-1α and FNDC5 expression, significantly elevating irisin secretion. In vivo, GABA treatment increased PGC-1α/FNDC5 expression in mouse skeletal muscle and raised serum irisin levels. Additionally, GABA-induced irisin promoted the browning of white adipose tissue by upregulating thermogenic genes and remodeling fat metabolism.

Conclusion

These findings reveal a novel role for GABA in regulating myokine secretion and suggest its potential as a therapeutic target for metabolic diseases such as obesity and type 2 diabetes.

γ-氨基丁酸（GABA）是一种经典的神经递质，还能调节骨骼肌——一种分泌鸢尾素的内分泌器官。这种fndc5衍生的肌因子诱导白色脂肪组织褐化，增强产热和代谢功能。目的：研究GABA对鸢尾素分泌的影响及其分子机制。方法：在L6肌管中，GABA激活GABAAR，引起膜去极化和钙内流，上调CREB磷酸化，增加PGC-1α和FNDC5表达，显著提高鸢尾素分泌。在体内，GABA处理增加了小鼠骨骼肌中PGC-1α/FNDC5的表达，提高了血清鸢尾素水平。此外，gaba诱导的鸢尾素通过上调产热基因和重塑脂肪代谢来促进白色脂肪组织的褐化。结论：这些发现揭示了GABA在调节肌因子分泌中的新作用，并提示其可能作为代谢性疾病（如肥胖和2型糖尿病）的治疗靶点。

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引用次数: 0

Early-life sex hormone deficiency promotes beneficial remodeling in white adipose tissue and whole-body metabolism 早期性激素缺乏促进白色脂肪组织和全身代谢的有益重塑。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-03 DOI: 10.1016/j.lfs.2025.124184

Ignacio Miguel , Ana Alzamendi , Alejandro Ezequiel Harnichar , Alejandra Paula Giordano , Carolina Carla Garraza , Eduardo Julio Spinedi , Andrés Giovambattista

Aims

This study investigates the impact of female sex hormone deficiency (FSHD) on white adipose tissue (WAT) development, focusing on two distinct depots: retroperitoneal adipose tissue (RPAT) and inguinal adipose tissue (IAT).

Materials and methods

Prepubertal ovariectomy was performed, and animals were pair-fed (FSHD-PF) to account for hyperphagia.

Key findings

FSHD-PF animals exhibited reduced plasma triglyceride and insulin levels, with improved glucose handling. A redistribution of adipose tissue was observed, with increased IAT mass and decreased RPAT mass, accompanied by a reduction in adipocyte size in RPAT. Expression markers of inflammation, such as ob and tnf-α, were significantly decreased in RPAT of FSHD-PF, suggesting a potential reduction in the inflammatory state. Likewise, we found that prepubertal ovariectomy also modulated adipocyte precursor cells (APCs), leading to increased cd34 expression in both depots, indicative of greater competency. However, RPAT showed elevated pparγ-2 levels, while IAT exhibited increased wnt10b, suggesting a depot-specific regulation. Notably, IAT-derived APCs from FSHD-PF animals display enhanced differentiation capacity in vitro. Cold exposure further modulated WAT browning, with a notable increase in UCP-1 protein expression although observed in IAT from FSHD-PF rats only.

Significance

This study is the first to examine FSHD in the context of WAT development, identifying early-life ovarian hormone loss as a critical and previously underexplored determinant of metabolic regulation. Accordingly, the consequences of early FSHD, together with its association with non-shivering thermogenesis, emerge as promising areas for further investigation with potential therapeutic relevance.

目的：本研究探讨女性性激素缺乏（FSHD）对白色脂肪组织（WAT）发育的影响，重点研究两个不同的部位：腹膜后脂肪组织（RPAT）和腹股沟脂肪组织（IAT）。材料和方法：行青春期前卵巢切除术，并对动物进行配对喂养（FSHD-PF）以解释贪食。主要发现：FSHD-PF动物表现出血浆甘油三酯和胰岛素水平降低，葡萄糖处理能力改善。观察到脂肪组织的重新分布，IAT质量增加，RPAT质量减少，同时RPAT中脂肪细胞大小减少。炎症标志物，如ob和tnf-α在FSHD-PF的RPAT中显著降低，提示炎症状态可能减轻。同样，我们发现青春期前卵巢切除术也会调节脂肪细胞前体细胞（APCs），导致cd34在两个库中的表达增加，表明更强的能力。然而，RPAT显示pparγ-2水平升高，而IAT显示wnt10b水平升高，提示储罐特异性调节。值得注意的是，来自FSHD-PF动物的iat衍生apc在体外表现出增强的分化能力。冷暴露进一步调节WAT褐变，UCP-1蛋白表达显著增加，尽管仅在FSHD-PF大鼠的IAT中观察到。意义：本研究首次在WAT发展的背景下检查FSHD，确定早期卵巢激素损失是代谢调节的关键因素，但以前未被充分探索。因此，早期FSHD的后果及其与非寒颤产热的关联，成为进一步研究的有希望的领域，具有潜在的治疗意义。

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引用次数: 0