Biomedicine & Pharmacotherapy最新文献_第2页

Polyelectrolyte complexed alginate–oligochitosan nanoparticles for co-delivery of doxorubicin and indocyanine green in triple negative breast cancer therapy 聚电解质络合海藻酸-低聚壳聚糖纳米颗粒在三阴性乳腺癌治疗中共同递送阿霉素和吲哚菁绿。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119067

Mariana Navarro-Real , Juan O. Zavala-López , Josué Juárez , Alberto Pardo , Silvia Barbosa , Pablo Taboada , Antonio Topete , Adrián Daneri-Navarro

Breast cancer remains the most prevalent malignancy affecting women worldwide. Nanomedicine offers promising strategies to drastically enhance the efficacy of current treatments by enabling spatiotemporal control over cancer diagnostics and therapy. Here, we developed a triple-modal nanocarrier integrating chemo-, photothermal and photodynamic therapies within a single nanoplatform to address the limitations of conventional monotherapies. The nanoparticles were synthesized via polyelectrolyte complexation of sodium alginate and oligochitosan, yielding a biocompatible, non-toxic nanosystem suitable for localized therapies. The designed nanocarriers displayed an average hydrodynamic diameter of 206.1 ± 6.8 nm, with a ζ-potential of −23.8 ± 2.5 mV, features that favor their tumor retention. Additionally, they demonstrated effective encapsulation of doxorubicin and indocyanine green, high photostability, and protection of the loaded drugs from degradation, while remaining responsive to near-infrared stimulation. In vitro, the nanoparticles demonstrate low drug release coupled with substantial cellular uptake and pronounced cytotoxicity against triple-negative breast cancer cells. These results highlight the potential of the designed alginate–oligochitosan-based nanoplatform as a multimodal therapeutic system, capable of additively combining multiple treatment modalities for localized breast cancer therapy, with predicted improvements in therapeutic efficacy and reduced off-target effects, pending validation in further studies.

乳腺癌仍然是影响全世界妇女的最普遍的恶性肿瘤。纳米医学通过实现对癌症诊断和治疗的时空控制，提供了有希望的策略，以大大提高当前治疗的疗效。在这里，我们开发了一种三模态纳米载体，将化学、光热和光动力疗法整合在一个纳米平台上，以解决传统单一疗法的局限性。该纳米颗粒是通过海藻酸钠和低聚壳聚糖的多电解质络合合成的，产生了一种适合局部治疗的生物相容性，无毒的纳米系统。所设计的纳米载体的平均水动力直径为206.1 ± 6.8 nm， ζ-电位为-23.8 ± 2.5 mV，这些特征有利于其肿瘤保留。此外，他们还证明了阿霉素和吲哚菁绿的有效包封，高光稳定性，保护负载药物不降解，同时对近红外刺激保持响应。在体外，纳米颗粒对三阴性乳腺癌细胞具有低药物释放和显著的细胞毒性。这些结果突出了设计的藻酸盐-寡壳聚糖纳米平台作为多模式治疗系统的潜力，能够将多种治疗方式加在一起用于局部乳腺癌治疗，预计治疗效果会有所改善，脱靶效应会减少，有待进一步研究的验证。

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引用次数: 0

Cyanidin-3-glucoside confers neuroprotection in ischemic stroke by targeting NOX4-mediated oxidative stress: A network pharmacology and experimental validation study 花青素-3-葡萄糖苷通过靶向nox4介导的氧化应激对缺血性脑卒中具有神经保护作用：网络药理学和实验验证研究

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119072

Xiaoting Li , Yikun Gao , Yingze Ye , Jin Wang , Xiaoxing Xiong , Jiehua Zhang , Liang Wei , Lijuan Gu

Background

To investigate the neuroprotective effect of the dietary anthocyanin cyanidin-3-glucoside (C-3-G) in cerebral ischemia–reperfusion injury and elucidate its underlying molecular mechanisms by a network pharmacology and transcriptomics methods.

Methods

We employed a network pharmacology and transcriptomics approach to identify NOX4 as a key therapeutic target. This prediction was validated in silico via molecular docking and Boolean network modeling, and experimentally in a mouse model of middle cerebral artery occlusion (MCAO) and in a neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) model.

Results

Network pharmacology and PPI analysis identified NOX4 as a central target, and molecular docking supported a stable interaction between C-3-G and NOX4. Transcriptomic profiling showed Nox4 upregulation with enrichment of oxidative-stress and cell-death pathways; Boolean network simulations indicated that inhibiting Nox4 attenuates the ROS–injury cascade. In experimental validation, C-3-G reduced infarct size and cerebral edema and improved neurological function in the MCAO mouse model, accompanied by decreased MDA, restoration of SOD and GSH activities, inhibition of Nox4 activity, and normalization of the Nrf2–Keap1–HO-1 axis toward homeostasis. The in vitro findings were concordant with the in vivo results. Co-administration of C-3-G with the Nox4-selective inhibitor GLX351322 produced no additive benefit, indicating that C-3-G exerts its neuroprotective effects predominantly via the Nox4 pathway.Crucially, the neuroprotective effects of C-3-G were not additive with a selective NOX4 inhibitor, confirming NOX4 as its primary molecular target.

Conclusion

C-3-G mitigates ischemia–reperfusion–induced oxidative stress and tissue injury by targeting Nox4 and modulating the Nrf2–Keap1–HO-1 antioxidant axis, supporting its potential as an adjunct therapy in the acute phase of ischemic stroke.

应用网络药理学和转录组学方法研究膳食花青素花青素-3-葡萄糖苷（C-3-G）对脑缺血再灌注损伤的神经保护作用，并阐明其潜在的分子机制。方法采用网络药理学和转录组学方法鉴定NOX4为关键治疗靶点。通过分子对接和布尔网络模型验证了这一预测，并在小鼠大脑中动脉闭塞（MCAO）模型和神经元氧-葡萄糖剥夺/再氧化（OGD/R）模型中进行了实验验证。结果网络药理学和PPI分析确定NOX4为中心靶点，分子对接支持C-3-G与NOX4稳定相互作用。转录组学分析显示Nox4上调，氧化应激和细胞死亡途径富集；布尔网络模拟表明，抑制Nox4可减弱ros损伤级联反应。在实验验证中，C-3-G减少了MCAO小鼠模型的梗死面积和脑水肿，改善了神经功能，同时降低了MDA，恢复了SOD和GSH的活性，抑制了Nox4的活性，使Nrf2-Keap1-HO-1轴向稳态正常化。体外实验结果与体内实验结果一致。C-3-G与Nox4选择性抑制剂GLX351322共给药没有附加效益，表明C-3-G主要通过Nox4途径发挥其神经保护作用。至关重要的是，C-3-G的神经保护作用与NOX4选择性抑制剂无关，这证实了NOX4是其主要分子靶点。结论c -3- g通过靶向Nox4和调节Nrf2-Keap1-HO-1抗氧化轴减轻缺血再灌注诱导的氧化应激和组织损伤，支持其作为缺血性脑卒中急性期辅助治疗的潜力。

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引用次数: 0

Simultaneous activation of apoptosis and cGAS-STING pathway with a mitochondria-targeted dehydrocholic acid compound for enhanced hepatocellular carcinoma chemoimmunotherapy 线粒体靶向去氢胆酸化合物同时激活细胞凋亡和cGAS-STING通路，增强肝癌化学免疫治疗

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119044

Fuwei Li , Sizhe Zhu , Xinyu Sun , Guangxin Geng , Jiawen Zhao , Jiaqi Han , Xiang Liu , Wenbo Zhu , Wenping Yang , Qinhang Wu

The activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway triggered by mitochondrial DNA (mtDNA) represents a highly promising strategy in tumor immunotherapy. Herein, we report a mitochondria-targeting small-molecule compound (3c), which contains dehydrocholic acid and acts as an activator of the cGAS-STING pathway in hepatocellular carcinoma (HCC). Specifically, 3c could target the mitochondria of HepG2 cells, regulate mitochondrial function, generate a large amount of reactive oxygen species (ROS), open the mitochondrial permeability transition pore (mPTP), and promote the release of mtDNA into the cytoplasm to further trigger the cGAS-STING pathway. Treatment of immunocompetent C57BL/6 mice bearing Hepa1–6 tumors with 3c activates their immune system, inducing an antitumor CD8⁺ T cell response and dendritic cell (DC) maturation; this process elicits a potent antitumor immune response by activating the cGAS-STING signaling pathway in HCC cells. Moreover, 3c can also induce apoptosis in HepG2 cells, which may be attributed to oxidative stress caused by elevated ROS levels. With the dual actions of cGAS-STING pathway activation and chemotherapy against HCC, 3c has great potential as an antitumor agent, and further serves as a preclinical proof-of-concept for chemoimmunotherapy. To the best of our knowledge, 3c is one of the few mitochondria-targeting small-molecule compounds that can induce an immunomodulatory response by activating the cGAS-STING pathway. Overall, we present a novel example of cGAS-STING pathway activation mediated by a mitochondria-targeted dehydrocholic acid-derived compound, which may provide an innovative strategy for designing chemoimmunotherapies for HCC.

线粒体DNA （mtDNA）触发干扰素基因环GMP-AMP合成酶刺激因子（cGAS-STING）通路的激活是肿瘤免疫治疗中极具前景的策略。在此，我们报道了一种靶向线粒体的小分子化合物（3c），它含有脱氢胆酸，在肝细胞癌（HCC）中作为cGAS-STING通路的激活剂。具体来说，3c可以靶向HepG2细胞的线粒体，调控线粒体功能，产生大量活性氧（ROS），打开线粒体通透性过渡孔（mPTP），促进mtDNA释放到细胞质中，进而触发cGAS-STING通路。用3c治疗携带Hepa1-6肿瘤的免疫活性C57BL/6小鼠，激活其免疫系统，诱导CD8 + T细胞应答和树突状细胞（DC）成熟；这一过程通过激活HCC细胞中的cGAS-STING信号通路引发了有效的抗肿瘤免疫应答。此外，3c还可以诱导HepG2细胞凋亡，这可能与ROS水平升高引起的氧化应激有关。3c具有cGAS-STING通路激活和化疗对HCC的双重作用，具有很大的抗肿瘤潜力，并可进一步作为化疗免疫治疗的临床前概念验证。据我们所知，3c是为数不多的可以通过激活cGAS-STING途径诱导免疫调节反应的线粒体靶向小分子化合物之一。总之，我们提出了一个线粒体靶向脱氢胆酸衍生化合物介导的cGAS-STING通路激活的新例子，这可能为设计HCC的化学免疫疗法提供一种创新策略。

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引用次数: 0

D- and L-Lactate enhance intestinal barrier function via activation of an apical HCAR1/Gαi pathway in a human colonic epithelial cell model 在人结肠上皮细胞模型中，D-和l -乳酸通过激活顶端HCAR1/Gαi通路增强肠道屏障功能

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119041

Annabelle J. Milner , Priyanka Anujan , Gary S. Frost , Aylin C. Hanyaloglu

The stereoisomers of lactate, L- and D- are not only metabolic substrates but also signalling molecules, capable of activating and signalling through its G protein-coupled receptor, Hydroxycarboxylic acid receptor 1 (HCAR1). These stereoisomers are both produced by the gut microbiota at millimolar concentrations creating a physiological environment for lactate-sensing unique to the gut yet, poorly understood. Here we identify a role for D-/L-lactate on intestinal barrier function. A human colonic epithelial cell model, Caco2, activated Gαi signalling in response to both L- and D-lactate, although L-lactate exhibited a more potent and rapid Gαi signal profile. When differentiated, apically but not basally treated D-/L-lactate enhanced tight junctions and reduced cell permeability, consistent with the apical localization of HCAR1. This improved barrier function occurred in a Gαi-dependent manner. In addition, apical lactate rescued the reduced intestinal barrier function induced by lipopolysaccharides. This work highlights the potential for D-/L-lactate supplementation in improving gut health.

乳酸、L-和D-的立体异构体不仅是代谢底物，而且是信号分子，能够通过其G蛋白偶联受体羟基羧酸受体1 （HCAR1）激活和信号传导。这些立体异构体都是由肠道微生物群以毫摩尔浓度产生的，为肠道独特的乳酸感知创造了一个生理环境，但人们对这一环境知之甚少。在这里，我们确定了D-/ l -乳酸在肠屏障功能中的作用。人类结肠上皮细胞模型Caco2对L-乳酸和d -乳酸均激活了g - αi信号，尽管L-乳酸表现出更有效和快速的g - αi信号谱。分化时，D-/ l -乳酸在根尖而非基部处理，增强了紧密连接，降低了细胞通透性，这与HCAR1的根尖定位一致。这种改善的屏障功能以g αi依赖的方式发生。此外，根尖乳酸恢复了脂多糖引起的肠道屏障功能下降。这项工作强调了补充D-/ l -乳酸在改善肠道健康方面的潜力。

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引用次数: 0

CD44 receptor-driven graphene oxide based nanocarriers for cancer therapy CD44受体驱动的氧化石墨烯纳米载体用于癌症治疗

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119036

Ludmila Žárská , Michaela Gapčová , Zuzana Chaloupková , Václav Ranc

Interactions between hyaluronic acid (HA) and the CD44 receptor represent a key mechanism in tumor cell recognition and selective drug uptake. In this study, we compare the efficacy of a graphene oxide (GO)-based nanoplatform in two cell lines with markedly different CD44 expression levels. The aim is to investigate how HA functionalization and its concentration influence the biological behavior of these GO nanocarriers designed for targeted delivery of doxorubicin (DOX). The nanoplatform was prepared by sequential PEGylation of nanosized GO, followed by HA conjugation at three concentrations (0.1, 1, and 10 mg/mL) and subsequent DOX loading. Spectroscopic and microscopic analyses confirmed stepwise surface modification, formation of a stable polymer coating, and successful DOX incorporation through π–π stacking and hydrogen bonding. Biological assays demonstrated that HA enhances CD44-mediated internalization and increases anticancer activity in CD44⁺ HT-1080 cells, while the GO@PEG carrier alone showed minimal cytotoxicity, highlighting its good biocompatibility. In contrast, CD44⁻ SKBR3 cells displayed limited uptake and higher viability, consistent with weaker HA–CD44 interactions and lower receptor expression. Confocal microscopy and Raman spectroscopy visualized effective intracellular accumulation and perinuclear localization of the nanocarrier, further confirming selective internalization mechanisms. Overall, the results provide important insight into the role of HA in improving the specificity, cellular uptake, and safety of GO-based nanoplatforms. The study underscores the significance of CD44 receptor levels in determining therapeutic efficiency and supports the development of receptor-targeted, biocompatible nanocarrier systems for precision cancer therapy.

透明质酸（HA）和CD44受体之间的相互作用是肿瘤细胞识别和选择性药物摄取的关键机制。在这项研究中，我们比较了氧化石墨烯（GO）纳米平台在两种CD44表达水平明显不同的细胞系中的效果。目的是研究透明质酸功能化及其浓度如何影响这些氧化石墨烯纳米载体的生物学行为，这些纳米载体设计用于靶向递送阿霉素（DOX）。纳米平台是通过纳米氧化石墨烯的顺序聚乙二醇化制备的，然后在三种浓度（0.1、1和10 mg/mL）下进行HA偶联，然后加载DOX。光谱和微观分析证实了逐步的表面改性，形成了稳定的聚合物涂层，并通过π -π堆叠和氢键成功地将DOX掺入。生物学实验表明，HA增强CD44介导的内化，增加CD44 + HT-1080细胞的抗癌活性，而GO@PEG载体单独表现出最小的细胞毒性，突出了其良好的生物相容性。相反，CD44 - SKBR3细胞表现出有限的摄取和更高的活力，与较弱的HA-CD44相互作用和较低的受体表达一致。共聚焦显微镜和拉曼光谱显示了纳米载体在细胞内的有效积累和核周定位，进一步证实了选择性内化机制。总的来说，这些结果为透明质酸在提高氧化石墨烯纳米平台的特异性、细胞摄取和安全性方面的作用提供了重要的见解。该研究强调了CD44受体水平在决定治疗效率中的重要性，并支持了受体靶向、生物相容性纳米载体系统用于精确癌症治疗的发展。

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引用次数: 0

Differential effects of the anti-obesity drug tirzepatide on adipose tissues: Brown fat as a key target 抗肥胖药物替西肽对脂肪组织的差异作用：棕色脂肪为关键靶点。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119057

Alberto Mestres-Arenas , Tania Quesada-López , Albert Blasco-Roset , Marta Giralt , Francesc Villarroya , Anna Planavila , Marion Peyrou

Tirzepatide is an anti-obesity drug based on dual agonism of the incretin receptors GLP-1R and GIPR. Its anti-obesity effect is largely based on its action of reducing food intake. However, there are indications that tirzepatide exerts effects on adipose tissues beyond those resulting from fat loss due to reduced food intake. To investigate this, we treated mice, previously been made obese through high-fat diet, with tirzepatide. We also established an experimental group of mice pair-fed with those treated with tirzepatide, key to distinguish the specific effect of tirzepatide from food intake reduction-mediated effects. Both groups experienced similar reduction in body weight, with a trend toward greater loss in visceral and subcutaneous white fat in mice under tirzepatide treatment. Glucose tolerance improved in tirzepatide-treated obese mice, independently of reduced food intake. Tirzepatide treatment also lowered the inflammatory status of obese mice, which in this case, was attributable to decreased food consumption. Tirzepatide exerted distinct effects on brown adipose tissue relative to white adipose tissues, significantly boosting thermogenic activity and modifying its gene expression pattern, including the upregulation of genes linked to thermogenesis and substrate oxidation. White adipose tissues responded differently, being primarily affected in their lipid metabolism. These effects were specific to tirzepatide treatment and not attributable to reduced food intake. Our results indicate that tirzepatide affects the function and metabolism of adipose tissues and especially induces activation of brown adipose tissue in mice, which may be relevant for future human studies to ascertain the mechanisms of tirzepatide metabolic benefits.

替西肽是一种基于肠促胰岛素受体GLP-1R和GIPR双重激动作用的抗肥胖药物。它的抗肥胖作用主要是基于它减少食物摄入的作用。然而，有迹象表明，替西肽对脂肪组织的影响超出了因减少食物摄入而导致的脂肪减少。为了研究这一点，我们用替西帕肽治疗了先前通过高脂肪饮食导致肥胖的小鼠。我们还建立了一个实验组，与替西肽治疗的小鼠配对喂养，以区分替西肽的特异性作用与食物摄入减少介导的作用。在替西肽治疗下，两组小鼠的体重都有相似的减少，内脏和皮下白色脂肪的减少趋势更大。替西肽治疗的肥胖小鼠的葡萄糖耐量得到改善，与减少食物摄入量无关。替西帕肽治疗还降低了肥胖小鼠的炎症状态，在这种情况下，这是由于减少了食物消耗。相对于白色脂肪组织，替西帕肽对棕色脂肪组织有明显的影响，显著提高了产热活性，并改变了其基因表达模式，包括与产热和底物氧化相关的基因上调。白色脂肪组织的反应不同，主要受到脂质代谢的影响。这些效果是替西肽治疗特有的，与减少食物摄入无关。我们的研究结果表明，替西肽影响小鼠脂肪组织的功能和代谢，特别是诱导棕色脂肪组织的激活，这可能与未来的人体研究有关，以确定替西肽代谢益处的机制。

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引用次数: 0

V-domain immunoglobulin suppressor of T-cell activation regulates CD4+ T cell activation and podocyte function through PI3K/AKT signaling pathway T细胞活化的v域免疫球蛋白抑制因子通过PI3K/AKT信号通路调控CD4+ T细胞活化和足细胞功能

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119038

Zhijie Luo , Qiqi Zhang , Tingting Zhang , Tianyi Yuan , Dingyi Yuan , Xueyan Zhao , Ting Gao , Ruixue Ma , Hai Qian , Xinzhi Wang , Jun Liu

The activation of V-domain immunoglobulin suppressor of T-cell activation (VISTA) has shown its therapeutic potential in murine lupus-like disease through immunoregulation, particularly suppressing CD4⁺ T cell activation. Podocytes are critical for preventing proteinuria in lupus nephritis (LN). However, the mechanisms by which VISTA regulate CD4⁺ T cells and renal podocytes remain unclear. Here, we demonstrated that CD4⁺ T cells from VISTA knockout mice showed upregulated phosphorylation of PI3K/AKT, increased secretion of IFN-γ, IL-17 and CD40L. Soluble VISTA mitigated inflammation and recovered the expression of structural proteins Podocin through inhibition of PI3K/AKT/mTOR signaling pathway and induction of autophagy. Moreover, previously demonstrated VISTA agonist Baloxavir marboxil decreased renal CD4⁺ T cells, restored the expression of Nephrin and Podocin, and promoted autophagy. Our study suggests that VISTA plays an important role in the pathogenesis of LN, which offers novel mechanisms and potential target for its application in LN therapy.

v域免疫球蛋白T细胞活化抑制因子（VISTA）的激活通过免疫调节，特别是抑制CD4+ T细胞活化，在小鼠狼疮样疾病中显示出其治疗潜力。足细胞是预防狼疮肾炎（LN）蛋白尿的关键。然而，VISTA调节CD4+ T细胞和肾足细胞的机制尚不清楚。在这里，我们证明了VISTA敲除小鼠的CD4+ T细胞表现出PI3K/AKT磷酸化上调，IFN-γ、IL-17和CD40L分泌增加。可溶性VISTA通过抑制PI3K/AKT/mTOR信号通路，诱导自噬，减轻炎症，恢复结构蛋白Podocin的表达。此外，先前证实的VISTA激动剂Baloxavir marboxil可降低肾CD4+ T细胞，恢复Nephrin和Podocin的表达，促进自噬。我们的研究表明，VISTA在LN的发病机制中发挥了重要作用，为其在LN治疗中的应用提供了新的机制和潜在的靶点。

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引用次数: 0

Myeloid-specific Exoc5 deficiency develops renal inflammation and hypertension 骨髓特异性Exoc5缺乏可导致肾脏炎症和高血压

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119061

Gwan Beom Lee , Ga-Eun Yoon , Phuong Quynh Luong , Masumi Eto , Joshua H. Lipschutz , Jee In Kim

Migration of macrophages into the kidney is a cause of inflammation and the pathogenesis of hypertension. The exocyst complex drives polarized exocytosis and cell migration, although the roles of the exocyst complex in macrophage infiltration have yet to be fully understood. Here, we determined the pathophysiological role of Exoc5, a major component of the exocyst complex, in the development of hypertension using myeloid-specific Exoc5-deficient (LysM-Exoc5 KO) mice and cells. Selective elimination of Exoc5 expression in bone marrow-derived macrophages (BMDM) of LysM-Exoc5 KO mice elevated blood pressures (BP) compared to WT mice. Simultaneously, elevations in BMDM infiltration and expression of pro-inflammatory markers, such as F4/80, TNF-α, IL-6, and MCP-1, as well as angiotensin II and various sodium transporters, occurred in the kidneys of LysM-Exoc5 KO mice. LysM-Exoc5 KO BMDM demonstrated reduced release of exosomes containing formin1, accumulating formin1 inside the cell, and the enhanced BMDM migration was reversed by an actin disruptor and formin1 inhibitor. On the other hand, levels of Rac1 and GTP-bound Rac1 were unchanged between LysM-Exoc5 KO and WT, nor did the Rac1 inhibitor show any effect on the migration. Silencing the Exoc5 gene in Raw264.7 cells reduced exosome release, leading to the accumulation of formin1 within cells, mimicking the LysM-Exoc5 KO phenotype. Exoc5-downregulated Raw264.7 cells injected into mice migrated into the kidney, inducing inflammation and increasing BP. These findings unravel an Exoc5-mediated selective exocytosis-regulated mechanism of inflammation and hypertension, providing Exoc5 and formin1 as potential therapeutic targets for hypertension.

巨噬细胞迁移到肾脏是引起炎症和高血压的发病机制之一。胞囊复合体驱动极化胞吐和细胞迁移，尽管胞囊复合体在巨噬细胞浸润中的作用尚未完全了解。在这里，我们利用骨髓特异性Exoc5缺陷（LysM-Exoc5 KO）小鼠和细胞，确定了Exoc5（外囊复合物的主要成分）在高血压发展中的病理生理作用。与WT小鼠相比，选择性消除LysM-Exoc5 KO小鼠骨髓源性巨噬细胞（BMDM）中Exoc5表达升高血压（BP）。同时，LysM-Exoc5 KO小鼠肾脏中BMDM浸润和促炎标志物（如F4/80、TNF-α、IL-6和MCP-1）以及血管紧张素II和各种钠转运蛋白的表达升高。LysM-Exoc5 KO BMDM显示含有formin1的外泌体释放减少，在细胞内积累formin1，并且增强的BMDM迁移被肌动蛋白干扰物和formin1抑制剂逆转。另一方面，在LysM-Exoc5 KO和WT之间，Rac1和gtp结合的Rac1的水平没有变化，Rac1抑制剂对迁移也没有任何影响。在Raw264.7细胞中沉默Exoc5基因减少了外泌体的释放，导致形成1在细胞内的积累，模拟了LysM-Exoc5 KO表型。将exoc5下调的Raw264.7细胞注射到小鼠体内，迁移到肾脏，引起炎症并升高血压。这些发现揭示了Exoc5介导的选择性胞吐调节炎症和高血压的机制，提供了Exoc5和formin1作为高血压的潜在治疗靶点。

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引用次数: 0

Cerebral dopamine neurotrophic factor and its functional fragments induce calcium signal through sigma-1 receptor and protect neurons against glutamate-induced excitotoxicity 脑多巴胺神经营养因子及其功能片段通过sigma-1受体诱导钙信号，保护神经元免受谷氨酸诱导的兴奋毒性

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-02-01 DOI: 10.1016/j.biopha.2026.119034

Nafisa Komilova , Noemi Esteras , Alessandra Preziuso , Lauren Millichap , Ausra Domanska , Anastasia Ludwig , Natalia Kulesskaya , Henri J. Huttunen , Kira M. Holmström , Andrey Y. Abramov , Plamena R. Angelova

Cerebral Dopamine Neurotrophic Factor (CDNF) is known to protect neurons in various pathologies. HER-096 is a CDNF-derived brain-penetrating peptidomimetic which also possesses neuroprotective properties. However, the mechanism underlying the cytoprotective effects is not fully understood. Using primary cortical co-culture of neurons and astrocytes we have found that both CDNF and HER-096 can induce intracellular calcium signals predominantly in astrocytes by release of Ca^2 + from endoplasmic reticulum to cytosol. This decrease in the ER Ca²⁺ pool activates store-operated calcium entrance (SOCE). Initial Ca²⁺ signal in these cells could be inhibited by the sigma-1 receptor antagonist BD-1047. CDNF and HER-096 reduced the glutamate-induced delayed Ca²⁺ deregulation and mitochondrial depolarisation which leads to significant protection against glutamate-induced excitotoxicity. Thus, the CDNF and HER-096 sigma-1 receptor mediated Ca²⁺ signal in astrocytes and neurons, from the ER, could modify the effects of high concentrations of glutamate that lead to neuroprotection.

已知脑多巴胺神经营养因子（CDNF）在各种病理中保护神经元。HER-096是一种cdnf衍生的脑穿透类肽，也具有神经保护作用。然而，细胞保护作用的机制尚不完全清楚。通过神经元和星形胶质细胞的原代皮质共培养，我们发现CDNF和HER-096都可以通过从内质网向细胞质溶胶释放Ca2 +来诱导星形胶质细胞内的细胞内钙信号。内质网Ca2+池的减少激活了储运钙入口（SOCE）。这些细胞中的初始Ca2+信号可以被sigma-1受体拮抗剂BD-1047抑制。CDNF和HER-096减少了谷氨酸诱导的延迟Ca2+解除管制和线粒体去极化，这对谷氨酸诱导的兴奋毒性有显著的保护作用。因此，来自内质网的CDNF和HER-096 sigma-1受体介导的星形胶质细胞和神经元中的Ca2+信号可以改变高浓度谷氨酸导致神经保护的作用。

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引用次数: 0

The dual role of extracellular vesicles in OA: Pathological mediators, diagnostic biomarkers, and therapeutic targets 细胞外囊泡在OA中的双重作用：病理介质、诊断生物标志物和治疗靶点

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-31 DOI: 10.1016/j.biopha.2026.119064

Yi Leng, Yuhang Gao, Jianzeng Zhang, Xin Qi

Osteoarthritis (OA) remains a formidable global health challenge, characterized by progressive articular cartilage degradation and a lack of effective disease-modifying interventions. Extracellular vesicles (EVs), previously categorized as mere cellular debris, have recently emerged as pivotal orchestrators of intercellular communication within the joint microenvironment. This review critically examines the dichotomous nature of EVs in OA. We characterize how endogenous EVs from stressed joint tissues drive pathology by disseminating pro-inflammatory and catabolic signals. Conversely, we highlight the therapeutic promise of exogenous EVs-particularly those derived from mesenchymal stem cells-as potent, cell-free regenerative agents capable of immunomodulation and cartilage repair. Beyond their biological roles, we discuss the emerging utility of synovial fluid EVs as liquid biopsies for early diagnosis and disease stratification. Finally, we address key translational bottlenecks, which demand standardization according to Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023) to accelerate clinical application.

骨关节炎（OA）仍然是一个巨大的全球健康挑战，其特点是进行性关节软骨退化和缺乏有效的疾病改善干预措施。细胞外囊泡（EVs），以前被归类为细胞碎片，最近在关节微环境中成为细胞间通讯的关键协调者。这篇综述批判性地探讨了OA中EVs的二分性。我们描述了来自受压关节组织的内源性ev如何通过传播促炎和分解代谢信号来驱动病理。相反，我们强调了外源性ev的治疗前景，特别是来自间充质干细胞的ev，作为有效的无细胞再生剂，具有免疫调节和软骨修复的能力。除了它们的生物学作用外，我们还讨论了滑液EVs作为早期诊断和疾病分层的液体活检的新兴用途。最后，我们解决了关键的翻译瓶颈，这些瓶颈需要根据细胞外囊泡研究最小信息2023 （MISEV2023）进行标准化，以加速临床应用。

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引用次数: 0