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microRNAs in pancreatic cancer: Key modulators of tumor progression and therapeutic resistance. 胰腺癌中的microrna:肿瘤进展和治疗耐药的关键调节因子。
IF 7.5 Pub Date : 2026-02-09 DOI: 10.1016/j.biopha.2026.119100
Hadi Sadeghi, Moein Kohkalani, Seyyed Amin Seyyed Rezaei, Saba Kargarmonhaser, Faezeh Mahd Gharebagh, Amin Nikdouz, Arezoo Hosseini

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers globally, with a five-year survival rate of less than 10 % due to its symptomless progression and late-stage diagnosis. The tumor microenvironment (TME), dense with immune and stromal cells, plays a key role in facilitating tumor growth and resistance to conventional therapies. Genetic changes-namely, in KRAS, TP53, CDKN2A, and SMAD4-drive abnormal signaling through the MAPK/ERK, PI3K/AKT, and NF-κB pathways, among others, that contribute to PDAC aggressiveness. microRNAs (miRNAs), tiny non-coding regulators of gene expression, have emerged as paramount modulators in PDAC, functioning either as oncogenes or tumor suppressors. Their dysregulation not only affects hallmark cancer traits but also holds great promise for diagnosis and treatment. Therapy using miRNA mimics and inhibitors aims to restore gene expression balance, but delivery and stability concerns persist. Advances in nanotechnology are enabling increasingly targeted and effective miRNA-based therapies, potentially transforming the clinical management of pancreatic cancer (PC).

胰腺导管腺癌(PDAC)是全球最致命的癌症之一,由于其无症状进展和晚期诊断,5年生存率低于10% %。肿瘤微环境(tumor microenvironment, TME)是免疫细胞和基质细胞密集的环境,在促进肿瘤生长和抵抗常规治疗方面起着关键作用。基因变化——即KRAS、TP53、CDKN2A和smad4——通过MAPK/ERK、PI3K/AKT和NF-κB等途径驱动异常信号传导,从而促进PDAC的侵袭性。microRNAs (miRNAs)是基因表达的微小非编码调节因子,在PDAC中已成为最重要的调节因子,可作为癌基因或肿瘤抑制因子发挥作用。它们的失调不仅影响标志性的癌症特征,而且对诊断和治疗也有很大的希望。使用miRNA模拟物和抑制剂的治疗旨在恢复基因表达平衡,但递送和稳定性问题仍然存在。纳米技术的进步使得基于mirna的治疗越来越有针对性和有效,潜在地改变了胰腺癌的临床管理。
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引用次数: 0
Non-coding RNA Trojan nanocarriers in CRC: Mechanistic crossroads and therapeutic challenges. 非编码RNA特洛伊纳米载体在结直肠癌:机械交叉和治疗挑战。
IF 7.5 Pub Date : 2026-02-07 DOI: 10.1016/j.biopha.2026.119098
Mingrong Cheng, Yucheng Ni, Wei Zhang, Qinghua Wu

Chemoresistance in colorectal cancer (CRC) represents a core bottleneck in clinical treatment, primarily driven by the cross-regulatory network formed by cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). Non-coding RNAs (ncRNAs) play a central role in this regulatory network, providing crucial molecular targets for chemoresistance intervention. However, the clinical translation of ncRNAs is limited by delivery challenges. The nanoscale "Trojan Horse" drug delivery system achieves precise delivery through triple-targeting design: at the tissue level, tumor accumulation is realized via the enhanced permeability and retention effect and targeted modification; at the cellular level, it targets CSCs and other chemoresistant cells; at the molecular level, it interferes with core pathways of stemness, EMT, and chemoresistance. Additionally, this system enables synergistic combination of chemotherapy with gene therapy, immunotherapy, phototherapy, and other modalities through multi-drug co-delivery, while integrating theranostic functions to synchronize chemoresistance monitoring and treatment. This review systematically elaborates on the mechanisms of ncRNA-mediated regulation of CRC chemoresistance, the design strategies and application efficacy of the nanoscale "Trojan Horse" system, providing critical insights for overcoming CRC cross-resistance and advancing the clinical translation of ncRNA nanotherapies.

结直肠癌(CRC)的化疗耐药是临床治疗的核心瓶颈,主要由癌症干细胞(CSCs)和上皮-间质转化(EMT)形成的交叉调控网络驱动。非编码rna (ncRNAs)在这一调控网络中发挥着核心作用,为化疗耐药干预提供了关键的分子靶点。然而,ncrna的临床翻译受到递送挑战的限制。纳米级“特洛伊木马”给药系统通过三重靶向设计实现精准给药:在组织层面,通过增强的通透性和滞留效应以及靶向修饰实现肿瘤蓄积;在细胞水平上,它针对CSCs和其他耐药细胞;在分子水平上,它干扰干性、EMT和化疗耐药的核心途径。此外,该系统通过多药共给药,使化疗与基因治疗、免疫治疗、光疗和其他方式协同结合,同时整合治疗功能,同步化疗耐药监测和治疗。本文系统阐述了ncRNA介导的结直肠癌化疗耐药调控机制、纳米级“特洛伊木马”系统的设计策略和应用效果,为克服结直肠癌交叉耐药和推进ncRNA纳米治疗的临床转化提供了重要见解。
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引用次数: 0
The addition of celecoxib enhances the therapeutic benefit of cabozantinib and anti-PD1 in hepatocellular carcinoma. 塞来昔布的加入增强了卡博赞替尼和抗pd1治疗肝细胞癌的疗效。
IF 7.5 Pub Date : 2026-02-07 DOI: 10.1016/j.biopha.2026.119102
Yu-Chen Hsu, Meng-Chuan Wu, Chien-Hung Chen, Ying-Te Lee, Ching-I Lin, Huei-Chi Chou, Hsuan-Shu Lee, Li-Fang Wang, Jin-Chuan Sheu, Meng-Tzu Weng

Combination therapy with targeted agents and immune checkpoint inhibitors (ICIs) represents a major advance in the treatment of advanced hepatocellular carcinoma (HCC), yet clinical efficacy remains modest. In the phase III COSMIC-312 trial, cabozantinib plus atezolizumab prolonged progression-free survival but did not improve overall survival, indicating the presence of tumor-intrinsic resistance mechanisms. In this study, we investigated the therapeutic and immunological effects of cabozantinib, celecoxib, and anti-programmed death-1 (anti-PD1), administered individually or in combination, in orthotopic and spontaneous metastatic HCC mouse models. Cabozantinib demonstrated hallmarks of immunogenic cell death (ICD) but concurrently activated COX-2/PGE₂-mediated immunosuppression, thereby limiting its antitumor efficacy. Celecoxib selectively inhibited PGE₂ production without affecting ICD, thereby enhancing dendritic cell activation and strengthening cytotoxic T-cell responses. Notably, triple therapy with cabozantinib, celecoxib, and anti-PD1 produced the most potent therapeutic outcome, markedly suppressing primary tumor growth, reducing lung metastases, and depleting regulatory T cells. These results reveal that celecoxib mitigates COX-2/PGE₂-driven immunosuppression while preserving ICD, thereby augmenting the efficacy of cabozantinib-anti-PD1 immunotherapy. This combination provides a strong mechanistic rationale for clinical translation and may inform future strategies to improve the durability of immune-based treatments for advanced HCC. This strategy may also guide future clinical trial designs and support the development of more effective, personalized therapies for patients with advanced HCC.

靶向药物和免疫检查点抑制剂(ICIs)联合治疗是晚期肝细胞癌(HCC)治疗的重大进展,但临床疗效仍然有限。在III期COSMIC-312试验中,卡博赞替尼联合阿特唑单抗延长了无进展生存期,但没有提高总生存期,表明存在肿瘤内在耐药机制。在这项研究中,我们研究了卡博替尼、塞来昔布和抗程序性死亡-1 (anti-程序性死亡-1)在原位和自发转移性HCC小鼠模型中的治疗和免疫效果,分别单独或联合给药。Cabozantinib表现出免疫原性细胞死亡(ICD)的特征,但同时激活了COX-2/ pge2介导的免疫抑制,从而限制了其抗肿瘤功效。塞来昔布选择性地抑制pge2的产生,而不影响ICD,从而增强树突状细胞的活化和增强细胞毒性t细胞反应。值得注意的是,卡博桑替尼、塞来昔布和抗pd1三联疗法产生了最有效的治疗效果,显著抑制原发肿瘤生长,减少肺转移,并消耗调节性T细胞。这些结果表明,塞来昔布减轻了COX-2/ pge2驱动的免疫抑制,同时保留了ICD,从而增强了cabozantinib抗pd1免疫治疗的疗效。这种结合为临床转化提供了强有力的机制基础,并可能为未来提高晚期HCC免疫治疗持久性的策略提供信息。这一策略也可以指导未来的临床试验设计,并为晚期HCC患者开发更有效、个性化的治疗方法提供支持。
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引用次数: 0
Corrigendum to "Oleuropein reduces LPS-induced inflammation via stimulating M2 macrophage polarization" [Biomed. Pharmacother. 163 (2023) 114857]. “橄榄苦苷通过刺激M2巨噬细胞极化减少脂多糖诱导的炎症”的勘误表[生物医学]。药理学杂志[j].中国药理学杂志,2016(5):357 - 357。
IF 7.5 Pub Date : 2026-02-07 DOI: 10.1016/j.biopha.2026.119109
Zahra Mirsanei, Neda Heidari, Ali Hazrati, Yahya Asemani, Bahare Niknam, Zahra Yousefi, Reza Jafari
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引用次数: 0
Mitoxyperilysis links organelle positioning to inflammatory lysis: A new lens for pharmacotherapy design. 丝裂细胞溶解将细胞器定位与炎症溶解联系起来:药物治疗设计的新视角。
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119103
Yen-Dun Tony Tzeng, Chen-Yueh Wen, Su-Boon Yong, Chia-Jung Li
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引用次数: 0
The ERK signaling pathway in cerebral ischemic stroke: Mechanism and therapeutic significance. ERK信号通路在缺血性脑卒中中的作用机制及治疗意义。
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119058
Xiumei Yin, Jun Chang, Lihong Yang, Lanyu Jia, Jiawei Han, Linling Chen, Jiangpeng Cao, Xujuan Chen, Ning Xie, Yuexin Lin, Man Zhang, Yuanhao Du

Cerebral ischemic stroke (CIS) represents a leading global cause of mortality and long-term disability, posing a significant public health challenge. The pathogenesis of CIS is complex, and effective therapies remain limited. Therefore, elucidating the underlying neurobiological mechanisms of CIS and exploring novel therapeutic strategies are essential. Extracellular signal-regulated kinase (ERK) has emerged as a critical regulator in CIS pathogenesis, playing pivotal roles in cellular processes such as growth, proliferation, differentiation, and signal transduction, while also demonstrating substantial neuroprotective potential. Targeted modulation of ERK signaling holds promise for mitigating multiple pathological cascades in CIS, including endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, apoptosis, excitotoxicity, autophagy, and neuroinflammation, while potentially promoting neural regeneration. Consequently, ERK represents an attractive potential therapeutic target for alleviating CIS. This review first delineates the structure, function, and activation of the ERK pathway. Subsequently, it summarizes current understandings of CIS pathogenesis and critically examines the involvement of ERK signaling in CIS pathophysiology. Finally, the review discusses the mechanistic basis and therapeutic potential of targeting the ERK pathway to ameliorate CIS, providing a scientific rationale for further investigation of ERK as a therapeutic target.

缺血性脑卒中是全球死亡和长期残疾的主要原因,对公共卫生构成重大挑战。CIS的发病机制复杂,有效的治疗方法仍然有限。因此,阐明CIS的潜在神经生物学机制和探索新的治疗策略是必不可少的。细胞外信号调节激酶(ERK)已成为CIS发病机制的关键调节因子,在细胞生长、增殖、分化和信号转导等过程中发挥关键作用,同时也显示出巨大的神经保护潜力。ERK信号的靶向调节有望减轻CIS中的多种病理级联反应,包括内质网应激、氧化应激、线粒体功能障碍、细胞凋亡、兴奋毒性、自噬和神经炎症,同时可能促进神经再生。因此,ERK是缓解CIS的一个有吸引力的潜在治疗靶点。这篇综述首先描述了ERK通路的结构、功能和激活。随后,总结了目前对CIS发病机制的理解,并批判性地研究了ERK信号在CIS病理生理中的作用。最后,本文讨论了靶向ERK通路改善CIS的机制基础和治疗潜力,为进一步研究ERK作为治疗靶点提供了科学依据。
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引用次数: 0
Amlodipine improves aortic dysfunction in atherosclerotic mice. 氨氯地平改善动脉粥样硬化小鼠主动脉功能障碍。
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119073
Sophia Marie Rasch, Benedikt Fels, Alexandra Schmalohr, Luis Daniel Hernandez Torres, Eva Peschke, Olga Maria Will, Jan-Bernd Hoevener, Leonie Achner, Tobias Klersy, Frauke Spiecker, Marcel Sauer, Carl Vahldieck, Tobias Reinberger, Urte Matschl, Susanne Hille, Oliver J Müller, Zouhair Aherrahrou, Kristina Kusche, Walter Raasch

Calcium channel blockers are established in treating hypertension or arrhythmias. They have also been suggested to have anti-atherosclerotic effects, although most such studies are limited mainly to histological or biochemical parameters. Therefore, the aim was to test the hypothesis that amlodipine (AMLO) improves vascular function in atherosclerosis in particular. Here, PCSK9DY-injected C57BL/6N-mice on a Western diet (WD) were orally treated with either AMLO (10 mg/kgbw) or vehicle (VEH), while controls received adeno-associated virus vector (AAV) and a chow diet. Pulse wave velocity (PWV) was measured in vivo by ultrasound. Cortical stiffness was determined ex vivo by atomic force microscopy and in vitro in endothelial cells. Compared to controls, plaque burden and calcification deposits in the thoracic aorta and plasma levels of lipids, TNFα, IL6, and NO were increased in PCSK9DY+WDVEH mice. Upon AMLO treatment, NO, calcification, and plaque burden were reduced, but not lipids. PWV (1.267 ± 0.232 vs. 0.908 ± 0.173 m/s) and cortical stiffness (1.412 ± 0.033 vs. 0.992 ± 0.015 pN/nm) were higher in the PCSK9DY+WDVEH than in AAV+chowVEH mice but remained almost normal despite PCSK9DY+WD intervention when treated with AMLO (0.987 ± 0.119 m/s or 1.181 ± 0.026 pN/nm). AMLO reduced PWV and stiffness in AAV+chow mice and decreased cortical stiffness and increased glycocalyx height in endothelial cells. We conclude that AMLO improves vascular function in atherosclerosis as PWV and cortical stiffness become normalized. Since AMLO also improved function in AAV+chow controls and in endothelial cells, we further conclude that the effect is independent of the development of atherosclerosis. Furthermore, our in vivo results point to a NO-dependent mechanism.

钙通道阻滞剂是治疗高血压或心律失常的常用药物。它们也被认为具有抗动脉粥样硬化作用,尽管大多数此类研究主要限于组织学或生化参数。因此,目的是验证氨氯地平(AMLO)改善动脉粥样硬化患者血管功能的假设。在这里,注射pcsk9dy的C57BL/ 6n小鼠在西方饮食(WD)中口服AMLO(10 mg/kgbw)或载体(VEH),而对照组则接受腺相关病毒载体(AAV)和饲料。超声法测定体内脉搏波速度(PWV)。在离体和离体内皮细胞中采用原子力显微镜测定皮质硬度。与对照组相比,PCSK9DY+WDVEH小鼠胸主动脉斑块负担和钙化沉积以及血浆脂质、TNFα、il - 6和NO水平均升高。经AMLO治疗后,NO、钙化和斑块负担减少,但脂质没有减少。采集(1.267 ±  0.232和0.908±0.173  m / s)和皮质刚度(1.412 ±  0.033和0.992±0.015 pN / nm)在PCSK9DY更高比AAV + + WDVEH chowVEH老鼠但仍几乎正常尽管PCSK9DY + WD干预治疗时AMLO(0.987 ±0.119  m / s或1.181 ±0.026 pN /海里)。AMLO降低了AAV阳性小鼠的PWV和僵硬度,降低了内皮细胞的皮质僵硬度和增加了糖萼高度。我们的结论是,随着PWV和皮质硬度正常化,AMLO改善动脉粥样硬化的血管功能。由于AMLO也改善了AAV+chow对照和内皮细胞的功能,我们进一步得出结论,这种作用与动脉粥样硬化的发展无关。此外,我们的体内实验结果指出了no依赖机制。
{"title":"Amlodipine improves aortic dysfunction in atherosclerotic mice.","authors":"Sophia Marie Rasch, Benedikt Fels, Alexandra Schmalohr, Luis Daniel Hernandez Torres, Eva Peschke, Olga Maria Will, Jan-Bernd Hoevener, Leonie Achner, Tobias Klersy, Frauke Spiecker, Marcel Sauer, Carl Vahldieck, Tobias Reinberger, Urte Matschl, Susanne Hille, Oliver J Müller, Zouhair Aherrahrou, Kristina Kusche, Walter Raasch","doi":"10.1016/j.biopha.2026.119073","DOIUrl":"https://doi.org/10.1016/j.biopha.2026.119073","url":null,"abstract":"<p><p>Calcium channel blockers are established in treating hypertension or arrhythmias. They have also been suggested to have anti-atherosclerotic effects, although most such studies are limited mainly to histological or biochemical parameters. Therefore, the aim was to test the hypothesis that amlodipine (AMLO) improves vascular function in atherosclerosis in particular. Here, PCSK9<sup>DY</sup>-injected C57BL/6N-mice on a Western diet (WD) were orally treated with either AMLO (10 mg/kg<sub>bw</sub>) or vehicle (VEH), while controls received adeno-associated virus vector (AAV) and a chow diet. Pulse wave velocity (PWV) was measured in vivo by ultrasound. Cortical stiffness was determined ex vivo by atomic force microscopy and in vitro in endothelial cells. Compared to controls, plaque burden and calcification deposits in the thoracic aorta and plasma levels of lipids, TNFα, IL6, and NO were increased in PCSK9<sup>DY</sup>+WD<sup>VEH</sup> mice. Upon AMLO treatment, NO, calcification, and plaque burden were reduced, but not lipids. PWV (1.267 ± 0.232 vs. 0.908 ± 0.173 m/s) and cortical stiffness (1.412 ± 0.033 vs. 0.992 ± 0.015 pN/nm) were higher in the PCSK9<sup>DY</sup>+WD<sup>VEH</sup> than in AAV+chow<sup>VEH</sup> mice but remained almost normal despite PCSK9<sup>DY</sup>+WD intervention when treated with AMLO (0.987 ± 0.119 m/s or 1.181 ± 0.026 pN/nm). AMLO reduced PWV and stiffness in AAV+chow mice and decreased cortical stiffness and increased glycocalyx height in endothelial cells. We conclude that AMLO improves vascular function in atherosclerosis as PWV and cortical stiffness become normalized. Since AMLO also improved function in AAV+chow controls and in endothelial cells, we further conclude that the effect is independent of the development of atherosclerosis. Furthermore, our in vivo results point to a NO-dependent mechanism.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"196 ","pages":"119073"},"PeriodicalIF":7.5,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146145042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Redox, inflammatory, and ferroptosis pathway modulation by methotrexate and dexamethasone in primary human RPE cells under basal and acute H₂O₂-induced oxidative stress: An in vitro study. 甲氨蝶呤和地塞米松在基础和急性h2o2诱导的氧化应激下对原代人RPE细胞氧化还原、炎症和铁凋亡途径的调节:一项体外研究。
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119106
Zahra Souri, Mohammad Malekahmadi

Purpose: Oxidative stress, inflammation, and ferroptosis drive retinal disease. Methotrexate (MTX) and dexamethasone (DEX) are clinically used to counter these insults, but their effects on retinal pigment epithelium (RPE) homeostasis remain unclear. This study investigates how MTX, DEX, and their combination affect cell viability, redox balance, inflammatory signaling, and ferroptosis-related gene expression in human RPE cells under basal and oxidative stress conditions.

Methods: Human RPE cells were exposed to 100 µM H2O2 for 24 h and treated with MTX (100 µg/ml), DEX (50 µg/ml), or their combination. Cell viability was assessed using MTT assay. Total oxidant status (TOS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were measured from cell lysates. IL-6, IL-8, IL-10, and TGF-β levels were quantified by ELISA, and GPX4, ACSL4, and SLC7A11 mRNA expression was measured by qPCR.

Results: Under basal conditions, treatments did not affect viability. DEX and combination increased TOS, with MDA elevated by combination only. CAT activity increased with DEX. MTX reduced IL-8, DEX reduced IL-6, and combination reduced IL-6, IL-8, and TGF-β. GPX4, ACSL4, and SLC7A11 decreased with all treatments. Under oxidative stress, viability declined. DEX restored CAT activity; IL-6 and IL-8 were reduced by both drugs, while combination additionally reduced TGF-β and IL-10. GPX4 increased with MTX and combination, ACSL4 with combination, and SLC7A11 with MTX.

Conclusions: MTX and DEX exert context-dependent effects in RPE cells. Basally, they induce adaptive preconditioning; under oxidative stress, combination therapy triggers a coordinated protective response. These findings support strategies integrating redox modulation, immune regulation, and ferroptosis control to preserve RPE function.

目的:氧化应激、炎症和上睑下垂驱动视网膜疾病。甲氨蝶呤(MTX)和地塞米松(DEX)在临床上用于对抗这些损伤,但它们对视网膜色素上皮(RPE)稳态的影响尚不清楚。本研究探讨了MTX、DEX及其组合在基础应激和氧化应激条件下如何影响人RPE细胞的细胞活力、氧化还原平衡、炎症信号和铁中毒相关基因表达。方法:将人RPE细胞暴露于100 µM H2O2中24 h,然后用MTX(100 µg/ml)、DEX(50 µg/ml)或两者联合处理。采用MTT法测定细胞活力。从细胞裂解物中测定总氧化状态(TOS)、丙二醛(MDA)、过氧化氢酶(CAT)和超氧化物歧化酶(SOD)。ELISA法检测IL-6、IL-8、IL-10、TGF-β水平,qPCR法检测GPX4、ACSL4、SLC7A11 mRNA表达。结果:在基础条件下,处理对存活率无影响。DEX和联合用药增加TOS, MDA仅联合用药升高。CAT活性随DEX的增加而增加。MTX降低IL-8, DEX降低IL-6,联合用药降低IL-6、IL-8和TGF-β。GPX4、ACSL4和SLC7A11均随各治疗组降低。氧化胁迫下,细胞活力下降。DEX恢复CAT活性;两药均可降低IL-6、IL-8,联合用药可降低TGF-β、IL-10。GPX4与MTX联合升高,ACSL4与MTX联合升高,SLC7A11与MTX联合升高。结论:MTX和DEX在RPE细胞中发挥情境依赖性作用。基本上,它们诱导适应性预处理;在氧化应激下,联合治疗触发协调的保护反应。这些发现支持整合氧化还原调节、免疫调节和铁下沉控制的策略,以保持RPE功能。
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引用次数: 0
Preventive effects of GABA-producing postbiotics derived from Levilactobacillus brevis against chronic sleep deprivation-induced gut-brain axis dysfunction, neuroinflammation, and behavioral impairments in mice. 短左乳杆菌产生gaba后生制剂对小鼠慢性睡眠剥夺引起的肠-脑轴功能障碍、神经炎症和行为障碍的预防作用
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119093
Yu-Tang Tung, Chia-Hsun Yang, Bo-Chao Chen, Cheng-Chia Hsieh, Yu-Chen S H Yang, Cheng-Tse Yang, Jin-Wei Xu, Jyh-Horng Wu

Chronic sleep deprivation (CSD) is increasingly recognized as a contributor to gut dysbiosis, systemic inflammation, and neurobehavioral impairments via the gut-brain axis. γ-Aminobutyric acid (GABA)-producing postbiotics, derived from microbial fermentation, offer potential in mitigating such dysfunctions. This study investigates the effects of GABA-producing postbiotics produced by Levilactobacillus brevis on CSD-induced gut and brain disturbances in mice. Male C57BL/6 mice were subjected to 30 days of sleep fragmentation and treated with low (250 mg/kg) or high (500 mg/kg) doses of postbiotics. Behavioral tests revealed that GABA-producing postbiotics significantly alleviated anxiety- and depression-like behaviors. Postbiotic treatment restored intestinal tight junction protein expression (ZO-1, Claudin-1), increased glutathione peroxidase activity, and reduced serum lipopolysaccharide and TNF-α levels, indicating improved intestinal barrier function and attenuated systemic inflammation. Postbiotic treatment promote the growth of beneficial genera such as Ruminococcus and Akkermansia, while also elevating fecal propanoic acid concentrations. In the brain, postbiotics upregulated blood-brain barrier (BBB) associated genes and reduced neuroinflammatory gene expression. Correlation analysis highlighted microbial signatures linked to short-chain fatty acids, intestinal tight junction proteins, serum LPS and TNF-α levels, as well as hypothalamic inflammatory, BBB gene expressions and anxiety. These findings suggest that GABA-producing postbiotics ameliorate CSD-induced gut-brain axis disruption by modulating the microbiota, restoring barrier functions, and suppressing systemic and neuroinflammation. This study supports the potential application of GABA-producing postbiotics as a dietary strategy to mitigate sleep loss-related physiological and behavioral impairments.

慢性睡眠剥夺(CSD)越来越被认为是肠道生态失调、全身性炎症和通过肠-脑轴神经行为障碍的一个因素。产生γ-氨基丁酸(GABA)的后生物制剂,来源于微生物发酵,提供了减轻这种功能障碍的潜力。本研究探讨短左乳杆菌生产的产gaba后生制剂对csd诱导小鼠肠道和大脑紊乱的影响。雄性C57BL/6小鼠接受30天的睡眠中断,并给予低剂量(250 mg/kg)或高剂量(500 mg/kg)的后生物制剂。行为测试显示,产生gaba的后生物制剂显著缓解了焦虑和抑郁样行为。生物后治疗恢复肠道紧密连接蛋白(ZO-1, cludin -1)表达,增加谷胱甘肽过氧化物酶活性,降低血清脂多糖和TNF-α水平,表明肠道屏障功能改善,全身炎症减轻。益生后处理促进了瘤胃球菌和Akkermansia等有益菌的生长,同时也提高了粪便中丙酸的浓度。在大脑中,益生后可上调血脑屏障(BBB)相关基因,并降低神经炎症基因的表达。相关性分析突出了与短链脂肪酸、肠道紧密连接蛋白、血清LPS和TNF-α水平、下丘脑炎症、血脑屏障基因表达和焦虑相关的微生物特征。这些发现表明,产生gaba的后生物制剂通过调节微生物群、恢复屏障功能和抑制全身和神经炎症,改善了csd诱导的肠-脑轴破坏。这项研究支持产生gaba的后生制剂作为一种饮食策略的潜在应用,以减轻与睡眠不足相关的生理和行为障碍。
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引用次数: 0
The role of NADPH oxidases in central nervous system regulation of hypertension: Mechanisms and therapeutic insights. NADPH氧化酶在高血压中枢神经系统调节中的作用:机制和治疗见解。
IF 7.5 Pub Date : 2026-02-06 DOI: 10.1016/j.biopha.2026.119096
Umm-E Kalsoom, Jing Jin, Wanying Meng, Yao Su, Changhao Wu, Qin Wu

Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with a significant proportion attributed to central nervous system (CNS) dysregulation. Emerging evidence implicates NADPH oxidases (Nox), particularly Nox2 and Nox4, as pivotal sources of reactive oxygen species (ROS) in brain regions critical for blood pressure control. This review explores the region-specific expression, activation mechanisms, and downstream effects of Nox isoforms within the CNS, focusing on the blood pressure regulatory brain regions, including paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), and circumventricular organs (CVOs). Nox-derived ROS disrupt redox homeostasis, impair baroreflex sensitivity, induce neuroinflammation, and enhance sympathetic nervous system (SNS) activity. The interplay between Nox, the renin-angiotensin system (RAS), and mitochondrial ROS amplifies oxidative signaling and establishes a vicious cycle of neurovascular dysfunction. Furthermore, we will highlight the potential of Nox-targeted interventions and antioxidant therapies, emphasizing their therapeutic promise in attenuating neurogenic hypertension. A deeper understanding of CNS Nox signaling may pave the way for more effective and precise antihypertensive strategies.

高血压仍然是全球心血管疾病发病率和死亡率的主要原因,其中很大一部分归因于中枢神经系统(CNS)失调。新出现的证据表明,NADPH氧化酶(Nox),特别是Nox2和Nox4,是大脑中控制血压的关键区域活性氧(ROS)的关键来源。本文探讨了Nox亚型在中枢神经系统内的区域特异性表达、激活机制和下游效应,重点关注血压调节脑区域,包括室旁核(PVN)、延髓吻侧腹侧(RVLM)、孤束核(NTS)和心室周围器官(CVOs)。一氧化氮衍生的活性氧破坏氧化还原稳态,损害气压反射敏感性,诱导神经炎症,增强交感神经系统(SNS)活性。Nox、肾素血管紧张素系统(RAS)和线粒体ROS之间的相互作用放大了氧化信号,并建立了神经血管功能障碍的恶性循环。此外,我们将强调nox靶向干预和抗氧化治疗的潜力,强调它们在减轻神经源性高血压方面的治疗前景。对中枢神经系统Nox信号的深入了解可能为更有效和精确的抗高血压策略铺平道路。
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引用次数: 0
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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
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