Biomedicine & Pharmacotherapy最新文献_第3页

The calcimimetic etelcalcetide attenuates pressure overload–induced cardiac hypertrophy in rats with and without chronic kidney disease 拟钙化乙酰胆肽可减轻有或无慢性肾脏疾病大鼠压力超载引起的心脏肥厚

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-30 DOI: 10.1016/j.biopha.2026.119054

Hidehisa Okamoto, Shunsuke Goto, Yuma Nose, Hayaki Okamoto, Hideki Fujii

Introduction

Calcimimetics such as etelcalcetide (ET) are used to manage secondary hyperparathyroidism patients with chronic kidney disease (CKD) on dialysis. While their cardiovascular benefits—including left ventricular hypertrophy (LVH) suppression—are recognized, the underlying mechanisms remain unclear. This study investigated how ET suppresses LVH using rat models.

Methods

LVH was induced via transverse aortic coarctation, and CKD by 5/6 nephrectomy. Rats were assigned to the sham, CKD, LVH, or CKD/LVH groups, with each pathological group further divided into vehicle- or ET-treated subgroups. After eight weeks of treatment, echocardiography, histological, biochemical, and molecular analyses were conducted.

Results

ET reduced serum parathyroid hormone and fibroblast growth factor 23 (FGF23) levels in the CKD and CKD/LVH groups but not in the LVH group, where these levels were not increased. ET did not affect serum calcium, phosphorus, or vitamin D levels in the LVH and CKD/LVH groups. Nonetheless, ET suppressed cardiac hypertrophy and cardiomyocyte enlargement in the LVH and CKD/LVH groups despite no changes in systemic mineral metabolism parameters. Mechanistically, ET attenuated cardiac hypertrophy, serum aldosterone levels, and cardiac renin-angiotensin-aldosterone system (RAAS) components in the LVH and CKD/LVH groups. Cardiac FGF23 expression, elevated in the LVH and CKD/LVH groups, was also decreased by ET. The calcineurin/nuclear factor of the activated T-cell signaling pathway was unaffected.

Conclusion

ET effectively suppressed LVH in the LVH and CKD/LVH groups. These findings suggest that ET’s cardioprotective effects are mediated via the modulation of the RAAS and cardiac FGF23 expression rather than solely through the correction of CKD-mineral bone disorder abnormalities.

钙化剂如依替钙化肽（ET）被用于治疗继发性甲状旁腺功能亢进合并慢性肾病（CKD）的透析患者。虽然它们对心血管的益处——包括抑制左心室肥厚（LVH）——已经得到了承认，但其潜在的机制仍不清楚。本研究利用大鼠模型研究ET如何抑制LVH。方法采用横断主动脉缩窄法诱导slvh， 5/6肾切除术诱导CKD。将大鼠分为假手术组、CKD组、LVH组或CKD/LVH组，每个病理组进一步分为给药组或et治疗组。治疗8周后，进行超声心动图、组织学、生化和分子分析。结果set降低了CKD组和CKD/LVH组的血清甲状旁腺激素和成纤维细胞生长因子23 （FGF23）水平，而LVH组没有升高。在LVH组和CKD/LVH组中，ET不影响血清钙、磷或维生素D水平。尽管如此，在LVH组和CKD/LVH组中，ET抑制了心肌肥大和心肌细胞扩大，尽管全身矿物质代谢参数没有变化。在机制上，ET减轻了LVH组和CKD/LVH组的心肌肥厚、血清醛固酮水平和心脏肾素-血管紧张素-醛固酮系统（RAAS）成分。在LVH和CKD/LVH组中升高的心脏FGF23表达也被ET降低。活化t细胞信号通路的钙调磷酸酶/核因子未受影响。结论et对LVH组和CKD/LVH组LVH均有抑制作用。这些发现表明，ET的心脏保护作用是通过调节RAAS和心脏FGF23的表达介导的，而不仅仅是通过纠正ckd -矿物质骨异常。

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引用次数: 0

Gigantol disrupts AR and iNOS conformation and promotes aggregation through direct molecular interaction to suppress diabetic cataract 巨巨醇破坏AR和iNOS构象，通过直接分子相互作用促进聚集，抑制糖尿病性白内障

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-24 DOI: 10.1016/j.biopha.2026.119027

Dan Chen , Chuanjun Lu , Meiling Wang , Xiaoyong Wei

Diabetic cataract (DC) is a major cause of vision impairment, partly driven by the pathological roles of aldose reductase (AR) and inducible nitric oxide synthase (iNOS). Gigantol, a bibenzyl compound derived from Dendrobium, has shown potential in preventing DC, yet its molecular mechanism remains incompletely understood. In this study, we investigated the modulation of conformational integrity and aggregation propensity of AR/iNOS by gigantol using fluorescent labeling, fluorescence resonance energy transfer (FRET), single-molecule imaging in living cells, fluorescence spectroscopy, confocal Raman spectroscopy, and atomic force microscopy (AFM). FRET analysis revealed interaction distances of 3.02 ± 0.22 nm for gigantol-AR and 5.07 ± 0.23 nm for gigantol-iNOS, with energy transfer efficiencies of 38.37 ± 4.76 % and 28.15 ± 3.52 %, respectively. Gigantol spontaneously bound to AR and iNOS via hydrogen bonds and van der Waals forces, inducing conformational changes in tyrosine and tryptophan microenvironments. Raman spectroscopy indicated significant alterations in α-helix and β-sheet structures, and AFM directly visualized protein aggregation upon gigantol treatment. These findings demonstrate that gigantol disrupts the conformational integrity of AR and iNOS and promotes their aggregation, thereby inhibiting their activity and providing a molecular basis for its anti-DC potential.

糖尿病性白内障（DC）是视力损害的主要原因，部分原因是醛糖还原酶（AR）和诱导型一氧化氮合酶（iNOS）的病理作用。巨石醇是一种从石斛中提取的联苯化合物，具有预防DC的潜力，但其分子机制尚不完全清楚。在这项研究中，我们利用荧光标记、荧光共振能量转移（FRET）、活细胞单分子成像、荧光光谱、共聚焦拉曼光谱和原子力显微镜（AFM）研究了巨巨醇对AR/iNOS构象完整性和聚集倾向的调节。烦恼分析显示交互的距离3.02 ±0.22  gigantol-AR和5.07 nm ±0.23  gigantol-iNOS nm,能量传递效率为38.37 ±4.76   %和28.15±3.52  %,分别。巨巨醇通过氢键和范德华力与AR和iNOS自发结合，诱导酪氨酸和色氨酸微环境的构象变化。拉曼光谱显示α-螺旋和β-片结构发生了显著变化，AFM直接显示了巨巨醇处理后蛋白质聚集的情况。这些发现表明巨巨醇破坏了AR和iNOS的构象完整性，促进了它们的聚集，从而抑制了它们的活性，并为其抗dc电位提供了分子基础。

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引用次数: 0

Targeting frataxin deficiency in DRG neurons and fibroblasts: omaveloxolone restores metabolic and iron balance to reduce ferroptosis 针对DRG神经元和成纤维细胞中fraataxin缺乏：omaveloxolone恢复代谢和铁平衡以减少铁下垂

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119031

Marta Portillo-Carrasquer , Arabela Sanz-Alcázar , Begoña Sánchez-López , Fabien Delaspre , Maria Pazos-Gil , Luiza Oliveira-Jorge , Laia Castells-Roca , Jordi Tamarit , Joaquim Ros , Elisa Cabiscol

Friedreich ataxia (FA) is a rare, multisystemic neurodegenerative disorder caused by a deficiency of the mitochondrial protein frataxin. It is characterized by degeneration of the large sensory neurons in the dorsal root ganglia (DRG) and spinocerebellar tracts, leading to progressive neurodegeneration and muscle weakness. Frataxin deficiency induces iron dyshomeostasis, defective energy production, and oxidative stress, all regulated by NRF2. Omaveloxolone, an NRF2 activator, is currently the only approved therapy for FA; however, its effects on DRG neurons remain unknown. Here we used frataxin-deficient DRG neurons to better understand the drug’s role in these sensory neurons. Omaveloxolone improved most of the analyzed parameters, including frataxin levels, cell survival, mitochondrial respiratory activity, iron homeostasis, oxidative stress, transferrin receptor 1 and glutathione peroxidase 4 levels, as well as the GSH/GSSG ratio. Moreover, lipid peroxidation, a key marker of ferroptosis that was increased in frataxin-deficient neurons, was almost completely rescued by omaveloxolone. Both total and nuclear NRF2 levels were decreased in frataxin-deficient neurons, and omaveloxolone treatment fully prevented this alteration. In addition, most of these results were validated in fibroblasts from FA patients. We also evaluated a combinatorial treatment using low doses of omaveloxolone together with honokiol, a SIRT3 activator with known neuroprotective properties. This combination enhanced cell survival and produced a synergistic effect increasing mitochondrial respiration in frataxin-deficient DRG neurons. In summary, these findings demonstrate the beneficial effects of omaveloxolone and further suggest that combination therapy with honokiol may provide an effective strategy for the treatment of FA, potentially mitigating adverse effects.

弗里德赖希共济失调（FA）是一种罕见的多系统神经退行性疾病，由线粒体蛋白fraataxin缺乏引起。其特点是背根神经节（DRG）和脊髓小脑束的大感觉神经元变性，导致进行性神经变性和肌肉无力。Frataxin缺乏会引起铁代谢失调、能量产生缺陷和氧化应激，这些都是由NRF2调节的。Omaveloxolone是一种NRF2激活剂，目前是唯一被批准的FA治疗药物；然而，其对DRG神经元的影响尚不清楚。在这里，我们使用frataxin缺乏的DRG神经元来更好地了解药物在这些感觉神经元中的作用。Omaveloxolone改善了大部分分析参数，包括frataxin水平、细胞存活、线粒体呼吸活性、铁稳态、氧化应激、转铁蛋白受体1和谷胱甘肽过氧化物酶4水平，以及GSH/GSSG比值。此外，脂质过氧化是铁凋亡的一个关键标志，在frataxin缺乏的神经元中增加，几乎完全被omaveloxolone拯救。在frataxin缺乏的神经元中，总NRF2水平和核NRF2水平都降低了，而奥马维洛酮治疗完全阻止了这种改变。此外，这些结果大多数在FA患者的成纤维细胞中得到了验证。我们还评估了使用低剂量奥马维洛酮和檀香醇（一种已知具有神经保护特性的SIRT3激活剂）的组合治疗。这种组合提高了细胞存活率，并产生了协同效应，增加了frataxin缺乏的DRG神经元的线粒体呼吸。总之，这些发现证明了奥马维洛酮的有益作用，并进一步表明，与厚朴酚联合治疗可能是治疗FA的有效策略，可能减轻不良反应。

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引用次数: 0

The inhibition of Il1β synthesis mediated by a novel pyridine-sulfonamide compound protects against the progression of metabolic dysfunction-associated steatotic liver disease 一种新型吡啶-磺胺化合物介导的il - 1β合成抑制可防止代谢功能障碍相关脂肪变性肝病的进展

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119052

Ángela Berlana , Esther Rey , Elena Fresno-Ventura , Patricia Gomez-Gutierrez , Miguel Vega , Carmelo García-Monzón , Águeda González-Rodríguez

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease worldwide. The increasing MASLD burden and the lack of effective therapies underscore the urgent need for new therapeutic approaches. Interleukin 1 beta (IL1β) has been identified as a key mediator of MASLD progression, and is considered a promising therapeutic target. This study evaluated the efficacy of AIK3a305, a novel allosteric inhibitor of cJun N-terminal kinase (JNK), in preventing MASLD progression through a selective inhibition of IL1β synthesis. Macrophages were treated with LPS and palmitate to assess IL1β modulation, and hepatocytes with palmitic acid (PA) to explore lipid accumulation, lipoapoptosis, and inflammatory signaling, in the presence or absence of this compound. Mice fed a high-fat diet (HFD) or a choline-deficient, L-amino acid-defined (CDAA) diet were orally treated with AIK3a305 or vehicle, and livers were collected for histopathological and molecular analysis. AIK3a305 selectively inhibited LPS- and palmitate-induced IL1β expression in macrophages, while protecting hepatocytes from intracellular lipid accumulation and lipoapoptosis. These hepatic effects were associated with a suppression of JNK signaling, which triggered a decrease in IL1β expression, and a transient inhibition of the transcription factor NFκB and p38 pathways, and, thus, tumor necrosis factor α (TNFα) synthesis. In preclinical models of MASLD, treatment with AIK3a305 attenuated disease progression in animals fed either a HFD or a CDAA diet, as evidenced by improved liver histopathology, including reduced steatosis and inflammation. These findings position AIK3a305 as a promising therapeutic candidate for MASLD treatment.

代谢功能障碍相关脂肪变性肝病（MASLD）是目前世界范围内慢性肝病的主要原因。日益增加的MASLD负担和缺乏有效的治疗方法强调了迫切需要新的治疗方法。白细胞介素1β (il - 1β)已被确定为MASLD进展的关键介质，并被认为是一个有希望的治疗靶点。这项研究评估了AIK3a305（一种新型的cJun n -末端激酶（JNK）变构抑制剂）通过选择性抑制il - 1β合成来阻止MASLD进展的功效。用脂多糖和棕榈酸处理巨噬细胞以评估il - 1β的调节，用棕榈酸（PA）处理肝细胞以探索存在或不存在这种化合物的脂质积累、脂质凋亡和炎症信号。饲喂高脂肪饮食（HFD）或缺乏胆碱的l -氨基酸（CDAA）饮食的小鼠口服AIK3a305或载药，并收集肝脏进行组织病理学和分子分析。AIK3a305选择性抑制LPS和棕榈酸盐诱导的巨噬细胞中il - 1β的表达，同时保护肝细胞免受细胞内脂质积累和脂肪凋亡。这些肝脏效应与JNK信号的抑制有关，JNK信号的抑制引发il - 1β表达的降低，转录因子NFκB和p38通路的短暂抑制，从而抑制肿瘤坏死因子α (TNFα)的合成。在MASLD的临床前模型中，AIK3a305治疗减轻了饲喂HFD或CDAA饮食的动物的疾病进展，肝脏组织病理学改善，包括脂肪变性和炎症减少，证明了这一点。这些发现表明AIK3a305是一种有希望的MASLD治疗候选药物。

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引用次数: 0

Potential effects of bexarotene on neural development and function in zebrafish embryos 贝沙罗汀对斑马鱼胚胎神经发育和功能的潜在影响

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119050

Wenwen Zha , Minglei Wang , Yunlong Meng , Kangyu Liu , Lirong Huang , Haining Li , Nan Yin , Yuanhai Xie , Jiayi Du , Mingxia Song , Zigang Cao , Jianjun Chen , Zilin Zhong

Bexarotene is a retinoid X receptor (RXR) agonist that plays a crucial role in cell growth and differentiation. It has shown potential in treating both early- and late-stage cutaneous T-cell lymphoma (CTCL). However, the impact of Bexarotene on the neurodevelopment of aquatic organisms, particularly aquatic vertebrates, remains poorly understood. This study aimed to investigate the effects of various concentrations of bexarotene (3 μg/L, 6 μg/L, and 9 μg/L) on the development of the zebrafish embryonic nervous system, using zebrafish as a model organism. The underlying molecular mechanisms were explored through a combination of pharmacological interventions, molecular biology, histopathology, and transcriptomics. Studies have shown that zebrafish embryos exposed to Bex show significant changes in development, including morphological abnormalities, head malformations, significantly shortened head length and width, reduced fluorescent area, cell apoptosis, shortened spinal motor neuron axon length, abnormal myelin development, decreased oligodendrocytes, cerebellar developmental damage, and abnormal behavior. Transcriptomics and qPCR results showed abnormal expression of neurodevelopmental genes (olig2, mbpa, atoh1a, gfap, ngn1, gap43, etc.). In addition, exposure to medium and high concentrations of bexarotene significantly increased acetylcholinesterase (AChE) activity. Bexarotene activates the Wnt signaling pathway, and treatment with the Wnt inhibitor IWR-1 can partially rescue the neurodevelopmental impairments in embryos. In summary, bexarotene offers new insights into the potential neurodevelopmental risks in zebrafish embryos, emphasizing the importance of preventing drug side effects and ensuring the safe and rational use of medications to protect the health of living organisms.

贝沙罗汀是一种类维甲酸X受体（RXR）激动剂，在细胞生长和分化中起着至关重要的作用。它已显示出治疗早期和晚期皮肤t细胞淋巴瘤（CTCL）的潜力。然而，贝沙罗汀对水生生物，特别是水生脊椎动物神经发育的影响仍然知之甚少。本研究以斑马鱼为模型生物，研究不同浓度贝沙罗汀（3 μg/L、6 μg/L和9 μg/L）对斑马鱼胚胎神经系统发育的影响。通过药物干预、分子生物学、组织病理学和转录组学的结合，探索了潜在的分子机制。研究表明，接触Bex的斑马鱼胚胎发育发生显著变化，包括形态异常、头部畸形、头长头宽明显缩短、荧光面积减少、细胞凋亡、脊髓运动神经元轴突长度缩短、髓磷脂发育异常、少突胶质细胞减少、小脑发育损伤、行为异常等。转录组学和qPCR结果显示神经发育基因（olig2、mbpa、atoh1a、gfap、ngn1、gap43等）表达异常。此外，暴露于中、高浓度贝沙罗汀显著增加乙酰胆碱酯酶（AChE）活性。贝沙罗汀激活Wnt信号通路，用Wnt抑制剂IWR-1治疗可以部分挽救胚胎的神经发育障碍。综上所述，贝沙罗汀对斑马鱼胚胎的潜在神经发育风险提供了新的见解，强调了预防药物副作用和确保安全合理使用药物对保护生物体健康的重要性。

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引用次数: 0

Astaxanthin improves behavioural and immune dysfunction in the Shank3b mouse model of autism spectrum disorder 虾青素改善自闭症谱系障碍Shank3b小鼠模型的行为和免疫功能障碍

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119051

Anjana Madhavan , Martina Schiano-Visconte , Lauren Dutton , Mattia Cantalupo , Luigi Balasco , Alessia Mavillonio , Gabriele Chelini , Yuri Bozzi , Luca Pangrazzi

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviours. Numerous studies have associated ASD with immune dysregulation and inflammation, with neuroinflammatory processes reported in ASD individuals and mouse models. Altered immune cell profiles and cytokine levels have been observed in the peripheral blood (PB), supporting systemic immune dysfunction. Recently we showed that the administration of antioxidant molecule N-acetylcysteine (NAC) reduced oxidative stress and inflammation and counteracted behavioural deficits in two mouse models of ASD, providing a rationale for exploring other redox-active compounds. Here, we investigated the effects of astaxanthin (AST), potent antioxidant and anti-inflammatory molecule, in the Shank3b model (Shank3b^-/- mice). AST treatment significantly improved core ASD-like behaviours, including social interaction deficits, motor incoordination, and repetitive grooming. In the cerebellum, AST reduced pro-inflammatory cytokines and counteracted microglial hyperactivation. In peripheral immune compartments, AST modulated cytokine expression. Pro-inflammatory markers were downregulated in Shank3b^-/- mice in the bone marrow and spleen while they were elevated in Shank3b controls, suggesting immune rebalancing (i.e. adaptive modulation suppressing harmful inflammation while supporting protective immunity). As a limitation, oxidative stress assays were not performed here. Receiver operating characteristic (ROC) analysis suggests that TNF and IFNγ expression in peripheral immune cells may be promising biomarkers of treatment response. Notably, unlike NAC, AST did not induce pro-inflammatory effects in Shank3b^+/+ animals. These findings show that AST administration may counteract behavioural deficits and immune dysfunction in Shank3b^-/- mice, therefore suggesting its potential as a safe immunomodulatory therapy for ASD.

自闭症谱系障碍（ASD）是一种神经发育疾病，其特征是社会沟通和互动缺陷以及重复行为。许多研究已经将ASD与免疫失调和炎症联系起来，并在ASD个体和小鼠模型中报道了神经炎症过程。在外周血（PB）中观察到免疫细胞谱和细胞因子水平的改变，支持全身免疫功能障碍。最近，我们发现抗氧化分子n -乙酰半胱氨酸（NAC）可以减少两种ASD小鼠模型的氧化应激和炎症，并抵消行为缺陷，为探索其他氧化还原活性化合物提供了理论基础。在此，我们研究了虾青素（AST）这一有效的抗氧化和抗炎分子在Shank3b模型（Shank3b-/-小鼠）中的作用。AST治疗显著改善核心asd样行为，包括社会互动缺陷、运动不协调和重复梳理。在小脑，谷草转氨酶减少促炎细胞因子和抵消小胶质细胞过度活化。外周免疫室中，AST调节细胞因子的表达。在骨髓和脾脏的Shank3b-/-小鼠中，促炎标志物下调，而在Shank3b对照组中，促炎标志物升高，表明免疫再平衡（即适应性调节抑制有害炎症，同时支持保护性免疫）。由于限制，这里没有进行氧化应激试验。受试者工作特征（ROC）分析表明，外周血免疫细胞中TNF和IFNγ的表达可能是治疗反应的有希望的生物标志物。值得注意的是，与NAC不同，AST在Shank3b+/+动物中没有诱导促炎作用。这些发现表明，AST给药可以抵消Shank3b-/-小鼠的行为缺陷和免疫功能障碍，因此表明其可能作为一种安全的ASD免疫调节疗法。

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引用次数: 0

Allicin ameliorates right heart dysfunction in rats suffering from pulmonary arterial hypertension by regulating Ca2+ communication between the sarcoplasmic reticulum and mitochondria 大蒜素通过调节肌浆网和线粒体之间的Ca2+通讯，改善肺动脉高压大鼠右心功能障碍

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119046

Juan Wang , Ying Wang , Rongmei Shi , Shaojun Xu , Shaorui Li , Xinxia Li , Yuduan Wang , Ruiting Liu , Le Zhao , Jinyan Zhang

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive increase in pulmonary vascular pressure and resistance, which subsequently leads to right ventricular dysfunction and is the main cause of death for patients. Most drugs used for treating PAH focus on blood vessels, but no definitive treatment for PAH-induced right ventricular dysfunction is known. Recent studies have shown that allicin has a beneficial effect on PAH; however, whether allicin has a protective effect on right ventricular dysfunction caused by PAH and its specific mechanism of action are still unclear. In this study, we established a model by injecting monocrotaline. We examined the function of the pulmonary artery and right ventricle via right heart catheterization and a small animal cardiac ultrasound system, as well as HE and Masson staining. We also detected the calcium transport process and the expression of key proteins involved in calcium transport in right ventricular cells to reveal the role of the calcium communication mechanism in the treatment of PAH with right ventricular dysfunction by allicin. The results showed that allicin not only significantly improved pulmonary artery function but also improved right heart dysfunction in rats with PAH. Additionally, allicin significantly improved the calcium transport function of cardiomyocytes, increased mitochondrial ATP production, and decreased the generation of intracellular ROS. Conclusion: Allicin protects against PAH-induced right ventricular dysfunction by regulating calcium communication between the SR and mitochondria, providing a new theoretical basis for the clinical intervention of PAH-related right heart failure.

肺动脉高压（Pulmonary arterial hypertension， PAH）是一种慢性疾病，其特征是肺血管压力和阻力进行性增加，进而导致右心室功能障碍，是患者死亡的主要原因。大多数用于治疗多环芳烃的药物都集中在血管上，但对于多环芳烃引起的右心室功能障碍尚无明确的治疗方法。最近的研究表明，大蒜素对多环芳烃有有益作用；然而，大蒜素对多环芳烃所致的右心室功能障碍是否具有保护作用及其具体作用机制尚不清楚。在本研究中，我们通过注射野罂粟碱建立了模型。我们通过右心导管和小动物心脏超声系统，以及HE和Masson染色检查肺动脉和右心室的功能。我们还检测了右心室细胞钙转运过程及钙转运关键蛋白的表达，以揭示钙转运机制在大蒜素治疗PAH合并右心室功能障碍中的作用。结果表明，大蒜素不仅能显著改善PAH大鼠肺动脉功能，还能改善右心功能障碍。此外，大蒜素显著改善心肌细胞钙转运功能，增加线粒体ATP的产生，减少细胞内ROS的产生。结论：大蒜素通过调节SR与线粒体之间的钙通讯，对pah所致的右心功能障碍具有保护作用，为pah相关性右心衰的临床干预提供了新的理论依据。

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引用次数: 0

Preclinical evaluation of DENV1 mRNA vaccines in mice: Toward improved neutralizing antibody and T cell responses DENV1 mRNA疫苗在小鼠中的临床前评估：改善中和抗体和T细胞反应

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-23 DOI: 10.1016/j.biopha.2026.119037

Chirayus Khawsang , Eakachai Prompetchara , Supichcha Saithong , Kittipan Tharakhet , Papatsara Kaewpang , Nongnaphat Yostrerat , Pachara Wangsoontorn , Patrawadee Pitakpolrat , Supranee Buranapraditkun , Chunya Puttikhunt , Kieu Lam , James Heyes , Chutitorn Ketloy , Drew Weissman , Kiat Ruxrungtham

Dengue virus (DENV) infection represents a significant public health concern in tropical and subtropical areas, with increasing cases in parts of Europe. Currently, licensed vaccines, Dengvaxia® and Qdenga®, rely on live-attenuated platforms but show limited efficacy due to imbalanced immune responses and risks associated with antibody-dependent enhancement (ADE). In this study, we developed and evaluated nucleoside-modified mRNA vaccine encoding the dengue virus serotype 1 (DENV1) pre-membrane and envelope (prME) proteins. To reduce the potential for ADE, we incorporated the F108A mutation in the fusion loop, substituted the pr region with that from Japanese encephalitis virus (JEV), and incorporated a consensus envelope domain III (cEDIII) sequence to broaden neutralizing antibody responses. Immunogenicity was assessed in BALB/C mice immunized twice at three-week intervals with 1, 2.5, or 10 μg doses. The WT prME construct induced the highest DENV1 neutralizing antibody (NtAb) titers in a dose-dependent manner and robust T cell responses, particularly with the 2.5 μg dose. While the F108A and cEDIII modifications modulated antigen expression and broadened cross-reactivity, they also slightly reduced DENV-1-specific neutralizing titers. Among constructs, F108A+cEDIII demonstrated reduced ADE activity with improved cross-neutralization, especially against DENV3. However, the prJEV chimera exhibited low immunogenicity, likely due to prM-E domain incompatibility. Overall, the WT prME construct showed the most favorable balance of immunogenicity and safety, supporting its advancement as a prototype for future tetravalent dengue mRNA vaccine development.

登革热病毒感染在热带和亚热带地区是一个重大的公共卫生问题，在欧洲部分地区病例不断增加。目前，获得许可的疫苗Dengvaxia®和Qdenga®依赖于减毒活疫苗平台，但由于免疫反应不平衡以及与抗体依赖性增强（ADE）相关的风险，其疗效有限。在这项研究中，我们开发并评估了编码登革热病毒血清型1 （DENV1）膜前和包膜（prME）蛋白的核苷修饰mRNA疫苗。为了降低ADE的可能性，我们在融合环中加入了F108A突变，用日本脑炎病毒（JEV）的pr区取代了pr区，并加入了一致的包膜结构域III （cEDIII）序列来扩大中和抗体反应。以1、2.5或10 μg剂量每隔三周免疫两次的BALB/C小鼠进行免疫原性评估。WT prME构建体以剂量依赖性方式诱导最高的DENV1中和抗体（NtAb）滴度和强大的T细胞反应，特别是2.5 μg剂量。虽然F108A和cEDIII修饰可调节抗原表达并拓宽交叉反应性，但它们也略微降低了denv -1特异性中和滴度。在构建体中，F108A+cEDIII表现出ADE活性降低，交叉中和改善，特别是对DENV3。然而，prJEV嵌合体表现出较低的免疫原性，可能是由于prM-E结构域不相容。总体而言，WT prME结构在免疫原性和安全性方面表现出最有利的平衡，支持其作为未来四价登革热mRNA疫苗开发的原型。

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引用次数: 0

Cell stress activates γ9δ2 T cells via endogenous phosphoantigens and butyrophilin complex dynamics 细胞应激通过内源性磷酸抗原和亲丁酸蛋白复合物动力学激活γ - 9δ2 T细胞

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-22 DOI: 10.1016/j.biopha.2026.119023

Yiming Jin , Khiem Nguyen , Sidra Bashir , Girija Pawge , Reagan M. Strand , Chia-Hung Christine Hsiao , Olga Vinogradova , Andrew J. Wiemer

Phosphoantigens (pAgs) are phosphate-containing small molecules that elicit an immune response. The pAgs bind to the intracellular domain of butyrophilin 3 (BTN3), enabling interactions with other butyrophilins to form complexes that trigger the T cell receptor (TCR) of Vγ9Vδ2 (γ9δ2) T cells. Despite multiple reports on this process, the conditions that regulate pAg levels leading to their detection remain unclear. Here we reveal a novel stress detection pathway, a type of lymphoid stress-surveillance response, in which mild cold stress triggers endogenous pAgs to engage with BTN family proteins, leading to the activation of γ9δ2 T cells. This stress response is dependent upon endogenous pAgs, as inhibition of HMG-CoA reductase abrogates the effect. It is also dependent upon BTN proteins, as depletion of BTN3A1 reduces the response. The ability of BTN2A1/BTN3A1 to respond is enhanced by the presence of BTN3A2 or BTN3A3. Furthermore, the internal domains of BTN2A1, BTN3A1, and BTN3A3 display differing abilities to dimerize, with BTN2A1 a constitutive dimer, BTN3A1 a monomer, and BTN3A3 a concentration dependent dimer. Full length BTN2A1/3A1 hybrid proteins additionally reveal that appropriately spaced multimers of BTN2A1 and BTN3A1 are critical in engaging the γ9δ2 TCR. In summary, our study uncovers a novel γ9δ2 T cell activation pathway mediated by cell stress and mevalonate pathway intermediates and highlights the critical roles of the BTN family members and their spacing in this process.

磷酸抗原（pAgs）是一种含有磷酸盐的小分子，可引起免疫反应。pAgs结合到亲丁酸蛋白3 （BTN3）的胞内结构域，使其与其他亲丁酸蛋白相互作用形成复合物，从而触发v γ - 9v - δ2 (γ - 9 - δ2) T细胞的T细胞受体（TCR）。尽管有许多关于这一过程的报道，但调节pAg水平导致其检测的条件仍不清楚。在这里，我们揭示了一种新的应激检测途径，一种淋巴细胞应激监测反应，其中轻度冷应激触发内源性pAgs与BTN家族蛋白结合，导致γ9δ2 T细胞的激活。这种应激反应依赖于内源性pAgs，因为抑制HMG-CoA还原酶消除了这种作用。它也依赖于BTN蛋白，因为BTN3A1的消耗会降低反应。BTN3A2或BTN3A3的存在增强了BTN2A1/BTN3A1的应答能力。此外，BTN2A1、BTN3A1和BTN3A3的内部结构域显示出不同的二聚能力，BTN2A1是组成二聚体，BTN3A1是单体，而BTN3A3是浓度依赖性二聚体。全长BTN2A1/ 3a1杂交蛋白还表明，适当间隔的BTN2A1和BTN3A1多聚体对于参与γ - 9δ2 TCR至关重要。综上所述，我们的研究揭示了一个新的由细胞应激和甲羟戊酸途径介导的γ - 9δ2 T细胞激活途径，并强调了BTN家族成员及其间距在这一过程中的关键作用。

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引用次数: 0

Saccharina japonica derived fucoidan potentiates immune checkpoint blockade therapy by modulating the survival and differentiation fate of myeloid-derived suppressor cells 通过调节髓源性抑制细胞的存活和分化命运，糖精衍生的岩藻糖聚糖增强了免疫检查点阻断治疗。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-21 DOI: 10.1016/j.biopha.2026.119005

Zhenzhen Deng , Bo Wang , Xiaohong Jiang , Lei Gao , Dawei Yang , Quanbin Zhang , Wei Zhang

Immunotherapy has revolutionized cancer treatment paradigms due to its high specificity, favorable safety profile, and remarkable clinical efficacy. Immune checkpoint blockade (ICB) therapy has been widely adopted in clinical practice for various malignancies. Unfortunately, its limited response rates restrict broader application. Myeloid-derived suppressor cells (MDSCs) serve as key mediators of ICB resistance. In this study, we demonstrated that fucoidan extracted from Saccharina japonica LMWF modulated MDSCs activity to sensitize tumors to ICB therapy. Mechanistically, LMWF activated the TLR7-IRF7/STAT1 signaling axis to drive MDSCs differentiation into M1 macrophages while impairing MDSCs survival. LMWF treatment downregulated immunosuppressive mediators in MDSCs, promoted cancer cell apoptosis, and suppressed tumor cell migration and angiogenesis. In vivo studies revealed that LMWF- modulated MDSCs suppressed tumor progression through dual mechanisms: (i) immunological remodeling of the immunosuppressive tumor microenvironment (TME) and (ii) non-immunological inhibition of angiogenesis, collectively enhancing tumor sensitivity to PD-1 blockade therapy. Collectively, our work unveiled a novel strategy whereby LMWF, as a TLR7 agonist, synergizes with ICB therapy to overcome ICB resistance. These findings provide critical insights for overcoming the bottleneck of ICB refractoriness in cancer immunotherapy.

免疫疗法因其高特异性、良好的安全性和显著的临床疗效而彻底改变了癌症治疗模式。免疫检查点阻断（ICB）疗法已广泛应用于临床治疗各种恶性肿瘤。不幸的是，其有限的响应率限制了其更广泛的应用。髓源性抑制细胞（MDSCs）是ICB耐药的关键介质。在这项研究中，我们证明了从日本糖精LMWF中提取的岩藻糖聚糖可以调节MDSCs的活性，使肿瘤对ICB治疗敏感。在机制上，LMWF激活TLR7-IRF7/STAT1信号轴，驱动MDSCs向M1巨噬细胞分化，同时损害MDSCs的存活。LMWF处理可下调MDSCs中的免疫抑制介质，促进癌细胞凋亡，抑制肿瘤细胞迁移和血管生成。体内研究表明，LMWF调节的MDSCs通过双重机制抑制肿瘤进展：(i)免疫抑制性肿瘤微环境（TME）的免疫重塑和（ii）血管生成的非免疫抑制，共同增强肿瘤对PD-1阻断治疗的敏感性。总之，我们的工作揭示了一种新的策略，即LMWF作为TLR7激动剂，与ICB治疗协同克服ICB耐药性。这些发现为克服癌症免疫治疗中ICB难治性的瓶颈提供了重要的见解。

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引用次数: 0