Biochemical and biophysical research communications最新文献_第9页

Macrophage polarization: A bridge connecting osteoarthritis and osteoporosis 巨噬细胞极化：连接骨关节炎和骨质疏松症的桥梁

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-20 DOI: 10.1016/j.bbrc.2026.153322

Jian Cheng , Mingming Liu , Qianyu Li , Lu Zhao , Qi Zhang

Macrophage polarization plays a pivotal role in maintaining bone homeostasis and serves as a crucial mechanistic bridge in the comorbidity of osteoarthritis (OA) and osteoporosis (OP). Macrophages exhibit functional plasticity, polarizing into pro-inflammatory M1 and anti-inflammatory M2 phenotypes in response to various environmental cues. Recent advances in macrophage biology have highlighted the significant heterogeneity of macrophages, which display a spectrum of phenotypic states beyond the classical M1/M2 dichotomy. Dysregulated macrophage polarization, particularly an excess of M1 macrophages, is central to the pathophysiological mechanisms underlying OA and OP. This review systematically explores how altered macrophage polarization influences OA and OP pathogenesis, emphasizing its role in inflammatory responses, metabolic syndrome, and the mechanical microenvironment. In particular, macrophage polarization within the subchondral bone-cartilage interface has emerged as a key factor in exacerbating joint and bone degeneration. Imbalances in macrophage polarization are shown to contribute to cartilage degradation, bone loss, and disrupted bone remodeling processes in these diseases. Additionally, exosomal non-coding RNAs (Exos-ncRNAs) have been identified as important modulators of macrophage polarization, offering potential therapeutic targets for restoring M2-mediated repair functions and reducing M1-driven inflammation. Targeting specific macrophage polarization pathways holds promise for developing integrated therapeutic strategies to address both OA and OP by restoring immune-metabolic homeostasis, enhancing tissue repair, and promoting bone regeneration.

巨噬细胞极化在维持骨稳态中起着关键作用，是骨关节炎（OA）和骨质疏松症（OP）共病的重要机制桥梁。巨噬细胞表现出功能可塑性，在各种环境因素的影响下分化为促炎M1和抗炎M2表型。巨噬细胞生物学的最新进展强调了巨噬细胞的显著异质性，巨噬细胞表现出超出经典M1/M2二分法的表型状态谱。巨噬细胞极化失调，特别是M1巨噬细胞的过量，是OA和OP的病理生理机制的核心。本文系统地探讨了巨噬细胞极化改变如何影响OA和OP的发病机制，强调了其在炎症反应、代谢综合征和机械微环境中的作用。特别是，软骨下骨-软骨界面内的巨噬细胞极化已成为加剧关节和骨退行性变的关键因素。在这些疾病中，巨噬细胞极化失衡会导致软骨退化、骨质流失和骨重塑过程中断。此外，外泌体非编码rna （Exos-ncRNAs）已被确定为巨噬细胞极化的重要调节剂，为恢复m2介导的修复功能和减少m1驱动的炎症提供了潜在的治疗靶点。针对特定的巨噬细胞极化途径，有望通过恢复免疫代谢稳态、增强组织修复和促进骨再生来开发综合治疗策略，以解决OA和OP。

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引用次数: 0

High-intensity interval training promotes cartilage repair and ameliorates ferroptosis via SIRT1 in osteoarthritis 高强度间歇训练促进软骨修复并通过SIRT1改善骨关节炎中的铁下垂

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-20 DOI: 10.1016/j.bbrc.2026.153303

Changsheng Lin , Chunyan Liu , Xiao Zhang , Fang Zhou , Yuqin Ma , Ziqi Ye , Kaizong Huang , Anliang Chen , Kai Cheng , Xueping Li

Osteoarthritis (OA) is a progressive degenerative joint disease characterized by cartilage degradation, inflammation, and pain. High-intensity interval training (HIIT) has emerged as a promising non-pharmacological intervention that may improve joint function by promoting cartilage repair and attenuating inflammation. This study investigated the effects of HIIT on cartilage ferroptosis and the underlying molecular mechanisms, focusing on SIRT1 in a rat model of knee OA.

Sprague–Dawley rats were induced with OA via intra-articular monosodium iodoacetate (MIA) and then subjected to a 6-week HIIT program. Outcomes included gait analysis, mechanical and thermal pain thresholds, histological staining, and molecular assays. HIIT significantly improved gait parameters and pain thresholds, indicating functional recovery. Histology showed enhanced cartilage matrix integrity and repair. HIIT modulated ferroptosis-related markers, including GPX4 and ACSL4, and upregulated SIRT1 with activation of NRF2 signaling and improved iron metabolism within cartilage. Pharmacologic inhibition of SIRT1 (EX527) reversed these benefits, underscoring SIRT1's pivotal role in mediating HIIT's therapeutic effects. In vitro, IL-1β-stimulated primary chondrocytes exhibited reduced SIRT1/NRF2/GPX4 and increased TFRC/ACSL4, whereas lentiviral SIRT1 overexpression restored NRF2-GPX4 signaling and decreased TFRC/ACSL4, supporting a chondrocyte-intrinsic SIRT1-NRF2-GPX4 axis in regulating ferroptosis-associated responses.

In conclusion, while direct evidence of ferroptosis markers such as lipid peroxidation and mitochondrial changes is lacking, HIIT alleviates ferroptosis-associated cartilage damage and promotes cartilage repair in OA through SIRT1-dependent mechanisms. These findings support HIIT as a potential non-pharmacological strategy for OA management and provide a mechanistic basis for exercise-based interventions aimed at preserving joint function and reducing OA-related disability.

骨关节炎（OA）是一种进行性退行性关节疾病，以软骨退化、炎症和疼痛为特征。高强度间歇训练（HIIT）已经成为一种很有前途的非药物干预手段，可以通过促进软骨修复和减轻炎症来改善关节功能。本研究探讨了HIIT对软骨铁下垂的影响及其潜在的分子机制，重点研究了大鼠膝关节炎模型中的SIRT1。Sprague-Dawley大鼠通过关节内碘乙酸钠（MIA）诱导OA，然后进行为期6周的HIIT计划。结果包括步态分析、机械和热痛阈值、组织学染色和分子分析。HIIT显著改善了步态参数和疼痛阈值，表明功能恢复。组织学显示软骨基质完整性和修复增强。HIIT调节铁细胞凋亡相关标志物，包括GPX4和ACSL4，并通过激活NRF2信号和改善软骨内铁代谢上调SIRT1。药物抑制SIRT1 （EX527）逆转了这些益处，强调了SIRT1在介导HIIT治疗效果中的关键作用。在体外，il -1β刺激的原代软骨细胞表现出SIRT1/NRF2/GPX4减少和TFRC/ACSL4增加，而慢病毒SIRT1过表达恢复NRF2-GPX4信号传导并降低TFRC/ACSL4，支持软骨细胞固有的SIRT1-NRF2-GPX4轴调节铁凋亡相关反应。总之，尽管缺乏脂质过氧化和线粒体变化等铁下垂标志物的直接证据，但HIIT可以通过sirt1依赖机制减轻铁下垂相关的软骨损伤，促进OA的软骨修复。这些发现支持HIIT作为OA管理的潜在非药物策略，并为旨在保护关节功能和减少OA相关残疾的运动干预提供了机制基础。

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引用次数: 0

Temporal changes in Krüppel-like factor 2 and thrombomodulin correlate with coagulation, endothelial, and liver damage in exertional heat stroke rats krppel样因子2和凝血调节蛋白的时间变化与运动性中热大鼠的凝血、内皮和肝损伤相关

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-20 DOI: 10.1016/j.bbrc.2026.153327

Yuqi Shen , Chunyang Liu , Zewei Wang , Hongxu Jin , Ying Liu

The Krüppel-like Factor 2 (KLF2) -Thrombomodulin (TM) axis is crucial for maintaining vascular homeostasis and coagulation balance. This study investigated its dynamic role and temporal characteristics in the development of coagulopathy following exertional heat stroke (EHS). Using a well-established rat model of EHS induced by strenuous exercise under high-temperature and high-humidity conditions, we conducted a detailed time-course analysis. Our findings revealed that plasma levels of KLF2 and TM underwent significant dynamic fluctuations following EHS induction. These alterations showed a clear correlation with progressive prolongations in standard coagulation parameters, specifically activated partial thromboplastin time (APTT) and prothrombin time (PT). The most profound disturbances in both the KLF2-TM axis and coagulation function were consistently observed at 4 h post-EHS. Notably, this critical time point was also associated with the peak severity of hepatic injury, as comprehensively assessed through histopathological examination and confirmatory liver function tests. Further analysis demonstrated that the aberrant expression of the KLF2-TM pathway within the liver tissue exhibited a distinct temporal consistency with the observed progression of hepatic pathological damage. Collectively, these results indicated that the KLF2-TM axis was actively involved in the pathogenic mechanisms underlying EHS-associated coagulopathy. Monitoring the dynamic changes of this axis may provide valuable predictive insights into the dysregulation of coagulation during EHS, suggesting its potential as a biomarker for disease severity.

kr pel-like Factor 2 (KLF2) -Thrombomodulin （TM）轴对于维持血管稳态和凝血平衡至关重要。本研究探讨了其在运动性中暑（EHS）后凝血功能障碍发展中的动态作用和时间特征。我们建立了高温高湿条件下剧烈运动致EHS大鼠模型，并对其进行了详细的时程分析。我们的研究结果表明，血浆中KLF2和TM的水平在EHS诱导后发生了显著的动态波动。这些改变与标准凝血参数、特异性激活部分凝血活素时间（APTT）和凝血酶原时间（PT）的进行性延长有明显的相关性。在ehs后4小时，KLF2-TM轴和凝血功能均出现最严重的紊乱。值得注意的是，通过组织病理学检查和确认性肝功能检查，这一关键时间点也与肝损伤的严重程度高峰有关。进一步分析表明，肝脏组织中KLF2-TM通路的异常表达与观察到的肝脏病理损伤的进展具有明显的时间一致性。总之，这些结果表明KLF2-TM轴积极参与ehs相关凝血病的致病机制。监测该轴的动态变化可能为EHS期间凝血失调提供有价值的预测性见解，表明其作为疾病严重程度的生物标志物的潜力。

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引用次数: 0

Transcription factor PITX2 protects intestinal epithelial cells against inflammatory stress: Implications for ulcerative colitis rectal predilection and therapeutic resistance 转录因子PITX2保护肠上皮细胞免受炎症应激：溃疡性结肠炎直肠偏好和治疗抵抗的意义

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-19 DOI: 10.1016/j.bbrc.2026.153312

Hirosumi Suzuki , Xiangning Guo , Taku Sawafuji , Satoshi Fukuda , Mikiya Fujiwara , Kazunori Sasaki , Takeshi Yamada , Yoshiyuki Yamamoto , Mariko Kobayashi , Toshiaki Narasaka , Hiroko Isoda , Kiichiro Tsuchiya

Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) primarily characterized by inflammation of the colonic mucosa. Although the disease frequently demonstrates a predilection for the rectum, the underlying mechanism for this specific localization and the reasons for the therapeutic resistance observed in the rectum remain unknown. This study hypothesized that differences in intestinal epithelial cells (IECs) between the lesional rectum and the non-lesional ascending colon contribute to UC pathogenesis. We analyzed gene expression in patient-matched colon organoids to control for individual variables. We identified the transcription factor PITX2 as being elevated in organoids derived from non-lesional ascending colon tissue. Under inflammatory stimulation, PITX2 knockdown significantly reduced the proliferative and sphere-formation capacity of IECs, driven by a marked increase in apoptosis. This heightened vulnerability was independent of enhanced inflammatory signaling (NF-κB) or reactive oxygen species (ROS) production. In conclusion, PITX2 exerts a protective function by promoting IEC survival and inhibiting apoptosis under inflammatory stress. Its relative absence in the rectum may explain why this segment is the primary site of UC onset and therapeutic resistance. PITX2 is a novel candidate molecule regulating the colonic epithelial defense response in IBD.

溃疡性结肠炎（UC）是一种以结肠黏膜炎症为主要特征的炎症性肠病（IBD）。尽管该疾病经常表现出对直肠的偏爱，但这种特定定位的潜在机制以及在直肠中观察到的治疗抵抗的原因尚不清楚。本研究假设病变直肠和非病变升结肠之间肠上皮细胞（IECs）的差异有助于UC的发病机制。我们分析了患者匹配结肠类器官的基因表达，以控制个体变量。我们发现转录因子PITX2在来自非病变升结肠组织的类器官中升高。在炎症刺激下，PITX2敲低显著降低IECs的增殖和成球能力，导致细胞凋亡显著增加。这种脆弱性的增加与炎症信号（NF-κB）或活性氧（ROS）的产生无关。综上所述，PITX2通过促进炎症应激下IEC存活和抑制细胞凋亡发挥保护作用。它在直肠中的相对缺失可以解释为什么这段是UC发病和治疗耐药的主要部位。PITX2是IBD中调节结肠上皮防御反应的一个新的候选分子。

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引用次数: 0

ERβ-PIK3R2 axis promotes estrogen-driven gastric cancer progression ERβ-PIK3R2轴促进雌激素驱动的胃癌进展

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-19 DOI: 10.1016/j.bbrc.2026.153271

Jingyi Yin , Lingmeng Li , Yinan Niu, Ling Zhang, Liyu Huang

Although hormones are well-established contributors to prostate and breast cancers, their role in gastric cancer remains poorly understood. Clinical observations have revealed a strong correlation between female hormone levels and the risk of developing gastric cancer, particularly in women with high estrogen levels during pregnancy or lactation, who tend to have worse prognoses. However, the precise mechanisms by which estrogen (E2) and its receptors drive gastric cancer progression are not fully elucidated. Our study demonstrates that estrogen receptor ERβ, but not ERα, promotes the proliferation of E2-responsive gastric cancer cells. Genetic ablation of ERβ significantly suppresses the growth of subcutaneous tumors in mice. RNA-seq analysis identified PIK3R2, a PI3K regulatory subunit, as the most significantly E2-regulated gene, and luciferase reporter assays further validated PIK3R2 as a direct transcriptional target of ERβ. Clinically, PIK3R2 is significantly upregulated in gastric cancer, with elevated expression levels correlating with poor prognosis specifically in female patients, whereas no significant prognostic association was observed in male patients. These findings underscore the critical role of the ERβ/PIK3R2 signaling axis in estrogen-related gastric cancer, providing a potential therapeutic strategy for this subset of patients.

虽然激素是前列腺癌和乳腺癌的公认诱因，但它们在胃癌中的作用仍知之甚少。临床观察显示，女性激素水平与发生胃癌的风险之间存在很强的相关性，特别是在怀孕或哺乳期雌激素水平较高的妇女，她们往往预后较差。然而，雌激素（E2）及其受体驱动胃癌进展的确切机制尚未完全阐明。我们的研究表明，雌激素受体ERβ而不是ERα促进e2反应性胃癌细胞的增殖。基因消融ERβ可显著抑制小鼠皮下肿瘤的生长。RNA-seq分析发现PI3K调控亚基PIK3R2是e2调控最显著的基因，荧光素酶报告基因分析进一步证实PIK3R2是ERβ的直接转录靶点。临床上，PIK3R2在胃癌中表达显著上调，且表达水平升高与预后不良相关，尤其是在女性患者中，而在男性患者中未见明显预后相关。这些发现强调了ERβ/PIK3R2信号轴在雌激素相关胃癌中的关键作用，为这类患者提供了潜在的治疗策略。

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引用次数: 0

Lactylation-mediated degradation of ANKS1B mitigates ischemic excitotoxicity by impairing GluN2B trafficking 乳酸化介导的ANKS1B降解通过损害GluN2B转运来减轻缺血性兴奋性毒性。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-17 DOI: 10.1016/j.bbrc.2026.153311

Ping Yang , Junzhao Liu , Xia Rong , Tongyao Li , Wensi Hu , Na Wang , Zizhong Liu , Lin Shi , Linna Luo , Haibo Tang

Ischemic stroke triggers a cascade of metabolic shifts and excitotoxicity, partially mediated by GluN2B-containing N-methyl-d-aspartate receptors (NMDARs). While protein lactylation has emerged as a key metabolic regulator, its role in modulating neurotoxicity remains underexplored. In this study, we integrated proteomics datasets from middle cerebral artery occlusion (MCAO) mouse models and identified ANKS1B as a unique protein that is both differentially lactylated and downregulated in ischemic tissue. Using an oxygen-glucose deprivation/reperfusion (OGD/R) model in SH-SY5Y cells, we demonstrated that ischemia induces ANKS1B lactylation at the conserved K1222 site. This modification targets ANKS1B for ubiquitin-proteasome-mediated degradation. Functionally, ANKS1B regulates the endoplasmic reticulum (ER) export of GluN2B. Lactylation-driven ANKS1B loss leads to GluN2B retention in the ER. Notably, expressing a lactylation-resistant mutant (ANKS1B–K1222R) prevented this degradation, resulting in restored GluN2B surface trafficking. However, this preservation of ANKS1B proved detrimental, as it exacerbated intracellular Ca²⁺ overload and increased neuronal death following OGD/R. These results indicate that ischemia-induced ANKS1B lactylation acts as an adaptive, neuroprotective feedback mechanism to limit excitotoxicity by downregulating surface NMDARs. This study reveals a novel link between metabolic reprogramming and synaptic protein trafficking, providing new insights into stroke pathophysiology and potential therapeutic targets.

缺血性中风触发一系列代谢变化和兴奋性毒性，部分由含glun2b的n -甲基-d-天冬氨酸受体（NMDARs）介导。虽然蛋白质乳酸化已成为一种关键的代谢调节剂，但其在调节神经毒性中的作用仍未得到充分探讨。在这项研究中，我们整合了来自大脑中动脉闭塞（MCAO）小鼠模型的蛋白质组学数据集，并鉴定出ANKS1B是一种在缺血组织中存在差异乳酸化和下调的独特蛋白。通过对SH-SY5Y细胞进行氧-葡萄糖剥夺/再灌注（OGD/R）模型，我们发现缺血诱导ANKS1B在保守的K1222位点发生乳酸化。这种修饰针对ANKS1B进行泛素蛋白酶体介导的降解。ANKS1B在功能上调控GluN2B的内质网（ER）输出。乳酸化驱动的ANKS1B缺失导致GluN2B在内质网中保留。值得注意的是，表达抗乳酸化突变体（ANKS1B-K1222R）阻止了这种降解，导致GluN2B表面转运恢复。然而，这种ANKS1B的保存被证明是有害的，因为它加剧了细胞内Ca2+超载，增加了OGD/R后的神经元死亡。这些结果表明，缺血诱导的ANKS1B乳酸化作为一种适应性的神经保护反馈机制，通过下调表面NMDARs来限制兴奋性毒性。这项研究揭示了代谢重编程和突触蛋白运输之间的新联系，为中风病理生理学和潜在的治疗靶点提供了新的见解。

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引用次数: 0

Teneurin-4 in the nucleus accumbens modulates affective-like behaviors with potential effects on astrocytes in male mice 伏隔核中的腱神经蛋白-4调节雄性小鼠的情感性行为，可能对星形胶质细胞产生影响。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-17 DOI: 10.1016/j.bbrc.2026.153309

Wenbing Chen , Tomoya Kaigawa , Jun Yokose , Yusuke Yano , Yuki Shigetsura , Shin-ichi Muramatsu , Atsumi Nitta

Affective disorders represent a major global health burden with limited therapeutic options. Teneurin-4 (TENM4), a cell adhesion molecule crucial for synaptic organization, has been implicated in neural circuit function, but its specific role in the nucleus accumbens (NAc) and its contribution to mood regulation are poorly understood. Here, we used adeno-associated virus (AAV)-mediated CRISPR for a targeted knockdown of Tenm4 mRNA in the mouse NAc. TENM4 knockdown (TENM4KD) induced robust anxiety- and depression-like behaviors, accompanied by simplified astrocyte morphology with reduced branching complexity and territorial area, without affecting microglia. To probe the underlying circuit deficit, we performed regimen with etizolam (ETZ), a positive allosteric modulator of GABA-A receptors, for seven days normalized both behavioral and astrocyte morphological alterations. Mechanistically, TENM4KD disrupted FAK/Wnt signaling, which was restored by ETZ. Our findings indicate that neuronal TENM4 in the NAc maintains astrocyte structure through neuron–glia crosstalk. Disruption of this interaction contributes to affective-like behaviors, revealing a novel neuron-to-astrocyte signaling mechanism for TENM4 in mood regulation.

情感性障碍是全球主要的健康负担，治疗选择有限。tenneurin -4 （TENM4）是一种对突触组织至关重要的细胞粘附分子，与神经回路功能有关，但其在伏隔核（NAc）中的具体作用及其对情绪调节的贡献尚不清楚。在这里，我们使用腺相关病毒（AAV）介导的CRISPR靶向敲低小鼠NAc中的Tenm4 mRNA。TENM4敲低（TENM4KD）诱导了强烈的焦虑和抑郁样行为，伴随着星形胶质细胞形态的简化，分支复杂性和领土面积减少，而不影响小胶质细胞。为了探索潜在的电路缺陷，我们使用乙替唑仑（ETZ）治疗，乙替唑仑是GABA-A受体的一种正变构调节剂，在7天内使行为和星形细胞形态改变正常化。从机制上讲，TENM4KD破坏了通过ETZ恢复的FAK/Wnt信号。我们的研究结果表明，NAc中的神经元TENM4通过神经元-胶质细胞串扰维持星形胶质细胞结构。这种相互作用的破坏有助于情感样行为，揭示了TENM4在情绪调节中的一种新的神经元到星形胶质细胞信号传导机制。

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引用次数: 0

Cytotoxic and anti-metastatic effects of Pllans-II from Porthidium lansbergii lansbergii venom against prostate cancer cells 兰氏卟啉- ii对前列腺癌细胞的细胞毒及抗转移作用。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-17 DOI: 10.1016/j.bbrc.2026.153307

Cesar Vela-Prieto, Mildrey Mosquera Escudero, Alejandro Montoya-Gómez, Eliécer Jiménez-Charris

Prostate cancer remains a major health challenge due to therapeutic resistance and the adverse effects of conventional treatments. Snake venom phospholipases A₂ have emerged as promising bioactive molecules with selective anti-cancer properties. In this study, we evaluated the cytotoxic and anti-metastatic effects of Pllans-II, an Asp-49 PLA₂ purified from Porthidium lansbergii lansbergii venom, on prostate cancer cell lines. Pllans-II exerted a dose-dependent cytotoxic effect on LNCaP, PC-3, and DU-145 cells, with the strongest activity observed in LNCaP cells (IC₅₀ = 100 μg/mL). In contrast, it spared non-tumorigenic prostate epithelial cells (PCS-440-010), unlike Docetaxel. Pllans-II did not compromise plasma membrane integrity, suggesting a non-lytic mechanism of action. Functional assays revealed that Pllans-II significantly inhibited LNCaP cell migration in both 2D wound-healing and 3D transwell models, reduced adhesion to fibronectin and Matrigel, and impaired clonogenic capacity. Western blot analysis revealed no change in the caspase-8 expression, but a marked upregulation of Beclin-1, probably related to autophagy cell death pathways. These findings highlight the selective cytotoxicity and anti-metastatic potential of Pllans-II, positioning it as a promising prototype for the development of novel therapeutic strategies against prostate cancer.

由于治疗抵抗和常规治疗的不良影响，前列腺癌仍然是一个主要的健康挑战。蛇毒磷脂酶A2已成为一种具有选择性抗癌特性的生物活性分子。在这项研究中，我们评估了从兰氏斑鲈毒液中纯化的asp49pla2蛋白plans - ii对前列腺癌细胞的细胞毒性和抗转移作用。pl兰斯- ii对LNCaP、PC-3和DU-145细胞均有剂量依赖性的细胞毒作用，其中对LNCaP细胞的作用最强（IC50 = 100 μg/mL）。相反，与多西紫杉醇不同，它对非致瘤性前列腺上皮细胞（PCS-440-010）没有影响。plan - ii没有损害质膜的完整性，表明其作用机制是非溶解性的。功能分析显示，plans - ii在2D创面愈合和3D transwell模型中均能显著抑制LNCaP细胞的迁移，减少对纤维连接蛋白和基质的粘附，并削弱克隆生成能力。Western blot分析显示caspase-8的表达没有变化，但Beclin-1的表达明显上调，可能与自噬细胞死亡途径有关。这些发现突出了plans - ii的选择性细胞毒性和抗转移潜力，将其定位为开发新的前列腺癌治疗策略的有希望的原型。

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引用次数: 0

High expression of angiotensin-converting enzyme in macrophages exacerbates renal interstitial damage in diabetic mice 巨噬细胞中血管紧张素转换酶的高表达加重了糖尿病小鼠肾间质损伤。

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-17 DOI: 10.1016/j.bbrc.2026.153308

Takayuki Uemura , Keigo Tomita , Masahiro Eriguchi , Kumiko Torisu , Masatoshi Nishimoto , Yushi Uchida , Jorge F. Giani , Kenneth E. Bernstein , Kazuhiko Tsuruya , Toshiaki Nakano

Angiotensin-converting enzyme (ACE), primarily expressed in vascular endothelial and renal tubular epithelial cells, regulates vascular tone and contributes to kidney injury, including in diabetic kidney disease (DKD). While tubular ACE deletion ameliorates tubulointerstitial injury in diabetic mice, the role of ACE in macrophages remains unclear. We investigated diabetic ACE 10/10 mice, which overexpress ACE exclusively in myelomonocytic cells and lack ACE in other tissues, including the kidney. In diabetic ACE 10/10 mice, the absence of endothelial ACE resulted in the elimination of glomerular hyperfiltration with preservation of podocyte structure. However, albuminuria levels remained comparable to those in diabetic WT mice. Furthermore, despite the lack of tubular ACE, which is recognized as a contributor to tubulointerstitial fibrosis, the extent of fibrosis was similarly unchanged. Flow cytometry revealed that ACE expression in kidney-resident macrophages increased approximately threefold in both diabetic WT and ACE 10/10 mice, but not in peritoneal macrophages. In vitro, ACE-overexpressing macrophages showed increased interleukin-6 production and enhanced chemotaxis upon lipopolysaccharide stimulation. These findings suggest that ACE expressed in kidney-resident macrophages contributes to proximal tubular albuminuria and tubulointerstitial fibrosis in DKD, independently of glomerular hyperfiltration and tubular ACE. Although macrophage ACE represents a minor fraction of total renal ACE, it may serve as a novel therapeutic target.

血管紧张素转换酶（ACE）主要在血管内皮细胞和肾小管上皮细胞中表达，调节血管张力并导致肾损伤，包括糖尿病肾病（DKD）。虽然小管ACE缺失可以改善糖尿病小鼠的小管间质损伤，但ACE在巨噬细胞中的作用尚不清楚。我们研究了糖尿病ACE 10/10小鼠，这些小鼠仅在骨髓单核细胞中过表达ACE，而在其他组织（包括肾脏）中缺乏ACE。在糖尿病ACE 10/10小鼠中，内皮ACE的缺失导致肾小球高滤过消除，并保留足细胞结构。然而，蛋白尿水平仍然与糖尿病WT小鼠相当。此外，尽管缺乏被认为是小管间质纤维化的一个因素的管状ACE，但纤维化的程度同样没有变化。流式细胞术显示，ACE在糖尿病WT和ACE 10/10小鼠肾内巨噬细胞中的表达增加了约3倍，但在腹膜巨噬细胞中没有。在体外，过表达ace的巨噬细胞在脂多糖刺激下，白细胞介素-6的产生增加，趋化性增强。这些发现表明，在肾内巨噬细胞中表达的ACE有助于DKD近端小管蛋白尿和小管间质纤维化，而不依赖于肾小球高滤过和小管ACE。尽管巨噬细胞ACE只占肾脏总ACE的一小部分，但它可能是一种新的治疗靶点。

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引用次数: 0

smFASTIA: A high-sensitivity platform for purification-free kinetic screening of protein–small molecule interactions smFASTIA：用于蛋白-小分子相互作用的无纯化动力学筛选的高灵敏度平台

IF 2.2 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochemical and biophysical research communications

Pub Date : 2026-01-16 DOI: 10.1016/j.bbrc.2026.153300

Yuki Tokunaga , Ryo Matsunaga , Satoru Nagatoishi , Kouhei Tsumoto

Elucidating the binding kinetics of protein–small molecule interactions is critical for optimizing drug efficacy and understanding mechanism of action. However, establishing structure–kinetic relationships is often hindered by the throughput of conditional assays that require protein purification. Herein, we present smFASTIA, a rapid, purification-free screening platform that integrates cell-free protein synthesis with high-sensitivity bio-layer interferometry. Using the SpyTag003–SpyCatcher003 system, we immobilized target proteins at high density directly from crude reaction mixtures, enabling the detection of weak small-molecule signals. Using human carbonic anhydrase II and its inhibitor as a model, we screened 32 variants. Instead of relying on equilibrium analysis, we utilized the initial slope of the association phase as a kinetic indicator proportional to the association rate constant. This approach successfully discriminated variants based on their kinetic profiles. Validation by surface plasmon resonance confirmed that variants classified as non-binders in our screening included those with significantly reduced on-rates, demonstrating the platform's ability to filter based on association kinetics. This workflow enables the kinetic assessment of dozens of variants within two days, providing a powerful tool for accelerating SKR studies and protein engineering.

阐明蛋白质-小分子相互作用的结合动力学对于优化药物疗效和了解作用机制至关重要。然而，建立结构-动力学关系往往受到需要蛋白质纯化的条件分析的吞吐量的阻碍。在此，我们提出了smFASTIA，一个快速，无需纯化的筛选平台，将无细胞蛋白合成与高灵敏度生物层干涉术相结合。使用SpyTag003-SpyCatcher003系统，我们直接从粗反应混合物中以高密度固定靶蛋白，从而能够检测微弱的小分子信号。以人类碳酸酐酶II及其抑制剂为模型，我们筛选了32个变体。我们没有依赖于平衡分析，而是利用结合相的初始斜率作为与结合速率常数成正比的动力学指标。该方法成功地根据它们的动力学特征来区分变体。表面等离子体共振验证证实，在我们的筛选中被归类为非结合物的变异包括那些显着降低的结合率，证明了该平台基于关联动力学的过滤能力。该工作流程可以在两天内对数十种变异进行动态评估，为加速SKR研究和蛋白质工程提供了强大的工具。

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引用次数: 0