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Siglec-5 as a novel receptor mediates endothelial cells oxLDL transcytosis to promote atherosclerosis Siglec-5 作为一种新型受体介导内皮细胞 oxLDL 转运,促进动脉粥样硬化。
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.trsl.2024.09.003
Xiong Jia , Xiangli Bai , Zhiqiang Yin , Qijun Zheng , Yin Zhao , Yajing Lu , Yan Shu , Yayu Wang , Yifei Zhang , Si Jin

Background

Excessive subendothelial retention of oxidized low-density lipoprotein (oxLDL) and subsequent oxLDL engulfment by macrophages leads to the formation of foam cells and the development of atherosclerosis. Our previous study showed that the plasma level of sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5) was a novel biomarker for the prognosis of atherosclerosis in diabetic patients. However, the role and underlying mechanisms of Siglec-5 in atherosclerosis have not been elucidated.

Methods

The interaction between oxLDL and Siglec-5 was detected by fluorescence colocalization and coimmunoprecipitation. The effect of oxLDL on Siglec-5 expression was detected in endothelial cells and macrophages, and the effect of Siglec-5 on oxLDL transcytosis and uptake was investigated. Siglec-5 was overexpressed in mice using recombinant adeno-associated virus vector serotype 9 (rAAV9-Siglec-5) to evaluate the effect of Siglec-5 on oxLDL uptake and atherogenesis in vivo. In addition, the effects of Siglec-5 antibodies and soluble Siglec-5 proteins on oxLDL transcytosis and uptake and their role in atherogenesis were investigated in vivo and in vitro.

Results

We found that oxLDL interacted with Siglec-5 and that oxLDL stimulated the expression of Siglec-5. Siglec-5 promotes the transcytosis and uptake of oxLDL, while both anti-Siglec-5 antibodies and soluble Siglec-5 protein attenuated oxLDL transcytosis and uptake. Interestingly, overexpression of Siglec-5 by recombinant adeno-associated viral vector serotype 9 (rAAV9-Siglec-5) promoted the retention of oxLDL in the aorta of C57BL/6 mice. Moreover, overexpression of Siglec-5 significantly accelerated the formation of atherosclerotic lesions in Apoe−/− mice. Moreover, both anti-Siglec-5 antibodies and soluble Siglec-5 protein significantly alleviated the retention of oxLDL in the aorta of rAAV9-Siglec-5-transfected C57BL/6 mice and the formation of atherosclerotic plaques in rAAV9-Siglec-5-transfected Apoe−/− mice.

Conclusion

Our results suggested that Siglec-5 was a novel receptor that mediated oxLDL transcytosis and promoted the formation of foam cells. Interventions that inhibit the interaction between oxLDL and Siglec-5, including anti-Siglec-5 antibody or soluble Siglec-5 protein treatment, may provide novel therapeutic strategies in treating atherosclerosis.
背景:氧化低密度脂蛋白(oxLDL)在内皮下的过度滞留以及随后被巨噬细胞吞噬导致泡沫细胞的形成和动脉粥样硬化的发展。我们之前的研究表明,血浆中的唾液酸结合免疫球蛋白样凝集素 5(Siglec-5)水平是糖尿病患者动脉粥样硬化预后的新型生物标志物。然而,Siglec-5在动脉粥样硬化中的作用和内在机制尚未阐明:方法:通过荧光共聚焦和共沉淀技术检测了 oxLDL 与 Siglec-5 之间的相互作用。方法:通过荧光共聚焦和共免疫沉淀检测了 oxLDL 与 Siglec-5 之间的相互作用,检测了内皮细胞和巨噬细胞中 oxLDL 对 Siglec-5 表达的影响,并研究了 Siglec-5 对 oxLDL 转运和摄取的影响。利用重组腺相关病毒载体血清型9(rAAV9-Siglec-5)在小鼠体内过表达Siglec-5,以评估Siglec-5对体内oxLDL摄取和动脉粥样硬化的影响。此外,还在体内和体外研究了Siglec-5抗体和可溶性Siglec-5蛋白对oxLDL转运和摄取的影响及其在动脉粥样硬化发生中的作用:结果:我们发现oxLDL与Siglec-5相互作用,并且oxLDL刺激Siglec-5的表达。Siglec-5能促进oxLDL的转囊和摄取,而抗Siglec-5抗体和可溶性Siglec-5蛋白都能减少oxLDL的转囊和摄取。有趣的是,通过重组腺相关病毒载体血清型 9(rAAV9-Siglec-5)过表达 Siglec-5 可促进 oxLDL 在 C57BL/6 小鼠主动脉中的滞留。此外,Siglec-5 的过表达明显加速了载脂蛋白/-小鼠动脉粥样硬化病变的形成。此外,抗Siglec-5抗体和可溶性Siglec-5蛋白都能明显减轻氧化LDL在转染rAAV9-Siglec-5的C57BL/6小鼠主动脉中的滞留以及转染rAAV9-Siglec-5的载脂蛋白-/-小鼠动脉粥样硬化斑块的形成:我们的研究结果表明,Siglec-5 是一种新型受体,可介导 oxLDL 转运并促进泡沫细胞的形成。抑制 oxLDL 与 Siglec-5 之间相互作用的干预措施,包括抗 Siglec-5 抗体或可溶性 Siglec-5 蛋白治疗,可能为治疗动脉粥样硬化提供新的治疗策略。
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Diagnostic, prognostic, and predictive biomarkers in gastric cancer: from conventional to novel biomarkers 胃癌的诊断、预后和预测生物标志物:从传统生物标志物到新型生物标志物。
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.trsl.2024.09.001
Ghazaleh Khalili-Tanha , Nima Khalili-Tanha , Arian Karimi Rouzbahani , Ramisa Mahdieh , Kimia Jasemi , Rosa Ghaderi , Fatemeh Khojasteh Leylakoohi , Elnaz Ghorbani , Majid Khazaei , Seyed Mahdi Hassanian , Ibrahim Saeed Gataa , Gordon A Ferns , Elham Nazari , Amir Avan
Gastric cancer is a major health concern worldwide. The survival rate of Gastric cancer greatly depends on the stage at which it is diagnosed. Early diagnosis is critical for improving survival outcomes. To improve the chances of early diagnosis, regular screening tests, such as an upper endoscopy or barium swallow, are recommended for individuals at a higher risk due to factors like family history or a previous diagnosis of gastric conditions. Biomarkers can be detected and measured using non-invasive methods such as blood tests, urine tests, breath analysis, or imaging techniques. These non-invasive approaches offer many advantages, including convenience, safety, and cost-effectiveness, making them valuable tools for disease diagnosis, monitoring, and research. Biomarker-based tests have emerged as a useful tool for identifying gastric cancer early, monitoring treatment response, assessing the recurrence risk, and personalizing treatment plans. In this current review, we have explored both classical and novel biomarkers for gastric cancer. We have centralized their potential clinical application and discussed the challenges in Gastric cancer research.
胃癌是全球关注的一大健康问题。胃癌的存活率在很大程度上取决于确诊时所处的阶段。早期诊断是提高生存率的关键。为了提高早期诊断的几率,建议因家族史或曾被诊断患有胃病等因素而患胃癌的高危人群进行定期筛查,如上消化道内窥镜检查或吞钡检查。生物标志物可通过血液检测、尿液检测、呼气分析或成像技术等非侵入性方法进行检测和测量。这些非侵入性方法具有许多优点,包括方便、安全和成本效益高,是疾病诊断、监测和研究的重要工具。基于生物标志物的检测已成为早期识别胃癌、监测治疗反应、评估复发风险和个性化治疗方案的有用工具。在本综述中,我们探讨了胃癌的经典和新型生物标记物。我们集中探讨了它们的潜在临床应用,并讨论了胃癌研究面临的挑战。
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IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-09 DOI: 10.1016/S1931-5244(24)00165-8
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IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-09 DOI: 10.1016/S1931-5244(24)00164-6
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IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-09 DOI: 10.1016/S1931-5244(24)00163-4
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J147 treatment protects against traumatic brain injury by inhibiting neuronal endoplasmic reticulum stress potentially via the AMPK/SREBP-1 pathway J147 可通过 AMPK/SREBP-1 途径抑制神经元内质网应激,从而保护大脑免受创伤性脑损伤。
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-07 DOI: 10.1016/j.trsl.2024.08.007
Rong Jin , Min Wang , Manish Shukla , Yuguo Lei , Dong An , Jiwen Du , Guohong Li

Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.

内质网(ER)应激被认为是创伤性脑损伤(TBI)进展的关键因素,也是治疗干预的潜在靶点。本研究旨在评估新型神经营养化合物 J147 通过调节相关信号通路缓解 ER 应激,从而促进创伤性脑损伤功能恢复的潜力。为此,成年小鼠接受可控皮质冲击(CCI)损伤以诱发创伤性脑损伤,然后在损伤后一小时口服 J147,每天服药 3 到 7 天。在35天的时间里进行了多项行为评估,结果显示,J147治疗对神经功能的恢复有显著的剂量依赖性改善。神经病理学分析表明,在创伤后 35 天,急性神经变性减少(通过 FJC 染色在三天内观察到),神经元长期存活率提高(H&E 和 Nissl 染色),神经可塑性改善(高尔基体染色)。在分子水平上,创伤后三天,TBI诱导AMP激活蛋白激酶(AMPK)去磷酸化、固醇调节元件结合蛋白-1(SREBP-1)活化,以及ER应激标志蛋白的上调,包括磷酸化真核细胞起始因子-2α(p-eIF2a)、激活转录因子4(ATF4)和C/EBP同源蛋白(CHOP)。值得注意的是,J147 治疗能显著减轻 AMPK 去磷酸化、SERBP-1 激活和 ER 应激标志物的表达。总之,这项研究揭示了 J147 通过调节 ER 应激途径减轻创伤性脑损伤引起的继发性脑损伤并改善长期功能恢复的治疗前景。
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Author Guidelines 作者指南
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/S1931-5244(24)00157-9
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IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/S1931-5244(24)00158-0
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Editorial Advisory Board 编辑顾问委员会
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-09-05 DOI: 10.1016/S1931-5244(24)00156-7
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引用次数: 0
DUSP5 deficiency suppresses the progression of acute kidney injury by enhancing autophagy through AMPK/ULK1 pathway 缺乏 DUSP5 可通过 AMPK/ULK1 途径增强自噬作用,从而抑制急性肾损伤的进展。
IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2024-08-30 DOI: 10.1016/j.trsl.2024.08.006
Fang Bai , Chunjie Wang , Sha Wang , Yuxuan Zhao , Feng Feng , Kuipeng Yu , Lei Liu , Xiangdong Yang

Acute kidney injury (AKI) represents a critical clinical disease characterized by the rapid decline in renal function, carrying a substantial burden of morbidity and mortality. The treatment of AKI is frequently limited by its variable clinical presentations and intricate pathophysiology, highlighting the urgent need for a deeper understanding of its pathogenesis and potential therapeutic targets. Dual-specific protein phosphatase 5 (DUSP5), a member of the serine-threonine phosphatase family, possesses the capability to dephosphorylate extracellular regulated protein kinases (ERK). DUSP5 has emerged as a pivotal player in modulating metabolic signals, inflammatory responses, and cancer progression, while also being closely associated with various kidney diseases. This study systematically scrutinized the function and mechanism of DUSP5 in AKI for the first time, unveiling a substantial increase in DUSP5 expression during AKI. Moreover, DUSP5 knockdown was observed to attenuate the production of inflammatory factors and apoptotic cells in renal tubular epithelial cells by enhancing AMPK/ULK1-mediated autophagy, thus improving renal function. In a word, DUSP5 knockdown in AKI effectively impede disease progression by activating autophagy. This finding holds promise for introducing fresh perspectives and targets for AKI treatment.

急性肾损伤(AKI)是一种严重的临床疾病,其特点是肾功能急剧下降,给发病率和死亡率带来沉重负担。急性肾损伤的临床表现多变,病理生理学错综复杂,治疗常常受到限制,因此迫切需要深入了解其发病机制和潜在的治疗靶点。双特异性蛋白磷酸酶 5(DUSP5)是丝氨酸-苏氨酸磷酸酶家族的成员,具有使细胞外调节蛋白激酶(ERK)去磷酸化的能力。DUSP5 已成为调节代谢信号、炎症反应和癌症进展的关键角色,同时也与各种肾脏疾病密切相关。本研究首次系统地研究了 DUSP5 在 AKI 中的功能和机制,发现 DUSP5 在 AKI 中的表达大幅增加。此外,研究还观察到敲除 DUSP5 能通过增强 AMPK/ULK1 介导的自噬作用,减少肾小管上皮细胞中炎性因子和凋亡细胞的产生,从而改善肾功能。总之,在 AKI 中敲除 DUSP5 可通过激活自噬有效阻止疾病进展。这一发现有望为 AKI 治疗提供新的视角和靶点。
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Translational Research
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