Acta materia medica最新文献

英文中文

In vitro characterization and cellular uptake profiles of TAMs-targeted lipid calcium carbonate nanoparticles for cancer immunotherapy 靶向tam的脂质碳酸钙纳米颗粒用于癌症免疫治疗的体外表征和细胞摄取谱

Acta materia medica

Pub Date : 2022-10-12 DOI: 10.15212/amm-2022-0030

Xiaoyan Xu, Renjie Li, Runqi Dong, Yan-fang Yang, Hongliang Wang, Jia Hua Cheng, Yuling Liu, Jun Ye

Tumor-associated macrophages (TAMs) are key contributors to tumor development, accelerated tumor invasion and metastasis, and induction of immunosuppression. Targeted delivery of immunomodulatory agents to promote polarization of TAMs may alleviate the immunosuppressive tumor microenvironment. Calcium carbonate nanoparticles (CCN), which exhibit excellent biocompatibility, pH sensitivity, and easy surface modification, have attracted substantial attention in targeted nano delivery. In this study, CCN were used as a matrix material to develop UNO-peptide-modified lipid CCN for targeted immunomodulation of TAMs by using the mannose receptor overexpressed on the surfaces of TAMs as targets. The preparation of CCN was optimized through single-factor testing with the gas diffusion method with the particle size as the index. The surface modification of CCN with UNO-peptide-modified phospholipids was performed, and its targeting effect on TAMs was investigated. The average particle size of the CCN and UNO-peptide-modified CCN was 144.5 ± 3.8 nm and 167.0 ± 1.3 nm, respectively. UNO-peptide-modified CCN entered TAMs via actively targeted uptake mediated by mannose receptors. Our results demonstrated that the developed UNO-peptide-modified CCN with controlled nano-size and excellent TAMs-targeting properties is a highly promising nanocarrier for targeted delivery of TAM immunomodulatory agents.

肿瘤相关巨噬细胞(tumor associated macrophages, tam)是肿瘤发展、加速肿瘤侵袭和转移以及诱导免疫抑制的关键因素。靶向递送免疫调节剂促进tam极化可能会缓解免疫抑制的肿瘤微环境。碳酸钙纳米颗粒(CCN)具有良好的生物相容性、pH敏感性和易于表面修饰等特点，在靶向纳米递送领域受到广泛关注。本研究以CCN为基质材料，利用在tam表面过表达的甘露糖受体作为靶点，制备了uno肽修饰的脂质CCN，用于tam的靶向免疫调节。以粒径为指标，采用气体扩散法对CCN的制备工艺进行单因素优化。用uno肽修饰的磷脂对CCN进行表面修饰，并研究其对tam的靶向作用。CCN和uno -peptide修饰的CCN的平均粒径分别为144.5±3.8 nm和167.0±1.3 nm。uno肽修饰的CCN通过甘露糖受体介导的主动靶向摄取进入tam。我们的研究结果表明，所开发的uno肽修饰的CCN具有可控的纳米尺寸和优异的TAM靶向性，是一种非常有前途的靶向递送TAM免疫调节剂的纳米载体。

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引用次数: 7

Protective effects of ginsenoside CK against oxidative stress-induced neuronal damage, assessed with 1H-NMR-based metabolomics 以1h - nmr为基础的代谢组学评估人参皂苷CK对氧化应激诱导的神经元损伤的保护作用

Acta materia medica

Pub Date : 2022-10-07 DOI: 10.15212/amm-2022-0009

Na Li, Yanhong Zhang, Jing-wei Lv, Dazhong Sun, Jianan Lin, Qihang Pang, Hui Li, Zhanhong Cao, Yaxin Liu, Zhuguo Li, Xingyu Fang, Dianyu Li, Haonan Bai, Yuanyuan An, Jun Jiang, Rui Zhang, Qing Yang

Oxidative stress is an important pathogenic mechanism in degenerative diseases such as Alzheimer’s disease. Although ginsenoside compound K (CK) is protective against neuronal oxidative damage, the underlying mechanism remains to be understood. In this study, the protective effects of ginsenoside CK against oxidative stress damage induced by hydrogen peroxide in HT22 cells were investigated with 1H nuclear magnetic resonance (1H-NMR)-based metabolomics. The optimal CK concentration for decreasing oxidative stress damage in nerves was determined with MTT assays. CK (8 μM) significantly increased the HT22 cell survival rate after the model was established. Cell lysates were subjected to 1H-NMR metabolomics, western blotting, and ATP assays for verification. Metabolic perturbation occurred in HT22 cells in the model group but not the control group. Twenty biomarkers were identified and used to analyze metabolic pathways. CK reversed metabolic changes in HT22 cells by altering taurine, glutamate, glycine, and glutathione metabolism. Subsequently, CK increased ATP content and the expression of components of the PI3K/AKT signaling pathway in HT22 cells. These findings demonstrated that CK prevents oxidative stress damage and protects nerves by regulating energy-metabolism pathways, such as those of taurine, glutamate, and other amino acids, thus providing a rationale for the use of CK in Alzheimer’s disease treatment.

氧化应激是阿尔茨海默病等退行性疾病的重要致病机制。尽管人参皂苷化合物K（CK）对神经元氧化损伤具有保护作用，但其潜在机制仍有待了解。本研究采用基于1H-NMR的代谢组学研究了人参皂苷CK对过氧化氢诱导的HT22细胞氧化应激损伤的保护作用。MTT法测定降低神经氧化应激损伤的最佳CK浓度。CK（8μM）可显著提高HT22细胞的存活率。对细胞裂解物进行1H-NMR代谢组学、蛋白质印迹和ATP测定以进行验证。模型组的HT22细胞发生代谢紊乱，而对照组没有。20种生物标志物被鉴定并用于分析代谢途径。CK通过改变牛磺酸、谷氨酸、甘氨酸和谷胱甘肽的代谢来逆转HT22细胞的代谢变化。随后，CK增加了HT22细胞中ATP含量和PI3K/AKT信号通路成分的表达。这些发现表明，CK通过调节能量代谢途径（如牛磺酸、谷氨酸和其他氨基酸）来预防氧化应激损伤并保护神经，从而为CK在阿尔茨海默病治疗中的应用提供了理论依据。

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引用次数: 3

The direct STAT3 inhibitor 6-ethoxydihydrosanguinarine exhibits anticancer activity in gastric cancer STAT3直接抑制剂6-乙氧基二氢血根碱对癌症具有抗癌活性

Acta materia medica

Pub Date : 2022-10-06 DOI: 10.15212/amm-2022-0027

Xue-wen Liu, Xin Jin, Hongling Ou, Chen Qian, Hui Wu, C. Zuo, Yuliang Ren, Miaoxin Fu, Te Zhang, Liang Zhang, Y. Si, Ying Liu

Signal transducer and activator of transcription 3 (STAT3) plays a key role in promoting tumor malignant progression. Suppression of hyperactivated STAT3 signaling has emerged as a potential therapeutic strategy for many cancer types. In this study, the effect of 6-ethoxydihydrosanguinarine (6-EDS), a secondary transformation product formed from dihydrosanguinarine, isolated from Macleaya (Papaveraceae), was evaluated in gastric cancer (GC). We demonstrated that 6-EDS inhibited the survival, migration, and invasiveness of GC cells in vitro. Moreover, 6-EDS inhibited STAT3 phosphorylation and transcriptional activity, thus suppressing the mRNA expression of downstream target genes associated with the malignant survival, migration, and invasiveness of GC cells. Molecular docking indicated that 6-EDS directly bound the SH2 domain of STAT3. Molecular dynamics simulations suggested that 6-EDS inhibited the binding of phosphorylated and non-phosphorylated STAT3 to target DNA. Cellular thermal-shift assays and microscale thermophoresis further confirmed the direct binding of 6-EDS to STAT3. Site-directed mutagenesis indicated that the S611 residue in the SH2 domain of STAT3 is critical for 6-EDS binding. In vivo, 6-EDS decreased tumor growth in xenografted nude mice by blocking STAT3 signaling. These findings indicated that 6-EDS, a direct STAT3 inhibitor, may be a potent anticancer candidate for GC therapy.

信号换能器和转录激活因子3 (STAT3)在促进肿瘤恶性进展中起关键作用。抑制过度激活的STAT3信号已成为许多癌症类型的潜在治疗策略。本研究评价了从木瓜科植物中分离得到的二氢血碱二级转化产物6-乙氧基二氢血碱(6-EDS)对胃癌(GC)的作用。我们证明了6-EDS在体外抑制GC细胞的存活、迁移和侵袭性。此外，6-EDS抑制STAT3的磷酸化和转录活性，从而抑制与胃癌细胞恶性存活、迁移和侵袭性相关的下游靶基因mRNA的表达。分子对接表明，6-EDS直接结合STAT3的SH2结构域。分子动力学模拟表明，6-EDS抑制磷酸化和非磷酸化STAT3与靶DNA的结合。细胞热移实验和微尺度热电泳进一步证实了6-EDS与STAT3的直接结合。定点突变表明，STAT3 SH2结构域的S611残基对6-EDS结合至关重要。在体内，6-EDS通过阻断STAT3信号传导抑制异种移植裸鼠的肿瘤生长。这些发现表明，6-EDS是一种直接的STAT3抑制剂，可能是一种有效的胃癌治疗候选药物。

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引用次数: 6

Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis 转运蛋白调控的分子机制及其在肝内胆汁淤积中的损害

Acta materia medica

Pub Date : 2022-10-06 DOI: 10.15212/amm-2022-0029

Xiping Li, Y. Zu, Guodong Li, Dong Xiang, Chengliang Zhang, Dong Liu

Intrahepatic cholestasis (IC) is a liver disease caused by disorders in bile formation and excretion, owing to structural and functional abnormalities in hepatocytes and/or bile capillaries. IC is commonly caused by hepatitis virus, alcohol consumption, drug-induced liver damage, autoimmune liver disease and heredity. In the absence of effective treatment, IC can progress to liver fibrosis, cirrhosis and ultimately liver failure. However, the mechanisms underlying IC remain poorly understood. IC is believed to be closely associated with changes in the transcription, function and localization of hepatocellular transport proteins. To better understand the molecular mechanisms of transport proteins in IC, herein, we review the roles of these transport proteins and discuss their underlying regulatory mechanisms in IC. Our aim is to provide a reference for understanding IC pathogenesis and developing effective drug therapies.

肝内胆汁淤积症(IC)是由于肝细胞和/或胆汁毛细血管结构和功能异常而引起的胆汁形成和排泄障碍引起的一种肝脏疾病。IC通常由肝炎病毒、饮酒、药物性肝损伤、自身免疫性肝病和遗传引起。在缺乏有效治疗的情况下，IC可发展为肝纤维化、肝硬化并最终导致肝功能衰竭。然而，IC背后的机制仍然知之甚少。IC被认为与肝细胞转运蛋白的转录、功能和定位的变化密切相关。为了更好地了解IC中转运蛋白的分子机制，本文综述了这些转运蛋白在IC中的作用，并讨论了它们在IC中的潜在调控机制，旨在为了解IC的发病机制和开发有效的药物治疗提供参考。

引用次数: 1

Advances in therapeutic nanodrug delivery systems for infectious lung diseases: a review 传染性肺部疾病纳米药物治疗系统的研究进展

Acta materia medica

Pub Date : 2022-08-30 DOI: 10.15212/amm-2022-0019

Gang Sheng, Na Tian, Huijuan Duan, Zhaogang Sun, Hong-qian Chu

Infectious lung diseases are inflammatory diseases of the lungs caused by infectious agents such as bacteria, viruses or fungi. Oral or intravenous administration of antibiotics is the most common method of treatment, but some drugs have poor release stability, high systemic toxicity and susceptibility to drug resistance. Nanodrug delivery systems are promising alternatives for the treatment of infectious lung diseases, because they provide the advantages of enhancing the stability and solubility of delivered drugs, increasing pulmonary accumulation, decreasing systemic toxicity and ameliorating drug resistance. This review provides a brief overview of recent advances in approaches and ideas in pulmonary drug delivery methods. We believe that nano-based therapeutic strategies offer great potential to broaden the scope of treatment of infectious lung diseases and enhance therapeutic efficacy.

传染性肺部疾病是由细菌、病毒或真菌等传染源引起的肺部炎症性疾病。口服或静脉注射抗生素是最常见的治疗方法，但有些药物释放稳定性差，全身毒性高，易产生耐药性。纳米药物递送系统是治疗感染性肺部疾病的有前途的替代品，因为它们具有增强递送药物的稳定性和溶解度、增加肺部积聚、降低全身毒性和改善耐药性的优点。这篇综述简要概述了肺部给药方法的最新进展和想法。我们认为，基于纳米的治疗策略在拓宽感染性肺部疾病的治疗范围和提高疗效方面具有巨大潜力。

引用次数: 8

Establishment of a protein thermal shift chip (PTSC) for COVID-19 and exploration of the future of protein chips in pharmacology 新型冠状病毒蛋白热移芯片(PTSC)的建立及蛋白芯片在药理学领域的未来探索

Acta materia medica

Pub Date : 2022-08-03 DOI: 10.15212/amm-2022-0016

Peng Chen, Zhao Cui, Caifeng Li, Shiwen Deng, Han Yang

Traditional protein chips are based on solid chips and cannot enable drug and target screening in a label-free manner. Herein, a protein thermal shift chip (PTSC) based on fluorescence signals is proposed, which enables low-cost, high-throughput, label-free screening. We developed a PTSC for COVID-19, containing 12 SARS-CoV-2 and host target proteins. A series of quality-control tests were performed for small-molecule drugs, macromolecular antibodies, and herbal-medicine extracts. This chip enabled high-throughput screening of COVID-19 drugs and thus may serve as a tool for screening drug targets clinically effective drugs.

传统的蛋白质芯片是基于固体芯片，不能以无标签的方式进行药物和靶标筛选。本文提出了一种基于荧光信号的蛋白质热移位芯片(PTSC)，该芯片可实现低成本、高通量、无标记的筛选。我们开发了COVID-19的PTSC，包含12个SARS-CoV-2和宿主靶蛋白。对小分子药物、大分子抗体和草药提取物进行了一系列质量控制试验。该芯片实现了COVID-19药物的高通量筛选，可作为筛选药物靶点的工具，临床有效药物。

引用次数: 0

Silybin has therapeutic efficacy against non-small cell lung cancer through targeting of Skp2 水飞蓟宾通过靶向Skp2对非小细胞肺癌具有治疗作用

Acta materia medica

Pub Date : 2022-08-03 DOI: 10.15212/amm-2022-0011

Shi-Bing Zhang, M. Hong, Xiao-Yang Sun, Da-xiong Huang, Dan-hua He, Yu-Fei Chen, Yong Yuan, Yongqiang Liu

Silybin (SB), a natural flavonoid isolated from Silybum marianum, has been used to treat hepatic fibrosis in clinical settings and as a dietary supplement, because of its hepatoprotective potential. Numerous studies have shown that SB also exerts promising anticancer effects; however, the anticancer targets of SB and the underlying mechanism were unclear. Herein, we found that SB significantly inhibited the proliferation of non-small cell lung cancer without causing cytotoxicity toward normal Beas-2B bronchial epithelial cells. Mechanistically, SB binds the F-box protein Skp2 and disrupts Skp1-Skp2 interaction, thereby decreasing Skp2 protein levels, inducing accumulation of Skp2 substrates, and leading to G1-phase cell-cycle arrest and the suppression of cell migration. In lung orthotopic xenografts, SB also significantly decreased Skp2 expression and increased p27/Kip1 protein levels. SB administration inhibited tumor growth and metastasis in lung tissue, thus prolonging survival time in mice without causing obvious toxicity. Thus, SB is a potential Skp2-targeting agent that warrants further clinical investigation.

水飞蓟宾(SB)是一种从水飞蓟中分离出来的天然类黄酮，由于其保护肝脏的潜力，已被用于临床治疗肝纤维化和作为膳食补充剂。大量研究表明SB还具有良好的抗癌作用;然而，SB的抗癌靶点及其作用机制尚不清楚。本研究发现，SB显著抑制非小细胞肺癌的增殖，而对正常的Beas-2B支气管上皮细胞不产生细胞毒性。从机制上说，SB结合F-box蛋白Skp2并破坏Skp1-Skp2相互作用，从而降低Skp2蛋白水平，诱导Skp2底物积累，导致g1期细胞周期阻滞和细胞迁移抑制。在肺原位异种移植物中，SB也显著降低了Skp2的表达，增加了p27/Kip1蛋白水平。给药SB可抑制肿瘤在肺组织中的生长和转移，从而延长小鼠的生存时间，且无明显毒性。因此，SB是一种潜在的skp2靶向药物，值得进一步的临床研究。

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引用次数: 6

MDM2-BCL-X_L PROTACs enable degradation of BCL-X_L and stabilization of p53. MDM2-BCL-XL PROTACs能够降解BCL-XL并稳定p53。

Acta materia medica

Pub Date : 2022-07-21 DOI: 10.15212/amm-2022-0022

Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang

Inhibition or degradation of anti-apoptotic protein BCL-X_L is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X_L, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X_L PROTACs using MDM2 as E3 ligase for degradation of BCL-X_L. Three MDM2-BCL-X_L PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X_L inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCL-X_L and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.

抑制或降解抗凋亡蛋白BCL-XL是一种可行的癌症治疗策略。尽管最近开发了用于降解BCL-XL的PROTACs，但E3连接酶仅限于常用的VHL和CRBN。本文报道了利用MDM2作为E3连接酶降解BCL-XL的MDM2-BCL-XL PROTACs的开发。我们设计、合成了3个MDM2-BCL-XL PROTACs，它们分别来源于同样能上调p53的MDM2抑制剂Nutlin-3和BCL-2/BCL-XL抑制剂ABT-263，它们具有不同的连接体长度。我们发现BMM4在U87、A549和MV-4-11癌细胞系中对BCL-XL和稳定肿瘤抑制因子p53具有有效的选择性降解活性。BMM4与BCL-2抑制剂ABT-199联合使用具有协同抗增殖作用。独特的双功能PROTACs为靶向蛋白降解提供了另一种策略。

引用次数: 4

Brusatol modulates diverse cancer hallmarks and signaling pathways as a potential cancer therapeutic Brusatol调节多种癌症特征和信号通路，作为潜在的癌症治疗药物

Acta materia medica

Pub Date : 2022-07-21 DOI: 10.15212/amm-2022-0014

Song-Bin Guo, Wei-Juan Huang, X. Tian

Cancer is a consequence of uncontrolled cell proliferation that is associated with cell-cycle disruption. It is a multifactorial disease that depends on the modulation of numerous oncogenic signaling pathways and targets. Although a battle against cancer has been waged for centuries, this disease remains a major cause of death worldwide. Because of the development of resistance to current anticancer drugs, substantial effort has been focused on discovering more effective agents for tumor therapy. Natural products have powerful prospects as anticancer drugs. Brusatol, a component isolated from the plant Brucea javanica, has been demonstrated to efficiently combat a wide variety of tumors. Extensive studies have indicated that brusatol exhibits anticancer effects by arresting the cell cycle; promoting apoptosis; inducing autophagy; attenuating epithelial-mesenchymal transition; inhibiting migration, invasion and angiogenesis; and increasing chemosensitivity and radiosensitivity. These effects involve various oncogenic signaling pathways, including the MAPK, NF-κB, PI3K/AKT/mTOR, JAK/STAT and Keap1/Nrf2/ARE signaling pathways. This review describes the evidence suggesting that brusatol is a promising drug candidate for cancer therapeutics.

癌症是与细胞周期中断相关的不受控制的细胞增殖的结果。它是一种多因素疾病，依赖于许多致癌信号通路和靶点的调节。尽管与癌症的斗争已经进行了几个世纪，但这种疾病仍然是全世界死亡的主要原因。由于对当前抗癌药物的耐药性的发展，大量的努力已经集中在发现更有效的肿瘤治疗药物上。天然产物作为抗癌药物具有强大的前景。Brusatol是一种从植物Brucea javanica中分离出来的成分，已被证明可以有效地对抗多种肿瘤。广泛的研究表明，brusatol通过阻止细胞周期表现出抗癌作用;促进细胞凋亡;诱导自噬;减弱上皮-间质转化;抑制迁移、侵袭和血管生成;增加化学敏感性和放射敏感性。这些作用涉及多种致癌信号通路，包括MAPK、NF-κB、PI3K/AKT/mTOR、JAK/STAT和Keap1/Nrf2/ARE信号通路。这篇综述描述了表明brusatol是一种很有前途的癌症治疗药物的证据。

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引用次数: 11

Statistical Evaluation of Absolute Change versus Responder Analysis in Clinical Trials. 临床试验中绝对变化与应答分析的统计评价。

Acta materia medica

Pub Date : 2022-07-21 DOI: 10.15212/amm-2022-0020

Peijin Wang, Sarah Peskoe, Rebecca Byrd, Patrick Smith, Rachel Breslin, Shein-Chung Chow

In clinical trials, the primary analysis is often either a test of absolute/relative change in a measured outcome or a corresponding responder analysis. Though each of these tests may be reasonable, determining which test is most suitable for a particular research study is still an open question. These tests may require different sample sizes, define different clinically meaningful differences, and most importantly, lead to different study conclusions. This paper aims to compare a typical non-inferiority test using absolute change as the study endpoint to the corresponding responder analysis in terms of sample size requirements, statistical power, and hypothesis testing results. From numerical analysis, using absolute change as an endpoint generally requires a larger sample size; therefore, when the sample size is the same, the responder analysis has higher power. The cut-off value and non-inferiority margin are critical which can meaningfully impact whether the two types of endpoints yield conflicting conclusions. Specifically, an extreme cut-off value is more likely to cause different conclusions. However, this impact decreases as population variance increases. One important reason for conflicting conclusions is that the population distribution is not normal. To eliminate conflicting results, researchers should pay attention to the population distribution and cut-off value selection.

在临床试验中，主要分析通常是测量结果的绝对/相对变化的测试或相应的应答者分析。虽然这些测试中的每一个都可能是合理的，但确定哪种测试最适合特定的研究仍然是一个悬而未决的问题。这些测试可能需要不同的样本量，定义不同的临床有意义的差异，最重要的是，得出不同的研究结论。本文旨在比较以绝对变化为研究终点的典型非劣效检验与相应的应答者分析在样本量要求、统计能力和假设检验结果等方面的差异。从数值分析来看，使用绝对变化作为终点通常需要更大的样本量;因此，在样本量相同的情况下，应答者分析具有更高的功效。截止值和非劣效性裕度是至关重要的，可以有意义地影响两种类型的终点是否产生冲突的结论。具体来说，一个极端的临界值更有可能导致不同的结论。然而，这种影响随着人口方差的增加而减小。得出相互矛盾的结论的一个重要原因是人口分布不正常。为了消除相互矛盾的结果，研究人员应注意总体分布和临界值的选择。

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引用次数: 2

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