Acta Pharmaceutica Sinica. B最新文献

英文中文

Author correction to “AI-integrated IQPD framework of quality prediction and diagnostics in small-sample multi-unit pharmaceutical manufacturing: advancing from experience-driven to data-driven manufacturing” [Acta Pharm Sin B 15 (2025) 4193–4209] 作者对“小样本多单位制药生产中质量预测和诊断的人工智能集成IQPD框架：从经验驱动向数据驱动的制造推进”的更正[医药学报B 15 (2025) 4193-4209]

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.10.017

Kaiyi Wang , Xinhai Chen , Nan Li , Huimin Feng , Xiaoyi Liu , Yifei Wang , Yanfei Wu , Yufeng Guo , Shuoshuo Xu , Lu Yao , Zhaohua Zhang , Jun Jia , Zhishu Tang , Zhisheng Wu

引用次数: 0

Emerging epigenetic modifications in renal fibrosis: From mechanisms to treatments 肾纤维化中新出现的表观遗传修饰：从机制到治疗

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.012

Xiaoguo Suo , Qinglin Ge , Lijin Peng , Qi Zhu , Mengmeng Zhang , Xinran Cheng , Fang Wang , Juan Jin , Jianan Wang , Xiaoming Meng

Chronic kidney disease (CKD) has emerged as a formidable global health challenge, with a marked increase in its incidence, prevalence, and mortality rates. Renal fibrosis is a central pathophysiological process that drives the progression of CKD to end-stage renal disease. Despite its crucial role in CKD progression, effective clinical interventions to delay or mitigate renal fibrosis remain limited. A deeper understanding of the molecular mechanisms underlying renal fibrosis, along with the identification of potential drug targets and the development of novel therapeutics, holds immense research significance and clinical value for the prevention and treatment of CKD. In recent years, epigenetic research has garnered widespread attention and plays a pivotal role in various disease processes. Against this backdrop, the mechanisms by which epigenetic modifications exert their effects on renal fibrosis are gradually being elucidated, offering novel insights into the understanding of CKD. In this review, we summarize and analyze the intricate regulatory network of epigenetic modifications in renal fibrosis. We explore the promising antifibrotic effects demonstrated by various epigenetically modified drugs in fibrotic kidney models and discuss the challenges and opportunities in current research. These findings provide crucial insights for a deeper understanding of the molecular mechanisms underlying renal fibrosis and the development of novel therapeutic approaches.

慢性肾脏疾病（CKD）已成为一个巨大的全球健康挑战，其发病率，患病率和死亡率显着增加。肾纤维化是一个中心病理生理过程，驱动CKD进展到终末期肾脏疾病。尽管它在CKD进展中起着至关重要的作用，但延迟或减轻肾纤维化的有效临床干预仍然有限。深入了解肾纤维化的分子机制，发现潜在的药物靶点，开发新的治疗方法，对CKD的防治具有重要的研究意义和临床价值。近年来，表观遗传学研究引起了广泛的关注，并在各种疾病过程中起着关键作用。在此背景下，表观遗传修饰对肾纤维化的影响机制逐渐被阐明，为理解CKD提供了新的见解。在这篇综述中，我们总结和分析了肾纤维化中表观遗传修饰的复杂调控网络。我们探讨了各种表观遗传修饰药物在纤维化肾模型中显示的有希望的抗纤维化作用，并讨论了当前研究中的挑战和机遇。这些发现为更深入地了解肾纤维化的分子机制和开发新的治疗方法提供了重要的见解。

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引用次数: 0

RDYH58 functional exosomes targeting myofibroblasts loaded with siFKBP10 for inhibition of collagen biosynthesis and secretion of IPF RDYH58功能外泌体靶向装载siFKBP10的肌成纤维细胞，抑制胶原生物合成和IPF分泌

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.08.017

Ranran Yuan , Zhen Mu , Houqian Zhang , Yu Tian , Quanlin Xin , Qingchao Tu , Yan Zhang , Yanqiu Li , Zhiwen Zhang , Yongchao Chu , Aiping Wang , Jingwei Tian , Hongbo Wang , Chong Qiu , Yanan Shi

Idiopathic pulmonary fibrosis (IPF) is a complex interstitial lung disease in which myofibroblasts are the primary effector cells. FK506-binding protein (FKBP10), a procollagen chaperone, is upregulated in IPF and primarily localizes to myofibroblasts. Exosomes have garnered significant attention as novel drug delivery vehicles, particularly when engineered. However, myofibroblasts remain underexplored in terms of engineered exosome-based therapies and associated drug targets. In this study, RDYH58, a peptide that targets myofibroblasts, was conjugated to the exosomal membrane protein Lamp2b to produce RDYH58-linked exosomes (RDYH58-exo). In vitro and in vivo experiments demonstrated that compared to unmodified exosomes (unm-exo), RDYH58-exo preferentially localized to myofibroblasts. A small interfering RNA targeting FKBP10 (siFKBP10) was loaded into exosomes using ultrasonic microfluidics method, and the antifibrotic effects of RDYH58-exo carrying siFKBP10 (RDYH58-siFKBP10) were assessed both in vitro and in vivo. The results demonstrated that RDYH58-siFKBP10 effectively silenced FKBP10 gene expression, significantly inhibiting fibroblast activation and extracellular matrix deposition, with superior antifibrotic efficacy compared to unmodified exosome vectors (unm-siFKBP10). RNA-seq analysis confirmed the pivotal regulatory role of FKBP10, providing critical evidence for the development of targeted therapeutic strategies. The RDYH58-siFKBP10 delivery system developed in this study demonstrates remarkable clinical translation potential.

特发性肺纤维化（IPF）是一种复杂的间质性肺疾病，其中肌成纤维细胞是主要的效应细胞。fk506结合蛋白（FKBP10）是一种前胶原伴侣蛋白，在IPF中上调，主要定位于肌成纤维细胞。外泌体作为一种新型的药物输送载体，特别是在经过工程设计的情况下，已经引起了人们的极大关注。然而，在工程外泌体治疗和相关药物靶点方面，肌成纤维细胞仍未得到充分的探索。在这项研究中，RDYH58，一种靶向肌成纤维细胞的肽，被结合到外泌体膜蛋白Lamp2b上产生RDYH58-linked外泌体（RDYH58-exo）。体外和体内实验表明，与未修饰的外泌体（unm-exo）相比，RDYH58-exo优先定位于肌成纤维细胞。采用超声微流体法将靶向FKBP10的小干扰RNA （siFKBP10）加载到外体中，并在体外和体内评估rdyh558 -exo携带siFKBP10 （rdyh558 -siFKBP10）的抗纤维化作用。结果表明，RDYH58-siFKBP10有效地沉默了FKBP10基因表达，显著抑制成纤维细胞活化和细胞外基质沉积，与未修饰的外显体载体（unm-siFKBP10）相比，具有更好的抗纤维化效果。RNA-seq分析证实了FKBP10的关键调控作用，为开发靶向治疗策略提供了关键证据。本研究开发的RDYH58-siFKBP10传递系统显示出显著的临床转化潜力。

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引用次数: 0

Development of a novel 18F-labeled reversible-binding radioligand for imaging monoacylglycerol lipase with positron emission tomography 一种新的18f标记的可逆结合放射配体的开发，用于用正电子发射断层成像单酰基甘油脂肪酶

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.05.041

Jian Rong , Chunyu Zhao , Ahmad F. Chaudhary , Tim Ware , Richard S. Van , Yinlong Li , Erick R. Calderon Leon , Vivi Dang , Jiahui Chen , Zhiwei Xiao , Xin Zhou , Wei Zhang , Chunyang Bi , Kuo Zhang , Jimmy S. Patel , Yihan Shao , Chongzhao Ran , Ludovic Collin , Achi Haider , Benjamin F. Cravatt , Steven H. Liang

Monoacylglycerol lipase (MAGL) constitutes a crucial serine hydrolase within the endocannabinoid system, which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders. While MAGL inhibitors have entered the clinical arena, a highly selective and MAGL-specific positron emission tomography (PET) ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients. Accordingly, this study aimed to develop a new series of reversible MAGL inhibitor candidates, based on a piperazinyl azetidine diamide scaffold. Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates. Subsequently, it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging, as well as ex vivo biodistribution and metabolite analysis experiments in rodents. Compound 3 exhibited a heterogeneous radioactivity distribution, favorable brain uptake, and excellent in vivo binding specificity. Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of [¹⁸F]3 in rat brains. In conclusion, [¹⁸F]3 ([¹⁸F]MAGL-2011) has the potential to serve as an effective MAGL PET ligand.

单酰基甘油脂肪酶（MAGL）是内源性大麻素系统中至关重要的丝氨酸水解酶，已被认为是治疗各种神经退行性疾病的潜在治疗靶点。虽然MAGL抑制剂已经进入临床领域，但一种高度选择性和MAGL特异性的正电子发射断层扫描（PET）配体有望通过量化MAGL水平和评估患者的靶标占用来显著促进临床药物开发。因此，本研究旨在基于哌嗪基氮杂啶二胺支架开发一系列新的可逆MAGL抑制剂候选物。与其他MAGL抑制剂候选物相比，化合物3在药理学评价中表现出最有希望的性能特征。随后，对其进行氟-18标记，并通过放射自显像和PET成像以及啮齿动物体内生物分布和代谢物分析实验进一步评估。化合物3具有不均匀的放射性分布、良好的脑吸收和良好的体内结合特异性。治疗性MAGL抑制剂的靶占用研究显示，大鼠脑中PET信号的剂量依赖性降低[18F]3。综上所述，[18F]3 （[18F]MAGL-2011）具有作为一种有效的MAGL PET配体的潜力。

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引用次数: 0

CELMoD–antibody conjugates unlock a CD38 feedback loop in multiple myeloma celmod抗体偶联物在多发性骨髓瘤中解锁CD38反馈环

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.11.017

Jian Jin

引用次数: 0

Butyrylated Smilax glabra starch relieves atopic dermatitis through gut–skin axis modulation via colon-targeted delivery 丁基化菝葜淀粉通过结肠靶向递送的肠道-皮肤轴调节缓解特应性皮炎

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.10.012

Nan Wang , Lingling Wu , Yaya Su , Chi Zhang , Xu Chen , Hailong Yuan

Atopic dermatitis (AD) is a prevalent cutaneous condition with chronic inflammation and immune dysregulation, posing a public health concern owing to its long-lasting and recurrent nature. Butyrate, a short-chain fatty acid produced by gut microbiota, exhibits significant anti-inflammatory effects in AD. Yet, its delivery via butyrylated starch for prolonged release in the colon has not been adequately investigated. In this study, butyrylated Smilax glabra starch (BSGS) was synthesized and its therapeutic potential against AD via modulation of the gut–skin axis was examined. BSGS exhibited a C-type crystalline structure and highly resistance to gastrointestinal digestion. In vitro anaerobic fermentation showed that BSGS effectively promoted the generation of short-chain fatty acids, especially butyrate, and positively influenced the gut microbial composition. In AD mice, BSGS administration considerably mitigated cutaneous inflammation, lowered serum proinflammatory cytokines, restored intestinal barrier integrity, and modulated gut microbiota by increasing Bacteroides and norank_f__Prevotellaceae while decreasing Alistipes and norank_o__RF39. This therapeutic effect was associated with butyrate release and NF-κB pathway suppression, as evidenced by the reduced phosphorylation of p65 and IκBα. These findings establish that BSGS, a novel colon-targeted butyrate donor, holds promising potential in AD treatment by modulating the immune system via the gut–skin axis.

特应性皮炎（AD）是一种常见的皮肤疾病，伴有慢性炎症和免疫失调，由于其长期性和复发性，引起了公众健康问题。丁酸盐是一种由肠道菌群产生的短链脂肪酸，在AD中具有显著的抗炎作用。然而，其通过丁基化淀粉在结肠中长期释放的递送尚未得到充分的研究。本研究合成了丁基化Smilax glabra starch (BSGS)，并对其通过调节肠-皮轴对AD的治疗潜力进行了研究。BSGS呈c型晶体结构，具有较强的抗胃肠道消化能力。体外厌氧发酵实验表明，BSGS能有效促进短链脂肪酸尤其是丁酸盐的生成，并对肠道微生物组成产生积极影响。在AD小鼠中，BSGS可显著减轻皮肤炎症，降低血清促炎细胞因子，恢复肠道屏障完整性，并通过增加拟杆菌和norank_f_ prevotellaceae而减少Alistipes和norank_o_ rf39来调节肠道微生物群。这种治疗效果与丁酸盐释放和NF-κB通路抑制有关，p65和i -κB α的磷酸化降低证明了这一点。这些发现表明BSGS，一种新的结肠靶向丁酸盐供体，通过肠道-皮肤轴调节免疫系统，在AD治疗中具有很大的潜力。

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引用次数: 0

Discovery of peptidomimetic inhibitors of CREB/CBP by targeting hydrophobic grooves on the surface of the CBP KIX domain 通过靶向CBP KIX结构域表面的疏水凹槽发现CREB/CBP的拟肽抑制剂

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.08.023

Bo Huang , Emily Gregory-Lott , Bingbing X. Li , Timothy H. Tran , Sihao Li , Menglin Xue , Shaohui Wang , Anabanadam Asokan , Ning Shen , Xingming Sun , Chuanhai Cao , Xiangshu Xiao , Gary Daughdrill , Jianfeng Cai

Cyclic AMP-response element binding protein (CREB), a downstream transcription factor of multiple signaling pathways, is overexpressed in many different types of cancers. Thus, targeting CREB has great potential for the development of antitumor agents. Peptidic foldamers have emerged as a powerful tool to disrupt disease-related protein–protein interactions (PPIs) with chemodiversity and high stability towards enzymatic degradation. Herein, we harnessed several hydrophobic groups of helical sulfonyl-γ-AApeptide foldamer targeting the hydrophobic grooves on the surface of the KIX domain of CREB binding protein (CBP), to disrupt CREB/CBP PPI. We showed that several stapled sulfonyl-γ-AApeptides could suppress CREB-mediated gene transcription and exhibit effective antiproliferative activity in cell-based assays and demonstrate its potency in inhibiting tumor growth in vivo. Our studies suggest that sulfonyl-γ-AApeptides as a class of helical foldamer could mimic the helical kinase-inducible activation domain of CREB (KID) to target the hydrophobic grooves on the surface of CBP KIX domain, and thereby inhibiting KIX–KID interaction, which provides a new strategy for the development of antitumor agent by targeting PPIs involving intrinsically disordered proteins (IDPs).

环状amp反应元件结合蛋白（CREB）是多种信号通路的下游转录因子，在许多不同类型的癌症中过度表达。因此，靶向CREB具有开发抗肿瘤药物的巨大潜力。肽折叠蛋白已成为破坏疾病相关蛋白-蛋白相互作用（PPIs）的有力工具，具有化学多样性和酶降解的高稳定性。本研究利用螺旋磺酰-γ-AApeptide折叠体的几个疏水基团靶向CREB结合蛋白（CBP） KIX结构域表面的疏水凹槽，破坏CREB/CBP PPI。我们在基于细胞的实验中发现，几种钉接的磺酰-γ-AApeptides可以抑制creb介导的基因转录，并表现出有效的抗增殖活性，并且在体内证明了其抑制肿瘤生长的效力。我们的研究表明，磺酰-γ-AApeptides作为一类螺旋折叠体，可以模拟螺旋激酶诱导的CREB活化结构域（KID），靶向CBP KIX结构域表面的疏水凹槽，从而抑制KIX - KID相互作用，这为通过靶向涉及内在无序蛋白（IDPs）的PPIs开发抗肿瘤药物提供了新的策略。

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引用次数: 0

Targeting renal tubular epithelial cells via a dual functionalized oligosaccharide self-assembly in the management of acute and chronic kidney diseases 通过双功能化寡糖自组装靶向肾小管上皮细胞在急性和慢性肾脏疾病的管理

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.017

Yingying Xu , Jiajia Gui , Yunxiao Zhang , Simin Nan , Yujie Che , Xi Cao , Xianjun Fang , Tao Gong , Zhirong Zhang , Yao Fu

The kidneys are susceptible to hypoxia, proteinuria, and toxins, which can trigger acute kidney injury (AKI). Maladaptive repair of AKI results in the development of chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) represents a pivotal mechanism underlying renal interstitial fibrosis (RIF). Myofibroblasts represent the primary effector cells of RIF with over 30% derived from renal tubular epithelial cells (RTECs). RTECs play a crucial role in CKD by generating part of EMT, while Snail1 is an effective inducer of EMT. Therefore, silencing Snail1 in RTECs and blocking the EMT process represents an original approach for treating RIF. Here, the positively charged l-arginine (L-Arg) and the hydrophobic fragment stearic acid (SA) were introduced on the chitosan oligosaccharide to afford a dual-targeted COA-SA micelle via size-, charge- and active targeting effects. The micelle overcomes the substantial disparity in physical and chemical properties between hydrophilic nucleic acid macromolecules and the anti-inflammatory small molecule celastrol and successfully establishes a codelivery platform. In vivo, COA-SA micelles can traverse the blood circulation, and glomerular filter, and overcome intracellular barriers to achieve efficient and precise drug delivery to RTECs. This results in the successful reversal of the EMT process in RTECs, thereby achieving a favorable anti-fibrosis effect.

肾脏易受缺氧、蛋白尿和毒素的影响，这些都会引发急性肾损伤（AKI）。AKI的不适应修复导致慢性肾脏疾病（CKD）的发展。上皮-间质转化（EMT）是肾间质纤维化（RIF）的关键机制。肌成纤维细胞是RIF的主要效应细胞，其中30%以上来自肾小管上皮细胞（RTECs）。rtec通过产生部分EMT在CKD中发挥关键作用，而Snail1是一种有效的EMT诱导剂。因此，沉默rtec中的Snail1并阻断EMT过程是治疗RIF的一种原始方法。本研究将带正电荷的l-精氨酸（L-Arg）和疏水片段硬脂酸（SA）引入壳聚糖低聚糖上，通过大小靶向、电荷靶向和活性靶向作用形成双靶向的COA-SA胶束。该胶束克服了亲水性核酸大分子与抗炎小分子雷公藤红素在理化性质上的巨大差异，成功建立了共传递平台。在体内，COA-SA胶束可以穿过血液循环和肾小球滤过器，克服细胞内屏障，实现高效、精准的给药。这导致成功逆转rtec中的EMT过程，从而获得良好的抗纤维化效果。

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引用次数: 0

Glutamine synthetase in astrocytes of the caudate and putamen is responsible for locomotor sensitization after nicotine exposure 尾状核和壳核星形胶质细胞中的谷氨酰胺合成酶是尼古丁暴露后运动致敏的原因

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.09.038

Ju Hwan Yang , Sumin Sohn , Sunghyun Kim , Jieun Kim , Su Yeon Seo , Aqsa Kazmi , Hanwoong Woo , John Q. Wang , Eun Sang Choe

Glutamine synthetase (GS) in astrocytes regulates glutamatergic neurotransmission by maintaining glutamate clearance in the brain. This study determined that GS in astrocytes of the caudate and putamen (CPu) regulates locomotor sensitization after repeated nicotine exposure. Nicotine increased phosphorylated c-Jun N-terminal kinase (pJNK) by stimulating α7 nicotinic acetylcholine receptors in cultured glioma C6 cells and primary astrocytes in a Ca²⁺-dependent manner. Active JNK phosphorylated metabotropic glutamate receptor 1a (mGluR1a) at the carboxyl terminus of glutathione S-transferase-tagged mGluR1a in vitro. Interference with the pJNK–mGluR1a interaction using the inhibitory peptide, Tat-mGluR1a-i (10 μmol/L), decreased the nicotine-induced increase in GS activity in glioma C6 cells and primary astrocytes. Similar results were obtained by bilateral intra-CPu infusion of the inhibitory peptide (2 nmol/side). Inhibition of GS activity by bilateral intra-CPu infusion of methionine sulfoximine (50 nmol/side) decreased the repeated nicotine-induced increase in locomotor activity. These findings suggest that astrocytes in the CPu upregulate locomotor sensitization by activating GS via the pJNK–mGluR1a interaction, which is linked to α7 nicotinic acetylcholine receptors in response to nicotine.

星形胶质细胞中的谷氨酰胺合成酶（GS）通过维持大脑中的谷氨酸清除来调节谷氨酸能神经传递。本研究确定尾状核和壳核（CPu）星形胶质细胞中的GS调节尼古丁反复暴露后的运动致敏。尼古丁通过刺激培养的胶质瘤C6细胞和原代星形胶质细胞中的α7烟碱乙酰胆碱受体，以Ca2+依赖的方式增加磷酸化的c-Jun n -末端激酶（pJNK）。活性JNK在体外磷酸化谷胱甘肽s转移酶标记的mGluR1a的羧基末端的代谢性谷氨酸受体1a （mGluR1a）。抑制肽Tat-mGluR1a-i （10 μmol/L）干扰pJNK-mGluR1a相互作用，可降低尼古丁诱导的胶质瘤C6细胞和初代星形胶质细胞中GS活性的增加。双侧cpu内注射抑制肽（2 nmol/侧）获得了类似的结果。双侧cpu内输注蛋氨酸亚砜胺（50 nmol/侧）对GS活性的抑制降低了尼古丁引起的运动活性的反复增加。这些发现表明，CPu中的星形胶质细胞通过pJNK-mGluR1a相互作用激活GS，从而上调运动敏化，而pJNK-mGluR1a相互作用与α7尼古丁乙酰胆碱受体有关。

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引用次数: 0

Preclinical characterization and anti-RSV efficacy of an oral C-nucleoside derivative 口服c -核苷衍生物的临床前特征和抗rsv疗效

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-12-01 DOI: 10.1016/j.apsb.2025.08.027

Yuanguang Chen , Yongqing Liu , Guanguan Li , Chao Peng , Dizhen Liang , Sidi Yang , Peisen Zheng , Shuo Li , Deyin Guo , Qifan Zhou , Xumu Zhang

引用次数: 0

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