Peptides最新文献

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Peptide therapeutics: current status and future opportunity with focus on nose-to-brain delivery☆

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-11 DOI: 10.1016/j.peptides.2025.171404

Eva-Maria Jülke, Annette G. Beck-Sickinger

Peptide drugs are a highly diverse group of therapeutic agents. Over the last decade, more than 40 peptides have been approved for clinical use. They target different structures, ranging from G protein-coupled receptors (GPCRs) to pathogens and are used to treat a variety of indications, including metabolic disorders, genetic diseases, acute illnesses and more. Structurally, peptide therapeutics are a heterogeneous class. This diversity allows them to bridge the gap between small molecules and biologics. However, limited metabolic stability and bioavailability must be addressed. Strategies to improve the half-life include backbone and sequence modification, cyclization and the addition of stabilizing moieties. Great strides have been made in recent years towards achieving sufficient drug uptake for oral application have been achieved within recent years. However, these methods require specialized peptide design or involve permeabilization of the gastrointestinal tract. Consequently, other routes of administration are being explored. One promising approach is the nasal application of peptides. This method can be used for systemic uptake, but also allows for direct nose-to-brain delivery of compounds. While successful nose-to-brain delivery is already used in the clinic, the underlining mechanisms are poorly understood. Strategies for rational optimization are needed to make this method more applicable to a wider range of compounds. Overall, approved peptide therapeutics cover a wide range of applications and have demonstrated a growing and novel potential in recent drug discovery.

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引用次数: 0

JHP-7 (QLLEELKR), a heptapeptide derived from Jinhua ham, may ameliorate intrauterine adhesion (IUA) via inhibiting inflammatory response and apoptosis

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-09 DOI: 10.1016/j.peptides.2025.171406

Yixiang Wang , Yang Wu , Luming Wu , Xue Fan , Tong Chen , Jijun Tao , Shiyan Tu , Yiqing Wang , Xuehong Zhang

Objective

This study aimed to investigate the effect of JHP-7(QLLEELKR) derived from Jinhua ham on IUA, in order to provide new methods and new ideas for the clinical treatment of IUA.

Methods

The JHP-7 was synthesized by solid-phase peptide synthesis (SPPS). An in vitro model (human endometrial epithelial cells (HEECs) induced by 10 ng/mL TGF-β1) and an in vivo model (C57BL/6 mice induced by mechanical curettage and LPS stimulation) were used in the study. In vitro, HEEC were co-cultured with TGF-β1with or without JHP-7 (1 μM and 10 μM) for 48 h, followed by RT-qPCR and Western blotting analysis. Meanwhile, the fluorescent ROS probe was employed to assess oxidative stress levels. In vivo, IUA mice were preventively treated with JHP-7 (150 μg/kg/d and 300 μg/kg/d) for 14 days, after which uterine tissues were collected for histopathological evaluation using H&E and Masson staining, as well as molecular analysis via RT-qPCR and Western blotting to measure mRNA and protein expression levels.

Results

In vitro, JHP-7 significantly inhibited the expression of proinflammatory and fibrosis markers, reduced the ROS, and protected endometrial function. Further studies showed that JHP-7 inhibited the apoptosis of TGF-β1-induced HEECs, and reduced the expression of TLR4, p-NF-κB, and p-MAPK. In vivo, JHP-7 significantly improved the uterine morphology and reduced collagen deposition in IUA mice. Reduced expression of TLR4, MyD88, p-NF-κB, p-MAPK and up-regulating expression of Bcl2 were also detected after JHP-7 treatment.

Conclusion

JHP-7 could ameliorate IUA via inhibiting inflammation and apoptosis, which may be related to the TLR4/MyD88/MAPK/NF-κB signaling pathway.

方法采用固相肽合成法（SPPS）合成JHP-7。研究采用了体外模型（10 ng/mL TGF-β1 诱导的人子宫内膜上皮细胞（HEECs））和体内模型（机械刮宫和 LPS 刺激诱导的 C57BL/6 小鼠）。在体外，将 HEEC 与含有或不含 JHP-7（1 μM 和 10 μM）的 TGF-β1 共同培养 48 小时，然后进行 RT-qPCR 和 Western 印迹分析。同时，采用荧光 ROS 探针评估氧化应激水平。在体内，用JHP-7（150 μg/kg/d和300 μg/kg/d）预防性治疗IUA小鼠14天，然后收集子宫组织，用H&E和Masson染色进行组织病理学评估，并通过RT-qPCR和Western印迹进行分子分析，以测量mRNA和蛋白质的表达水平。结果在体外，JHP-7 能显著抑制促炎和纤维化标志物的表达，减少 ROS，保护子宫内膜功能。进一步的研究表明，JHP-7 可抑制 TGF-β1 诱导的 HEECs 的凋亡，并降低 TLR4、p-NF-κB 和 p-MAPK 的表达。在体内，JHP-7 能明显改善 IUA 小鼠的子宫形态并减少胶原沉积。结论 JHP-7可通过抑制炎症和细胞凋亡改善IUA，这可能与TLR4/MyD88/MAPK/NF-κB信号通路有关。

{"title":"JHP-7 (QLLEELKR), a heptapeptide derived from Jinhua ham, may ameliorate intrauterine adhesion (IUA) via inhibiting inflammatory response and apoptosis","authors":"Yixiang Wang , Yang Wu , Luming Wu , Xue Fan , Tong Chen , Jijun Tao , Shiyan Tu , Yiqing Wang , Xuehong Zhang","doi":"10.1016/j.peptides.2025.171406","DOIUrl":"10.1016/j.peptides.2025.171406","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the effect of <strong>JHP-7</strong>(QLLEELKR) derived from Jinhua ham on IUA, in order to provide new methods and new ideas for the clinical treatment of IUA.</div></div><div><h3>Methods</h3><div>The <strong>JHP-7</strong> was synthesized by solid-phase peptide synthesis (SPPS). An in vitro model (human endometrial epithelial cells (HEECs) induced by 10 ng/mL TGF-β1) and an in vivo model (C57BL/6 mice induced by mechanical curettage and LPS stimulation) were used in the study. In vitro, HEEC were co-cultured with TGF-β1with or without <strong>JHP-7</strong> (1 μM and 10 μM) for 48 h, followed by RT-qPCR and Western blotting analysis. Meanwhile, the fluorescent ROS probe was employed to assess oxidative stress levels. In vivo, IUA mice were preventively treated with <strong>JHP-7</strong> (150 μg/kg/d and 300 μg/kg/d) for 14 days, after which uterine tissues were collected for histopathological evaluation using H&E and Masson staining, as well as molecular analysis <em>via</em> RT-qPCR and Western blotting to measure mRNA and protein expression levels.</div></div><div><h3>Results</h3><div>In vitro, <strong>JHP-7</strong> significantly inhibited the expression of proinflammatory and fibrosis markers, reduced the ROS, and protected endometrial function. Further studies showed that <strong>JHP-7</strong> inhibited the apoptosis of TGF-β1-induced HEECs, and reduced the expression of TLR4, p-NF-κB, and p-MAPK. In vivo, <strong>JHP-7</strong> significantly improved the uterine morphology and reduced collagen deposition in IUA mice. Reduced expression of TLR4, MyD88, p-NF-κB, p-MAPK and up-regulating expression of Bcl2 were also detected after <strong>JHP-7</strong> treatment.</div></div><div><h3>Conclusion</h3><div><strong>JHP-7</strong> could ameliorate IUA <em>via</em> inhibiting inflammation and apoptosis, which may be related to the TLR4/MyD88/MAPK/NF-κB signaling pathway.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"188 ","pages":"Article 171406"},"PeriodicalIF":2.8,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spexin expression in the human bile duct and perihilar cholangiocarcinoma

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-05 DOI: 10.1016/j.peptides.2025.171405

Sara Huber , Theresia Fitzner , René G. Feichtinger , Theo Kraus , Stefanie Gaisbauer , Sarah Hochmann , Karl Sotlar , Barbara Kofler , Martin Varga

The bile duct transports bile fluid from the liver to the gallbladder and small intestine. It contains bioactive peptides, including galanin (GAL) and its receptors (GAL_1–3-R). Spexin (SPX), a member of the GAL peptide family, activates GAL₂-R and GAL₃-R. Its expression in perihilar bile ducts or in perihilar cholangiocarcinoma (pCCA), the most common biliary cancer, is largely unknown. This study investigated SPX expression in healthy, cholestatic, and malignant bile duct tissues. Immunohistochemistry was used to evaluate SPX in healthy (n = 4), peritumoral (PIT) (n = 23) and pCCA (n = 34) tissues. Score values of SPX expression were calculated and statistically analyzed. In healthy and PIT tissues with or without cholestasis, SPX expression was predominantly observed in cholangiocytes and nerve fibers. In pCCA, tumor cells also expressed SPX. SPX levels were similar across healthy, peritumoral, and cholangiocytes/tumor cells. In a small pCCA patient cohort (n = 19), SPX expression did not correlate with tumor grade or patient survival (p = 0.0838). The substantial expression of SPX in cholangiocytes and nerve fibers in the bile duct indicates that SPX contributes via galaninergic signaling to gall bladder function. The presence of SPX in submucosal nerve fibers suggests a neuromodulatory role, possibly involving bile duct motility. SPX expression did not correlate with survival in pCCA, whereas previous findings on GAL suggest a prognostic value. This highlights the need for joint studies of SPX and GAL in larger cohorts.

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引用次数: 0

Oxyntomodulin - past, present and future

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-03 DOI: 10.1016/j.peptides.2025.171393

Jens Juul Holst , Mette M. Rosenkilde

Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).

引用次数: 0

Irisin prevents visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-26 DOI: 10.1016/j.peptides.2025.171394

Tsukasa Nozu , Saori Miyagishi , Masatomo Ishioh , Kaoru Takakusaki , Toshikatsu Okumura

Visceral hypersensitivity and impaired gut barrier function, accompanied by minor inflammation, are crucial components of the pathophysiology of irritable bowel syndrome (IBS). Research has demonstrated that corticotropin-releasing factor (CRF) and toll-like receptor 4 (TLR4) signaling mutually activate to produce proinflammatory cytokines, which modulate these gastrointestinal changes. Irisin, a myokine, has been shown to inhibit TLR4-proinflammatory cytokine signaling, thereby improving inflammation driven by obesity and metabolic syndrome. Based on this, we hypothesized that irisin could improve visceral hypersensitivity and impaired gut barrier function induced by lipopolysaccharide (LPS) or CRF (IBS rat models), and tested this hypothesis. The visceral pain threshold, triggered by colonic balloon distention, was assessed by electrophysiologically monitoring abdominal muscle contractions in male Sprague-Dawley rats. Colonic permeability was evaluated by measuring the amount of Evans blue dye absorbed within the colonic tissue. Intraperitoneal irisin prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Irisin also prevented CRF-induced gastrointestinal alterations. The beneficial effects of irisin in the LPS model were reversed by compound C, an AMP-activated protein kinase (AMPK) inhibitor; N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor; sulpiride or domperidone, a dopamine D₂ receptor antagonist; atropine and intracisternal injection of SB-334867, a selective orexin 1 receptor antagonist. Overall, these findings suggest that irisin improves visceral sensation and colonic barrier function through AMPK, NO and dopamine D₂, cholinergic and brain orexin signaling in IBS model. Thus, irisin may be a promising therapeutic agent for treating IBS.

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引用次数: 0

Evaluation of plasma arginine vasopressin during hypertonic saline loading: A comparison of radioimmunoassay and liquid chromatography–tandem mass spectrometry

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-18 DOI: 10.1016/j.peptides.2025.171392

Narantsatsral Daramjav , Junko Takagi , Fumio Nomura , Kazuo Otake , Akiyoshi Takami

Plasma arginine vasopressin (AVP) measurement is critical for diagnosing central diabetes insipidus (CDI). Conventional radioimmunoassay (RIA) is widely used for AVP quantification, but its limited sensitivity, specificity, and dynamic range have prompted exploration of alternative methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising technique for AVP measurement, offering potential advantages over RIA. This study aimed to evaluate LC-MS/MS performance for AVP quantification during hypertonic saline loading and compare its diagnostic accuracy with that of RIA in differentiating CDI patients from controls. A total of 335 plasma samples were collected from 77 individuals—23 diagnosed with CDI and 54 controls—during hypertonic saline loading. AVP concentrations were measured using both LC-MS/MS and RIA. Statistical analyses included Wilcoxon tests to compare AVP levels, correlation analysis between LC-MS/MS and RIA, and receiver operating characteristic (ROC) curve analysis to assess diagnostic performance. LC-MS/MS demonstrated a lower detection limit (0.3 pg/mL) and a broader quantification range than RIA. Regression analysis showed a strong correlation between LC-MS/MS and RIA in the control group, but no correlation in the CDI group. ROC analysis indicated that LC-MS/MS provided diagnostic accuracy comparable to RIA for distinguishing CDI patients from controls. Bland-Altman analysis showed the agreement between two methods at the low range of AVP. LC-MS/MS offers equivalent specificity and sensitivity to RIA for AVP measurement, while providing added benefits in time efficiency, cost-effectiveness, and differential diagnosis of CDI. These findings suggest that LC-MS/MS is a viable alternative to RIA for clinical AVP quantification.

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引用次数: 0

Adropin: A cardio-metabolic hormone in the periphery, a neurohormone in the brain?

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-15 DOI: 10.1016/j.peptides.2025.171391

Andrew A. Butler , Peter J. Havel

Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (ENHO) gene. First described as a feeding-responsive, liver-secreted peptide (“hepatokine”) involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.

{"title":"Adropin: A cardio-metabolic hormone in the periphery, a neurohormone in the brain?","authors":"Andrew A. Butler , Peter J. Havel","doi":"10.1016/j.peptides.2025.171391","DOIUrl":"10.1016/j.peptides.2025.171391","url":null,"abstract":"<div><div>Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (<em>ENHO</em>) gene<em>.</em> First described as a feeding-responsive, liver-secreted peptide (“hepatokine”) involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171391"},"PeriodicalIF":2.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-11 DOI: 10.1016/j.peptides.2025.171380

Clifford J. Bailey , Peter R. Flatt , J. Michael Conlon

Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and ‘real-world’ studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).

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引用次数: 0

A novel regulator of NLRP3 inflammasome: Peptides

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-08 DOI: 10.1016/j.peptides.2025.171381

Zhuo Zuo, Yaxing Wang, Yanwei Fang, Mengya Zhao, Zhe Wang, Zhouqi Yang, Bin Jia, Yulong Sun

The NLRP3 inflammasome plays a crucial role as a critical regulator of the immune response and has been implicated in the pathogenesis of numerous diseases. Peptides, known for their remarkable potency, selectivity, and low toxicity, have been extensively employed in disease treatment. Recent research has unveiled the potential of peptides in modulating the activity of the NLRP3 inflammasome. This review begins by examining the structure of the NLRP3 inflammasome, encompassing NLRP3, ASC, and Caspase-1, along with the three activation pathways: canonical, non-canonical, and alternative. Subsequently, we provide a comprehensive summary of peptide modulators targeting the NLRP3 inflammasome and elucidate their underlying mechanisms. The efficacy of these modulators has been validated through in vitro and in vivo experiments on NLRP3 inflammasome regulation. Furthermore, we conduct sequence alignment of the identified peptides and investigate their binding sites on the NLRP3 protein. This work is a foundational exploration for advancing peptides as potential therapeutic agents for NLRP3-related diseases.

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引用次数: 0

Corrigendum to “Oxytocin attenuates cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis” [Peptides 182 (2024) 171323]

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-08 DOI: 10.1016/j.peptides.2025.171365

Yuqiao Yang , Jin Liu , Lingyan Wang , Wen Wu, Quan Wang, Yu Zhao, Xi Qian, Zhuoran Wang, Na Fu, Yanqiong Wang, Jinqiao Qian

引用次数: 0

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