BIOMATERIALS
·
2018
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IF 8.806
Qian Wang,Hao Yan,Yushen Jin,Zihua Wang,Wenhui Huang,Jia Qiu,Feiyu Kang,Kun Wang,Xinming Zhao,Jie Tian
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies with poor patient outcomes often resulting from delayed diagnosis. Therefore, early diagnosis can lead to a better prognosis and improved outcomes. In this study, we have developed a novel conjugate complex of plectin/integrin-targeted bispecific molecular probe , termed Gd-Cy7-PTP/RGD, to be used for magnetic resonance/near-infrared imaging (MRI/NIRF) of pancreatic cancer in vivo . This bispecific molecular probe comprises four parts: Gd(III) for MRI, cyanine 7 (Cy7) for NIRF, the peptide PTP for binding to plectin-1 specifically overexpressed on the surface of PDAC cells, and the peptide RGD for targeting integrin widely expressed on pancreatic duct epithelial cells and angiogenesis . Remarkably, the combination of PTP and RGD greatly increased the targeting efficiency in vitro and in vivo compared to that of either single peptide. Moreover, such bispecific molecular probes target pancreatic neoplasms and angiogenesis simultaneously, producing a “multi-level” targeting effect confirmed by immunofluorescence testing in vitro and in vivo . Under the guidance of MRI/NIRF dual-modality imaging, NIRF-guided delineation of surgical margins during operations was successfully achieved in orthotopic pancreatic cancer. This study promotes further exploration of bispecific molecular probes for clinical application.
研究领域:
肿瘤学
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医学影像学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2016
·Vol. 6
·期 1
·1-10
·
IF 5.228
Zhang Chao,Zhang Lin,Zhang Youcai,Sun Na,Jiang Shaoyi,Fujihara Timothy J.,Sun Yan
An antithrombotic nanoconjugate was designed in which a designed biomimetic peptide LWWNSYY was immobilized to the surface of poly(glycidyl methacrylate) nanoparticles (PGMA NPs). Our previous work has demonstrated LWWNSYY to be an effective inhibitor of integrin α2β1-collagen interaction and subsequent thrombus formation, however its practical application suffered from the formation of clusters in physiological environment caused by its high hydrophobicity. In our present study, the obtained LWWNSYY-PGMA nanoparticles (L-PGMA NPs) conjugate, with an improved dispersibility of LWWNSYY by PGMA NPs, have shown binding to collagen receptors with a K d of 3.45 ± 1.06 μM. L-PGMA NPs have also proven capable of inhibiting platelet adhesion in vitro with a reduced IC 50 of 1.83 ± 0.29 μg/mL. High inhibition efficiency of L-PGMA NPs in thrombus formation was further confirmed in vivo with a 50% reduction of thrombus weight. Therefore, L-PGMA NPs were developed as a high-efficiency antithrombotic nanomedicine targeted for collagen exposed on diseased blood vessel wall.
研究领域:
药学
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生物医学工程
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分子生物学
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PubMed
高影响因子
Nature Communications
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2026
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IF 18.1
Wu Fan,An Yanxin,Zhao Yuqing,Yu Jiazhi,Wu Gaoyi,Tay Franklin R.,Jiao Yang,Wang Jing
Reconstruction of large segmental bone defects remains challenging because current grafting strategies often fail to coordinate angiogenesis, neurogenesis, and osteogenesis. Here we developed a functional scaffold (peptide/Talin1 plasmid/PLA–HA/GelMA, PTPG) capable of simultaneously delivering peptides and Talin1 plasmids. We hypothesized that this scaffold enables neurovascularized bone regeneration through bidirectional activation of integrin β1 (ITGB1). The REDV–IKVAV (Arg-Glu-Asp-Val-Gly-Gly-Gly-Ile-Lys-Val-Ala-Val) peptide triggers “outside-in” ITGB1 signaling in endothelial and Schwann cells, while Talin1 plasmid-mediated “inside-out” activation. This PTPG scaffold synergistically enhances cell proliferation, migration and secretion, which are eliminated by ITGB1 silencing. In vivo, PTPG scaffold promotes aligned neurovascular networks guiding bone deposition. Single-cell RNA sequencing demonstrates enrichment of endothelial H-type signatures and repair-associated Schwann cell phenotypes, with activation of ITGB1–focal adhesion kinase–paxillin signaling. Collectively, this scaffold integrates structural support with peptide and genetic cues to promote coordinated angiogenesis, neurogenesis, and osteogenesis, offering a promising strategy for functional bone regeneration.
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PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
Li Lei,Peng Ruilong,Wang Cong,Chen Xin,Gheyret Dilmurat,Guan Siyu,Chen Bo,Liu Yafan,Liu Xilei,Cao Yiyao,Han Cha,Xiong Jianhua,Li Fanjian,Lu Taoyuan,Jia Haoran,Li Kaiji,Wang Jinchao,Zhang Xu,Xu Jianye,Wang Yajuan,Xu Xin,Li Tuo,Zhang Jianning,Zhang Shu
Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood–brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.
研究领域:
神经科学
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免疫学
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创伤医学
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药理学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
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2019
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IF 8.456
Renuka Khatik,Zhengyun Wang,Debo Zhi,Sonia Kiran,Pankaj Dwivedi,Gaolin Liang,Bensheng Qiu,Qing Yang
Multifunctional nanomaterials with targeted imaging and chemotherapy have high demand with great challenge. Herein, we rationally aimed to design multifunctional drug delivery systems by RGD-modified chitosan (CH)-coated nanoneedles (NDs) of gadolinium arsenate (RGD-CH-Gd-AsNDs). These NDs have multifunctionality for imaging and targeted therapy. NDs on intravenous administration demonstrated significant accumulation of As ions/species in tumor tissues, which was monitored by the change in T1-weighted magnetic resonance (MR) imaging. Moreover, NDs were well opsonized in cells with high specificity, subsequently inducing apoptosis to the HepG2 cells. Consequent to this, the in vivo results demonstrated biosafety, enhanced tumor targeting, and tumor regression in a subcutaneously transplanted xenograft model in nude mice. These RGD-CH-Gd-AsNDs have great potential, and we anticipate that they could serve as a novel platform for real-time T1-weighted MR diagnosis and chemotherapy.
研究领域:
医学影像学
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药物递送系统
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肿瘤学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 4
·3859
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IF 5.6
Jingyi Zhu,Xiangning Li,Wenling Gao,Jian Jing
Malignant melanoma, an increasingly common form of skin cancer, is a major threat to public health, especially when the disease progresses past skin lesions to the stage of advanced metastasis. Targeted drug development is an effective strategy for the treatment of malignant melanoma. In this work, a new antimelanoma tumor peptide, the lebestatin–annexin V (designated LbtA5) fusion protein, was developed and synthesized by recombinant DNA techniques. As a control, annexin V (designated ANV) was also synthesized by the same method. The fusion protein combines annexin V, which specifically recognizes and binds phosphatidylserine, with the disintegrin lebestatin (lbt), a polypeptide that specifically recognizes and binds integrin α1β1. LbtA5 was successfully prepared with good stability and high purity while retaining the dual biological activity of ANV and lbt. MTT assays demonstrated that both ANV and LbtA5 could reduce the viability of melanoma B16F10 cells, but the activity of the fusion protein LbtA5 was superior to that of ANV. The tumor volume growth was slowed in a mouse xenograft model treated with ANV and LbtA5, and the inhibitory effect of high concentrations of LbtA5 was significantly better than that of the same dose of ANV and was comparable to that of DTIC, a drug used clinically for melanoma treatment. The hematoxylin and eosin (H&E) staining test showed that ANV and LbtA5 had antitumor effects, but LbtA5 showed a stronger ability to induce melanoma necrosis in mice. Immunohistochemical experiments further showed that ANV and LbtA5 may inhibit tumor growth by inhibiting angiogenesis in tumor tissue. Fluorescence labeling experiments showed that the fusion of ANV with lbt enhanced the targeting of LbtA5 to mouse melanoma tumor tissue, and the amount of target protein in tumor tissue was significantly increased. In conclusion, effective coupling of the integrin α1β1-specific recognition molecule lbt confers stronger biological antimelanoma effects of ANV, which may be achieved by the dual effects of effective inhibition of B16F10 melanoma cell viability and inhibition of tumor tissue angiogenesis. The present study describes a new potential strategy for the application of the promising recombinant fusion protein LbtA5 in the treatment of various cancers, including malignant melanoma.Keywords:malignant melanoma;annexin V;lebestatin;antitumor
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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PubMed
高影响因子
LABORATORY INVESTIGATION
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2023
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IF 5
Zhiguang Chen,Haibin Zhao,Lingshuai Meng,Shengwei Yu,Zhenning Liu,Jinqi Xue
Fracture healing is a complex physiological process in which angiogenesis plays an essential role. Microfibril-associated glycoprotein-2 (MAGP2) has been reported to possess a proangiogenic activity via integrin αvβ3, yet its role in bone repair is unexplored. In this study, a critical-sized femoral defect (2 mm) was created in mice, followed by the delivery of an adenovirus-based MAGP2 overexpression vector or its negative control at the fracture site. At days 7, 14, 21, and 28 postfracture, bone fracture healing was evaluated by radiography, micro–computed tomography, and histopathologic analysis. Adenovirus-based MAGP2 overexpression vector–treated mice exhibited increased bone mineral density and bone volume fraction. MAGP2 overexpression contributed to an advanced stage of endochondral ossification and induced cartilage callus into the bony callus. Further analysis indicated that MAGP2 was associated with enhanced angiogenesis, as evidenced by marked MAGP2 and integrin αvβ3 costaining and increased levels of endothelial cell markers such as endomucin and CD31, as well as elevated phosphorylation of protein tyrosine kinase 2 (PTK2) and AKT serine/threonine kinase 1 (AKT) in the callus. In vitro , recombinant human MAGP2 treatment enhanced the viability, migration, and tube formation ability of human microvascular endothelial cells, which was partially reversed by integrin αvβ3 inhibition or MK-2206, a specific AKT inhibitor. Inhibition of integrin αvβ3 abolished MAGP2-induced PTK2 and AKT activation. Taken together, our data provide the first evidence that MAGP2 promotes angiogenesis and bone formation by activating the integrin αvβ3/PTK2/AKT signaling pathway.
研究领域:
骨科
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生物学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ATHEROSCLEROSIS
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2025
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IF 5.7
Zhenyu Zhu,Hao Liu,Liyun Feng,Lihe Lu,Jiahui Zhu,Qingchun Liang,Zirong Lan,Yuanzhi Ye,Siyi Wang,An Chen,Jianyun Yan
Introduction Extracellular matrix (ECM) proteases have been closely linked to the pathogenesis of vascular calcification. A disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS5) is an ECM-degrading enzyme involved in ECM remodeling. Versican, a critical ECM component in the arteries, can be proteolytically cleaved by ADAMTS5 and activates integrin β1. However, whether ADAMTS5 is involved in the regulation of the pathogenesis of vascular calcification remains unclear. This study investigates the regulatory role of ADAMTS5 in vascular calcification and its mechanistic link to versican-integrin β1/FAK signaling. Methods and results Western blot, immunofluorescence, and immunohistochemistry analysis revealed that ADAMTS5 expression was significantly downregulated in rat and human vascular smooth muscle cells (VSMCs), as well as in rat and human arteries during vascular calcification. In addition, both pharmacological inhibition of ADAMTS5 and knockdown of ADAMTS5 by siRNA significantly aggravated mineral deposition in rat and human VSMCs under osteogenic conditions. Moreover, adenovirus-mediated ADAMTS5 overexpression markedly attenuated calcification of VSMCs and aortic calcification in rats with chronic kidney disease. Furthermore, inhibition of ADAMTS5 promoted aortic calcification in VitD 3 -overloaded mice. Mechanistically, overexpression of ADAMTS5 significantly reduced versican protein levels, and inhibited integrin β1 and FAK phosphorylation in rat VSMCs, but increased versikine protein levels. Moreover, either knockdown of versican or pharmacological inhibition of FAK phosphorylation repressed VSMC calcification mediated by loss of ADAMTS5. Conclusions We have demonstrated for the first time that ADAMTS5 deficiency promotes versican accumulation and activates integrin β1/FAK signaling. These findings suggest ADAMTS5 as a potential therapeutic target for vascular calcification.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
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IF 8.3
Qiuhui Hu,Yongzhao Su,Siying Ma,Peiying Wei,Chengbin He,Di Yang,Yue Qian,Youqing Shen,Xiaoxuan Zhou,Zhuxian Zhou,Hongjie Hu
Liver fibrosis is the critical stage in the development of chronic liver disease (CLD), from simple injury to irreversible cirrhosis. Timely detection and intervention of liver fibrosis are crucial for preventing CLD from progressing into a fatal condition. Herein, we developed iron oxide (Fe3O4) nanoparticles (IONPs) and ferulic acid (FA) coencapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), followed by surface modification with cRGD peptides (cRGD-PLGA/IOFA) for integrin-targeted clinical magnetic resonance imaging (MRI)-traceable treatment of liver fibrosis. The cRGD peptide linked on the surface of the PLGA/IOFA NPs could specifically bind to the overexpressed integrin αvβ3 on activated hepatic stellate cells (HSCs) in the fibrotic liver, enabling the high-sensitive clinical MR imaging (3 T) and precise staging of liver fibrosis. The FA encapsulated in cRGD-PLGA/IOFA showed excellent efficacy in reducing oxidative stress and inhibiting the activation of HSCs through the transforming growth factor-β (TGF-β)/Smad pathway. Notably, the IONPs encapsulated in cRGD-PLGA/IOFA NPs could alleviate liver fibrosis by regulating hepatic macrophages through the NF-κB pathway, lowering the proportion of Ly6Chigh/CD86+, and degrading collagen fibers. The FA and IONPs in the cRGD-PLGA/IOFA produced a synergistic enhancement effect on collagen degradation, which was more effective than the IONPs treatment alone. This study demonstrates that cRGD-PLGA/IOFA NPs could effectively relieve liver fibrosis by acting on macrophages and HSCs and provide a new strategy for the clinical MRI-traceable treatment of liver fibrosis.
研究领域:
纳米技术
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生物医学工程
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药理学
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医学影像
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肝病学
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PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2021
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IF 5.268
Shuang Fu,Yinan Zhao,Jiao Sun,Ting Yang,Defu Zhi,Enxia Zhang,Fangli Zhong,Yuhong Zhen,Shufen Zhang,Shubiao Zhang
Conventional chemotherapy for tumor treatment remains flawed because it fails to limit cytotoxicity to a small set of selectable tissues. Active targeting techniques for the delivery of drugs to specific sites are increasingly used to enhance drug accumulation at tumor sites with the aim of reducing side effects in vivo . Liposomes, modified with different targeting ligands, are considered to be one of the most promising targeted drug carriers. Herein, novel linear and cyclic arginine-glycine-aspartate (RGD) peptide-based lipids were synthesized to develop modified liposomal drug delivery systems with active targeting and pH-sensitivity. The RGD-modified liposomes showed excellent active targeting ability for integrin α v β 3 receptors, resulting in improved cellular uptake. The modified liposomes also enhanced intracellular doxorubicin (DOX) release because of their degradation in an acidic environment. Consequently, the RGD-modified, DOX-loaded liposomes exhibited significant antitumor efficacy and low toxicity in vitro and in vivo . In particular, 5% cRGD-lipid modified DOX-loaded liposome showed the greatest inhibition of tumor growth in mice among the tested formulations, and much less toxicity than free DOX. In conclusion, the DOX-loaded pH-sensitive liposome modified with 5% cRGD-lipid developed in the current study provides a potential approach for improved tumor therapy.
研究领域:
药学
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癌症研究
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药物递送系统
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR & CELLULAR PROTEOMICS
·
2018
·Vol. 17
·期 10
·2005-2017
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IF 5.236
Weixuan Wang,Yadong Hu,Changmei Yang,Songbiao Zhu,Xiaofei Wang,Zhenyu Zhang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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衰老研究
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高影响因子
TOXICOLOGY LETTERS
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2023
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IF 3.5
Wei Chen,Haotian Yu,Chengbiao Sun,Mingxin Dong,Na Zhao,Yan Wang,Kaikai Yu,Jianxu Zhang,Na Xu,Wensen Liu
γ-bungarotoxin (γ-BGT) is an RGD motif-containing protein, derived from the venom of Bungarus multicinctus , leading to acute death in mice. These RGD motif-containing proteins from snake venom belonging to the disintegrin family can interfere with vascular endothelial homeostasis by directly binding cell surface integrins . Targeting integrins that generate vascular endothelial dysfunction may contribute to γ-BGT poisoning, however, the underlying mechanisms have not been investigated in detail. In this study, the results showed that γ-BGT played a role in -promoting the permeability of the vascular endothelial barrier. Depending on its selective binding to integrin α5 in vascular endothelium (VE), γ-BGT initiated downstream events, including focal adhesion kinase dephosphorylation and cytoskeleton remodeling, resulting in the intercellular junction interruption. Those alternations facilitated paracellular permeability of VE and barrier dysfunction. Proteomics profiling identified that as a downstream effector of the integrin α5 / FAK signaling pathway cyclin D1 partially mediated the cellular structural changes and barrier dysfunction. Furthermore, VE-released plasminogen activator urokinase and platelet-derived growth factor D could serve as potential diagnostic biomarkers for γ-BGT-induced vascular endothelial dysfunction. Our results indicate the mechanisms through which γ-BGT as a novel disintegrin directly interacts with the VE, with consequences for barrier dysfunction.
研究领域:
毒理学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
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