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He Y, Sun H, Bao H, Hou J, Zhou Q, Wu F, Wang X, Sun M, Shi J, Tang G, Bai H. A natural adhesive-based nanomedicine initiates photothermal-directed in situ immunotherapy with durability and maintenance. Biomaterials 2025; 312:122751. [PMID: 39121726 DOI: 10.1016/j.biomaterials.2024.122751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/30/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
Tumor immunotherapies have emerged as a promising frontier in the realm of cancer treatment. However, challenges persist in achieving localized, durable immunostimulation while counteracting the tumor's immunosuppressive environment. Here, we develop a natural mussel foot protein-based nanomedicine with spatiotemporal control for tumor immunotherapy. In this nanomedicine, an immunoadjuvant prodrug and a photosensitizer are integrated, which is driven by their dynamic bonding and non-covalent assembling with the protein carrier. Harnessing the protein carrier's bioadhesion, this nanomedicine achieves a drug co-delivery with spatiotemporal precision, by which it not only promotes tumor photothermal ablation but also broadens tumor antigen repertoire, facilitating in situ immunotherapy with durability and maintenance. This nanomedicine also modulates the tumor microenvironment to overcome immunosuppression, thereby amplifying antitumor responses against tumor progression. Our strategy underscores a mussel foot protein-derived design philosophy of drug delivery aimed at refining combinatorial immunotherapy, offering insights into leveraging natural proteins for cancer treatment.
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Affiliation(s)
- Yunhong He
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China
| | - Hong Sun
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China
| | - Hanxiao Bao
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China
| | - Jue Hou
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China
| | - Qiaomei Zhou
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310028 Hangzhou, PR China
| | - Fan Wu
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China; Department of Neurosurgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 310028 Hangzhou, PR China
| | | | - Mingli Sun
- Zhejiang Laboratory, 311100 Hangzhou, PR China
| | - Junhui Shi
- Zhejiang Laboratory, 311100 Hangzhou, PR China
| | - Guping Tang
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China; Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 310028 Hangzhou, PR China
| | - Hongzhen Bai
- Institute of Chemical Biology and Pharmaceutical Chemistry, Department of Chemistry, Zhejiang University, 310028 Hangzhou, PR China.
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Hu JJ, Yang J, Liu Y, Lu G, Zhao Z, Xia F, Lou X. Tuning the affinity of probes with transmembrane proteins by constructing peptide-conjugated cis/ trans isomers based on molecular scaffolds. J Mater Chem B 2024; 12:12523-12529. [PMID: 39494739 DOI: 10.1039/d4tb01801j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
For protein analysis, the current peptide-based probes rely almost on the specific recognition of the protein while neglecting the potential influence of the environment near the protein. Herein, we propose that to achieve high recognition of transmembrane protein integrin αvβ3, the interactions from the membrane substrate could be helpful. Moreover, to guarantee the additive effect of different interactions, the cis and trans isomers of peptide-based probes are distinguished. In detail, we synthesized the peptide-conjugated cis/trans isomers (cis-RTP and trans-RTP) by modifying the Arg-Gly-Asp (RGD)-targeting peptide and palmitic acid-conjugated Arg-Arg-Arg-Arg (Pal-RRRR) peptide to the two ends of the molecular scaffold-tetraphenylethene derivative. Due to the difference in spatial structure, isothermal titration calorimetry and simulation experiments demonstrated that cis-RTP can bind more stably to integrin αvβ3 than trans-RTP. As a result, cis-RTP has shown more excellent properties in inhibiting cell migration and killing cells by regulating actin and extracellular signal-regulated kinase. Unlike the existing probe design for protein, this study provides a concept of microenvironment-helpful recognition and a promising strategy of cis/trans isomers to modulate the interaction between proteins and probes.
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Affiliation(s)
- Jing-Jing Hu
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
| | - Juliang Yang
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
| | - Yiheng Liu
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
| | - Guangwen Lu
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
| | - Zujin Zhao
- Department State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, South China University of Technology, Guangzhou 510640, China
| | - Fan Xia
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
| | - Xiaoding Lou
- State Key Laboratory of Biogeology and Environmental Geology, Faculty Materials Science and Chemistry, China University of Geosciences, Wuhan 430078, China.
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Zhao R, Gu J, Zhao H, Wang Z, Liu X, Yuan C, Zheng X, Yang T, Xu X, Cai Y. Expression of integrin α4β1 and α4β7 on B cells correlates with autoimmune responses in Graves' disease. Int Immunopharmacol 2024; 142:113218. [PMID: 39317053 DOI: 10.1016/j.intimp.2024.113218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 09/14/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Integrins are upregulated on endothelial cells and T-lymphocytes in autoimmune thyroid disease (AITD), potentially contributing to immune response localization. The role of integrins on B-cells in AITD remains unclear. METHODS Peripheral blood samples were collected from healthy controls (n = 56), patients with Graves' disease (GD) (n = 37) and Hashimoto's thyroiditis (HT) (n = 52). Ultrasound-guided fine-needle aspiration (FNA) of the thyroid was performed in patients with non-autoimmune thyroid disease (nAITD) (n = 19), GD (n = 11), and HT (n = 40). Integrins α4β7, α4β1, and αEβ7 in B cells were measured by flow cytometry. Serum zonulin levels were quantified via ELISA. Associations of integrins on B cells with thyroid hormones, thyroid autoantibodies, AITD duration, and zonulin were analyzed. RESULTS HT patients exhibited lower α4β7 and higher α4β1 expression on B cells compared to healthy controls and GD patients. While α4β7 was predominant on circulating B cells, the dominant integrin expressed on intrathyroidal B cells varied with specific thyroid diseases. In GD patients, α4β7 and α4β1 expression on circulating B cells correlated positively and negatively with thyroid function and thyroid stimulating immunoglobulins (TSI) levels, respectively. Intrathyroidal α4β1+ B cells positively correlated with TSH levels in HT patients. Additionally, serum zonulin was elevated in HT patients, and intrathyroidal α4β7+ B cells and α4β1+ B cells correlated negatively and positively with zonulin levels, respectively. Integrin αEβ7 on B cells showed no significant association with AITD. CONCLUSION Integrins expressed on B cells potentially play a role in the pathogenesis of AITD and might serve as immune biomarkers for the disease.
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Affiliation(s)
- Ruiling Zhao
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Junjie Gu
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Hang Zhao
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhixiao Wang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaoyun Liu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Cuiping Yuan
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xuqin Zheng
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Tao Yang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xinyu Xu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
| | - Yun Cai
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Dasetty S, Bidone TC, Ferguson AL. Data-driven prediction of α IIbβ 3 integrin activation paths using manifold learning and deep generative modeling. Biophys J 2024; 123:2716-2729. [PMID: 38098231 PMCID: PMC11393677 DOI: 10.1016/j.bpj.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/05/2023] [Accepted: 12/11/2023] [Indexed: 01/06/2024] Open
Abstract
The integrin heterodimer is a transmembrane protein critical for driving cellular process and is a therapeutic target in the treatment of multiple diseases linked to its malfunction. Activation of integrin involves conformational transitions between bent and extended states. Some of the conformations that are intermediate between bent and extended states of the heterodimer have been experimentally characterized, but the full activation pathways remain unresolved both experimentally due to their transient nature and computationally due to the challenges in simulating rare barrier crossing events in these large molecular systems. An understanding of the activation pathways can provide new fundamental understanding of the biophysical processes associated with the dynamic interconversions between bent and extended states and can unveil new putative therapeutic targets. In this work, we apply nonlinear manifold learning to coarse-grained molecular dynamics simulations of bent, extended, and two intermediate states of αIIbβ3 integrin to learn a low-dimensional embedding of the configurational phase space. We then train deep generative models to learn an inverse mapping between the low-dimensional embedding and high-dimensional molecular space and use these models to interpolate the molecular configurations constituting the activation pathways between the experimentally characterized states. This work furnishes plausible predictions of integrin activation pathways and reports a generic and transferable multiscale technique to predict transition pathways for biomolecular systems.
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Affiliation(s)
- Siva Dasetty
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois
| | - Tamara C Bidone
- Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah; Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, Utah
| | - Andrew L Ferguson
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois.
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Montes AR, Barroso A, Wang W, O'Connell GD, Tepole AB, Mofrad MRK. Integrin mechanosensing relies on a pivot-clip mechanism to reinforce cell adhesion. Biophys J 2024; 123:2443-2454. [PMID: 38872310 PMCID: PMC11630637 DOI: 10.1016/j.bpj.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 05/01/2024] [Accepted: 06/07/2024] [Indexed: 06/15/2024] Open
Abstract
Cells intricately sense mechanical forces from their surroundings, driving biophysical and biochemical activities. This mechanosensing phenomenon occurs at the cell-matrix interface, where mechanical forces resulting from cellular motion, such as migration or matrix stretching, are exchanged through surface receptors, primarily integrins, and their corresponding matrix ligands. A pivotal player in this interaction is the α5β1 integrin and fibronectin (FN) bond, known for its role in establishing cell adhesion sites for migration. However, upregulation of the α5β1-FN bond is associated with uncontrolled cell metastasis. This bond operates through catch bond dynamics, wherein the bond lifetime paradoxically increases with greater force. The mechanism sustaining the characteristic catch bond dynamics of α5β1-FN remains unclear. Leveraging molecular dynamics simulations, our approach unveils a pivot-clip mechanism. Two key binding sites on FN, namely the synergy site and the RGD (Arg-Gly-Asp) motif, act as active points for structural changes in α5β1 integrin. Conformational adaptations at these sites are induced by a series of hydrogen bond formations and breaks at the synergy site. We disrupt these adaptations through a double mutation on FN, known to reduce cell adhesion. A whole-cell finite-element model is employed to elucidate how the synergy site may promote dynamic α5β1-FN binding, resisting cell contraction. In summary, our study integrates molecular- and cellular-level modeling to propose that FN's synergy site reinforces cell adhesion through enhanced binding dynamics and a mechanosensitive pivot-clip mechanism. This work sheds light on the interplay between mechanical forces and cell-matrix interactions, contributing to our understanding of cellular behaviors in physiological and pathological contexts.
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Affiliation(s)
- Andre R Montes
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California
| | - Anahi Barroso
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California
| | - Wei Wang
- Berkeley City College, Berkeley, California; Berkeley Biomechanics Laboratory, Department of Mechanical Engineering, University of California, Berkeley, Berkeley, California
| | - Grace D O'Connell
- Berkeley Biomechanics Laboratory, Department of Mechanical Engineering, University of California, Berkeley, Berkeley, California
| | - Adrian B Tepole
- Tepole Mechanics and Mechanobiology Laboratory, School of Mechanical Engineering, Purdue University, West Lafayette, Indiana.
| | - Mohammad R K Mofrad
- Molecular Cell Biomechanics Laboratory, Departments of Bioengineering and Mechanical Engineering, University of California, Berkeley, Berkeley, California; Molecular Biophysics and Integrative Bioimaging Division, Lawrence Berkeley National Lab, Berkeley, California.
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6
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Lee LCC, Lo KKW. Shining New Light on Biological Systems: Luminescent Transition Metal Complexes for Bioimaging and Biosensing Applications. Chem Rev 2024; 124:8825-9014. [PMID: 39052606 PMCID: PMC11328004 DOI: 10.1021/acs.chemrev.3c00629] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Luminescence imaging is a powerful and versatile technique for investigating cell physiology and pathology in living systems, making significant contributions to life science research and clinical diagnosis. In recent years, luminescent transition metal complexes have gained significant attention for diagnostic and therapeutic applications due to their unique photophysical and photochemical properties. In this Review, we provide a comprehensive overview of the recent development of luminescent transition metal complexes for bioimaging and biosensing applications, with a focus on transition metal centers with a d6, d8, and d10 electronic configuration. We elucidate the structure-property relationships of luminescent transition metal complexes, exploring how their structural characteristics can be manipulated to control their biological behavior such as cellular uptake, localization, biocompatibility, pharmacokinetics, and biodistribution. Furthermore, we introduce the various design strategies that leverage the interesting photophysical properties of luminescent transition metal complexes for a wide variety of biological applications, including autofluorescence-free imaging, multimodal imaging, organelle imaging, biological sensing, microenvironment monitoring, bioorthogonal labeling, bacterial imaging, and cell viability assessment. Finally, we provide insights into the challenges and perspectives of luminescent transition metal complexes for bioimaging and biosensing applications, as well as their use in disease diagnosis and treatment evaluation.
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Affiliation(s)
- Lawrence Cho-Cheung Lee
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
- Laboratory for Synthetic Chemistry and Chemical Biology Limited, Units 1503-1511, 15/F, Building 17W, Hong Kong Science Park, New Territories, Hong Kong, P. R. China
| | - Kenneth Kam-Wing Lo
- Department of Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
- State Key Laboratory of Terahertz and Millimeter Waves, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, P. R. China
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7
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Miao MZ, Lee JS, Yamada KM, Loeser RF. Integrin signalling in joint development, homeostasis and osteoarthritis. Nat Rev Rheumatol 2024; 20:492-509. [PMID: 39014254 PMCID: PMC11886400 DOI: 10.1038/s41584-024-01130-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2024] [Indexed: 07/18/2024]
Abstract
Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellular responses necessary for maintaining joint tissue integrity. Dysregulated integrin signalling, triggered by matrix degradation products such as matrikines, disrupts this delicate balance, tipping the scales towards an environment conducive to OA pathogenesis. The interplay between integrin signalling and growth factor pathways further underscores the multifaceted nature of OA. Moreover, emerging insights into the role of endocytic trafficking in regulating integrin signalling add a new layer of complexity to the understanding of OA development. To harness the therapeutic potential of targeting integrins for mitigation of OA, comprehensive understanding of their molecular mechanisms across joint tissues is imperative. Ultimately, deciphering the complexities of integrin signalling will advance the ability to treat OA and alleviate its global burden.
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Affiliation(s)
- Michael Z Miao
- Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Janice S Lee
- Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Office of the Clinical Director, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Kenneth M Yamada
- Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
| | - Richard F Loeser
- Division of Rheumatology, Allergy, and Immunology and the Thurston Arthritis Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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8
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Zhang L, Ye P, Zhu H, Zhu L, Ren Y, Lei J. Bioinspired and biomimetic strategies for inflammatory bowel disease therapy. J Mater Chem B 2024; 12:3614-3635. [PMID: 38511264 DOI: 10.1039/d3tb02995f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory bowel disease with high morbidity and an increased risk of cancer or death, resulting in a heavy societal medical burden. While current treatment modalities have been successful in achieving long-term remission and reducing the risk of complications, IBD remains incurable. Nanomedicine has the potential to address the high toxic side effects and low efficacy in IBD treatment. However, synthesized nanomedicines typically exhibit some degree of immune rejection, off-target effects, and a poor ability to cross biological barriers, limiting the development of clinical applications. The emergence of bionic materials and bionic technologies has reshaped the landscape in novel pharmaceutical fields. Biomimetic drug-delivery systems can effectively improve biocompatibility and reduce immunogenicity. Some bioinspired strategies can mimic specific components, targets or immune mechanisms in pathological processes to produce targeting effects for precise disease control. This article highlights recent research on bioinspired and biomimetic strategies for the treatment of IBD and discusses the challenges and future directions in the field to advance the treatment of IBD.
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Affiliation(s)
- Limei Zhang
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
| | - Peng Ye
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
| | - Huatai Zhu
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
| | - Liyu Zhu
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
| | - Yuting Ren
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
| | - Jiandu Lei
- Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing 100083, P. R. China.
- MOE Engineering Research Center of Forestry Biomass Materials and Bioenergy, Beijing Forestry University, Beijing 100083, P. R. China
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9
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Sun M, Liu C, Liu J, Wen J, Hao T, Chen D, Shen Y. A microthrombus-driven fixed-point cleaved nanosystem for preventing post-thrombolysis recurrence via inhibiting ferroptosis. J Control Release 2024; 367:587-603. [PMID: 38309306 DOI: 10.1016/j.jconrel.2024.01.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 02/05/2024]
Abstract
Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.
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Affiliation(s)
- Mengjuan Sun
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China
| | - Chang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China
| | - Ji Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China
| | - Jing Wen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China
| | - Tianjiao Hao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China
| | - Daquan Chen
- School of Pharmacy, Yantai University, 30 Qingquan Road, Yantai 264005, China
| | - Yan Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China; Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 639 Long Mian Da Dao, Nanjing 211198, China.
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10
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Akompong SK, Li Y, Gong W, Ye L, Liu J. Recently reported cell migration inhibitors: Opportunities and challenges for antimetastatic agents. Drug Discov Today 2024; 29:103906. [PMID: 38309689 DOI: 10.1016/j.drudis.2024.103906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/17/2024] [Accepted: 01/25/2024] [Indexed: 02/05/2024]
Abstract
Antimetastatic agents are highly desirable for cancer treatment because of the severe medical challenges and high mortality resulting from tumor metastasis. Having demonstrated antimetastatic effects in numerous in vitro and in vivo studies, migration inhibitors present significant opportunities for developing a new class of anticancer drugs. To provide a useful overview on the latest research in migration inhibitors, this article first discusses their therapeutic significance, targetable proteins, and developmental avenues. Subsequently it reviews over 20 representative migration inhibitors reported in recent journals in terms of their inhibitory mechanism, potency, and potential clinical utility. The relevance of the target proteins to cellular migratory function is focused on as it is crucial for assessing the overall efficacy of the inhibitors.
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Affiliation(s)
- Samuel K Akompong
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Yang Li
- Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wenxue Gong
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China
| | - Long Ye
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China.
| | - Jinping Liu
- Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
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11
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Péter B, Szekacs I, Horvath R. Label-free biomolecular and cellular methods in small molecule epigallocatechin-gallate research. Heliyon 2024; 10:e25603. [PMID: 38371993 PMCID: PMC10873674 DOI: 10.1016/j.heliyon.2024.e25603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/30/2024] [Accepted: 01/30/2024] [Indexed: 02/20/2024] Open
Abstract
Small molecule natural compounds are gaining popularity in biomedicine due to their easy access to wide structural diversity and their proven health benefits in several case studies. Affinity measurements of small molecules below 100 Da molecular weight in a label-free and automatized manner using small amounts of samples have now become a possibility and reviewed in the present work. We also highlight novel label-free setups with excellent time resolution, which is important for kinetic measurements of biomolecules and living cells. We summarize how molecular-scale affinity data can be obtained from the in-depth analysis of cellular kinetic signals. Unlike traditional measurements, label-free biosensors have made such measurements possible, even without the isolation of specific cellular receptors of interest. Throughout this review, we consider epigallocatechin gallate (EGCG) as an exemplary compound. EGCG, a catechin found in green tea, is a well-established anti-inflammatory and anti-cancer agent. It has undergone extensive examination in numerous studies, which typically rely on fluorescent-based methods to explore its effects on both healthy and tumor cells. The summarized research topics range from molecular interactions with proteins and biological films to the kinetics of cellular adhesion and movement on novel biomimetic interfaces in the presence of EGCG. While the direct impact of small molecules on living cells and biomolecules is relatively well investigated in the literature using traditional biological measurements, this review also highlights the indirect influence of these molecules on the cells by modifying their nano-environment. Moreover, we underscore the significance of novel high-throughput label-free techniques in small molecular measurements, facilitating the investigation of both molecular-scale interactions and cellular processes in one single experiment. This advancement opens the door to exploring more complex multicomponent models that were previously beyond the reach of traditional assays.
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Affiliation(s)
- Beatrix Péter
- Nanobiosensorics Laboratory, Institute of Technical Physics and Materials Science, HUN-REN Centre for Energy Research, Konkoly-Thege M. út 29-33., 1121 Budapest, Hungary
| | - Inna Szekacs
- Nanobiosensorics Laboratory, Institute of Technical Physics and Materials Science, HUN-REN Centre for Energy Research, Konkoly-Thege M. út 29-33., 1121 Budapest, Hungary
| | - Robert Horvath
- Nanobiosensorics Laboratory, Institute of Technical Physics and Materials Science, HUN-REN Centre for Energy Research, Konkoly-Thege M. út 29-33., 1121 Budapest, Hungary
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12
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Huang R, Ding J, Xie WF. Liver cancer. SINUSOIDAL CELLS IN LIVER DISEASES 2024:349-366. [DOI: 10.1016/b978-0-323-95262-0.00017-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Sun L, Guo S, Xie Y, Yao Y. The characteristics and the multiple functions of integrin β1 in human cancers. J Transl Med 2023; 21:787. [PMID: 37932738 PMCID: PMC10629185 DOI: 10.1186/s12967-023-04696-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/02/2023] [Indexed: 11/08/2023] Open
Abstract
Integrins, which consist of two non-covalently linked α and β subunits, play a crucial role in cell-cell adhesion and cell-extracellular matrix (ECM) interactions. Among them, integrin β1 is the most common subunit and has emerged as a key mediator in cancer, influencing various aspects of cancer progression, including cell motility, adhesion, migration, proliferation, differentiation and chemotherapy resistance. However, given the complexity and sometimes contradictory characteristics, targeting integrin β1 for therapeutics has been a challenge. The emerging understanding of the mechanisms regulating by integrin β1 may guide the development of new strategies for anti-cancer therapy. In this review, we summarize the multiple functions of integrin β1 and signaling pathways which underlie the involvement of integrin β1 in several malignant cancers. Our review suggests the possibility of using integrin β1 as a therapeutic target and highlights the need for patient stratification based on expression of different integrin receptors in future clinical studies.
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Affiliation(s)
- Li Sun
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China
| | - Shuwei Guo
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People's Republic of China
| | - Yiping Xie
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China
| | - Yongliang Yao
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, People's Republic of China.
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14
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Jiang X, Xu Z, Jiang S, Wang H, Xiao M, Shi Y, Wang K. PDZ and LIM Domain-Encoding Genes: Their Role in Cancer Development. Cancers (Basel) 2023; 15:5042. [PMID: 37894409 PMCID: PMC10605254 DOI: 10.3390/cancers15205042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/13/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
PDZ-LIM family proteins (PDLIMs) are a kind of scaffolding proteins that contain PDZ and LIM interaction domains. As protein-protein interacting molecules, PDZ and LIM domains function as scaffolds to bind to a variety of proteins. The PDLIMs are composed of evolutionarily conserved proteins found throughout different species. They can participate in cell signal transduction by mediating the interaction of signal molecules. They are involved in many important physiological processes, such as cell differentiation, proliferation, migration, and the maintenance of cellular structural integrity. Studies have shown that dysregulation of the PDLIMs leads to tumor formation and development. In this paper, we review and integrate the current knowledge on PDLIMs. The structure and function of the PDZ and LIM structural domains and the role of the PDLIMs in tumor development are described.
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Affiliation(s)
| | | | | | | | | | - Yueli Shi
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China; (X.J.); (Z.X.); (S.J.); (H.W.); (M.X.)
| | - Kai Wang
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China; (X.J.); (Z.X.); (S.J.); (H.W.); (M.X.)
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15
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Dai Y, Zhang X, Ou Y, Zou L, Zhang D, Yang Q, Qin Y, Du X, Li W, Yuan Z, Xiao Z, Wen Q. Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment. Cell Commun Signal 2023; 21:190. [PMID: 37537585 PMCID: PMC10399053 DOI: 10.1186/s12964-023-01183-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/04/2023] [Indexed: 08/05/2023] Open
Abstract
Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.
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Affiliation(s)
- Yalan Dai
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Oncology, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Xinyi Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shenzhen, China
| | - Yingjun Ou
- Clinical Medicine School, Southwest Medicial Univercity, Luzhou, China
- Orthopaedics, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Linglin Zou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Duoli Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qingfan Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Qin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiuju Du
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wei Li
- Southwest Medical University, Luzhou, China
| | | | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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16
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Xu Z, Chen Y, Wang Y, Han W, Xu W, Liao X, Zhang T, Wang G. Matrix stiffness, endothelial dysfunction and atherosclerosis. Mol Biol Rep 2023; 50:7027-7041. [PMID: 37382775 DOI: 10.1007/s11033-023-08502-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/28/2023] [Indexed: 06/30/2023]
Abstract
Atherosclerosis (AS) is the leading cause of the human cardiovascular diseases (CVDs). Endothelial dysfunction promotes the monocytes infiltration and inflammation that participate fundamentally in atherogenesis. Endothelial cells (EC) have been recognized as mechanosensitive cells and have different responses to distinct mechanical stimuli. Emerging evidence shows matrix stiffness-mediated EC dysfunction plays a vital role in vascular disease, but the underlying mechanisms are not yet completely understood. This article aims to summarize the effect of matrix stiffness on the pro-atherosclerotic characteristics of EC including morphology, rigidity, biological behavior and function as well as the related mechanical signal. The review also discusses and compares the contribution of matrix stiffness-mediated phagocytosis of macrophages and EC to AS progression. These advances in our understanding of the relationship between matrix stiffness and EC dysfunction open the avenues to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.
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Affiliation(s)
- Zichen Xu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Yi Chen
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Yi Wang
- College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Wenbo Han
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Wenfeng Xu
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Xiaoling Liao
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Tao Zhang
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China.
| | - Guixue Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China.
- Bioengineering College of Chongqing University, NO.174, Shazheng Street, Shapingba District, Chongqing, 400030, PR China.
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17
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Hiroyama S, Matsunaga K, Ito M, Iimori H, Morita I, Nakamura J, Shimosegawa E, Abe K. Evaluation of an Integrin α vβ 3 Radiotracer, [ 18F]F-FPP-RGD 2, for Monitoring Pharmacological Effects of Integrin α v siRNA in the NASH Liver. Nucl Med Mol Imaging 2023; 57:172-179. [PMID: 37483876 PMCID: PMC10359219 DOI: 10.1007/s13139-023-00791-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/19/2023] [Accepted: 02/07/2023] [Indexed: 03/09/2023] Open
Abstract
Purpose Integrin αv is a key regulator in the pathophysiology of hepatic fibrosis. In this study, we evaluated the potential utility of an integrin αvβ3 positron emission tomography (PET) radiotracer, 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ([18F]F-FPP-RGD2), for detecting hepatic integrin αv and function in nonalcoholic steatohepatitis (NASH) model rats using integrin αv siRNA. Methods NASH model rats were produced by feeding a choline-deficient, low-methionine, high-fat diet for 8 weeks. PET/computerized tomography imaging and quantification of integrin αv protein, serum aspartate aminotransferase, and alanine aminotransferase were performed 1 week after single intravenous injection of integrin αv siRNA. Results Integrin αv siRNA (0.1 and 0.5 mg/kg) dose-dependently decreased hepatic integrin αv protein concentrations in control and NASH model rats. The hepatic mean standard uptake value of [18F]F-FPP-RGD2 was decreased dose-dependently by integrin αv siRNA. The mean standard uptake value was positively correlated with integrin αv protein levels in control and NASH model rats. Serum aspartate aminotransferase and alanine aminotransferase concentrations were also decreased by siRNA injection and correlated with liver integrin αv protein expression levels in NASH model rats. Conclusion This study suggests that [18F]F-FPP-RGD2 PET imaging is a promising radiotracer for monitoring hepatic integrin αv protein levels and hepatic function in NASH pathology.
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Affiliation(s)
- Shuichi Hiroyama
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
| | - Keiko Matsunaga
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Miwa Ito
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
| | - Hitoshi Iimori
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Ippei Morita
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Jun Nakamura
- Laboratory for Advanced Medicine Research, Shionogi & Co., Ltd., Osaka, Japan
| | - Eku Shimosegawa
- Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kohji Abe
- Biomarker R&D Department, Shionogi & Co., Ltd., 3-1-1 Futaba-Cho, Toyonaka, Osaka 561-0825 Japan
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Abstract
Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated intravascular coagulation (DIC), the sepsis-associated coagulopathy. Many of the pathogens, both bacterial and viral, that cause sepsis also directly activate platelets, which suggests that pathogen-induced platelet activation leads to systemic thrombosis and drives the multi-organ failure of DIC. In this paper we review the mechanisms of platelet activation by pathogens and the evidence for a role for anti-platelet agents in the management of sepsis.
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Affiliation(s)
- Dermot Cox
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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19
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Huang Y, Guo DM, Bu S, Xu W, Cai QC, Xu J, Jiang YQ, Teng F. Systematic Analysis of the Prognostic Significance and Roles of the Integrin Alpha Family in Non-Small Cell Lung Cancers. Adv Ther 2023; 40:2186-2204. [PMID: 36892810 DOI: 10.1007/s12325-023-02469-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 02/17/2023] [Indexed: 03/10/2023]
Abstract
INTRODUCTION Lung cancer is one of the most common cancer malignancies and the principal cause of cancer-associated deaths worldwide. Non-small cell lung cancers (NSCLCs) account for more than 80% of all lung cancer cases. Recent studies showed that the genes of the integrin alpha (α) (ITGA) subfamily play a fundamental role in various cancers. However, little is known about the expression and roles of distinct ITGA proteins in NSCLCs. METHODS Gene Expression Profiling Interactive Analysis and UALCAN (University of ALabama at Birmingham CANcer) web resources and The Cancer Genome Atlas (TCGA), ONCOMINE, cBioPortal, GeneMANIA, and Tumor Immune Estimation Resource databases were used to evaluate differential expression, correlations between the expression levels of individual genes, the prognostic value of overall survival (OS) and stage, genetic alterations, protein-protein interactions, and the immune cell infiltration of ITGAs in NSCLCs. We used R (v. 4.0.3) software to conduct gene correlation, gene enrichment, and clinical correlation of RNA sequencing data of 1016 NSCLCs from TCGA. To evaluate the expression of ITGA5/8/9/L at the expression and protein levels, qRT-PCR, immunohistochemistry (IHC), and hematoxylin and eosin (H&E) were performed, respectively. RESULTS Upregulated levels of ITGA11 messenger RNA and downregulated levels of ITGA1/3/5/7/8/9/L/M/X were observed in the NSCLC tissues. Lower expression of ITGA5/6/8/9/10/D/L was discovered to be expressively associated with advanced tumor stage or poor patient prognosis in patients with NSCLC. A high mutation rate (44%) of the ITGA family was observed in the NSCLCs. Gene Ontology functional enrichment analyses results revealed that the differentially expressed ITGAs could be involved in roles related to extracellular matrix (ECM) organization, collagen-containing ECM cellular components, and ECM structural constituent molecular functions. The results of the Kyoto Encyclopedia of Genes and Genomes analysis revealed that ITGAs may be involved in focal adhesion, ECM-receptor interaction, and amoebiasis; the expression of ITGAs was significantly correlated with the infiltration of diverse immune cells in NSCLCs. ITGA5/8/9/L was also highly correlated with PD-L1 expression. The validation results for marker gene expression in NSCLC tissues by qRT-PCR, IHC, and H&E staining indicated that the expression of ITGA5/8/9/L decreased compared with that in normal tissues. CONCLUSION As potential prognostic biomarkers in NSCLCs, ITGA5/8/9/L may fulfill important roles in regulating tumor progression and immune cell infiltration.
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Affiliation(s)
- Yu Huang
- School of Medicine, Chongqing University, Chongqing, 400030, China
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Dong-Ming Guo
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Shi Bu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Wei Xu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Qing-Chun Cai
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Jian Xu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Yue-Quan Jiang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China.
| | - Fei Teng
- Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), Chongqing University Cancer Hospital, No. 181 of Hanyu Road, Shapingba District, Chongqing, 400030, China.
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20
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Rike WA, Stern S. Proteins and Transcriptional Dysregulation of the Brain Extracellular Matrix in Parkinson's Disease: A Systematic Review. Int J Mol Sci 2023; 24:ijms24087435. [PMID: 37108598 PMCID: PMC10138539 DOI: 10.3390/ijms24087435] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/06/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational, and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect cellular functions and may result in disease. However, most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix in disease pathogenesis. Thus, due to the ECM's diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson's disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. Here, in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google Scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson's disease (PD). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. According to proteomic studies, proteins such as collagens, fibronectin, annexins, and tenascins were recognized to be differentially expressed in Parkinson's disease. Transcriptomic studies displayed dysregulated pathways including ECM-receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson's disease. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out to better understand the roles of the ECM in neurodegeneration and Parkinson's disease. However, we believe that our review will elicit focused primary studies and thus support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson's disease.
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Affiliation(s)
- Wote Amelo Rike
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel
| | - Shani Stern
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel
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21
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Fan X, Meng M, Li B, Chen H, Tan J, Xu K, Xiao S, Kwan HY, Liu Z, Su T. Brevilin A is a potent anti-metastatic CRC agent that targets the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay. J Transl Med 2023; 21:260. [PMID: 37062842 PMCID: PMC10105967 DOI: 10.1186/s12967-023-04087-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/25/2023] [Indexed: 04/18/2023] Open
Abstract
BACKGROUND More than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC). METHODS Conditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis. RESULTS In the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo. CONCLUSIONS We are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.
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Affiliation(s)
- Xueying Fan
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Mingjing Meng
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Baoting Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Hui Chen
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Jincheng Tan
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Keyang Xu
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Shilin Xiao
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hiu-Yee Kwan
- Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Zhongqiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
| | - Tao Su
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China.
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, China.
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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David V, Wermelinger LS, Frattani FS, Lima AGF, Santos YFS, Mourão PADS, Almeida FCL, Kurtenbach E, Zingali RB. rJararacin, a recombinant disintegrin from Bothrops jararaca venom: Exploring its effects on hemostasis and thrombosis. Arch Biochem Biophys 2023; 738:109557. [PMID: 36878339 DOI: 10.1016/j.abb.2023.109557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Integrins are a family of heterodimeric transmembrane receptors which link the extracellular matrix to the cell cytoskeleton. These receptors play a role in many cellular processes: adhesion, proliferation, migration, apoptosis, and platelet aggregation, thus modulating a wide range of scenarios in health and disease. Therefore, integrins have been the target of new antithrombotic drugs. Disintegrins from snake venoms are recognized by the ability to modulate the activity of integrins, such as integrin αIIbβ3, a fundamental platelet glycoprotein, and αvβ3 expressed on tumor cells. For this reason, disintegrins are unique and potential tools for examining integrin-matrix interaction and the development of novel antithrombotic agents. The present study aims to obtain the recombinant form of jararacin and evaluate the secondary structure and its effects on hemostasis and thrombosis. rJararacin was expressed in the Pichia pastoris (P. pastoris) expression system and purified the recombinant protein with a yield of 40 mg/L of culture. The molecular mass (7722 Da) and internal sequence were confirmed by mass spectrometry. Structure and folding analysis were obtained by Circular Dichroism and 1H Nuclear Magnetic Resonance spectra. Disintegrin structure reveals properly folded with the presence of β-sheet structure. rJararacin significantly demonstrated inhibition of the adhesion of B16F10 cells and platelets to the fibronectin matrix under static conditions. rJararacin inhibited platelet aggregation induced by ADP (IC50 95 nM), collagen (IC50 57 nM), and thrombin (IC50 22 nM) in a dose-dependent manner. This disintegrin also inhibited 81% and 94% of the adhesion of platelets to fibrinogen and collagen under continuous flow, respectively. In addition, rjararacin efficaciously prevents platelet aggregation in vitro and ex vivo with rat platelets and thrombus occlusion at an effective dose (5 mg/kg). The data here provides evidence that rjararacin possesses the potential as an αIIbβ3 antagonist, capable of preventing arterial thrombosis.
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Affiliation(s)
- Victor David
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
| | - Luciana Serrão Wermelinger
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-170, Brazil.
| | - Flávia Serra Frattani
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-170, Brazil.
| | - Antonio Gilclêr Ferreira Lima
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
| | - Yasmyn Fernandes Silva Santos
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
| | - Paulo Antônio de Souza Mourão
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
| | - Fabio Ceneviva Lacerda Almeida
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
| | - Eleonora Kurtenbach
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-170, Brazil.
| | - Russolina Benedeta Zingali
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, CEP 21941-902, Brazil.
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23
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Tvaroška I, Kozmon S, Kóňa J. Molecular Modeling Insights into the Structure and Behavior of Integrins: A Review. Cells 2023; 12:cells12020324. [PMID: 36672259 PMCID: PMC9856412 DOI: 10.3390/cells12020324] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Integrins are heterodimeric glycoproteins crucial to the physiology and pathology of many biological functions. As adhesion molecules, they mediate immune cell trafficking, migration, and immunological synapse formation during inflammation and cancer. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential. Despite the great effort in the last thirty years, up to now, only seven integrin-based drugs have entered the market. Recent progress in deciphering integrin functions, signaling, and interactions with ligands, along with advancement in rational drug design strategies, provide an opportunity to exploit their therapeutic potential and discover novel agents. This review will discuss the molecular modeling methods used in determining integrins' dynamic properties and in providing information toward understanding their properties and function at the atomic level. Then, we will survey the relevant contributions and the current understanding of integrin structure, activation, the binding of essential ligands, and the role of molecular modeling methods in the rational design of antagonists. We will emphasize the role played by molecular modeling methods in progress in these areas and the designing of integrin antagonists.
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Affiliation(s)
- Igor Tvaroška
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Correspondence:
| | - Stanislav Kozmon
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Medical Vision o. z., Záhradnícka 4837/55, 821 08 Bratislava, Slovakia
| | - Juraj Kóňa
- Institute of Chemistry, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
- Medical Vision o. z., Záhradnícka 4837/55, 821 08 Bratislava, Slovakia
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24
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Lin QY, Bai J, Zhang YL, Li HH. Integrin CD11b Contributes to Hypertension and Vascular Dysfunction Through Mediating Macrophage Adhesion and Migration. Hypertension 2023; 80:57-69. [PMID: 36377602 DOI: 10.1161/hypertensionaha.122.20328] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Leukocyte adhesion to endothelium is an early inflammatory response and is mainly controlled by the β2-integrins. However, the role of integrin CD11b/CD18 in the pathogenesis of hypertension and vascular dysfunction is unclear. METHODS Hypertension was established by angiotensin II (490 ng/kg·per min) or deoxycorticosterone acetate salt. Hypertensive responses were studied in CD11b-deficient (CD11b-/-) mice, bone marrow transplanted and wild-type (WT) mice that were administered anti-CD11b neutralizing antibody or agonist leukadherin-1. Blood pressure was monitored with tail-cuff method and radiotelemetry. Blood and vascular inflammatory cells were assessed by flow cytometry. Aortic remodeling and function were examined using histology and aortic ring analysis. Cell adhesion and migration were evaluated in vitro. The relationship between circulating CD11b+ immune cells and hypertension was analyzed in patients with hypertension. RESULTS We found that CD11b and CD18 expression as well as the CD45+CD11b+CD18+ myeloid cells were highly increased in the aorta of angiotensin II-infused mice. Ablation or pharmacological inhibition of CD11b in mice significantly alleviated hypertension, aortic remodeling, superoxide generation, vascular dysfunction, and the infiltration of CD11b+ macrophages through reducing macrophage adhesion and migration. These effects were confirmed in WT mice reconstituted with CD11b-deficient bone marrow cells. Conversely, angiotensin II-induced hypertensive response was exacerbated by CD11b agonist leukadherin-1. Notably, circulating CD45+CD11b+CD18+ myeloid cells and the ligand levels in hypertensive patients were significantly higher than in normotensive controls. CONCLUSIONS We demonstrated a critical significance of CD11b+ myeloid cells in hypertension and vascular dysfunction. Targeting CD11b may represent a novel therapeutic option for hypertension.
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Affiliation(s)
- Qiu-Yue Lin
- Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Q.-Y.L., J.B., H.-H.L.)
| | - Jie Bai
- Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Q.-Y.L., J.B., H.-H.L.)
| | - Yun-Long Zhang
- Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (Y.-L.Z., H.-H.L.)
| | - Hui-Hua Li
- Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (Q.-Y.L., J.B., H.-H.L.).,Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China (Y.-L.Z., H.-H.L.)
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25
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Fujioka K, Hay BA, Godugu K, Mousa SA. Pharmacokinetics of fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (NP751), a novel anticancer thyrointegrin α vβ 3 antagonist. Front Pharmacol 2022; 13:902141. [PMID: 36518666 PMCID: PMC9742531 DOI: 10.3389/fphar.2022.902141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvβ3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5 ng/μL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.
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Affiliation(s)
| | | | | | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences and Nanopharmaceuticals, LLC, Rensselaer, NY, United States
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26
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Zhang YY, Li QL, Wong HM. Fabrication of Multilayered Biofunctional Material with an Enamel-like Structure. Int J Mol Sci 2022; 23:13810. [PMID: 36430289 PMCID: PMC9692533 DOI: 10.3390/ijms232213810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
The oral cavity is an environment with diverse bacteria; thus, antibacterial materials are crucial for treating and preventing dental diseases. There is a high demand for materials with an enamel-like architecture because of the high failure rate of dental restorations, due to the physical differences between dental materials and enamel. However, recreating the distinctive apatite composition and hierarchical architecture of enamel is challenging. The aim of this study was to synthesize a novel material with an enamel-like structure and antibacterial ability. We established a non-cell biomimetic method of evaporation-based bottom-up self-assembly combined with a layer-by-layer technique and introduced an antibacterial agent (graphene oxide) to fabricate a biofunctional material with an enamel-like architecture and antibacterial ability. Specifically, enamel-like graphene oxide-hydroxyapatite crystals, formed on a customized mineralization template, were assembled into an enamel-like prismatic structure with a highly organized orientation preferentially along the c-axis through evaporation-based bottom-up self-assembly. With the aid of layer-by-layer absorption, we then fabricated a bulk macroscopic multilayered biofunctional material with a hierarchical enamel-like architecture. This enamel-inspired biomaterial could effectively resolve the problem in dental restoration and brings new prospects for the synthesis of other enamel-inspired biomaterials.
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Affiliation(s)
- Yu Yuan Zhang
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong 000000, China
| | - Quan Li Li
- Collage and Hospital of Stomatology, Anhui Medical University, No. 69, Meishan Road, Heifei 230000, China
| | - Hai Ming Wong
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong 000000, China
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27
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Mittendorf F, Celik IE, Kirsch SF. Total Synthesis of Cryptoconcatone D via Construction of 1,3-Diol Units Using Chiral Horner-Wittig Reagents. J Org Chem 2022; 87:14899-14908. [PMID: 36195315 DOI: 10.1021/acs.joc.2c01737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The modular synthesis of 1,3-polyols using a chiral phosphine oxide building block is reported. This versatile building block works in a repetitive way for the stereocontrolled synthesis of a tetraol key intermediate, which serves for the first total synthesis of the potentially anti-inflammatory natural product cryptoconcatone D. A new route toward the chiral building block is also presented: Starting from 2-deoxy-d-ribose, the optimized sequence now makes the use of the building block more attractive to practicing chemists again.
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Affiliation(s)
- Fabia Mittendorf
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
| | - Ibrahim-Ethem Celik
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
| | - Stefan F Kirsch
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
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28
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Gao Y, Fang Y, Huang Y, Ma R, Chen X, Wang F, Pei X, Gao Y, Chen X, Liu X, Shan J, Li P. MIIP functions as a novel ligand for ITGB3 to inhibit angiogenesis and tumorigenesis of triple-negative breast cancer. Cell Death Dis 2022; 13:810. [PMID: 36130933 PMCID: PMC9492696 DOI: 10.1038/s41419-022-05255-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 01/23/2023]
Abstract
Migration and invasion inhibitory protein (MIIP) has been identified as a tumor suppressor in various cancer types. Although MIIP is reported to exert tumor suppressive functions by repressing proliferation and metastasis of cancer cells, the detailed mechanism is poorly understood. In the present study, we found MIIP is a favorable indicator of prognosis in triple-negative breast cancer. MIIP could inhibit tumor angiogenesis, proliferation, and metastasis of triple-negative breast cancer cells in vivo and in vitro. Mechanistically, MIIP directly interacted with ITGB3 and suppressed its downstream signaling. As a result, β-catenin was reduced due to elevated ubiquitin-mediated degradation, leading to downregulated VEGFA production and epithelial mesenchymal transition. More importantly, we found RGD motif is essential for MIIP binding with ITGB3 and executing efficient tumor-suppressing effect. Our findings unravel a novel mechanism by which MIIP suppresses tumorigenesis in triple-negative breast cancer, and MIIP is thus a promising molecular biomarker or therapeutic target for the disease.
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Affiliation(s)
- Yujing Gao
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, China
| | - Yujie Fang
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yongli Huang
- grid.412194.b0000 0004 1761 9803National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, China ,grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Rui Ma
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xixi Chen
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Wang
- grid.413385.80000 0004 1799 1445Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiuying Pei
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yuanqi Gao
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuehua Chen
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinrui Liu
- grid.412194.b0000 0004 1761 9803Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Jingxuan Shan
- grid.5386.8000000041936877XDepartment of Genetic Medicine, Weill Cornell Medicine, New York, NY USA
| | - Pu Li
- grid.412277.50000 0004 1760 6738Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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29
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Lin FY, Li J, Xie Y, Zhu J, Huong Nguyen TT, Zhang Y, Zhu J, Springer TA. A general chemical principle for creating closure-stabilizing integrin inhibitors. Cell 2022; 185:3533-3550.e27. [PMID: 36113427 PMCID: PMC9494814 DOI: 10.1016/j.cell.2022.08.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 07/07/2022] [Accepted: 08/04/2022] [Indexed: 01/26/2023]
Abstract
Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.
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Affiliation(s)
- Fu-Yang Lin
- Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jing Li
- Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yonghua Xie
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PRC
| | - Jianghai Zhu
- Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Thi Thu Huong Nguyen
- Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Yonghui Zhang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PRC.
| | - Jieqing Zhu
- Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
| | - Timothy A Springer
- Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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30
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Iglesias M, Brennan DC, Larsen CP, Raimondi G. Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection. Front Immunol 2022; 13:926648. [PMID: 36119093 PMCID: PMC9478663 DOI: 10.3389/fimmu.2022.926648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
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Affiliation(s)
- Marcos Iglesias
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christian P. Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Giorgio Raimondi
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
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31
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Succar BB, Saldanha-Gama RFG, Valle AS, Wermelinger LS, Barja-Fidalgo C, Kurtenbach E, Zingali RB. The recombinant disintegrin, jarastatin, inhibits platelet adhesion and endothelial cell migration. Toxicon 2022; 217:87-95. [PMID: 35981667 DOI: 10.1016/j.toxicon.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 07/16/2022] [Accepted: 08/10/2022] [Indexed: 11/19/2022]
Abstract
Integrins are transmembrane heterodimeric glycoproteins, present in most cell types that act as mechanoreceptors, connecting extracellular matrix proteins to the cytoskeleton of the cell, mediating several physiological and pathological processes. The disintegrins are peptides capable of modulating the activity of integrins, such as αIIbβ3, responsible for the platelet aggregation and αvβ3, related to angiogenesis. The aim of this study was to produce the recombinant disintegrin jarastatin (rJast), to evaluate its secondary structure and biological activity. rJast was expressed in the yeast Komagataella phaffii (earlier Pichia pastoris) purified using molecular exclusion chromatography and the internal sequence and molecular mass were confirmed by mass spectrometry. The yield was approximately 40 mg/L of culture. rJast inhibited platelet aggregation induced by 2-4 μM ADP, 10 nM thrombin, and 1 μg/mL collagen (IC50 of 244.8 nM, 166.3 nM and 223.5 nM, respectively). It also blocked the adhesion of platelets to collagen under continuous flow in approximately 60% when used 1 μM. We also evaluated the effect of rJast on HMEC-1 cells. rJast significantly inhibited the adhesion of these cells to vitronectin, as well as cell migration (IC50 1.77 μM) without changing the viability. Conclusions: rJast was successfully expressed with activity in human platelets aggregation identical to the native molecule. Also, rJast inhibits adhesion and migration of endothelial cells. Thus, being relevant for the development of anti-thrombotic and anti-angiogenic drugs.
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Affiliation(s)
- Barbara Barbosa Succar
- Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica Leopoldo de Meis, And Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (Inbeb) - Universidade Federal do Rio de Janeiro -UFRJ, RJ, Brazil
| | - Roberta F G Saldanha-Gama
- Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro - UERJ, RJ, Brazil
| | - Aline Sol Valle
- Laboratório de Biologia Molecular e Bioquímica de Proteínas, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro - UFRJ, RJ, Brazil
| | - Luciana Serrão Wermelinger
- Departamento de Análises Clínicas e Toxicológicas - Faculdade de Farmácia, Universidade Federal do Rio de Janeiro - UFRJ, RJ, Brazil
| | - Christina Barja-Fidalgo
- Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro - UERJ, RJ, Brazil
| | - Eleonora Kurtenbach
- Laboratório de Biologia Molecular e Bioquímica de Proteínas, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro - UFRJ, RJ, Brazil
| | - Russolina Benedeta Zingali
- Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica Leopoldo de Meis, And Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (Inbeb) - Universidade Federal do Rio de Janeiro -UFRJ, RJ, Brazil.
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32
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Yasmin F, Najeeb H, Shaikh S, Hasanain M, Naeem U, Moeed A, Koritala T, Hasan S, Surani S. Novel drug delivery systems for inflammatory bowel disease. World J Gastroenterol 2022; 28:1922-1933. [PMID: 35664964 PMCID: PMC9150062 DOI: 10.3748/wjg.v28.i18.1922] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/22/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic illness characterized by relapsing inflammation of the intestines. The disorder is stratified according to the severity and is marked by its two main phenotypical representations: Ulcerative colitis and Crohn's disease. Pathogenesis of the disease is ambiguous and is expected to have interactivity between genetic disposition, environmental factors such as bacterial agents, and dysregulated immune response. Treatment for IBD aims to reduce symptom extent and severity and halt disease progression. The mainstay drugs have been 5-aminosalicylates (5-ASAs), corticosteroids, and immunosuppressive agents. Parenteral, oral and rectal routes are the conventional methods of drug delivery, and among all, oral administration is most widely adopted. However, problems of systematic drug reactions and low specificity in delivering drugs to the inflamed sites have emerged with these regular routes of delivery. Novel drug delivery systems have been introduced to overcome several therapeutic obstacles and for localized drug delivery to target tissues. Enteric-coated microneedle pills, various nano-drug delivery techniques, prodrug systems, lipid-based vesicular systems, hybrid drug delivery systems, and biologic drug delivery systems constitute some of these novel methods. Microneedles are painless, they dislodge their content at the affected site, and their release can be prolonged. Recombinant bacteria such as genetically engineered Lactococcus Lactis and eukaryotic cells, including GM immune cells and red blood cells as nanoparticle carriers, can be plausible delivery methods when evaluating biologic systems. Nano-particle drug delivery systems consisting of various techniques are also employed as nanoparticles can penetrate through inflamed regions and adhere to the thick mucus of the diseased site. Prodrug systems such as 5-ASAs formulations or their derivatives are effective in reducing colonic damage. Liposomes can be modified with both hydrophilic and lipophilic particles and act as lipid-based vesicular systems, while hybrid drug delivery systems containing an internal nanoparticle section for loading drugs are potential routes too. Leukosomes are also considered as possible carrier systems, and results from mouse models have revealed that they control anti- and pro-inflammatory molecules.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Hala Najeeb
- Department of Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Shehryar Shaikh
- Department of Medicine, Dow OJha University Hospital, Karachi 74200, Pakistan
| | - Muhammad Hasanain
- Department of Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Unaiza Naeem
- Department of Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Abdul Moeed
- Department of Medicine, Dow University of Health Science, Karachi 74200, Pakistan
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic Health System, Mankato, MN 56001, United States
| | - Syedadeel Hasan
- Department of Medicine, University of Louisville, Louisville, KY 40292, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55901, United States
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33
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Joseph C, Tatler AL. Pathobiology of Airway Remodeling in Asthma: The Emerging Role of Integrins. J Asthma Allergy 2022; 15:595-610. [PMID: 35592385 PMCID: PMC9112045 DOI: 10.2147/jaa.s267222] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/25/2022] [Indexed: 12/19/2022] Open
Abstract
Airway remodeling is a complex clinical feature of asthma that involves long-term disruption and modification of airway architecture, which contributes significantly to airway hyperresponsiveness (AHR) and lung function decline. It is characterized by thickening of the airway smooth muscle layer, deposition of a matrix below the airway epithelium, resulting in subepithelial fibrosis, changes within the airway epithelium, leading to disruption of the barrier, and excessive mucous production and angiogenesis within the airway wall. Airway remodeling contributes to stiffer and less compliant airways in asthma and leads to persistent, irreversible airflow obstruction. Current asthma treatments aim to reduce airway inflammation and exacerbations but none are targeted towards airway remodeling. Inhibiting the development of airway remodeling or reversing established remodeling has the potential to dramatically improve symptoms and disease burden in asthmatic patients. Integrins are a family of transmembrane heterodimeric proteins that serve as the primary receptors for extracellular matrix (ECM) components, mediating cell-cell and cell-ECM interactions to initiate intracellular signaling cascades. Cells present within the lungs, including structural and inflammatory cells, express a wide and varying range of integrin heterodimer combinations and permutations. Integrins are emerging as an important regulator of inflammation, repair, remodeling, and fibrosis in the lung, particularly in chronic lung diseases such as asthma. Here, we provide a comprehensive summary of the current state of knowledge on integrins in the asthmatic airway and how these integrins promote the remodeling process, and emphasize their potential involvement in airway disease.
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Affiliation(s)
- Chitra Joseph
- Centre for Respiratory Research, National Institute for Health Research Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Amanda L Tatler
- Centre for Respiratory Research, National Institute for Health Research Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK
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Pritchard JR, Lee MJ, Peyton SR. Materials-driven approaches to understand extrinsic drug resistance in cancer. SOFT MATTER 2022; 18:3465-3472. [PMID: 35445686 PMCID: PMC9380814 DOI: 10.1039/d2sm00071g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Metastatic cancer has a poor prognosis, because it is broadly disseminated and associated with both intrinsic and acquired drug resistance. Critical unmet needs in effectively killing drug resistant cancer cells include overcoming the drug desensitization characteristics of some metastatic cancers/lesions, and tailoring therapeutic regimens to both the tumor microenvironment and the genetic profiles of the resident cancer cells. Bioengineers and materials scientists are developing technologies to determine how metastatic sites exclude therapies, and how extracellular factors (including cells, proteins, metabolites, extracellular matrix, and abiotic factors) at metastatic sites significantly affect drug pharmacodynamics. Two looming challenges are determining which feature, or combination of features, from the tumor microenvironment drive drug resistance, and what the relative impact is of extracellular signals vs. intrinsic cell genetics in determining drug response. Sophisticated systems biology tools that can de-convolve a crowded network of signals and responses, as well as controllable microenvironments capable of providing discrete and tunable extracellular cues can help us begin to interrogate the high dimensional interactions governing drug resistance in patients.
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Affiliation(s)
- Justin R Pritchard
- Department of Biomedical Engineering, Pennsylvania State University, State College PA, USA
| | - Michael J Lee
- Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Shelly R Peyton
- Department of Chemical Engineering, University of Massachusetts Amherst, 240 Thatcher Way, Life Sciences Laboratory N531, Amherst, MA 01003, USA.
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Combination Effect of Cilengitide with Erlotinib on TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Human Non-Small Cell Lung Cancer Cells. Int J Mol Sci 2022; 23:ijms23073423. [PMID: 35408781 PMCID: PMC8999066 DOI: 10.3390/ijms23073423] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is important for morphogenesis during development and is mainly induced by transforming growth factor (TGF)-β. In lung cancer, EMT is characterized by the transformation of cancer cells into a mobile, invasive form that can transit to other organs. Here, using a non–small cell lung cancer (NSCLC) cell line, we evaluated the EMT-related effects of the epidermal growth factor receptor inhibitor erlotinib alone and in combination with cilengitide, a cyclic RGD-based integrin antagonist. Erlotinib showed anti-proliferative and inhibitory effects against the TGF-β1–induced EMT phenotype in NSCLC cells. Compared with erlotinib alone, combination treatment with cilengitide led to an enhanced inhibitory effect on TGF-β1–induced expression of mesenchymal markers and invasion in non–small cell lung cancer A549 cells. These results suggest that cilengitide could improve anticancer drug efficacy and contribute to improved treatment strategies to inhibit and prevent EMT-based cancer progression.
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36
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Lagarrigue F, Tan B, Du Q, Fan Z, Lopez-Ramirez MA, Gingras AR, Wang H, Qi W, Sun H. Direct Binding of Rap1 to Talin1 and to MRL Proteins Promotes Integrin Activation in CD4 + T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1378-1388. [PMID: 35197328 PMCID: PMC9644409 DOI: 10.4049/jimmunol.2100843] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/27/2021] [Indexed: 12/26/2022]
Abstract
Agonist-induced Rap1 GTP loading results in integrin activation involved in T cell trafficking and functions. MRL proteins Rap1-interacting adapter molecule (RIAM) and lamellipodin (LPD) are Rap1 effectors that can recruit talin1 to integrins, resulting in integrin activation. Recent work also implicates direct Rap1-talin1 interaction in integrin activation. Here, we analyze in mice the connections between Rap1 and talin1 that support integrin activation in conventional CD4+ T (Tconv) and CD25HiFoxp3+CD4+ regulatory T (Treg) cells. Talin1(R35E, R118E) mutation that disrupts both Rap1 binding sites results in a partial defect in αLβ2, α4β1, and α4β7 integrin activation in both Tconv and Treg cells with resulting defects in T cell homing. Talin1(R35E,R118E) Tconv manifested reduced capacity to induce colitis in an adoptive transfer mouse model. Loss of RIAM exacerbates the defects in Treg cell function caused by the talin1(R35E,R118E) mutation, and deleting both MRL proteins in combination with talin1(R35E,R118E) phenocopy the complete lack of integrin activation observed in Rap1a/b-null Treg cells. In sum, these data reveal the functionally significant connections between Rap1 and talin1 that enable αLβ2, α4β1, and α4β7 integrin activation in CD4+ T cells.
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Affiliation(s)
- Frederic Lagarrigue
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, Toulouse, France
| | - Boyang Tan
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Qinyi Du
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Zhichao Fan
- Department of Immunology, School of Medicine, University of Connecticut, UConn Health, Farmington, CT
| | | | - Alexandre R Gingras
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Hsin Wang
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Weiwei Qi
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
| | - Hao Sun
- Department of Medicine, University of California, San Diego, La Jolla, CA; and
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Huynh TT, Sreekumar S, Mpoy C, Rogers BE. Therapeutic Efficacy of 177Lu-Labeled A20FMDV2 Peptides Targeting ανβ6. Pharmaceuticals (Basel) 2022; 15:ph15020229. [PMID: 35215341 PMCID: PMC8876964 DOI: 10.3390/ph15020229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 12/27/2022] Open
Abstract
Integrin ανβ6 promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting ανβ6 with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for ανβ6. However, one concern of these ανβ6 integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either 68Ga for imaging or 177Lu for therapy. PET imaging with [68Ga]Ga-DOTA-(PEG28)2-A20FMDV2 revealed specific tumor uptake in ανβ6-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)2-A20FMDV2 and IBA-DOTA-(PEG28)2-A20FMDV2 were radiolabeled with 177Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both 177Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an ανβ6-positive tumor.
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Affiliation(s)
- Truc Thao Huynh
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Sreeja Sreekumar
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
| | - Cedric Mpoy
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
| | - Buck Edward Rogers
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; (T.T.H.); (S.S.); (C.M.)
- Correspondence:
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38
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Moritz MNDO, Casali BC, Stotzer US, Karina dos Santos P, Selistre-de-Araujo HS. Alternagin-C, an alpha2beta1 integrin ligand, attenuates collagen-based adhesion, stimulating the metastasis suppressor 1 expression in triple-negative breast tumor cells. Toxicon 2022; 210:1-10. [DOI: 10.1016/j.toxicon.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/17/2022] [Accepted: 02/02/2022] [Indexed: 11/28/2022]
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The extracellular matrix of hematopoietic stem cell niches. Adv Drug Deliv Rev 2022; 181:114069. [PMID: 34838648 PMCID: PMC8860232 DOI: 10.1016/j.addr.2021.114069] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/18/2021] [Accepted: 11/21/2021] [Indexed: 12/21/2022]
Abstract
Comprehensive overview of different classes of ECM molecules in the HSC niche. Overview of current knowledge on role of biophysics of the HSC niche. Description of approaches to create artificial stem cell niches for several application. Importance of considering ECM in drug development and testing. Hematopoietic stem cells (HSCs) are the life-long source of all types of blood cells. Their function is controlled by their direct microenvironment, the HSC niche in the bone marrow. Although the importance of the extracellular matrix (ECM) in the niche by orchestrating niche architecture and cellular function is widely acknowledged, it is still underexplored. In this review, we provide a comprehensive overview of the ECM in HSC niches. For this purpose, we first briefly outline HSC niche biology and then review the role of the different classes of ECM molecules in the niche one by one and how they are perceived by cells. Matrix remodeling and the emerging importance of biophysics in HSC niche function are discussed. Finally, the application of the current knowledge of ECM in the niche in form of artificial HSC niches for HSC expansion or targeted differentiation as well as drug testing is reviewed.
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40
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Umbilical Cord Mesenchymal Stromal Cells for Cartilage Regeneration Applications. Stem Cells Int 2022; 2022:2454168. [PMID: 35035489 PMCID: PMC8758292 DOI: 10.1155/2022/2454168] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/13/2021] [Accepted: 11/23/2021] [Indexed: 11/30/2022] Open
Abstract
Chondropathies are increasing worldwide, but effective treatments are currently lacking. Mesenchymal stromal cell (MSCs) transplantation represents a promising approach to counteract the degenerative and inflammatory environment characterizing those pathologies, such as osteoarthritis (OA) and rheumatoid arthritis (RA). Umbilical cord- (UC-) MSCs gained increasing interest due to their multilineage differentiation potential, immunomodulatory, and anti-inflammatory properties as well as higher proliferation rates, abundant supply along with no risks for the donor compared to adult MSCs. In addition, UC-MSCs are physiologically adapted to survive in an ischemic and nutrient-poor environment as well as to produce an extracellular matrix (ECM) similar to that of the cartilage. All these characteristics make UC-MSCs a pivotal source for a stem cell-based treatment of chondropathies. In this review, the regenerative potential of UC-MSCs for the treatment of cartilage diseases will be discussed focusing on in vitro, in vivo, and clinical studies.
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41
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Yu J, Yang K, Zheng J, Sun X, Zhao W. Establishment of a novel prognostic signature based on an identified expression profile of integrin superfamily to predict overall survival of patients with colorectal adenocarcinoma. Gene 2022; 808:145990. [PMID: 34624456 DOI: 10.1016/j.gene.2021.145990] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/14/2021] [Accepted: 10/01/2021] [Indexed: 12/02/2022]
Abstract
The abnormal expression of integrin superfamily members commonly related to kinds of malignancies. However, the role of integrins in predicting the prognosis of cancers is still little known, especially for colorectal cancer that is one of the leading causes of cancer-related death. RNA-seq data and clinical features of colorectal adenocarcinoma (COAD) patients were derived from The Cancer Genome Atlas (TCGA), used to analyze the expression pattern and genomic alterations of integrin genes in the COAD cohort. Unsupervised hierarchical clustering divided COAD patients into two clusters (clusters 1 & 2), and we observed that patients in cluster 2 with high expressions of most integrin genes had worse clinical features and shorter overall survival (a median OS: 67.25 months vs 99.93 months, p = 0.012), compared to those in cluster 1. Combined with univariate Cox regression analysis, Pearson Correlation Coefficients (PCC), and Principal Component Analysis (PCA), an integrin-related signature was established, including ITGA1, ITGA5, ITGA7, ITGA11, ITGAX, ITGAM, ITGB1, and ITGB5. And the AUC values for OS at 1, 3, and 5 years was 0.61, 0.59, and 0.56, further demonstrating the predicting capacity of our signature. Furthermore, overexpression of which also significantly correlated with poorer prognosis of colon cancer patients in a separate validation cohort, GSE17536 (p < 0.05). Meanwhile, the AUC values for OS in the validation cohort at 1, 3, and 5 years was 0.62, 0.59, and 0.59. Additionally, enrichment analysis indicated significant differences between cluster 1 and cluster 2 in the biological processes of cell adhesion, signal transduction, extracellular matrix, immune system, and in tumor microenvironment (TME), which were crucial to the progression of tumor. The findings supplied compelling evidence that our signature could be a novel prognostic biomarker for COAD patients, and these genes had the potential to be therapeutic targets.
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Affiliation(s)
- Junhui Yu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China.
| | - Kui Yang
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China.
| | - Jianbao Zheng
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China.
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China.
| | - Wei Zhao
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, People's Republic of China.
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Kim JH, Kim S, Han S, Ahn EK, Cho YR, Jeong W, Kim SJ, Bae GU, Oh JS, Seo DW. Broussonin A- and B-mediated inhibition of angiogenesis by blockade of VEGFR-2 signalling pathways and integrin β1 expression. J Cell Mol Med 2022; 26:1194-1205. [PMID: 34994065 PMCID: PMC8831976 DOI: 10.1111/jcmm.17173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 11/28/2022] Open
Abstract
In the present study, we demonstrate the regulatory effects and mechanism of broussonin A and B, diphenylpropane derivatives isolated from Broussonetia kazinoki, on vascular endothelial growth factor‐A (VEGF‐A)–stimulated endothelial cell responses in vitro and microvessel sprouting ex vivo. Treatment with broussonin A or B suppressed VEGF‐A‐stimulated endothelial cell proliferation by regulating the expression of cell cycle–related proteins and the phosphorylation status of retinoblastoma protein. In addition, treatment with broussonin A or B abrogated VEGF‐A‐stimulated angiogenic responses including endothelial cell migration, invasion, tube formation and microvessel formation from rat aortic rings. These anti‐angiogenic activities of broussonin A and B were mediated through inactivation of VEGF‐A‐stimulated downstream signalling pathways, localization of vascular endothelial‐cadherin at cell‐cell contacts, and down‐regulation of integrin β1 and integrin‐liked kinase. Furthermore, treatment with broussonin A or B inhibited proliferation and invasion of non–small cell lung cancer and ovarian cancer cells. Taken together, our findings suggest the pharmacological potential of broussonin A and B in the regulation of angiogenesis, cancer cell growth and progression.
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Affiliation(s)
- Jae Hyeon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Sunho Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Surim Han
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Eun-Kyung Ahn
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Young-Rak Cho
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Wonsik Jeong
- Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Republic of Korea
| | - Sung Joon Kim
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Gyu-Un Bae
- Department of Pharmacy, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Joa Sub Oh
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
| | - Dong-Wan Seo
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Republic of Korea
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Lee LCC, Lo KKW. Strategic design of photofunctional transition metal complexes for cancer diagnosis and therapy. ADVANCES IN INORGANIC CHEMISTRY 2022. [DOI: 10.1016/bs.adioch.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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44
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Chang Z, Dang T, Meng X, Chai J. The Role of CCN1 in Esophageal Adenocarcinoma: What We Have Learned From the Lab. Cancer Control 2022; 29:10732748221074734. [PMID: 35291889 PMCID: PMC8935545 DOI: 10.1177/10732748221074734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: Esophageal cancer is one of the most common and deadliest cancers in the world, particularly esophageal adenocarcinoma. There has never been a special drug to treat it.Purpose: This article summarizes the work that we have done in our laboratory about the role of CCN1 in esophageal cancer and gives a new perspective of CCN1 biology.Research Design: This is a review article. Study Sample: The work was done using validated cell lines and fixed human tissue slides.Data Collection and Analysis: This is a review article, therefore, no data collection or analysis was involved.Results: CCN1 is a matricellular protein supporting adhesion, migration, and survival in normal cells, but in the esophageal cancer cells, it induces TRAIL-mediated apoptosis. CCN1 promotes TRAIL and its death receptor expression but downregulates the decoy receptors and survivin in a p53-dependant manner. It was thought that CCN1 relies on TNF to induce apoptosis, but our study found that these two molecules antagonize each other. CCN1 promotes TNFR1 cleavage and uses the soluble product to block TNF signaling, while TNF upregulates PGLYRP1 to overcome this obstacle because PGLYRP1 is a secreted protein that competes with TNF for TNFR1 binding. As a result, when CCN1 and TNF are present together in the vicinity of esophageal tumors, they cancel each other out.Conclusions: Based on our laboratory study, CCN1 has much potential to be a candidate for the treatment of esophageal cancer.
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Affiliation(s)
- Zhiheng Chang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Tong Dang
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Xianmei Meng
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Jianyuan Chai
- Inner Mongolia Institute of Digestive Diseases, Inner Mongolia Engineering Research Center for Prevention and Treatment of Digestive Diseases, Inner Mongolia University of Science and Technology, 74506The Second Affiliated Hospital of Baotou Medical College, Baotou, China.,Laboratory of Gastrointestinal Injury and Cancer, VA Long Beach Healthcare System, Long Beach, CA, USA.,College of Medicine, University of California, Irvine, CA, USA
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45
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Zhou J, Shen JY, Man XY, Li W, Chen JQ, Cai SQ, Zheng M. Differential Regulation of Integrin α5 and β4 in Normal and Psoriatic Epidermal Keratinocytes. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e19685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Jiong Zhou
- Zhejiang University School of Medicine, China
| | | | | | - Wei Li
- Zhejiang University School of Medicine, China
| | - Jia-Qi Chen
- Zhejiang University School of Medicine, China
| | | | - Min Zheng
- Zhejiang University School of Medicine, China
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Vasconcelos AA, Estrada JC, David V, Wermelinger LS, Almeida FCL, Zingali RB. Structure-Function Relationship of the Disintegrin Family: Sequence Signature and Integrin Interaction. Front Mol Biosci 2021; 8:783301. [PMID: 34926583 PMCID: PMC8678471 DOI: 10.3389/fmolb.2021.783301] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/11/2021] [Indexed: 01/09/2023] Open
Abstract
Disintegrins are small cysteine-rich proteins found in a variety of snake venom. These proteins selectively modulate integrin function, heterodimeric receptors involved in cell-cell and cell-matrix interaction that are widely studied as therapeutic targets. Snake venom disintegrins emerged from the snake venom metalloproteinase and are classified according to the sequence size and number of disulfide bonds. Evolutive structure and function diversification of disintegrin family involves a stepwise decrease in the polypeptide chain, loss of cysteine residues, and selectivity. Since the structure elucidation of echistatin, the description of the structural properties of disintegrins has allowed the investigation of the mechanisms involved in integrin-cell-extracellular matrix interaction. This review provides an analysis of the structures of all family groups enabling the description of an expanded classification of the disintegrin family in seven groups. Each group presents a particular disulfide pattern and sequence signatures, facilitating the identification of new disintegrins. The classification was based on the disintegrin-like domain of the human metalloproteinase (ADAM-10). We also present the sequence and structural signatures important for disintegrin-integrin interaction, unveiling the relationship between the structure and function of these proteins.
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Affiliation(s)
- Ariana A Vasconcelos
- Instituto de Bioquímica Médica (IBqM) Leopoldo de Meis, Centro Nacional de Ressonância Magnética Nuclear, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Centro Nacional de Ressonância Magnética Nuclear (CNRMN), Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jorge C Estrada
- Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica (IBqM) Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Victor David
- Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica (IBqM) Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luciana S Wermelinger
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabio C L Almeida
- Instituto de Bioquímica Médica (IBqM) Leopoldo de Meis, Centro Nacional de Ressonância Magnética Nuclear, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.,Centro Nacional de Ressonância Magnética Nuclear (CNRMN), Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Russolina B Zingali
- Laboratório de Hemostase e Venenos, Instituto de Bioquímica Médica (IBqM) Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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47
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Lucana MC, Arruga Y, Petrachi E, Roig A, Lucchi R, Oller-Salvia B. Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics. Pharmaceutics 2021; 13:2065. [PMID: 34959346 PMCID: PMC8708026 DOI: 10.3390/pharmaceutics13122065] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 12/20/2022] Open
Abstract
Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.
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Affiliation(s)
| | | | | | | | | | - Benjamí Oller-Salvia
- Grup d’Enginyeria de Materials (GEMAT), Institut Químic de Sarrià (IQS), Universitat Ramon Llull, 08017 Barcelona, Spain; (M.C.L.); (Y.A.); (E.P.); (A.R.); (R.L.)
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Péter B, Boldizsár I, Kovács GM, Erdei A, Bajtay Z, Vörös A, Ramsden JJ, Szabó I, Bősze S, Horvath R. Natural Compounds as Target Biomolecules in Cellular Adhesion and Migration: From Biomolecular Stimulation to Label-Free Discovery and Bioactivity-Based Isolation. Biomedicines 2021; 9:1781. [PMID: 34944597 PMCID: PMC8698624 DOI: 10.3390/biomedicines9121781] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 01/07/2023] Open
Abstract
Plants and fungi can be used for medical applications because of their accumulation of special bioactive metabolites. These substances might be beneficial to human health, exerting also anti-inflammatory and anticancer (antiproliferative) effects. We propose that they are mediated by influencing cellular adhesion and migration via various signaling pathways and by directly inactivating key cell adhesion surface receptor sites. The evidence for this proposition is reviewed (by summarizing the natural metabolites and their effects influencing cellular adhesion and migration), along with the classical measuring techniques used to gain such evidence. We systematize existing knowledge concerning the mechanisms of how natural metabolites affect adhesion and movement, and their role in gene expression as well. We conclude by highlighting the possibilities to screen natural compounds faster and more easily by applying new label-free methods, which also enable a far greater degree of quantification than the conventional methods used hitherto. We have systematically classified recent studies regarding the effects of natural compounds on cellular adhesion and movement, characterizing the active substances according to their organismal origin (plants, animals or fungi). Finally, we also summarize the results of recent studies and experiments on SARS-CoV-2 treatments by natural extracts affecting mainly the adhesion and entry of the virus.
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Affiliation(s)
- Beatrix Péter
- Nanobiosensorics Group, Research Centre for Energy Research, Institute for Technical Physics and Materials Science, Konkoly-Thege u 29-33, 1120 Budapest, Hungary; (A.V.); (R.H.)
| | - Imre Boldizsár
- Department of Plant Anatomy, Institute of Biology, Eötvös Loránd University, 1117 Budapest, Hungary; (I.B.); (G.M.K.)
- Department of Pharmacognosy, Semmelweis University, Üllői út 26, 1085 Budapest, Hungary
| | - Gábor M. Kovács
- Department of Plant Anatomy, Institute of Biology, Eötvös Loránd University, 1117 Budapest, Hungary; (I.B.); (G.M.K.)
- Plant Protection Institute, Centre for Agricultural Research, Hungarian Academy of Sciences, 1022 Budapest, Hungary
| | - Anna Erdei
- Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary; (A.E.); (Z.B.)
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, 1117 Budapest, Hungary
| | - Zsuzsa Bajtay
- Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary; (A.E.); (Z.B.)
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, 1117 Budapest, Hungary
| | - Alexandra Vörös
- Nanobiosensorics Group, Research Centre for Energy Research, Institute for Technical Physics and Materials Science, Konkoly-Thege u 29-33, 1120 Budapest, Hungary; (A.V.); (R.H.)
| | - Jeremy J. Ramsden
- Clore Laboratory, University of Buckingham, Buckingham MK18 1EG, UK;
| | - Ildikó Szabó
- MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary; (I.S.); (S.B.)
- National Public Health Center, Albert Flórián út 2-6, 1097 Budapest, Hungary
| | - Szilvia Bősze
- MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary; (I.S.); (S.B.)
- National Public Health Center, Albert Flórián út 2-6, 1097 Budapest, Hungary
| | - Robert Horvath
- Nanobiosensorics Group, Research Centre for Energy Research, Institute for Technical Physics and Materials Science, Konkoly-Thege u 29-33, 1120 Budapest, Hungary; (A.V.); (R.H.)
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Yokosaki Y, Nishimichi N. New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells. Int J Mol Sci 2021; 22:12794. [PMID: 34884600 PMCID: PMC8657911 DOI: 10.3390/ijms222312794] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/24/2022] Open
Abstract
A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, "disease specificity" has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, "disease specific" integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather "pathology specific" nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.
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Affiliation(s)
- Yasuyuki Yokosaki
- Integrin-Matrix Biomedical Science, Translational Research Center, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan;
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Li Y, Chen J, Bolinger AA, Chen H, Liu Z, Cong Y, Brasier AR, Pinchuk IV, Tian B, Zhou J. Target-Based Small Molecule Drug Discovery Towards Novel Therapeutics for Inflammatory Bowel Diseases. Inflamm Bowel Dis 2021; 27:S38-S62. [PMID: 34791293 DOI: 10.1093/ibd/izab190] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Indexed: 12/14/2022]
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a class of severe and chronic diseases of the gastrointestinal (GI) tract with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is a major contributing factor to neoplastic transformation and the development of colitis-associated colorectal cancer. Conversely, persistence of transmural inflammation in CD is associated with formation of fibrosing strictures, resulting in substantial morbidity. The recent introduction of biological response modifiers as IBD therapies, such as antibodies neutralizing tumor necrosis factor (TNF)-α, have replaced nonselective anti-inflammatory corticosteroids in disease management. However, a large proportion (~40%) of patients with the treatment of anti-TNF-α antibodies are discontinued or withdrawn from therapy because of (1) primary nonresponse, (2) secondary loss of response, (3) opportunistic infection, or (4) onset of cancer. Therefore, the development of novel and effective therapeutics targeting specific signaling pathways in the pathogenesis of IBD is urgently needed. In this comprehensive review, we summarize the recent advances in drug discovery of new small molecules in preclinical or clinical development for treating IBD that target biologically relevant pathways in mucosal inflammation. These include intracellular enzymes (Janus kinases, receptor interacting protein, phosphodiesterase 4, IκB kinase), integrins, G protein-coupled receptors (S1P, CCR9, CXCR4, CB2) and inflammasome mediators (NLRP3), etc. We will also discuss emerging evidence of a distinct mechanism of action, bromodomain-containing protein 4, an epigenetic regulator of pathways involved in the activation, communication, and trafficking of immune cells. We highlight their chemotypes, mode of actions, structure-activity relationships, characterizations, and their in vitro/in vivo activities and therapeutic potential. The perspectives on the relevant challenges, new opportunities, and future directions in this field are also discussed.
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Affiliation(s)
- Yi Li
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Jianping Chen
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Andrew A Bolinger
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Haiying Chen
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Zhiqing Liu
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Allan R Brasier
- Institute for Clinical and Translational Research (ICTR), University of Wisconsin, Madison, WI, USA
| | - Irina V Pinchuk
- Department of Medicine, Penn State Health Milton S. Hershey Medical Center, PA, USA
| | - Bing Tian
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
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