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Jing B, Gao Y, Wang L, Guo F, Jiang D, Qin S, He M, Bai Y, An R, Xie M, Zhang L. Probiotic membrane vesicles ameliorate atherosclerotic plaques by promoting lipid efflux and polarization of foamy macrophages. J Nanobiotechnology 2025; 23:296. [PMID: 40241138 PMCID: PMC12004830 DOI: 10.1186/s12951-025-03360-8] [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: 08/12/2024] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
Foamy macrophages are pivotal contributors to the development and progression of atherosclerotic plaques, posing a substantial threat to human health. Presently, there is no pharmaceutical intervention available to effectively eliminate foamy macrophages. In this study, we demonstrate that probiotic membrane vesicles (MVs) can induce atherosclerotic plaque regression by modulating foamy macrophages. MVs isolated from Lactobacillus rhamnosus exhibited a specific uptake by foamy macrophages. Near-infrared fluorescence (NIRF) imaging, aortic oil red O staining, and hematoxylin and eosin staining showed reductions in the plaque area following MVs treatment. Mechanistically, bioinformatics analysis provided insights into how MVs exert their effects, revealing that they promote lipid efflux and macrophage polarization. Notably, MVs treatment upregulated NR1H3, which in turn increased ABCA1 expression, facilitating lipid efflux from foamy macrophages. Moreover, MVs shifted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, highlighting their potential to create a more protective environment against plaque progression. This study is significant as it introduces MVs as a novel therapeutic platform for the targeted delivery of anti-inflammatory agents to atherosclerotic sites. By specifically modulating macrophage function, MVs hold considerable potential for the treatment of atherosclerosis and related cardiovascular diseases, addressing an unmet need in current therapeutic strategies.
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Affiliation(s)
- Boping Jing
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yu Gao
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lufang Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Feng Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Dawei Jiang
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Saimei Qin
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Mengrong He
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Ying Bai
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Rui An
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Mingxing Xie
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China.
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Li Zhang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, Hubei Province, China.
- Clinical Research Center for Medical Imaging in Hubei Province, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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Qin YS, Yi J, Chen YJ, Zhang W, Tang SF. Recent Advances in Micro/Nanomotor for the Therapy and Diagnosis of Atherosclerosis. ACS APPLIED MATERIALS & INTERFACES 2025; 17:11443-11468. [PMID: 39648908 DOI: 10.1021/acsami.4c15165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Atherosclerotic cardiovascular disease poses a significant global public health threat with a high incidence that can result in severe mortality and disability. The lack of targeted effects from traditional therapeutic drugs on atherosclerosis may cause damage to other organs and tissues, necessitating the need for a more focused approach to address this dilemma. Micro/nanomotors are self-propelled micro/nanoscale devices capable of converting external energy into autonomous movement, which offers advantages in enhancing penetration depth and retention while increasing contact area with abnormal sites, such as atherosclerotic plaque, inflammation, and thrombosis, within blood vessel walls. Recent studies have demonstrated the crucial role micro/nanomotors play in treating atherosclerotic cardiovascular disease. Hence, this review highlights the recent progress of micro/nanomotor technology in atherosclerotic cardiovascular disease, including the effective promotion of micro/nanomotors in the circulatory system, overcoming hemorheological barriers, targeting the atherosclerotic plaque microenvironment, and targeting intracellular drug delivery, to facilitate atherosclerotic plaque localization and therapy. Furthermore, we also describe the potential application of micro/nanomotors in the imaging of vulnerable plaque. Finally, we discuss key challenges and prospects for treating atherosclerotic cardiovascular disease while emphasizing the importance of designing individualized management strategies specific to its causes and microenvironmental factors.
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Affiliation(s)
- Yu-Sheng Qin
- Department of Laboratory Medicine, Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Guangxi Health Commission Key Laboratory of Clinical Biotechnology (Liuzhou People's Hospital), Liuzhou People's Hospital, Liuzhou 545006, China
| | - Juan Yi
- Department of Laboratory Medicine, Liuzhou Traditional Chinese Medical Hospital, The Third Affiliated Hospital of Guangxi University of Chinese Medicine, Liuzhou 545006, China
| | - Yan-Jun Chen
- Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Wei Zhang
- Department of Radiology, Liuzhou People's Hospital, Liuzhou 545006, China
| | - Shi-Fu Tang
- Department of Laboratory Medicine, Liuzhou Key Laboratory of Precision Medicine for Viral Diseases, Guangxi Health Commission Key Laboratory of Clinical Biotechnology (Liuzhou People's Hospital), Liuzhou People's Hospital, Liuzhou 545006, China
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Zhou Q, Wang Y, Si G, Chen X, Mu D, Zhang B. Application of Nanomaterials in Early Imaging and Advanced Treatment of Atherosclerosis. CHEMICAL & BIOMEDICAL IMAGING 2025; 3:51-76. [PMID: 40018650 PMCID: PMC11863161 DOI: 10.1021/cbmi.4c00064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 11/26/2024] [Accepted: 11/26/2024] [Indexed: 03/01/2025]
Abstract
Atherosclerosis (AS) is a serious disease that poses a significant threat to the global population. In this review, we analyze the development of AS from multiple perspectives, aiming to elucidate its molecular mechanisms. We also focus on imaging techniques and therapeutic approaches, highlighting the crucial role of nanomaterials in both imaging and therapy for AS. By leveraging their compatibility and targeting capabilities, nanomaterials can be integrated with traditional medical imaging and therapeutic agents to achieve targeted drug delivery, controlled release, and precise localization and imaging of atherosclerotic plaques.
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Affiliation(s)
- Qianru Zhou
- Department
of Radiology, Nanjing Drum Tower Hospital Clinical College of Traditional
Chinese and Western Medicine, Nanjing University
of Chinese Medicine, Nanjing 210008, China
| | - Yujie Wang
- Department
of Radiology, Nanjing Drum Tower Hospital
Clinical College of Jiangsu University, Nanjing 210008, China
| | - Guangxiang Si
- Jiangsu
Key Laboratory for Biomaterials and Devices, School of Biological
Science and Medical Engineering, Southeast
University, Nanjing 210000, China
| | - Xingbiao Chen
- Clinical
Science, Philips Healthcare, Shanghai 200233, China
| | - Dan Mu
- Department
of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of
Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing 210008, China
| | - Bing Zhang
- Department
of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of
Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing 210008, China
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Wang X, Chen X, Ji H, Han A, Wu C, Jiang J, Nie Y, Li C, Zhou X. Dual-Responsive Methotrexate-Human Serum Albumin Complex-Encapsulated Liposomes for Targeted and Enhanced Atherosclerosis Therapy. Int J Nanomedicine 2025; 20:2305-2322. [PMID: 40007906 PMCID: PMC11853999 DOI: 10.2147/ijn.s502850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
Introduction In plaque sites of atherosclerosis (AS), the physiological barrier caused by the thick fiber cap due to the overmigration of vascular smooth muscle cells (VSMCs) prevents efficient drug delivery to damaged macrophages. How to ensure precise targeted delivery of drugs to plaque sites and their on-demand release to dysfunctional cells under the thick fibrous cap are feasible solutions to enhance AS treatment. Methods A small complex of methotrexate (MTX)-human serum albumin (HSA) with strong, thick fibrous cap penetration ability was encapsulated in a cholesterol hemisuccinate (CHEM) prepared pH-sensitive liposome, modifying with ROS-responsive PEG2000-TK-DSPE (PTD), termed PTD/Lipo/MTX-HSA. Results PTD/Lipo/MTX-HSA can achieve precise targeting and on-demand release in response to plaques environments of AS. The designed formulation accelerated the release of the small-sized MTX-HSA complex in response to excess ROS and acidic pH conditions, and it better penetrated the macrophage spheroids. Furthermore, it has precise targeting ability in the AS mouse model and can produce good anti-inflammatory efficacy by inhibiting p65 entry into the nucleus turn out inflammatory factor. Conclusion Our formulations work with safety in mind, and it also highlights the potential of precisely targeted and on-demand-released dual-responsive smart nanoplatforms as promising therapeutic options to penetrate deeper plaques for the effective treatment of AS.
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Affiliation(s)
- Xueqin Wang
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
| | - Xiaodong Chen
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
| | - Huawen Ji
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
| | - Along Han
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic‒Inorganic Composites, State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of Bioprocess, Beijing University of Chemical Technology, Beijing, People’s Republic of China
| | - Chengxi Wu
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
| | - Jun Jiang
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yu Nie
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, People’s Republic of China
| | - Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, People’s Republic of China
| | - Xiangyu Zhou
- Department of Thyroid Surgery, Affiliated Hospital, Southwest Medical University, Luzhou, People’s Republic of China
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Yang Y, Dong M. Exploring the role of oxidative stress in carotid atherosclerosis: insights from transcriptomic data and single-cell sequencing combined with machine learning. Biol Direct 2025; 20:15. [PMID: 39881407 PMCID: PMC11780792 DOI: 10.1186/s13062-025-00600-7] [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: 09/20/2024] [Accepted: 01/07/2025] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Carotid atherosclerotic plaque is the primary cause of cardiovascular and cerebrovascular diseases. It is closely related to oxidative stress and immune inflammation. This bioinformatic study was conducted to identify key oxidative stress-related genes and key immune cell infiltration involved in the formation, progression, and stabilization of plaques and investigate the relationship between them. RESULTS We show that the up-regulation of oxidative stress-related genes such as IDH1 and CD36 in resident-like macrophages and foam macrophages play a key role in the formation and progression of carotid atherosclerotic plaques. CONCLUSIONS We discuss the role of oxidative stress and immune inflammation in the formation, progression, and stabilization of plaques by combining predictive models with analysis of single-cell data. It introduced novel insights into the mechanisms underlying carotid atherosclerosis formation and plaque progression and may assist in identifying potential therapeutic targets for their treatment.
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Affiliation(s)
- Yiqin Yang
- The Second School of Clinical Medicine, Shandong University, Jinan, China
| | - Mei Dong
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China.
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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Tang C, Wang H, Guo L, Cui Y, Zou C, Hu J, Zhang H, Yang G, Zhou W. Multifunctional Nanomedicine for Targeted Atherosclerosis Therapy: Activating Plaque Clearance Cascade and Suppressing Inflammation. ACS NANO 2025; 19:3339-3361. [PMID: 39812806 DOI: 10.1021/acsnano.4c12131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Atherosclerosis (AS) is a prevalent inflammatory vascular disease characterized by plaque formation, primarily composed of foam cells laden with lipids. Despite lipid-lowering therapies, effective plaque clearance remains challenging due to the overexpression of the CD47 molecule on apoptotic foam cells, inhibiting macrophage-mediated cellular efferocytosis and plaque resolution. Moreover, AS lesions are often associated with severe inflammation and oxidative stress, exacerbating disease progression. Herein, we introduce a multifunctional nanomedicine (CEZP) targeting AS pathogenesis via a "cell efferocytosis-lipid degradation-cholesterol efflux" paradigm, with additional anti-inflammatory properties. CEZP comprises poly(lactic-co-glycolic acid) nanoparticles encapsulated within a metal-organic framework shell coordinated with zinc ions (Zn2+) and epigallocatechin gallate (EGCG), enabling CpG encapsulation. Upon intravenous administration, CEZP accumulates at AS plaque sites, facilitating macrophage uptake and orchestrating AS treatment through synergistic mechanisms. CpG enhances cellular efferocytosis, Zn2+ promotes intracellular lipid degradation, and EGCG upregulates adenosine 5'-triphosphate-binding cassette transporters for cholesterol efflux while also exhibiting antioxidant and anti-inflammatory effects. In vivo validation confirms CEZP's ability to stabilize plaques, reduce lipid burden, and modulate the macrophage phenotype. Moreover, CEZP is excreted from the body without safety concerns, offering a low-toxicity nonsurgical strategy for AS plaque eradication.
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Affiliation(s)
- Cui Tang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Hui Wang
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Lina Guo
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, China
| | - Chan Zou
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Jianming Hu
- First Department of Pathology, Affiliated Hospital, Shihezi University, Xinjiang Uygur Autonomous Region, Shihezi City 832002, China
| | - Hanyong Zhang
- Academician Workstation, Changsha Medical University, Changsha 410219, China
| | - Guoping Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology, Changsha, Hunan 410000, China
- Hunan Engineering Research Center for Optimization of Drug Formulation and Early Clinical Evaluation, Changsha, Hunan 410013, China
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Academician Workstation, Changsha Medical University, Changsha 410219, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Affiliated Hospital, Shihezi University, Shihezi City, Xinjiang 832002, China
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Du H, Ma Y, Wang X, Zhang J, Zhu L, Guan G, Pan S, Zhang Y, Wang J, Liu Z. Therapeutic Suppression of Atherosclerotic Burden and Vulnerability via Dll4 Inhibition in Plaque Macrophages Using Dual-Targeted Liposomes. ACS APPLIED BIO MATERIALS 2024; 7:7219-7232. [PMID: 39392531 DOI: 10.1021/acsabm.4c00923] [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] [Indexed: 10/12/2024]
Abstract
Atherosclerosis, characterized by chronic inflammation within the arterial wall, remains a pivotal concern in cardiovascular health. We developed a dual-targeted liposomal system encapsulating Dll4-targeting siRNA, designed to selectively bind to pro-inflammatory M1 macrophages through surface conjugation with anti-F4/80 and anti-CD68 antibodies. The Dll4-targeting siRNA is then delivered to the macrophages, where it silences Dll4 expression, inhibiting Notch signaling and reducing plaque vulnerability. Emphasizing accuracy in targeting, the system demonstrates effective suppression of Dll4, a key modulator of atherosclerotic progression, and vulnerability via VSMCs phenotypic conversion and senescence. By employing liposomes for siRNA delivery, we observed enhanced stability and specificity of the siRNA. Alongside the therapeutic efficacy, our study also evaluated the safety profile and pharmacokinetics of the dual-targeted liposomal system, revealing favorable outcomes with minimal off-target effects and optimal biodistribution. The integration of RNA interference techniques with advanced nanotechnological methodologies signifies the importance of targeted delivery in this therapeutic approach. Preliminary findings suggest a potential attenuation in plaque development and vulnerability, indicating the therapeutic promise of this approach. This research emphasizes the potential of nanocarrier-mediated precision targeting combined with a reassuring safety and pharmacokinetic profile for advancing atherosclerosis therapeutic strategies.
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Affiliation(s)
- Haixia Du
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Department 403, PLA Rocket Force University of Engineering, Xi'an 710025, China
| | - Yanpeng Ma
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Xiqiang Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Junbo Zhang
- Department of Peripheral Vascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ling Zhu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Gongchang Guan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Shuo Pan
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Yong Zhang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Junkui Wang
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
| | - Zhongwei Liu
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Atherosclerosis Integrated Chinese and Western Medicine Key Research Laboratory, Research Office of Shaanxi Administration of Traditional Chinese Medicine, Xi'an 710003, China
- Traditional Chinese Medicine Inheritance and Innovation Platform, Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Northwestern Polytechnical University, Affiliated Shaanxi Provincial People's Hospital, Xi'an 710068, China
- Shaanxi Cardiovascular and Cerebrovascular Disease Precision Medicine "Belt and Road" Joint Laboratory, Xi'an 710068, China
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Chaiter Y, Fink DL, Machluf Y. Vascular medicine in the 21 st century: Embracing comprehensive vasculature evaluation and multidisciplinary treatment. World J Clin Cases 2024; 12:6032-6044. [PMID: 39328850 PMCID: PMC11326099 DOI: 10.12998/wjcc.v12.i27.6032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/25/2024] [Accepted: 07/10/2024] [Indexed: 07/29/2024] Open
Abstract
The field of vascular medicine has undergone a profound transformation in the 21st century, transforming our approach to assessment and treatment. Atherosclerosis, a complex inflammatory disease that affects medium and large arteries, presents a major challenge for researchers and healthcare professionals. This condition, characterized by arterial plaque formation and narrowing, poses substantial challenges to vascular health at individual, national, and global scales. Its repercussions are far-reaching, with clinical outcomes including ischemic heart disease, ischemic stroke, and peripheral arterial disease-conditions with escalating global prevalence. Early detection of vascular changes caused by atherosclerosis is crucial in preventing these conditions, reducing morbidity, and averting mortality. This article underscored the imperative of adopting a holistic approach to grappling with the intricacies, trajectories, and ramifications of atherosclerosis. It stresses the need for a thorough evaluation of the vasculature and the implementation of a multidisciplinary treatment approach. By considering the entire vascular system, healthcare providers can explore avenues for prevention, early detection, and effective management of this condition, ultimately leading to improved patient outcomes. We discussed current practices and proposed new directions made possible by emerging diagnostic modalities and treatment strategies. Additionally, we considered healthcare expenditure, resource allocation, and the transformative potential of new innovative treatments and technologies.
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Affiliation(s)
- Yoram Chaiter
- The Israeli Center for Emerging Technologies in Hospitals and Hospital-Based Health Technology Assessment, Shamir (Assaf Harofeh) Medical Center, Zerifin 7030100, Israel
| | - Daniel Lyon Fink
- Department of Pediatric Cardiology Unit, HaEmek Medical Center, Afula 1834111, Israel
| | - Yossy Machluf
- Shamir Research Institute, University of Haifa, Kazerin 1290000, Israel
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Chen L, Qu H, Liu B, Chen BC, Yang Z, Shi DZ, Zhang Y. Low or oscillatory shear stress and endothelial permeability in atherosclerosis. Front Physiol 2024; 15:1432719. [PMID: 39314624 PMCID: PMC11417040 DOI: 10.3389/fphys.2024.1432719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024] Open
Abstract
Endothelial shear stress is a tangential stress derived from the friction of the flowing blood on the endothelial surface of the arterial wall and is expressed in units of force/unit area (dyne/cm2). Branches and bends of arteries are exposed to complex blood flow patterns that generate low or oscillatory endothelial shear stress, which impairs glycocalyx integrity, cytoskeleton arrangement and endothelial junctions (adherens junctions, tight junctions, gap junctions), thus increasing endothelial permeability. The lipoproteins and inflammatory cells penetrating intima due to the increased endothelial permeability characterizes the pathological changes in early stage of atherosclerosis. Endothelial cells are critical sensors of shear stress, however, the mechanisms by which the complex shear stress regulate endothelial permeability in atherosclerosis remain unclear. In this review, we focus on the molecular mechanisms of the endothelial permeability induced by low or oscillatory shear stress, which will shed a novel sight in early stage of atherosclerosis.
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Affiliation(s)
- Li Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Hua Qu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- NMPA Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Beijing, China
| | - Bin Liu
- The First Affiliated Hospital, Hainan Medical University, Haikou, China
| | - Bing-Chang Chen
- Graduate school, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Zhen Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Da-Zhuo Shi
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Ying Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
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Tripathi S, Rani K, Raj VS, Ambasta RK. Drug repurposing: A multi targetted approach to treat cardiac disease from existing classical drugs to modern drug discovery. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 207:151-192. [PMID: 38942536 DOI: 10.1016/bs.pmbts.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Cardiovascular diseases (CVDs) are characterized by abnormalities in the heart, blood vessels, and blood flow. CVDs comprise a diverse set of health issues. There are several types of CVDs like stroke, endothelial dysfunction, thrombosis, atherosclerosis, plaque instability and heart failure. Identification of a new drug for heart disease takes longer duration and its safety efficacy test takes even longer duration of research and approval. This chapter explores drug repurposing, nano-therapy, and plant-based treatments for managing CVDs from existing drugs which saves time and safety issues with testing new drugs. Existing drugs like statins, ACE inhibitor, warfarin, beta blockers, aspirin and metformin have been found to be useful in treating cardiac disease. For better drug delivery, nano therapy is opening new avenues for cardiac research by targeting interleukin (IL), TNF and other proteins by proteome interactome analysis. Nanoparticles enable precise delivery to atherosclerotic plaques, inflammation areas, and damaged cardiac tissues. Advancements in nano therapeutic agents, such as drug-eluting stents and drug-loaded nanoparticles are transforming CVDs management. Plant-based treatments, containing phytochemicals from Botanical sources, have potential cardiovascular benefits. These phytochemicals can mitigate risk factors associated with CVDs. The integration of these strategies opens new avenues for personalized, effective, and minimally invasive cardiovascular care. Altogether, traditional drugs, phytochemicals along with nanoparticles can revolutionize the future cardiac health care by identifying their signaling pathway, mechanism and interactome analysis.
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Affiliation(s)
- Shyam Tripathi
- Centre for Drug Design Discovery and Development (C4D), Department of Biotechnology and Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat, Haryana, India
| | - Kusum Rani
- Centre for Drug Design Discovery and Development (C4D), Department of Biotechnology and Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat, Haryana, India
| | - V Samuel Raj
- Centre for Drug Design Discovery and Development (C4D), Department of Biotechnology and Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat, Haryana, India.
| | - Rashmi K Ambasta
- Centre for Drug Design Discovery and Development (C4D), Department of Biotechnology and Microbiology, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat, Haryana, India.
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Zeng M, Yang Y, Wang Z, Zhao X, Zhu D, Wang M, Chen Y, Wei X. CTRP9 prevents atherosclerosis progression through changing autophagic status of macrophages by activating USP22 mediated-de-ubiquitination on Sirt1 in vitro. Mol Cell Endocrinol 2024; 584:112161. [PMID: 38280475 DOI: 10.1016/j.mce.2024.112161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND Atherosclerosis (AS) is commonly regarded as a key driver accounted for the leading causes of morbidity and mortality among cardiovascular and cerebrovascular diseases. A growing body of evidence indicates that autophagy in macrophages involved in AS might be a potential therapeutic target. C1q/TNF-related protein 9 (CTRP9) has been proven to delay the progression of cardiovascular diseases. However, the relations between CTRP9 and Sirt1, as well as their effects on macrophages autophagy have not been fully explored. METHODS Macrophages were differentiated from mononuclear cells collected from peripheral blood samples of healthy donors. The in vitro AS models were constructed by ox-LDL treatment. Cell viability was determined by CCK-8 assay. Immunofluorescence assay of LC3 was implemented for evaluating autophagy activity. Oil Red O staining was performed for lipid accumulation detection. ELISA, cholesterol concentration assay and cholesterol efflux analysis were conducted using commercial kits. Cycloheximide assay was implemented for revealing protein stability. RT-qPCR was used for mRNA expression detection, and western blotting was performed for protein level monitoring. RESULTS CTRP9 attenuated impaired cell viability, autophagy inhibition and increased lipid accumulation induced by ox-LDL. Moreover, CTRP9 maintained Sirt1 protein level through enhancing its stability through de-ubiquitination, which was mediated by upregulated USP22 level. CRTP9 exerted its protective role in promoting autophagy and reducing lipid accumulation through the USP22/Sirt1 axis. CONCLUSION Collectively, CTRP9 alleviates lipid accumulation and facilitated the macrophages autophagy by upregulating USP22 level and maintaining Sirt1 protein expression, thereby exerting a protective role in AS progression in vitro.
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Affiliation(s)
- Min Zeng
- Medical Center, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, Hainan Province, PR China.
| | - Yali Yang
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Ziyan Wang
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Xiuyang Zhao
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Dianshu Zhu
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Mengdi Wang
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Yue Chen
- Hainan Medical University, Haikou, 570311, Hainan Province, PR China
| | - Xin Wei
- Otolaryngology Department, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, Hainan Province, PR China.
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12
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Amani A, Farajollahi AH. Drug Delivery Angle for Various Atherosclerosis and Aneurysm Percentages of the Carotid Artery. Mol Pharm 2024; 21:1777-1793. [PMID: 38478900 DOI: 10.1021/acs.molpharmaceut.3c01109] [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] [Indexed: 04/04/2024]
Abstract
Stroke is the second cause of mortality among adult males and the first cause of death in adult females all around the world. It is also recognized as one of the most important causes of morbidity and dementia in adults. Stenosis or rupture of the only channels of the blood supply from the heart to the brain (carotid arteries) is among the main causes of stroke. In this regard, treatment of the lesions of carotid arteries, including atherosclerosis and aneurysm, could be a huge step in preventing stroke and improving brain performance. Targeted drug delivery by drug-carrying nanoparticles is the latest method for optimal delivery of drug to the damaged parts of the artery. In this study, a wide range of carotid artery lesions, including different percentages of atherosclerosis and aneurysm, were considered. After analyzing the dynamics of the fluid flow in different damaged regions and selecting the magnetic framework with proper ligand (Fe3O4@MOF) as the drug carrier, the size of the particles and their number per cycle were analyzed. Based on the results, the particle size of 100 nm and the use of 300 particles per injection at each cardiac cycle can result in maximum drug delivery to the target site. Then, the effect of the hospital bed angle on drug delivery was investigated. The results showed a unique optimal drug delivery angle for each extent of atherosclerosis or aneurysm. For example, in a 50% aneurysm, drug delivery at an angle of 30° is about 387% higher than that at an angle of 15°. Finally, simulation of real geometry indicated the effectiveness of simple geometry instead of real geometry for the simulation of carotid arteries, which can remarkably decrease the computational time and costs.
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Affiliation(s)
- Ali Amani
- School of Mechanical Engineering, Sharif University of Technology, Tehran 11155-9466, Iran
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13
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Zou L, Zhang Y, Cheraga N, Abodunrin OD, Qu KY, Qiao L, Ma YQ, Hang Y, Huang NP, Chen LJ. M2 Macrophage Membrane-Camouflaged Fe 3 O 4 -Cy7 Nanoparticles with Reduced Immunogenicity for Targeted NIR/MR Imaging of Atherosclerosis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2304110. [PMID: 37806756 DOI: 10.1002/smll.202304110] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/27/2023] [Indexed: 10/10/2023]
Abstract
Atherosclerosis （AS） is the primary reason behind cardiovascular diseases, leading to approximately one-third of global deaths. Developing a novel multi-model probe to detect AS is urgently required. Macrophages are the primary cells from which AS genesis occurs. Utilizing natural macrophage membranes coated on the surface of nanoparticles is an efficient delivery method to target plaque sites. Herein, Fe3 O4 -Cy7 nanoparticles (Fe3 O4 -Cy7 NPs), functionalized using an M2 macrophage membrane and a liposome extruder for Near-infrared fluorescence and Magnetic resonance imaging, are synthesized. These macrophage membrane-coated nanoparticles (Fe3 O4 @M2 NPs) enhance the recognition and uptake using active macrophages. Moreover, they inhibit uptake using inactive macrophages and human coronary artery endothelial cells. The macrophage membrane-coated nanoparticles (Fe3 O4 @M0 NPs, Fe3 O4 @M1 NPs, Fe3 O4 @M2 NPs) can target specific sites depending on the macrophage membrane type and are related to C-C chemofactor receptor type 2 protein content. Moreover, Fe3 O4 @M2 NPs demonstrate excellent biosafety in vivo after injection, showing a significantly higher Fe concentration in the blood than Fe3 O4 -Cy7 NPs. Therefore, Fe3 O4 @M2 NPs effectively retain the physicochemical properties of nanoparticles and depict reduced immunological response in blood circulation. These NPs mainly reveal enhanced targeting imaging capability for atherosclerotic plaque lesions.
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Affiliation(s)
- Lin Zou
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Yao Zhang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 210009, Nanjing, China
| | - Nihad Cheraga
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Oluwatosin David Abodunrin
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Kai-Yun Qu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Li Qiao
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Yu-Qing Ma
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Yue Hang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Ning-Ping Huang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, 210096, Nanjing, China
| | - Li-Juan Chen
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 210009, Nanjing, China
- Department of Cardiology, Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, 211200, Nanjing, China
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14
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Tang C, Wang H, Guo L, Zou C, Hu J, Zhang H, Zhou W, Yang G. CpG-Conjugated Silver Nanoparticles as a Multifunctional Nanomedicine to Promote Macrophage Efferocytosis and Repolarization for Atherosclerosis Therapy. ACS APPLIED MATERIALS & INTERFACES 2023. [PMID: 37910772 DOI: 10.1021/acsami.3c11227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Atherosclerosis (AS) is a major contributor to cardiovascular diseases, necessitating the development of novel therapeutic strategies to alleviate plaque burden. Macrophage efferocytosis, the process by which macrophages clear apoptotic and foam cells, plays a crucial role in plaque regression. However, this process is impaired in AS lesions due to the overexpression of CD47, which produces a "do not eat me" signal. In this study, we investigated the potential of CpG, a toll-like receptor 9 agonist, to enhance macrophage efferocytosis for AS therapy. We demonstrated that CpG treatment promoted the engulfment of CD47-positive apoptotic cells and foam cells by macrophages. Mechanistically, CpG induced a metabolic shift in macrophages characterized by enhanced fatty acid oxidation and de novo lipid biosynthesis, contributing to its pro-efferocytic effect. To enable in vivo application, we conjugated CpG on silver nanoparticles (AgNPs) to form CpG-AgNPs, which could protect CpG from biological degradation, promote its cellular uptake, and release CpG in response to intracellular glutathione. Combining the intrinsic antioxidative and anti-inflammatory abilities of AgNPs, such nanomedicine displayed multifunctionalities to simultaneously promote macrophage efferocytosis and repolarization. In an ApoE-/- mouse model, intravenous administration of CpG-AgNPs effectively targeted atherosclerotic plaques and exhibited potent therapeutic efficacy with excellent biocompatibility. Our study provides valuable insights into CpG-induced macrophage efferocytosis and highlights the potential of CpG-AgNPs as a promising therapeutic strategy for AS.
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Affiliation(s)
- Cui Tang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Hui Wang
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Lina Guo
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Chan Zou
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Jianming Hu
- First Department of Pathology, Affiliated Hospital, Shihezi University, Shihezi City 832002, Xinjiang Uygur Autonomous Region, China
| | - Hanyong Zhang
- Academician Workstation, Changsha Medical University, Changsha 410219, China
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Academician Workstation, Changsha Medical University, Changsha 410219, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Affiliated Hospital, Shihezi University, Shihezi City, Xinjiang 832002, China
| | - Guoping Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
- National-Local Joint Engineering Laboratory of Drug Clinical Evaluation Technology, Changsha, Hunan 410000, China
- Hunan Engineering Research Center for Optimization of Drug Formulation and Early Clinical Evaluation, Changsha, Hunan 410013, China
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Liu Y, Wu H, Wang T, Shi X, He H, Huang H, Yang Y, Dai M. Paeonol reduces microbial metabolite α-hydroxyisobutyric acid to alleviate the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in atherosclerosis mice. Chin J Nat Med 2023; 21:759-774. [PMID: 37879794 DOI: 10.1016/s1875-5364(23)60506-0] [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: 08/12/2023] [Indexed: 10/27/2023]
Abstract
Gut microbiota dysbiosis is an avenue for the promotion of atherosclerosis (AS) and this effect is mediated partly via the circulating microbial metabolites. More microbial metabolites related to AS vascular inflammation, and the mechanisms involved need to be clarified urgently. Paeonol (Pae) is an active compound isolated from Paeonia suffruticoas Andr. with anti-AS inflammation effect. However, considering the low oral bioavailability of Pae, it is worth exploring the mechanism by which Pae reduces the harmful metabolites of the gut microbiota to alleviate AS. In this study, ApoE-/- mice were fed a high-fat diet (HFD) to establish an AS model. AS mice were administrated with Pae (200 or 400 mg·kg-1) by oral gavage and fecal microbiota transplantation (FMT) was conducted. 16S rDNA sequencing was performed to investigate the composition of the gut microbiota, while metabolomics analysis was used to identify the metabolites in serum and cecal contents. The results indicated that Pae significantly improved AS by regulating gut microbiota composition and microbiota metabolic profile in AS mice. We also identified α-hydroxyisobutyric acid (HIBA) as a harmful microbial metabolite reduced by Pae. HIBA supplementation in drinking water promoted AS inflammation in AS mice. Furthermore, vascular endothelial cells (VECs) were cultured and stimulated by HIBA. We verified that HIBA stimulation increased intracellular ROS levels, thereby inducing VEC inflammation via the TXNIP/NLRP3 pathway. In sum, Pae reduces the production of the microbial metabolite HIBA, thus alleviating the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in AS. Our study innovatively confirms the mechanism by which Pae reduces the harmful metabolites of gut microbiota to alleviate AS and proposes HIBA as a potential biomarker for AS clinical judgment.
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Affiliation(s)
- Yarong Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei 230012, China
| | - Hongfei Wu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei 230012, China
| | - Tian Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Xiaoyan Shi
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Hai He
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Hanwen Huang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Yulong Yang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Min Dai
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Hefei 230012, China.
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16
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Shen M, Jiang H, Zhao Y, Wu L, Yang H, Yao Y, Meng H, Yang Q, Liu L, Li Y. Shear Stress and ROS Dual-Responsive RBC-Hitchhiking Nanoparticles for Atherosclerosis Therapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:43374-43386. [PMID: 37669139 DOI: 10.1021/acsami.3c07371] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Atherosclerosis (AS), a leading cause of death worldwide, is a chronic inflammatory disease rich in lipids and reactive oxygen species (ROS) within plaques. Therefore, lowering lipid and ROS levels is effective in treating AS and reducing AS-induced mortality. In this study, an intelligent biomimetic drug delivery system that specifically responded to both shear stress and ROS microenvironment was developed, consisting of red blood cells (RBCs) and cross-linked polyethyleneimine nanoparticles (SA PEI) loaded with a lipid-lowering drug simvastatin acid (SA), and RBCs were self-assembled with SA PEI to obtain biresponsive SA PEI@RBCs for the treatment of AS. SA PEI could achieve sustained release of SA in response to ROS and reduce ROS and lipid levels to achieve the purpose of treating AS. Shear stress model experiments showed that SA PEI@RBCs could respond to the high shear stress level (100 dynes/cm2) at plaques, realizing the desorption and enrichment of SA PEI and improving the therapeutic efficiency of SA PEI@RBCs. In vitro and in vivo experiments have confirmed that SA PEI@RBCs exhibits better in vivo safety and therapeutic efficacy than SA PEI and free SA. Therefore, shaping SA PEI@RBCs into a biomimetic drug delivery system with dual sensitivity to ROS and shear stress is an effective strategy and treatment to facilitate their delivery into plaques.
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Affiliation(s)
- Meili Shen
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin, China
| | - Hui Jiang
- Department of Blood Purification, Tong Liao City Hospital, Tong Liao 028000, Inner Mongolia, China
| | - Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin, China
| | - Liangqiang Wu
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
| | - Haiqin Yang
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
| | - Yixuan Yao
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
| | - Hao Meng
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin, China
| | - Qingbiao Yang
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
| | - Linlin Liu
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin, China
| | - Yapeng Li
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, Jilin, China
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Du Z, Zhao X, Sun L, Chi B, Ma Z, Tian Z, Liu Y. Untargeted lipidomics-based study reveals the treatment mechanism of Qingxue Bawei tablets on atherosclerotic in ApoE -/- mice. J Chromatogr B Analyt Technol Biomed Life Sci 2023; 1229:123889. [PMID: 37738809 DOI: 10.1016/j.jchromb.2023.123889] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/24/2023]
Abstract
Qingxue Bawei (QXBW) tablets, a Mongolian medicine prescription, have proved to possess good lipid-lowering and antihypertensive effects in previous studies. However, the therapeutic effects and potential mechanisms of QXBW tablets on atherosclerosis (AS) have not been well studied yet. This study aimed to investigate the potential liver-protective mechanism of QXBW tablets on AS mice by hepatic lipidomics analysis. After 10 weeks of administration, serum and liver were collected for biochemical, histopathological, and lipid metabolomics analysis to evaluate the efficacy of the QXBW tablets on high-fat diet (HFD) induced mice. The experimental results indicated that QXBW tablets could ameliorate liver injury and inflammatory response in AS mice. Liver lipid data from different groups of mice were collected by UPLC-Q-Orbitrap-MS, and a total of 22 potential biomarkers with significant differences between the model and control groups were identified finally, of which 16 potential biomarkers were back-regulated after the QXBW tablets intervention. These 22 potential differential metabolic markers were mainly involved in glycerolipid metabolism, glycerophospholipid metabolism, and cholesterol ester metabolism pathways. The results of this study showed that serum inflammatory factors, liver function indices, and lipid metabolism disorders were positively alleviated in AS mice after QXBW tablets treatment.
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Affiliation(s)
- Zhen Du
- Innovation Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Xin Zhao
- Pharmacy Department of Boshan District Hospital, Zibo City, Shandong Province, Zibo 255000, China
| | - Luping Sun
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Bingqing Chi
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Zhen Ma
- Innovation Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Zhenhua Tian
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Yuecheng Liu
- Shandong Academy of Chinese Medicine, Jinan 250014, China.
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Liu Y, He M, Yuan Y, Nie C, Wei K, Zhang T, Chen T, Chu X. Neutrophil-Membrane-Coated Biomineralized Metal-Organic Framework Nanoparticles for Atherosclerosis Treatment by Targeting Gene Silencing. ACS NANO 2023; 17:7721-7732. [PMID: 37023215 DOI: 10.1021/acsnano.3c00288] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Antisense oligonucleotides (ASOs) are promising tools for gene silencing and have been exploited as therapeutics for human disease. However, delivery of therapeutic ASOs to diseased tissues or cells and subsequent escape from the endosomes and release of ASO in the cytosol remain a challenge. Here, we reported a neutrophil-membrane-coated zeolitic imidazolate framework-8 (ZIF-8) nanodelivery platform (AM@ZIF@NM) for the targeted transportation of ASOs against microRNA-155 (anti-miRNA-155) to the endothelial cells in atherosclerotic lesions. Neutrophil membrane could improve plaque endothelial cells targeting through the interaction between neutrophil membrane protein CD18 and endothelial cell membrane protein intercellular adhesion molecule-1 (ICAM-1). The ZIF-8 "core" provided high loading capacity and efficient endolysosomal escaping ability. Delivery of anti-miR-155 effectively downregulated miR-155 expression and also saved the expression of its target gene BCL6. Moreover, RELA expression and the expression of its downstream target genes CCL2 and ICAM-1 were correspondingly reduced. Consequently, this anti-miR-155 nanotherapy can inhibit the inflammation of atherosclerotic lesions and alleviate atherosclerosis. Our study shows that the designed biomimetic nanodelivery system has great application prospects in the treatment of other chronic diseases.
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Affiliation(s)
- Yi Liu
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Mengyun He
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Yi Yuan
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Cunpeng Nie
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Kaiji Wei
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Tong Zhang
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Tingting Chen
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Xia Chu
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
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Tang Y, Jin L, Qi W, Gao Y, Xie Y, Xie X, Lv J, Jiang Z, Jiang H, Fan C, Yan J. N-acetyl-L-cysteine attenuated the toxicity of ZIF-8 on EA.hy926 endothelial cells by wnt/β-catenin pathway. Toxicol In Vitro 2023; 88:105553. [PMID: 36634885 DOI: 10.1016/j.tiv.2023.105553] [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: 09/13/2022] [Revised: 01/07/2023] [Accepted: 01/07/2023] [Indexed: 01/11/2023]
Abstract
As kinds of porous crystalline compounds, zeolitic imidazolate frameworks (ZIFs) have been developed quickly and attracted considerable attention for use in nano drug delivery systems, which raised concerns about cardiovascular disorders. At the present, the cytotoxic mechanism of ZIFs in cardiovascular disorders was still unclear. Our experiment explored the toxicity of ZIF-8, a typical kind of ZIFs, on human EA.hy926 vascular endothelial cells. The cell viability, ROS formation, apoptosis level, inflammatory response level, wound healing ability and atherosclerosis-related indicators of EA.hy926 endothelial cells were analyzed after ZIF-8 treatment. Meanwhile, we evaluated the ability of antioxidant N-Acetyl-L-cysteine (NAC) to attenuate the toxicity of ZIF-8 on EA.hy926 endothelial cells. As results, NAC attenuated ROS formation, cell apoptosis, LDH formation and endothelial dysfunction caused by ZIF-8. As the Wnt/β-catenin pathway was involved in endothelial cell dysfunction, we also studied the expression level of β-catenin and LEF1 in ZIF-8 and/or NAC treated EA.hy926 cells. As expected, ZIF-8 increased the protein expressions of β-catenin and LEF1in the IC50 group, which was significantly inhibited by co-treatment with NAC. Taken together, this study could help improve our understanding about the mechanism of ZIF-8-induced endothelial cells injury and NAC had therapeutic potential in preventing ZIF-8-associated endothelial dysfunction by wnt/β-catenin pathway.
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Affiliation(s)
- Yaxin Tang
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Lifang Jin
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China; Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University, Shaoxing, Zhejiang, China
| | - Wenwen Qi
- Xiangzhou District People's Hospital, Xiangyang, Hubei, China
| | - Yue Gao
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yixia Xie
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Xueying Xie
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Jianan Lv
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhikai Jiang
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - He Jiang
- The First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, China
| | - Caixia Fan
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China.
| | - Junyan Yan
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China.
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Montelione N, Loreni F, Nenna A, Catanese V, Scurto L, Ferrisi C, Jawabra M, Gabellini T, Codispoti FA, Spinelli F, Chello M, Stilo F. Tissue Engineering and Targeted Drug Delivery in Cardiovascular Disease: The Role of Polymer Nanocarrier for Statin Therapy. Biomedicines 2023; 11:798. [PMID: 36979777 PMCID: PMC10045667 DOI: 10.3390/biomedicines11030798] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/09/2023] Open
Abstract
Atherosclerosis-related coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. This requires effective primary and secondary prevention in reducing the complications related to CAD; the regression or stabilization of the pathology remains the mainstay of treatment. Statins have proved to be the most effective treatment in reducing adverse effects, but there are limitations related to the administration and achievement of effective doses as well as side effects due to the lack of target-related molecular specificity. The implemented technological steps are polymers and nanoparticles for the administration of statins, as it has been seen how the conjugation of drug delivery systems (DDSs) with statins increases bioavailability by circumventing the hepatic-renal filter and increases the related target specificity, enhancing their action and decreasing side effects. Reduction of endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth, and increased reendothelialization are all drug-related effects of statins enhanced by binding with DDSs. Recent preclinical studies demonstrate how the effect of statins stimulates the differentiation of endogenous cardiac stem cells. Poly-lactic-co-glycolic acid (PLGA) seems to be the most promising DDS as it succeeds more than the others in enhancing the effect of the bound drug. This review intends to summarize the current evidence on polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.
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Affiliation(s)
- Nunzio Montelione
- Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Francesco Loreni
- Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Antonio Nenna
- Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Vincenzo Catanese
- Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Lucia Scurto
- Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Chiara Ferrisi
- Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Mohamad Jawabra
- Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Teresa Gabellini
- Residency Program of Vascular and Endovascular Surgery, University of Ferrara, 44121 Ferrara, Italy
| | | | - Francesco Spinelli
- Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Massimo Chello
- Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Francesco Stilo
- Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
- Head of Research Unit of Vascular Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
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Wu H, Dai R, Wang M, Chen C. Uric acid promotes myocardial infarction injury via activating pyrin domain-containing 3 inflammasome and reactive oxygen species/transient receptor potential melastatin 2/Ca 2+pathway. BMC Cardiovasc Disord 2023; 23:10. [PMID: 36627567 PMCID: PMC9830724 DOI: 10.1186/s12872-023-03040-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Cardiomyocytes injury has been considered as a key contributor for myocardial infarction (MI). Uric acid (UA) can induce cardiomyocytes injury, which is closely related to NLRP3 activation and inflammatory factor generation. However, the mechanism how UA modulates cardiomyocytes remains elusive. Western blotting and qRT-PCR were applied for measuring protein and mRNA expression, respectively. ROS production and Ca2+ influx were measured by flow cytometry. Patch clamp technique was used for measuring transient receptor potential melastatin 2 (TRPM2) channel. Ligation of left anterior descending for 2 h was performed to induce MI animal model. The rats were treated by different concentration of uric acid. The artery tissues were stained by HE and collected for measurement of NLRP3 and inflammatory factors. Supplementation of UA significantly promoted apoptosis, and augmented the expression of intercellular adhesion molecule-1, chemoattractant protein-1, vascular cell adhesion molecule-1, and NLRP3 inflammasome. Knockdown of NLRP3 reversed the influence of UA on MI by decreasing collagen deposition, fibrotic area, apoptosis. The expression of NLRP3 inflammasome increased markedly after treatment of UA. UA activated ROS/TRPM2/Ca2+ pathway through targeting NLRP3. UA activated NLRP3 inflammasome and augments inflammatory factor production, which in turn exacerbates cardiomyocytes injury. Knockdown of NLRP3 reversed the influence of UA on apoptosis and cell cycle. UA may promote cardiomyocytes injury through activating NLRP3 inflammasome and ROS/TRPM2 channel/Ca2+ pathway.
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Affiliation(s)
- Haiyun Wu
- grid.412683.a0000 0004 1758 0400Department of Cardiology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Quanzhou, 362000 China
| | - Ruozhu Dai
- grid.412683.a0000 0004 1758 0400Department of Cardiology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Quanzhou, 362000 China
| | - Min Wang
- grid.412683.a0000 0004 1758 0400Department of Cardiology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Quanzhou, 362000 China
| | - Chengbo Chen
- grid.412683.a0000 0004 1758 0400Department of Cardiology, Quanzhou First Hospital Affiliated to Fujian Medical University, No. 250 East Street, Quanzhou, 362000 China
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22
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Tu Y, Ma X, Chen H, Fan Y, Jiang L, Zhang R, Cheng Z. Molecular Imaging of Matrix Metalloproteinase-2 in Atherosclerosis Using a Smart Multifunctional PET/MRI Nanoparticle. Int J Nanomedicine 2022; 17:6773-6789. [PMID: 36600879 PMCID: PMC9805955 DOI: 10.2147/ijn.s385679] [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: 09/04/2022] [Accepted: 11/09/2022] [Indexed: 12/29/2022] Open
Abstract
Background Matrix metalloproteinases from macrophages are important intraplaque components that play pivotal roles in plaque progression and regression. This study sought to develop a novel multifunctional positron emission tomography (PET) and magnetic resonance imaging (MRI) contrast agents based on MMP-2 cleavable nanoparticles to noninvasive assessment of MMP-2 activity in mouse carotid atherosclerotic plaques. Results Macrophage-rich vascular lesions were induced by carotid ligation plus high-fat diet and streptozotocin-induced diabetes in CL57/BL6 mice. To render iron oxide nanoparticles (IONP) specific for the extracellular MMP-2, the magnetic nanoparticle base material has been derivatized with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for the nuclear tracer 64Cu labeling and the MMP-2-cleavable peptide modified with polyethylene glycol 2000, yielding a multi-modality reporter (64Cu-NOTA-IONP@MMP2c-PEG2K, MMP2cNPs) for PET/MR imaging. Small animal PET imaging and biodistribution data revealed that MMP2cNPs exhibited remarkable plaque uptake (3.06 ± 0.87% ID/g and 1.83 ± 0.28% ID/g at 4 and 12 h, respectively). And MMP2cNPs were rapidly cleared from the contralateral normal carotid artery, resulting in excellent plaque-to-normal carotid artery contrasts. Furthermore, in vivo MRI showed a preferential accumulation of MMP2cNPs in atherosclerotic lesions compared with the non-cleavable reference compound, MMP2ncNPs. In addition, histological analyses revealed iron accumulations in the carotid atherosclerotic plaque, in colocalization with MMP-2 expression and macrophages. Conclusion Using a combination of innovative imaging modalities, in this study, we demonstrate the feasibility of applying the novel smart MMP2cNPs as a PET/MR hybrid imaging contrast agent for detection of MMP-2 in atherosclerotic plaque in vivo.
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Affiliation(s)
- Yingfeng Tu
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China,Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, USA
| | - Xiaowei Ma
- Department of Nuclear Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
| | - Hao Chen
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, USA,Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Yuhua Fan
- College of Pharmacy, Harbin Medical University, Daqing, Heilongjiang, People’s Republic of China
| | - Lei Jiang
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, USA
| | - Ruiping Zhang
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, USA,The Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, People’s Republic of China,Ruiping Zhang, Department of Radiology, the Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, 030032, People’s Republic of China, Email
| | - Zhen Cheng
- Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University, Stanford, CA, USA,Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China,Correspondence: Zhen Cheng, Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection, 1201 Welch Road, Lucas Expansion, P095, Stanford University, Stanford, CA, 94305, USA, Tel +01-650-723-7866, Email
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Zhou J, Yang R, Sun Y, Luo F, Zhang J, Ma H, Guan M. HClO-triggered interventional probe enabled early detection and intervention of atherosclerosis. Analyst 2022; 148:163-174. [PMID: 36464987 DOI: 10.1039/d2an01374f] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Foam cell formation and further accumulation in the subendothelial space of the vascular wall is a hallmark of early atherosclerosis (AS). Targeting foam cell formation can be a promising approach for the early detection and prevention of AS. However, only a few studies have actually examined foam cells in vivo, and most methods combined nanotechnology with angiography, which is complex and could cause further damage to the endothelium. Herein, based on methylene blue, a biosafe NIR dye approved by the FDA, an interventional probe (HMB-NA@Mp) triggered by hypochlorous acid (HClO) was designed for imaging foam cells easily, safely, and effectively in the early stage of AS. Here, encapsulation of the probe by foam cells targeted platelet membrane (Mp) increased probe targeting and reduced toxicity. Cell and animal experimental results showed that the probe could accumulate at the lesion site and significantly enhance fluorescence in the early AS model group. Remarkably, at the same time, it could also release the metabolite niacin, which played a role in inhibiting atherosclerosis. Thus, HMB-NA@Mp is expected to be a powerful means for the early detection and timely intervention of early AS in the absence of clinical symptoms.
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Affiliation(s)
- Jie Zhou
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Ruhe Yang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Yiwen Sun
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Fusui Luo
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Jin Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Huili Ma
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Min Guan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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Huang S, Gao Y, Lv Y, Wang Y, Cao Y, Zhao W, Zuo D, Mu H, Hua Y. Applications of Nano/Micromotors for Treatment and Diagnosis in Biological Lumens. MICROMACHINES 2022; 13:mi13101780. [PMID: 36296133 PMCID: PMC9610721 DOI: 10.3390/mi13101780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/14/2022] [Accepted: 10/16/2022] [Indexed: 06/01/2023]
Abstract
Natural biological lumens in the human body, such as blood vessels and the gastrointestinal tract, are important to the delivery of materials. Depending on the anatomic features of these biological lumens, the invention of nano/micromotors could automatically locomote targeted sites for disease treatment and diagnosis. These nano/micromotors are designed to utilize chemical, physical, or even hybrid power in self-propulsion or propulsion by external forces. In this review, the research progress of nano/micromotors is summarized with regard to treatment and diagnosis in different biological lumens. Challenges to the development of nano/micromotors more suitable for specific biological lumens are discussed, and the overlooked biological lumens are indicated for further studies.
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Affiliation(s)
- Shandeng Huang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Yinghua Gao
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Yu Lv
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Yun Wang
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Yinghao Cao
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Weisong Zhao
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Dongqing Zuo
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Haoran Mu
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
| | - Yingqi Hua
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
- Shanghai Bone Tumor Institution, Shanghai 201620, China
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Li B, Wang C, Lu P, Ji Y, Wang X, Liu C, Lu X, Xu X, Wang X. IDH1 Promotes Foam Cell Formation by Aggravating Macrophage Ferroptosis. BIOLOGY 2022; 11:biology11101392. [PMID: 36290297 PMCID: PMC9598283 DOI: 10.3390/biology11101392] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary In our study, the involvement of IDH1 in atherosclerotic foam cells was explored. Inhibiting macrophage ferroptosis and foam cell formation by knocking down IDH1 is a promising study direction for better understanding the occurrence and progression of atherosclerosis, as well as the treatment targets for atherosclerosis. Abstract A distinctive feature of ferroptosis is intracellular iron accumulation and the impairment of antioxidant capacity, resulting in a lethal accumulation of lipid peroxides leading to cell death. This study was conducted to determine whether inhibiting isocitrate dehydrogenase 1 (IDH1) may help to prevent foam cell formation by reducing oxidized low-density lipoprotein (ox-LDL)-induced ferroptosis in macrophages and activating nuclear factor erythroid 2-related factor 2 (NRF2). Gene expression profiling (GSE70126 and GSE70619) revealed 21 significantly different genes, and subsequent bioinformatics research revealed that ferroptosis and IDH1 play essential roles in foam cell production. We also confirmed that ox-LDL elevates macrophage ferroptosis and IDH1 protein levels considerably as compared with controls. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reduced ox-LDL-induced elevated Fe2+ levels, lipid peroxidation (LPO) buildup, lactate dehydrogenase (LDH) buildup, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4), ferritin heavy polypeptide 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11) protein downregulation. More crucially, inhibiting IDH1 reduced Fe2+ overload, lipid peroxidation, LDH, and glutathione depletion, and elevated GPX4, FTH1, and SLC7A11 protein expression, resulting in a reduction in ox-LDL-induced macrophage ferroptosis. IDH1 inhibition suppressed ox-LDL-induced macrophage damage and apoptosis while raising NRF2 protein levels. We have demonstrated that inhibiting IDH1 reduces ox-LDL-induced ferroptosis and foam cell formation in macrophages, implying that IDH1 may be an important molecule regulating foam cell formation and may be a promising molecular target for the treatment of atherosclerosis.
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Affiliation(s)
- Ben Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Chufan Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Peng Lu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Yumeng Ji
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Xufeng Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Chaoyang Liu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Xiaohu Lu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
| | - Xiaohan Xu
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
- The Friendship Hospital of Ili Kazakh Autonomous Prefecture Ili, Jiangsu Joint Institute of Health, Yining 835000, China
- Correspondence: (X.X.); (X.W.)
| | - Xiaowei Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210000, China
- Correspondence: (X.X.); (X.W.)
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Synthesis and Characterization of Fucoidan-Chitosan Nanoparticles Targeting P-Selectin for Effective Atherosclerosis Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8006642. [PMID: 36120595 PMCID: PMC9481351 DOI: 10.1155/2022/8006642] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022]
Abstract
Atherosclerosis is the key pathogenesis of cardiovascular diseases; oxidative stress, which is induced by the generated excess reactive oxygen species (ROS), has been a crucial mechanism underlying this pathology. Nanoparticles (NPs) represent a novel strategy for the development of potential therapies against atherosclerosis, and multifunctional NPs possessing antioxidative capacities hold promise for amelioration of vascular injury caused by ROS and for evading off-target effects; materials that are currently used for NP synthesis often serve as vehicles that do not possess intrinsic biological activities; however, they may affect the surrounding healthy environment due to decomposition of products. Herein, we used nontoxic fucoidan, a sulfated polysaccharide derived from a marine organism, to develop chitosan–fucoidan nanoparticles (CFNs). Then, by binding to P-selectin, an inflammatory adhesion exhibited molecule expression on the endothelial cells and activated platelets, blocking leukocyte recruitment and rolling on platelets and endothelium. CFNs exhibit antioxidant and anti-inflammatory properties. Nevertheless, by now, the application of CFNs for the target delivery regarding therapeutics specific to atherosclerotic plaques is not well investigated. The produced CFNs were physicochemically characterized using transmission electron microscopy (TEM), together with Fourier transform infrared spectroscopy (FTIR). Evaluations of the in vitro antioxidant as well as anti-inflammatory activities exhibited by CFNs were based on the measurement of their ROS scavenging abilities and investigating inflammatory mediator levels. The in vivo pharmacokinetics and binding efficiency of the CFNs to atherosclerotic plaques were also evaluated. The therapeutic effects indicated that CFNs effectively suppressed local oxidative stress and inflammation by targeting P-selectin in atheromatous plaques and thereby preventing the progression of atherosclerosis.
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Effect of Chemically Modified Carbon-Coated Iron Nanoparticles on the Structure of Human Atherosclerotic Plaques Ex Vivo and on Adipose Tissue in Chronic Experiment In Vivo. Int J Mol Sci 2022; 23:ijms23158241. [PMID: 35897812 PMCID: PMC9331237 DOI: 10.3390/ijms23158241] [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: 05/26/2022] [Revised: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 02/01/2023] Open
Abstract
The high mortality rate caused by atherosclerosis makes it necessary to constantly search for new and better treatments. In previous reports, chemically modified carbon-coated iron nanoparticles (Fe@C NPs) have been demonstrated a high biocompatibility and promising anti-plaque properties. To further investigate these effects, the interaction of these nanoparticles with the adipose tissue of Wistar rats (in vivo) and human atherosclerotic plaques (ex vivo) was studied. For the in vivo study, cobalt-chromium (CoCr) alloy tubes, which are used for coronary stent manufacturing, were prepared with a coating of polylactic acid (PLA) which contained either modified or non-modified Fe@C NPs in a 5% by weight concentration. The tubes were implanted into an area of subcutaneous fat in Wistar rats, where changes in the histological structure and functional properties of the surrounding tissue were observed in the case of coatings modified with Fe@C NPs. For the ex vivo study, freshly explanted human atherosclerotic plaques were treated in the physiological solution with doses of modified Fe@C NPs, with mass equal to 5% or 25% relative to the plaques. This treatment resulted in the release of cholesterol-like compounds from the surface of the plaques into the solution, thus proving a pronounced destructive effect on the plaque structure. Chemically modified Fe@C NPs, when used as an anti-atherosclerosis agent, were able to activate the activity of macrophages, which could lead to the destruction of atherosclerotic plaques structures. These findings could prove the fabrication of next-generation vascular stents with built-in anti-atherosclerotic agents.
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Liu Y, Sun Y, Bai X, Li L, Zhu G. Albiflorin Alleviates Ox-LDL-Induced Human Umbilical Vein Endothelial Cell Injury through IRAK1/TAK1 Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6584645. [PMID: 35601145 PMCID: PMC9122697 DOI: 10.1155/2022/6584645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 11/21/2022]
Abstract
Introduction Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid metabolism disorder and vascular endothelial damage. Albiflorin (AF) has been certified to be effective in the therapy of certain inflammatory diseases, while the therapeutic effect and mechanism of AF on AS have not been fully elucidated. Material and Methods. Model cells for AS were created by inducing oxidized low-density lipoprotein (Ox-LDL) in human umbilical vein endothelial cells (HUVECs). After processing with AF and interleukin-1 receptor-associated kinase 1- (IRAK1-) overexpressed plasmid, cell viability was assessed by CCK-8; cholesterol efflux was tested using liquid scintillation counter; IL-6 and TNF-α levels were determined with ELISA kits; ROS and apoptosis were confirmed using Flow cytometry. Besides, IRAK1-TAK1 pathway and apoptosis- and mitochondrial fusion-related proteins were monitored with western blotting analysis. Results Our results verified that AF could not only dramatically accelerate viability and cholesterol efflux but also attenuate inflammation, ROS production, and apoptosis in Ox-LDL-induced HUVECs. Meanwhile, AF could prominently prevent the activation of IRAK1-TAK1 pathway, downregulate apoptosis-related proteins, and upregulate mitochondrial fusion-related proteins in Ox-LDL-induced HUVECs. Moreover, we testified that IRAK1 overexpression memorably could reverse suppression of AF on inflammation, apoptosis, and IRAK1-TAK1 pathway and enhancement of AF on viability, cholesterol efflux, and mitochondrial fusion in Ox-LDL-induced HUVECs. Conclusions By blocking the IRAK1/TAK1 pathway, AF can significantly slow the course of AS, suggesting that it could be a viable therapeutic option for AS.
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Affiliation(s)
- Yeling Liu
- Department of Pharmacy, Tai'an City Central Hospital, Tai'an, Shandong 271000, China
| | - Yilai Sun
- Department of Pancreatic & Hernial Surgery Tai'an City Central Hospital, Tai'an, Shandong 271000, China
| | - Xue Bai
- Department of Cardiovascular Medicine, Tai'an City Central Hospital, Tai'an, Shandong 271000, China
| | - Lingxing Li
- Department of Cardiovascular Medicine, Tai'an City Central Hospital, Tai'an, Shandong 271000, China
| | - Guihua Zhu
- Department of Pharmacy, Tai'an City Central Hospital, Tai'an, Shandong 271000, China
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Cai Z, He X, Liu S, Bai Y, Pan B, Wu K. Linear ubiquitination modification of NR6A1 by LUBAC inhibits RIPK3 kinase activity and attenuates apoptosis of vascular smooth muscle cells. J Biochem Mol Toxicol 2022; 36:e23091. [PMID: 35543488 DOI: 10.1002/jbt.23091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 11/30/2021] [Accepted: 04/19/2022] [Indexed: 11/12/2022]
Abstract
Nuclear receptor subfamily 6 group A member 1 (NR6A1) is involved in promoting the apoptotic process of vascular smooth muscle cells (VSMCs) which is a critical process involved in atherosclerosis, but the action mechanism remains to be determined. Therefore, we studied the underlying mechanisms by which NR6A1 accelerated VSMC apoptosis in atherosclerosis. An atherosclerosis model has been established in apolipoprotein E-deficient rats with a high-fat diet for 12 weeks, which was characterized by pathological aortic plaques, increased lipid deposition and collagen content in aortic tissues, and high cholesterol and triglycerides levels in the serum. NR6A1 was experimentally shown to increase at protein level rather than messenger RNA level in atherosclerotic rats. Immunofluorescence exhibited the main location of NR6A1 in the cell nucleus of rat aortic tissues. By performing ectopic expression experiments, NR6A1 was demonstrated to suppress the viability and expedite the apoptosis of VSMCs, corresponding to augmented caspase-3, caspase-8, and caspase-9 activities. It was further unraveled that NR6A1 could activate receptor-interacting serine/threonine-protein kinase 3 (RIPK3) by inducing its phosphorylation. Conversely, RIPK3 inhibitor GSK872 undermined the proapoptotic effect of NR6A1 on VSMCs. The co-immunoprecipitation assay identified that linear ubiquitin chain assembly complex (LUBAC) can be pulled down by NR6A1. Furthermore. LUBAC inhibited the expression of NR6A1 by promoting its linear ubiquitination, thereby dephosphorylating RIPK3 and consequently inhibiting the VSMC apoptosis. Overall, LUBAC-induced linear ubiquitination of NR6A1 can potentially arrest the apoptosis of VSMCs in atherosclerosis by downregulating RIPK3 and attenuating caspase activity. This finding suggests promising athero-protective targets by limiting VSMC apoptosis.
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Affiliation(s)
- Zhou Cai
- Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, P. R. China
| | - Xin He
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, P. R. China
| | - Shuai Liu
- Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, P. R. China
| | - Yang Bai
- Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, P. R. China
| | - Baihong Pan
- Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, P. R. China
| | - Kemin Wu
- Department of General and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, P. R. China
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Huang Y, Zou L, Wang J, Jin Q, Ji J. Stimuli-responsive nanoplatforms for antibacterial applications. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1775. [PMID: 35142071 DOI: 10.1002/wnan.1775] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/13/2022]
Abstract
The continuously increasing bacterial resistance has become a big threat to public health worldwide, which makes it urgent to develop innovative antibacterial strategies. Nanotechnology-based drug delivery systems are considered as promising strategies in combating bacterial infections which are expected to improve the therapeutic efficacy and minimize the side effects. Unfortunately, the conventional nanodrug delivery systems always suffer from practical dilemmas, including incomplete and slow drug release, insufficient accumulation in infected sites, and weak biofilm penetration ability. Stimuli-responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles. In this review, we provide an extensive review of the recent progress of endogenous and exogenous stimuli-responsive nanoplatforms in the antibacterial area, including planktonic bacteria, intracellular bacteria, and bacterial biofilms. Taking advantage of the specific infected microenvironment (pH, enzyme, redox, and toxin), the mechanisms and strategies of the design of endogenous stimuli-responsive nanoplatforms are discussed, with an emphasis on how to improve the therapeutic efficacy and minimize side effects. How to realize controlled drug delivery using exogenous stimuli-responsive nanoplatforms especially light-responsive nanoparticles for improved antibacterial effects is another topic of this review. We especially highlight photothermal-triggered drug delivery systems by the combination of photothermal agents and thermo-responsive materials. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Affiliation(s)
- Yue Huang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Lingyun Zou
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Jing Wang
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Qiao Jin
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Jian Ji
- MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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Qiu J, Chen R, Zhao L, Lian C, Liu Z, Zhu X, Cui J, Wang S, Wang M, Huang Y, Wang S, Wang J. Circular RNA circGSE1 promotes angiogenesis in ageing mice by targeting the miR-323-5p/NRP1 axis. Aging (Albany NY) 2022; 14:3049-3069. [PMID: 35366240 PMCID: PMC9037273 DOI: 10.18632/aging.203988] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Age is an important factor in many cardiovascular diseases, in which endothelial cells (ECs) play an important role. Circular RNAs (circRNAs) have been reported in many cardiovascular diseases, but their role in ageing EC-related angiogenesis is unclear. We aimed to identify a functional circRNA that regulates angiogenesis during ageing and explore its specific mechanism. In this study, we searched for differentially expressed circRNAs in old endothelial cells (OECs) and young endothelial cells (YECs) by circRNA sequencing and found that circGSE1 was significantly downregulated in OECs. Our study showed that circGSE1 could promote the proliferation, migration and tube formation of OECs in vitro. In a mouse model of femoral artery ligation and ischemia, circGSE1 promoted blood flow recovery and angiogenesis in the ischemic limbs of ageing mice. Mechanistically, we found that overexpressing circGSE1 reduced miR-323-5p expression, increased neuropilin-1 (NRP1) expression, and promoted proliferation, migration, and tube formation in OECs, while knocking down circGSE1 increased miR-323-5p expression, reduced NRP1 expression, and inhibited proliferation, migration, and tube formation in YECs. During EC ageing, circGSE1 may act through the miR-323-5p/NRP1 axis and promote endothelial angiogenesis in mice. Finally, the circGSE1/miR-323-5p/NRP1 axis could serve as a potential and promising therapeutic target for angiogenesis during ageing.
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Affiliation(s)
- Jiacong Qiu
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Rencong Chen
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Lei Zhao
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Chong Lian
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Zhen Liu
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Xiaonan Zhu
- Department of Pharmacology Laboratory, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Jin Cui
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Siwen Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Mingshan Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Yingxiong Huang
- Department of Emergency, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China
| | - Shenming Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
| | - Jinsong Wang
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.,National-Local Joint Engineering Laboratory of Vascular Disease Treatment, Guangzhou 510080, Guangdong, China.,Guangdong Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, Guangdong, China
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Leal BH, Velasco B, Cambón A, Pardo A, Fernandez-Vega J, Arellano L, Al-Modlej A, Mosquera VX, Bouzas A, Prieto G, Barbosa S, Taboada P. Combined Therapeutics for Atherosclerosis Treatment Using Polymeric Nanovectors. Pharmaceutics 2022; 14:pharmaceutics14020258. [PMID: 35213991 PMCID: PMC8879452 DOI: 10.3390/pharmaceutics14020258] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023] Open
Abstract
Atherosclerosis is an underlying risk factor in cardiovascular diseases (CVDs). The combination of drugs with microRNAs (miRNA) inside a single nanocarrier has emerged as a promising anti-atherosclerosis strategy to achieve the exploitation of their complementary mechanisms of action to achieve synergistic therapeutic effects while avoiding some of the drawbacks associated with current systemic statin therapies. We report the development of nanometer-sized polymeric PLGA nanoparticles (NPs) capable of simultaneously encapsulating and delivering miRNA-124a and the statin atorvastatin (ATOR). The polymeric NPs were functionalized with an antibody able to bind to the vascular adhesion molecule-1 (VCAM1) overexpressed in the inflamed arterial endothelium. The dual-loaded NPs were non-toxic to cells in a large range of concentrations, successfully attached overexpressed VCAM receptors and released the cargoes in a sustainable manner inside cells. The combination of both ATOR and miRNA drastically reduced the levels of proinflammatory cytokines such as IL-6 and TNF-α and of reactive oxygen species (ROS) in LPS-activated macrophages and vessel endothelial cells. In addition, dual-loaded NPs precluded the accumulation of low-density lipoproteins (LdL) inside macrophages as well as morphology changes to a greater extent than in single-loaded NPs. The reported findings validate the present NPs as suitable delivery vectors capable of simultaneously targeting inflamed cells in atherosclerosis and providing an efficient approach to combination nanomedicines.
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Affiliation(s)
- Baltazar Hiram Leal
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
| | - Brenda Velasco
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Adriana Cambón
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Correspondence: (A.C.); (S.B.); (P.T.); Tel.: +34-881814056 (A.C.); +34-881814115 (S.B.); +34-881814111 (P.T.)
| | - Alberto Pardo
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Javier Fernandez-Vega
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Lilia Arellano
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
| | - Abeer Al-Modlej
- Department of Physics and Astronomy, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Víctor X. Mosquera
- Cardiac Surgery Department, University Hospital of A Coruña, Biomedical Research Institute of A Coruña (INIBIC), 15006 A Coruña, Spain; (V.X.M.); (A.B.)
| | - Alberto Bouzas
- Cardiac Surgery Department, University Hospital of A Coruña, Biomedical Research Institute of A Coruña (INIBIC), 15006 A Coruña, Spain; (V.X.M.); (A.B.)
| | - Gerardo Prieto
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Biophysics and Interfaces Group, Department of Applied Physics, Faculty of Physics, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Silvia Barbosa
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Correspondence: (A.C.); (S.B.); (P.T.); Tel.: +34-881814056 (A.C.); +34-881814115 (S.B.); +34-881814111 (P.T.)
| | - Pablo Taboada
- Colloids and Polymers Physics Group, Department of Particle Physics, Faculty of Physics and Health Research Institute, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (B.H.L.); (B.V.); (A.P.); (J.F.-V.); (L.A.)
- Institute of Materials, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;
- Correspondence: (A.C.); (S.B.); (P.T.); Tel.: +34-881814056 (A.C.); +34-881814115 (S.B.); +34-881814111 (P.T.)
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Yang P, Wu Q, Sun L, Fang P, Liu L, Ji Y, Park JY, Qin X, Yang X, Wang H. Adaptive Immune Response Signaling Is Suppressed in Ly6C high Monocyte but Upregulated in Monocyte Subsets of ApoE-/- Mice - Functional Implication in Atherosclerosis. Front Immunol 2021; 12:809208. [PMID: 34987524 PMCID: PMC8721109 DOI: 10.3389/fimmu.2021.809208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/23/2021] [Indexed: 11/26/2022] Open
Abstract
Rationale Inflammatory monocyte (MC) subset differentiation is a major feature in tissue inflammatory and atherosclerosis. The underlying molecular mechanism remains unclear. Objective This study aims to explore molecule targets and signaling which determinate immunological features in MC subsets. Methods and Results Blood Ly6Chigh and Ly6Clow MC subsets from control and ApoE-/- mice were isolated by flow cytometry sorting and subjected for bulk high-throughput RNA-sequencing. Intensive bioinformatic studies were performed by analyzing transcriptome through four pairs of comparisons: A) Ly6Chigh vs Ly6Clow in control mice; B) Ly6Chigh vs Ly6Clow in ApoE-/- mice; C) ApoE-/- Ly6Chigh vs control Ly6Chigh MC; D) ApoE-/- Ly6Clow vs control Ly6Clow MC. A total of 80 canonical pathways and 16 enriched pathways were recognized by top-down analysis using IPA and GSEA software, and further used for overlapping analysis. Immunological features and signaling were assessed on four selected functional groups, including MHCII, immune checkpoint, cytokine, and transcription factor (TF). Among the total 14578 significantly differentially expressed (SDE) genes identified though above four comparison, 1051 TF and 348 immunological genes were discovered. SDE immunological genes were matched with corresponding upstream SDE TF by IPA upstream analysis. Fourteen potential transcriptional axes were recognized to modulate immunological features in the Ly6C MC subset. Based on an intensive literature search, we found that the identified SDE immune checkpoint genes in Ly6Chigh MC are associated with pro-inflammatory/atherogenic balance function. Immune checkpoint genes GITR, CTLA4, and CD96 were upregulated in Ly6Clow MC from all mice and presented anti-inflammatory/atherogenic features. Six cytokine genes, including Ccl2, Tnfsf14, Il1rn, Cxcl10, Ccl9, and Cxcl2, were upregulated in Ly6Chigh MC from all mice and associated with pro-inflammatory/atherogenic feature. Cytokine receptor gene Il12rb2, Il1r1, Il27ra, Il5ra, Ngfr, Ccr7, and Cxcr5 were upregulated in Ly6Clow MC from all mice and presented anti-inflammatory/atherogenic features. MHCII genes (H2-Oa, H2-DMb2, H2-Ob, H2-Eb2, H2-Eb1, H2-Aa, and Cd74) were elevated in Ly6Clow MC from all mice. ApoE-/- augmented pro-atherogenic/inflammatory and antigen-presenting cells (APC) feature in both subsets due to elevated expression of cytokine genes (Cxcl11, Cntf, Il24, Xcl, Ccr5, Mpl, and Acvr2a) and MHCII gene (H2-Aa and H2-Ea-ps). Finally, we modeled immunological gene expression changes and functional implications in MC differentiation and adaptive immune response for MC subsets from control and ApoE-/- mice. Conclusions Ly6Chigh MC presented pro-inflammatory/atherogenic features and lower APC potential. Ly6Clow MC displayed anti-inflammatory/atherogenic features and higher APC potential. ApoE-/- confers upon both subsets with augmented pro-atherogenic/inflammatory function and APC potential.
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Affiliation(s)
- Pingping Yang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lizhe Sun
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Pu Fang
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
| | - Lu Liu
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
| | - Joon-Young Park
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
| | - Xuebin Qin
- Tulane National Primate Research Center, School of Medicine, Tulane University, Covington, LA, United States
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
| | - Hong Wang
- Center for Metabolic Disease Research, Department of Cardiovascular Science, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, United States
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Xu M, Mao C, Chen H, Liu L, Wang Y, Hussain A, Li S, Zhang X, Tuguntaev RG, Liang XJ, Guo W, Cao F. Osteopontin targeted theranostic nanoprobes for laser-induced synergistic regression of vulnerable atherosclerotic plaques. Acta Pharm Sin B 2021; 12:2014-2028. [PMID: 35847489 PMCID: PMC9279717 DOI: 10.1016/j.apsb.2021.12.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/30/2021] [Accepted: 12/05/2021] [Indexed: 01/14/2023] Open
Abstract
Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
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Affiliation(s)
- Mengqi Xu
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases & Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Cong Mao
- Department of Minimally Invasive Interventional Radiology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Haoting Chen
- Department of Minimally Invasive Interventional Radiology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Lu Liu
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Yabin Wang
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases & Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Abid Hussain
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Sulei Li
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases & Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xu Zhang
- Department of Urology, Chinese PLA General Hospital, Beijing 100853, China
| | - Ruslan G. Tuguntaev
- Department of Minimally Invasive Interventional Radiology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
- Corresponding authors.
| | - Xing-Jie Liang
- Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China
| | - Weisheng Guo
- Department of Minimally Invasive Interventional Radiology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
- Corresponding authors.
| | - Feng Cao
- Department of Cardiology, National Clinical Research Center for Geriatric Diseases & Second Medical Center of Chinese PLA General Hospital, Beijing 100853, China
- Corresponding authors.
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35
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Zhu F, Zuo L, Hu R, Wang J, Yang Z, Qi X, Feng L. A ten-genes-based diagnostic signature for atherosclerosis. BMC Cardiovasc Disord 2021; 21:513. [PMID: 34688276 PMCID: PMC8540101 DOI: 10.1186/s12872-021-02323-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 10/12/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Atherosclerosis is the leading cause of cardiovascular disease with a high mortality worldwide. Understanding the atherosclerosis pathogenesis and identification of efficient diagnostic signatures remain major problems of modern medicine. This study aims to screen the potential diagnostic genes for atherosclerosis. METHODS We downloaded the gene chip data of 135 peripheral blood samples, including 57 samples with atherosclerosis and 78 healthy subjects from GEO database (Accession Number: GSE20129). The weighted gene co-expression network analysis was applied to identify atherosclerosis-related genes. Functional enrichment analysis was conducted by using the clusterProfiler R package. The interaction pairs of proteins encoded by atherosclerosis-related genes were screened using STRING database, and the interaction network was further optimized with the cytoHubba plug-in of Cytoscape software. RESULTS The logistic regression diagnostic model was constructed to predict normal and atherosclerosis samples. A gene module which included 532 genes related to the occurrence of atherosclerosis were screened. Functional enrichment analysis basing on the 532 genes identified 235 significantly enriched GO terms and 44 significantly enriched KEGG pathways. The top 50 hub genes of the protein-protein interaction network were identified. The final logistic regression diagnostic model was established by the optimal 10 key genes, which could distinguish atherosclerosis samples from normal samples. CONCLUSIONS A predictive model based on 10 potential atherosclerosis-related genes was obtained, which should shed light on the diagnostic research of atherosclerosis.
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Affiliation(s)
- Feng Zhu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Department of Traditional Chinese Medicine, Hebei North University, Zhangjiakou City, Hebei Province, China.,Department of Cardiology, Tianjin Union Medical Center, Tianjin, China
| | - Lili Zuo
- Department of Neonatal, ZiBo Maternal and Child Health Hospital, Zibo City, Shandong Province, China
| | - Rui Hu
- Center for Drug Monitoring and Evaluation Department, Center for Drug Monitoring and Evaluation in Zhangjiakou, Zhangjiakou City, Hebei Province, China
| | - Jin Wang
- Department of Cardiovascular Disease, ZiBo Hospital of Traditional Chinese Medicine, Zibo City, Shandong Province, China
| | - Zhihua Yang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China.,First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xin Qi
- Department of Cardiology, Tianjin Union Medical Center, Tianjin, China
| | - Limin Feng
- Department of Cardiology, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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Pan Q, Xu J, Wen CJ, Xiong YY, Gong ZT, Yang YJ. Nanoparticles: Promising Tools for the Treatment and Prevention of Myocardial Infarction. Int J Nanomedicine 2021; 16:6719-6747. [PMID: 34621124 PMCID: PMC8491866 DOI: 10.2147/ijn.s328723] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/17/2021] [Indexed: 12/12/2022] Open
Abstract
Despite several recent advances, current therapy and prevention strategies for myocardial infarction are far from satisfactory, owing to limitations in their applicability and treatment effects. Nanoparticles (NPs) enable the targeted and stable delivery of therapeutic compounds, enhance tissue engineering processes, and regulate the behaviour of transplants such as stem cells. Thus, NPs may be more effective than other mechanisms, and may minimize potential adverse effects. This review provides evidence for the view that function-oriented systems are more practical than traditional material-based systems; it also summarizes the latest advances in NP-based strategies for the treatment and prevention of myocardial infarction.
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Affiliation(s)
- Qi Pan
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jing Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Cen-Jin Wen
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yu-Yan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhao-Ting Gong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
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Guo J, Yang Z, Wang X, Xu Y, Lu Y, Qin Z, Zhang L, Xu J, Wang W, Zhang J, Tang J. Advances in Nanomaterials for Injured Heart Repair. Front Bioeng Biotechnol 2021; 9:686684. [PMID: 34513807 PMCID: PMC8424111 DOI: 10.3389/fbioe.2021.686684] [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: 03/27/2021] [Accepted: 08/09/2021] [Indexed: 11/30/2022] Open
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of mortality worldwide. Because of the limited regenerative capacity of adult myocardium to compensate for the loss of heart tissue after ischemic infarction, scientists have been exploring the possible mechanisms involved in the pathological process of ASCVD and searching for alternative means to regenerate infarcted cardiac tissue. Although numerous studies have pursued innovative solutions for reversing the pathological process of ASCVD and improving the effectiveness of delivering therapeutics, the translation of those advances into downstream clinical applications remains unsatisfactory because of poor safety and low efficacy. Recently, nanomaterials (NMs) have emerged as a promising new strategy to strengthen both the efficacy and safety of ASCVD therapy. Thus, a comprehensive review of NMs used in ASCVD treatment will be useful. This paper presents an overview of the pathophysiological mechanisms of ASCVD and the multifunctional mechanisms of NM-based therapy, including antioxidative, anti-inflammation and antiapoptosis mechanisms. The technological improvements of NM delivery are summarized and the clinical transformations concerning the use of NMs to treat ASCVD are examined. Finally, this paper discusses the challenges and future perspectives of NMs in cardiac regeneration to provide insightful information for health professionals on the latest advancements in nanotechnologies for ASCVD treatment.
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Affiliation(s)
- Jiacheng Guo
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Zhenzhen Yang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xu Wang
- Department of Medical Record Management, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanyan Xu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Yongzheng Lu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Zhen Qin
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Li Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Jing Xu
- Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei Wang
- Henan Medical Association, Zhengzhou, China
| | - Jinying Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
| | - Junnan Tang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, China
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Friedrich RP, Cicha I, Alexiou C. Iron Oxide Nanoparticles in Regenerative Medicine and Tissue Engineering. NANOMATERIALS 2021; 11:nano11092337. [PMID: 34578651 PMCID: PMC8466586 DOI: 10.3390/nano11092337] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 12/13/2022]
Abstract
In recent years, many promising nanotechnological approaches to biomedical research have been developed in order to increase implementation of regenerative medicine and tissue engineering in clinical practice. In the meantime, the use of nanomaterials for the regeneration of diseased or injured tissues is considered advantageous in most areas of medicine. In particular, for the treatment of cardiovascular, osteochondral and neurological defects, but also for the recovery of functions of other organs such as kidney, liver, pancreas, bladder, urethra and for wound healing, nanomaterials are increasingly being developed that serve as scaffolds, mimic the extracellular matrix and promote adhesion or differentiation of cells. This review focuses on the latest developments in regenerative medicine, in which iron oxide nanoparticles (IONPs) play a crucial role for tissue engineering and cell therapy. IONPs are not only enabling the use of non-invasive observation methods to monitor the therapy, but can also accelerate and enhance regeneration, either thanks to their inherent magnetic properties or by functionalization with bioactive or therapeutic compounds, such as drugs, enzymes and growth factors. In addition, the presence of magnetic fields can direct IONP-labeled cells specifically to the site of action or induce cell differentiation into a specific cell type through mechanotransduction.
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Oshi MA, Haider A, Siddique MI, Zeb A, Jamal SB, Khalil AAK, Naeem M. Nanomaterials for chronic inflammatory diseases: the current status and future prospects. APPLIED NANOSCIENCE 2021. [DOI: 10.1007/s13204-021-02019-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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40
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Wu Y, Vazquez-Prada KX, Liu Y, Whittaker AK, Zhang R, Ta HT. Recent Advances in the Development of Theranostic Nanoparticles for Cardiovascular Diseases. Nanotheranostics 2021; 5:499-514. [PMID: 34367883 PMCID: PMC8342263 DOI: 10.7150/ntno.62730] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. CVD includes a group of disorders of the heart and blood vessels such as myocardial infarction, ischemic heart, ischemic injury, injured arteries, thrombosis and atherosclerosis. Amongst these, atherosclerosis is the dominant cause of CVD and is an inflammatory disease of the blood vessel wall. Diagnosis and treatment of CVD remain the main challenge due to the complexity of their pathophysiology. To overcome the limitations of current treatment and diagnostic techniques, theranostic nanomaterials have emerged. The term "theranostic nanomaterials" refers to a multifunctional agent with both therapeutic and diagnostic abilities. Theranostic nanoparticles can provide imaging contrast for a diversity of techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT). In addition, they can treat CVD using photothermal ablation and/or medication by the drugs in nanoparticles. This review discusses the latest advances in theranostic nanomaterials for the diagnosis and treatment of CVDs according to the order of disease development. MRI, CT, near-infrared spectroscopy (NIR), and fluorescence are the most widely used strategies on theranostics for CVDs detection. Different treatment methods for CVDs based on theranostic nanoparticles have also been discussed. Moreover, current problems of theranostic nanoparticles for CVDs detection and treatment and future research directions are proposed.
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Affiliation(s)
- Yuao Wu
- Queensland Micro- and Nanotechnology, Griffith University, Brisbane, Queensland 4111, Australia
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
| | - Karla X. Vazquez-Prada
- Queensland Micro- and Nanotechnology, Griffith University, Brisbane, Queensland 4111, Australia
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
| | - Yajun Liu
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
| | - Andrew K. Whittaker
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, the University of Queensland, QLD 4072, Australia
| | - Run Zhang
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
| | - Hang T. Ta
- Queensland Micro- and Nanotechnology, Griffith University, Brisbane, Queensland 4111, Australia
- School of Environment and Science, Griffith University, Brisbane, Queensland 4111, Australia
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, Queensland 4072, Australia
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Wang Z, Huang H, Chen Y, Zheng Y. Current Strategies for Microbubble-Based Thrombus Targeting: Activation-Specific Epitopes and Small Molecular Ligands. Front Bioeng Biotechnol 2021; 9:699450. [PMID: 34336810 PMCID: PMC8322734 DOI: 10.3389/fbioe.2021.699450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/22/2021] [Indexed: 11/26/2022] Open
Abstract
Microbubbles with enhanced ultrasound represent a potentially potent evolution to the administration of a free drug in the treatment of thrombotic diseases. Conformational and expressional changes of several thrombotic biological components during active coagulation provide epitopes that allow site-specific delivery of microbubble-based agents to the thrombus for theranostic purpose. Through the interaction with these epitopes, emerging high-affinity small molecular ligands are able to selectively target the thrombi with tremendous advantages over traditional antibody-based strategy. In this mini-review, we summarize recent novel strategies for microbubble-based targeting of thrombus through epitopes located at activated platelets and fibrin. We also discuss the challenges of current targeting modalities and supramolecular carrier systems for their translational use in thrombotic pathologies.
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Affiliation(s)
- Zhaojian Wang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Huaigu Huang
- Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yuexin Chen
- Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yuehong Zheng
- Department of Vascular Surgery, Peking Union Medical College Hospital, Beijing, China
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42
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Akhmedov S, Afanasyev S, Trusova M, Postnikov P, Rogovskaya Y, Grakova E, Kopeva K, Carreon Paz RK, Balakin S, Wiesmann HP, Opitz J, Kruppke B, Beshchasna N, Popov S. Chemically Modified Biomimetic Carbon-Coated Iron Nanoparticles for Stent Coatings: In Vitro Cytocompatibility and In Vivo Structural Changes in Human Atherosclerotic Plaques. Biomedicines 2021; 9:biomedicines9070802. [PMID: 34356866 PMCID: PMC8301308 DOI: 10.3390/biomedicines9070802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 11/21/2022] Open
Abstract
Atherosclerosis, a systematic degenerative disease related to the buildup of plaques in human vessels, remains the major cause of morbidity in the field of cardiovascular health problems, which are the number one cause of death globally. Novel atheroprotective HDL-mimicking chemically modified carbon-coated iron nanoparticles (Fe@C NPs) were produced by gas-phase synthesis and modified with organic functional groups of a lipophilic nature. Modified and non-modified Fe@C NPs, immobilized with polycaprolactone on stainless steel, showed high cytocompatibility in human endothelial cell culture. Furthermore, after ex vivo treatment of native atherosclerotic plaques obtained during open carotid endarterectomy surgery, Fe@C NPs penetrated the inner structures and caused structural changes of atherosclerotic plaques, depending on the period of implantation in Wistar rats, serving as a natural bioreactor. The high biocompatibility of the Fe@C NPs shows great potential in the treatment of atherosclerosis disease as an active substance of stent coatings to prevent restenosis and the formation of atherosclerotic plaques.
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Affiliation(s)
- Shamil Akhmedov
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
- Correspondence: (S.A.); (M.T.); (N.B.); Tel.: +7-3822-558142 (S.A.); +7-9069-583171 (T.M.); +49-351-88815619 (N.B.)
| | - Sergey Afanasyev
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
| | - Marina Trusova
- Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia;
- Correspondence: (S.A.); (M.T.); (N.B.); Tel.: +7-3822-558142 (S.A.); +7-9069-583171 (T.M.); +49-351-88815619 (N.B.)
| | - Pavel Postnikov
- Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia;
| | - Yulia Rogovskaya
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
| | - Elena Grakova
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
| | - Kristina Kopeva
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
| | - Rosa Karen Carreon Paz
- Fraunhofer Institute for Ceramic Technologies and Systems IKTS, 01109 Dresden, Germany; (R.K.C.P.); (S.B.); (J.O.)
| | - Sascha Balakin
- Fraunhofer Institute for Ceramic Technologies and Systems IKTS, 01109 Dresden, Germany; (R.K.C.P.); (S.B.); (J.O.)
| | - Hans-Peter Wiesmann
- Max Bergmann Center of Biomaterials, Institute of Materials Science, Technische Universität Dresden, 01069 Dresden, Germany; (H.-P.W.); (B.K.)
| | - Joerg Opitz
- Fraunhofer Institute for Ceramic Technologies and Systems IKTS, 01109 Dresden, Germany; (R.K.C.P.); (S.B.); (J.O.)
| | - Benjamin Kruppke
- Max Bergmann Center of Biomaterials, Institute of Materials Science, Technische Universität Dresden, 01069 Dresden, Germany; (H.-P.W.); (B.K.)
| | - Natalia Beshchasna
- Fraunhofer Institute for Ceramic Technologies and Systems IKTS, 01109 Dresden, Germany; (R.K.C.P.); (S.B.); (J.O.)
- Correspondence: (S.A.); (M.T.); (N.B.); Tel.: +7-3822-558142 (S.A.); +7-9069-583171 (T.M.); +49-351-88815619 (N.B.)
| | - Sergey Popov
- Tomsk National Research Medical Center of the Russian Academy of Sciences, Cardiology Research Institute, 634012 Tomsk, Russia; (S.A.); (Y.R.); (E.G.); (K.K.); (S.P.)
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Li X, Wu R, Chen H, Li T, Jiang H, Xu X, Tang X, Wan M, Mao C, Shi D. Near-Infrared Light-Driven Multifunctional Tubular Micromotors for Treatment of Atherosclerosis. ACS APPLIED MATERIALS & INTERFACES 2021; 13:30930-30940. [PMID: 34156244 DOI: 10.1021/acsami.1c03600] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
One of the difficulties in atherosclerosis treatment is that the ablation of inflammatory macrophages, repair of vascular endothelial injury, and anti-tissue proliferation should be considered. However, there are few studies that can solve the abovementioned problems simultaneously. Herein, we present a kind of near-infrared (NIR) light-driven multifunctional mesoporous/macroporous tubular micromotor which can rapidly target the damaged blood vessels and release different drugs. Their motion effect can promote themselves to penetrate into the plaque site, and the generated heat effect caused by NIR irradiation can realize the photothermal ablation of inflammatory macrophages. Furthermore, these micromotors can rapidly release the vascular endothelial growth factor for endothelialization and slowly release paclitaxel for antiproliferation to achieve synergistic treatment of atherosclerosis. In vivo results demonstrated that the micromotors can achieve a good therapeutic effect for atherosclerosis. This kind of micro/nanomotor technology with a complex porous structure for drug loading will bring a more potential treatment platform for the disease.
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Affiliation(s)
- Xiaoyun Li
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Rui Wu
- Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Huan Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Ting Li
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Huiming Jiang
- Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Xingquan Xu
- Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Xueting Tang
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Dongquan Shi
- Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
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Wang P, Zhang W, Feng Z, Zhang J, Sun Y, Zhang W. LDL‑induced NLRC3 inflammasome activation in cardiac fibroblasts contributes to cardiomyocytic dysfunction. Mol Med Rep 2021; 24:526. [PMID: 34036387 PMCID: PMC8170230 DOI: 10.3892/mmr.2021.12165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 02/10/2021] [Indexed: 11/09/2022] Open
Abstract
Heart failure (HF) is a progressive myocardial disease that affects pulse rate. Notably, chronic inflammation serves a crucial role in cardiac dysfunction and HF. Appropriate cardiomyocyte‑fibroblast communication is essential for cardiac function. In addition, cardiac fibroblasts (CFs) are the main cellular population in the cardiac microenvironment; therefore, determining the role of CFs in HF progression and the associated molecular basis is important. In the present study, ELISAs were performed to detect inflammatory factors in the sera of patients with HF and their association with CF activation was analyzed using Pearson's correlation coefficient. The mechanism underlying the proinflammatory phenotype of CFs was investigated via western blotting. Notably, the levels of IL10 and TNF‑α were significantly increased in the sera of patients with HF. Further analysis revealed that CFs were extensively activated in the cardiac tissues of patients with HF and released excessive amounts of cytokines, which could impair the viability of cardiomyocytes. Moreover, low‑density lipoprotein (LDL)‑induced NLRC3 inflammasome was activated in CFs, which gave rise to proinflammatory phenotypes. Targeting LDL in CFs significantly improved the functioning of cardiomyocytes and inhibited apoptosis. These findings highlighted the critical role of LDL in inflammasome activation; to the best of our knowledge, the present study is the first to reveal that CF‑induced microenvironmental inflammation may suppress cardiomyocyte viability. The present study established the cellular basis for CF activation during HF progression and provided information on the cellular interactions important for HF treatment.
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Affiliation(s)
- Peng Wang
- Department of Cardiology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
| | - Wenbo Zhang
- Department of Cardiology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
| | - Zhen Feng
- Department of Cardiology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
| | - Jian Zhang
- Department of Gastroenterology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
| | - Ying Sun
- Department of Cardiology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
| | - Wei Zhang
- Department of Gastroenterology, Feicheng Mining Center Hospital, Feicheng, Shandong 271600, P.R. China
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Nakamura M, Kosuge H, Oyane A, Kuroiwa K, Shimizu Y, Aonuma K. In vivostudy of iron oxide-calcium phosphate composite nanoparticles for delivery to atherosclerosis. NANOTECHNOLOGY 2021; 32:345101. [PMID: 34057430 DOI: 10.1088/1361-6528/ac007d] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/12/2021] [Indexed: 06/12/2023]
Abstract
Atherosclerosis is a macrophage-related inflammatory disease that remains a leading cause of death worldwide. Magnetic iron oxide (IO) nanocrystals are clinically used as magnetic resonance imaging contrast agents and their application as a detection agent for macrophages in arterial lesions has been studied extensively. We recently fabricated heparin-modified calcium phosphate (CaP) nanoparticles loaded with a large number of IO nanocrystals via coprecipitation from a supersaturated CaP solution supplemented with heparin and ferucarbotran (IO nanocrystals coated with carboxydextran). In this study, we further increased the content of IO nanocrystals in the heparin-modified IO-CaP composite nanoparticles by increasing the ferucarbotran concentration in the supersaturated CaP solution. The increase in nanoparticle IO content caused a decrease in particle diameter without impairing its dispersibility; the nanoparticles remained dispersed in water for up to 2 h due to electrostatic repulsion between particles due to the surface modification with heparin. The nanoparticles were more effectively taken up by murine RAW264.7 macrophages compared to free ferucarbotran without showing significant cytotoxicity. A preliminaryin vivostudy showed that the nanoparticles injected intravenously into mice delivered more IO nanocrystals to macrophage-rich carotid arterial lesions than free ferucarbotran. Our nanoparticles have potential as a delivery agent of IO nanocrystals to macrophages in arterial lesions.
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Affiliation(s)
- Maki Nakamura
- Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Hisanori Kosuge
- Department of Cardiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Ayako Oyane
- Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Kiyoko Kuroiwa
- Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Yoshiki Shimizu
- Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Kazutaka Aonuma
- Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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46
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Zhang Y, Yin Y, Zhang W, Li H, Wang T, Yin H, Sun L, Su C, Zhang K, Xu H. Reactive oxygen species scavenging and inflammation mitigation enabled by biomimetic prussian blue analogues boycott atherosclerosis. J Nanobiotechnology 2021; 19:161. [PMID: 34059078 PMCID: PMC8166117 DOI: 10.1186/s12951-021-00897-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/13/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND As one typical cardiovascular disease, atherosclerosis severely endanger people' life and cause burden to people health and mentality. It has been extensively accepted that oxidative stress and inflammation closely correlate with the evolution of atherosclerotic plaques, and they directly participate in all stages of atherosclerosis. Regarding this, anti-oxidation or anti-inflammation drugs were developed to enable anti-oxidative therapy and anti-inflammation therapy against atherosclerosis. However, current drugs failed to meet clinical demands. METHODS Nanomedicine and nanotechnology hold great potential in addressing the issue. In this report, we engineered a simvastatin (Sim)-loaded theranostic agent based on porous manganese-substituted prussian blue (PMPB) analogues. The biomimetic PMPB carrier could scavenge ROS and mitigate inflammation in vitro and in vivo. Especially after combining with Sim, the composite Sim@PMPB NC was expected to regulate the processes of atherosclerosis. As well, Mn2+ release from PMPB was expected to enhance MRI. RESULTS The composite Sim@PMPB NC performed the best in regulating the hallmarks of atherosclerosis with above twofold decreases, typically such as oxidative stress, macrophage infiltration, plaque density, LDL internalization, fibrous cap thickness and foam cell birth, etc. Moreover, H2O2-induced Mn2+ release from PMPB NC in atherosclerotic inflammation could enhance MRI for visualizing plaques. Moreover, Sim@PMPB exhibited high biocompatibility according to references and experimental results. CONCLUSIONS The biomimetic Sim@PMPB theranostic agent successfully stabilized atherosclerotic plaques and alleviated atherosclerosis, and also localized and magnified atherosclerosis, which enabled the monitoring of H2O2-associated atherosclerosis evolution after treatment. As well, Sim@PMPB was biocompatible, thus holding great potential in clinical translation for treating atherosclerosis.
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Affiliation(s)
- Yan Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
| | - Yifei Yin
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
| | - Wei Zhang
- Department of Radiology, Affiliated Hospital of Guilin Medical University, No. 15 Le-Qun Road, Xiufeng District, Guilin, 541001, Guangxi, People's Republic of China
| | - Hongyan Li
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
| | - Taixia Wang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
| | - Haohao Yin
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
| | - Liping Sun
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China.
| | - Chunxia Su
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, No. 507 Zheng-Min Road, Shanghai, 200433, People's Republic of China.
| | - Kun Zhang
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China.
| | - Huixiong Xu
- Department of Medical Ultrasound and Central Laboratory, Shanghai Tenth People's Hospital, Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, Tongji University School of Medicine, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center for Interventional Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, People's Republic of China
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Shen M, Li H, Yao S, Wu X, Liu S, Yang Q, Zhang Y, Du J, Qi S, Li Y. Shear stress and ROS-responsive biomimetic micelles for atherosclerosis via ROS consumption. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 126:112164. [PMID: 34082967 DOI: 10.1016/j.msec.2021.112164] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Abstract
Reactive oxygen species (ROS) are well-known important initiating factors required for atherosclerosis formation, which leads to endothelial dysfunction and plaque formation. Most of the existing antithrombotic therapies use ROS-responsive drug delivery systems, which have a certain therapeutic effect but cannot eliminate excess ROS. Therefore, the atherosclerosis cannot be treated from the source. Moreover, nanoparticles are easily cleared by the immune system during blood circulation, which is not conducive to long-term circulation. In this study, we developed an intelligent response system that could simultaneously respond to ROS and the shear stress microenvironment of atherosclerotic plaques. This system was formed by red blood cells (RBCs) and simvastatin-loaded micelles (SV MC). The micelles consisted of poly(glycidyl methacrylate)-polypropylene sulfide (PGED-PPS). The hydrophobic PPS could react with excess ROS to become hydrophilic, which forced the micelle rupture, resulting in drug release. Most importantly, PPS could also significantly deplete the ROS level, realizing the synergistic treatment of atherosclerosis with drugs and materials. The positively charged SV MC and negatively charged RBCs were self-assembled through electrostatic adsorption to obtain SV MC@RBCs. The SV MC@RBCs could respond to the high shear stress at the atherosclerotic plaque, and the shear stress induced SV MC desorption from the RBC surface. Using biomimetic methods to evade the SV MC@RBCs elimination by the immune system and to reduce the ROS plays a vital role in improving atherosclerosis treatment. The results of in vitro and in vivo experiments showed that SV MC@RBCs could effectively treat atherosclerosis. Moreover, not only does the SV MC@RBCs system avoid the risk of bleeding, but it also has excellent in vivo safety. The study results indicate that the SV MC@RBCs system is a promising therapeutic nanomedicine for treating ROS-related diseases.
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Affiliation(s)
- Meili Shen
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China
| | - Hongli Li
- National and Local Joint Engineering Research Center for Green Preparation Technology of Biobased Materials, Yunnan Minzu University, Kunming 650500, China
| | - Shunyu Yao
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China
| | - Xiaodong Wu
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China
| | - Shun Liu
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China
| | - Qingbiao Yang
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China
| | - Yanjiao Zhang
- The First Bethune Hospital of Jilin University, Changchun 130012, China
| | - Jianshi Du
- Key Laboratory of Lymphatic Surgery Jilin Province, Engineering Laboratory of Lymphatic Surgery Jilin Province, China-Japan Union Hospital of Jilin University, Changchun 130031, China
| | - Shaolong Qi
- Key Laboratory of Lymphatic Surgery Jilin Province, Engineering Laboratory of Lymphatic Surgery Jilin Province, China-Japan Union Hospital of Jilin University, Changchun 130031, China
| | - Yapeng Li
- Key Laboratory of Special Engineering Plastics Ministry of Education, College of Chemistry, Jilin University, Changchun 130012, China.
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Cavalcante MF, Adorne MD, Turato WM, Kemmerer M, Uchiyama MK, Asbahr ACC, Alves ADCS, Farsky SHP, Drewes C, Spatti MC, Kazuma SM, Boss M, Guterres SS, Araki K, Brüne B, Namgaladze D, Pohlmann AR, Abdalla DSP. scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression. Front Med (Lausanne) 2021; 8:652137. [PMID: 33959626 PMCID: PMC8095373 DOI: 10.3389/fmed.2021.652137] [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: 01/11/2021] [Accepted: 03/17/2021] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in Ldlr -/- mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages in vitro by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of IL1B and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing Ldlr -/- mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.
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Affiliation(s)
- Marcela Frota Cavalcante
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Márcia Duarte Adorne
- Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Walter Miguel Turato
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marina Kemmerer
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Mayara Klimuk Uchiyama
- Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Ana Carolina Cavazzin Asbahr
- Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Aline de Cristo Soares Alves
- Department of Production and Control of Medicines, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Sandra Helena Poliselli Farsky
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Carine Drewes
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marina Cecília Spatti
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Soraya Megumi Kazuma
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marcel Boss
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Silvia Stanisçuaski Guterres
- Department of Production and Control of Medicines, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Koiti Araki
- Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Bernhard Brüne
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Dmitry Namgaladze
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Adriana Raffin Pohlmann
- Department of Organic Chemistry, Chemistry Institute, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Dulcineia Saes Parra Abdalla
- Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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49
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Craparo EF, Cabibbo M, Conigliaro A, Barreca MM, Musumeci T, Giammona G, Cavallaro G. Rapamycin-Loaded Polymeric Nanoparticles as an Advanced Formulation for Macrophage Targeting in Atherosclerosis. Pharmaceutics 2021; 13:pharmaceutics13040503. [PMID: 33916918 PMCID: PMC8067637 DOI: 10.3390/pharmaceutics13040503] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 12/20/2022] Open
Abstract
Recently, rapamycin (Rapa) represents a potential drug treatment to induce regression of atherosclerotic plaques; however, its use requires site-specific accumulation in the vessels involved in the formation of the plaques to avoid the systemic effects resulting from its indiscriminate biodistribution. In this work, a stable pharmaceutical formulation for Rapa was realized as a dried powder to be dispersed extemporaneously before administration. The latter was constituted by mannitol (Man) as an excipient and a Rapa-loaded polymeric nanoparticle carrier. These nanoparticles were obtained by nanoprecipitation and using as a starting polymeric material a polycaprolactone (PCL)/α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) graft copolymer. To obtain nanoparticles targeted to macrophages, an oxidized phospholipid with a high affinity for the CD36 receptor of macrophages, the 1-(palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdia-PC), was added to the starting organic phase. The chemical–physical and technological characterization of the obtained nanoparticles demonstrated that: both the drug loading (DL%) and the entrapment efficiency (EE%) entrapped drug are high; the entrapped drug is in the amorphous state, protected from degradation and slowly released from the polymeric matrix; and the KOdia-PC is on the nanoparticle surface (KP-Nano). The biological characterization demonstrated that both systems are quickly internalized by macrophages while maintaining the activity of the drug. In vitro studies demonstrated that the effect of KP-Nano Rapa-loaded, in reducing the amount of the Phospo-Ser757-ULK1 protein through the inhibition of the mammalian target of rapamycin (mTOR), is comparable to that of the free drug.
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Affiliation(s)
- Emanuela Fabiola Craparo
- Department of Biological, Chemical and Pharmaceutical Science and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; (M.C.); (G.G.)
- Correspondence: (E.F.C.); (G.C.); Tel.: +39-091-23891937 (E.F.C.); +39-091-23891931 (G.C.)
| | - Marta Cabibbo
- Department of Biological, Chemical and Pharmaceutical Science and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; (M.C.); (G.G.)
| | - Alice Conigliaro
- Department of BioMedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, Via Divisi 83, 90133 Palermo, Italy; (A.C.); (M.M.B.)
| | - Maria Magdalena Barreca
- Department of BioMedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), University of Palermo, Via Divisi 83, 90133 Palermo, Italy; (A.C.); (M.M.B.)
| | - Teresa Musumeci
- Laboratory of Drug Delivery Technology, Department of Drug Sciences, University of Catania, Via Santa Sofia 64, 95125 Catania, Italy;
| | - Gaetano Giammona
- Department of Biological, Chemical and Pharmaceutical Science and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; (M.C.); (G.G.)
| | - Gennara Cavallaro
- Department of Biological, Chemical and Pharmaceutical Science and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; (M.C.); (G.G.)
- Correspondence: (E.F.C.); (G.C.); Tel.: +39-091-23891937 (E.F.C.); +39-091-23891931 (G.C.)
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50
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Kaku TS, Lim S. Protein nanoparticles in molecular, cellular, and tissue imaging. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1714. [PMID: 33821568 DOI: 10.1002/wnan.1714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/12/2021] [Accepted: 03/08/2021] [Indexed: 01/10/2023]
Abstract
The quest to develop ideal nanoparticles capable of molecular, cellular, and tissue level imaging is ongoing. Since certain imaging probes and nanoparticles face drawbacks such as low aqueous solubility, increased ROS generation leading to DNA damage, apoptosis, and high cellular/organ toxicities, the development of versatile and biocompatible nanocarriers becomes necessary. Protein nanoparticles (PNPs) are one such promising class of nanocarriers that possess most of the desirable properties of an ideal nanocarrier for bioimaging applications. PNPs demonstrate high aqueous solubility, minimal cytotoxicity, and multi-cargo loading capacity. They are also amenable to surface-functionalization, as well as modulation of their hydrophobicity and hydrophilicity. The use of PNPs for bioimaging applications has made rapid advancements in the past two decades. Being comparatively less explored, the field opens up a plethora of opportunities and focus areas to engineer ideal bioimaging protein nanocarriers. The use of PNPs as carriers of their natural ligands as well as other heavy metals and fluorescent probes, along with drug molecules for combined theranostic applications has been reported. In addition, surface functionalization to impart specificity of targeting the PNPs has been shown to reduce nonspecific cellular interactions, thus reducing systemic toxicity. PNPs have been explored for their application in imaging of numerous cancers, cardiovascular diseases as well as imaging of the brain using near infrared fluorescence (NIRF) imaging, magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), ultrasound (US), and photoacoustic (PA) imaging. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.
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Affiliation(s)
- Tanvi Sushil Kaku
- School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
| | - Sierin Lim
- School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore
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