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1
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Che Z, Wang W, Zhang L, Lin Z. Therapeutic strategies targeting CD47-SIRPα signaling pathway in gastrointestinal cancers treatment. J Pharm Anal 2025; 15:101099. [PMID: 39881799 PMCID: PMC11772969 DOI: 10.1016/j.jpha.2024.101099] [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: 03/28/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 01/31/2025] Open
Abstract
Gastrointestinal (GI) cancers are prevalent globally, with leading incidence and mortality rates among malignant tumors. Despite notable advancements in surgical resection, radiotherapy, and chemotherapy, the overall survival rates remain low. Hence, it is imperative to explore alternative approaches that enhance patient outcomes. Cluster of differentiation 47 (CD47), serving as an early diagnostic marker, is predominantly overexpressed in GI cancers and associated with poor prognosis. Targeting the CD47-signal regulatory protein alpha (SIRPα) signaling pathway may provide a novel strategy for GI cancers treatment. This study summarizes current knowledge of the structure and function of CD47 and SIRPα, their roles in signaling pathways, the prognostic significance of CD47, therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer, and highlights key issues for future investigations.
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Affiliation(s)
- Zhengping Che
- School of Life Sciences, Chongqing University, Chongqing, 401331, China
| | - Wei Wang
- Department of Cancer Center, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing, 404000, China
| | - Lin Zhang
- Department of Gastroenterology, Chongqing University Jiangjin Hospital, Chongqing, 402260, China
| | - Zhenghong Lin
- School of Life Sciences, Chongqing University, Chongqing, 401331, China
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2
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Zhang F, Li W, Zheng X, Ren Y, Li L, Yin H. The novel immune landscape of immune-checkpoint blockade in EBV-associated malignancies. FASEB J 2024; 38:e70139. [PMID: 39520274 DOI: 10.1096/fj.202301980rr] [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: 09/27/2023] [Revised: 09/15/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
The Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV-related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune-suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor-infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune-checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD-1 and CTLA-4 blockades in treating EBV-associated tumors, several novel inhibitory receptors (e.g., CD47, LAG-3, TIM-3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV-associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV-associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies.
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Affiliation(s)
- Feng Zhang
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wenjing Li
- The First Class Ward 2 of the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xinglong Zheng
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yinlong Ren
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lijun Li
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Haiyan Yin
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
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3
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Wang Y, Xiao T, Zhao C, Li G. The Regulation of Exosome Generation and Function in Physiological and Pathological Processes. Int J Mol Sci 2023; 25:255. [PMID: 38203424 PMCID: PMC10779122 DOI: 10.3390/ijms25010255] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/16/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Exosomes, a type of extracellular vesicle with a diameter of approximately 100 nm that is secreted by all cells, regulate the phenotype and function of recipient cells by carrying molecules such as proteins, nucleic acids, and lipids and are important mediators of intercellular communication. Exosomes are involved in various physiological and pathological processes such as immunomodulation, angiogenesis, tumorigenesis, metastasis, and chemoresistance. Due to their excellent properties, exosomes have shown their potential application in the clinical diagnosis and treatment of disease. The functions of exosomes depend on their biogenesis, uptake, and composition. Thus, a deeper understanding of these processes and regulatory mechanisms can help to find new targets for disease diagnosis and therapy. Therefore, this review summarizes and integrates the recent advances in the regulatory mechanisms of the entire biological process of exosomes, starting from the formation of early-sorting endosomes (ESCs) by plasma membrane invagination to the release of exosomes by fusion of multivesicular bodies (MVBs) with the plasma membrane, as well as the regulatory process of the interactions between exosomes and recipient cells. We also describe and discuss the regulatory mechanisms of exosome production in tumor cells and the potential of exosomes used in cancer diagnosis and therapy.
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Affiliation(s)
| | | | | | - Guiying Li
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China; (Y.W.); (T.X.); (C.Z.)
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4
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CHEN QIUQIANG, GUO XUEJUN, MA WENXUE. Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy. Oncol Res 2023; 32:49-60. [PMID: 38188674 PMCID: PMC10767231 DOI: 10.32604/or.2023.042383] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/09/2023] [Indexed: 01/09/2024] Open
Abstract
Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.
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Affiliation(s)
- QIUQIANG CHEN
- Key Laboratory for Translational Medicine, The First Affiliated Hospital, Huzhou University School of Medicine, Huzhou, 313000, China
| | - XUEJUN GUO
- Department of Hematology, Puyang Youtian General Hospital, Puyang, 457001, China
| | - WENXUE MA
- Department of Medicine, Moores Cancer Center, Sanford Stem Cell Institute, University of California San Diego, La Jolla, San Diego, 92093, USA
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5
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Jin Q, Zhao T, Lin L, Yao X, Teng Y, Zhang D, Jin Y, Yang M. PIAS1 impedes vascular endothelial injury and atherosclerotic plaque formation in diabetes by blocking the RUNX3/TSP-1 axis. Hum Cell 2023; 36:1915-1927. [PMID: 37584829 DOI: 10.1007/s13577-023-00952-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 07/03/2023] [Indexed: 08/17/2023]
Abstract
The protein PIAS1 functions as a type of ubiquitin-protease, which is known to play an important regulatory role in various diseases, including cardiovascular diseases and cancers. Its mechanism of action primarily revolves around regulating the transcription, translation, and modification of target proteins. This study investigates role and mechanism of PIAS1 in the RUNX3/TSP-1 axis and confirms its therapeutic effects on diabetes-related complications in animal models. A diabetic vascular injury was induced in human umbilical vein endothelial cells (HUVECs) by stimulation with H2O2 and advanced glycation end product (AGE), and a streptozotocin (STZ)-induced mouse model of diabetes was constructed, followed by detection of endogenous PIAS1 expression and SUMOylation level of RUNX3. Effects of PIAS1 concerning RUNX3 and TSP-1 on the HUVEC apoptosis and inflammation were evaluated using the ectopic expression experiments. Down-regulated PIAS1 expression and SUMOylation level of RUNX3 were identified in the H2O2- and AGE-induced HUVEC model of diabetic vascular injury and STZ-induced mouse models of diabetes. PIAS1 promoted the SUMOylation of RUNX3 at the K148 site of RUNX3. PIAS1-mediated SUMOylation of RUNX3 reduced RUNX3 transactivation activity, weakened the binding of RUNX3 to the promoter region of TSP-1, and caused downregulation of TSP-1 expression. PIASI decreased the expression of TSP-1 by inhibiting H2O2- and AGE-induced RUNX3 de-SUMOylation, thereby arresting the inflammatory response and apoptosis of HUVECs. Besides, PIAS1 reduced vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes by inhibiting the RUNX3/TSP-1 axis. Our study proved that PIAS1 suppressed vascular endothelial injury and atherosclerotic plaque formation in mouse models of diabetes via the RUNX3/TSP-1 axis.
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Affiliation(s)
- Qingsong Jin
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Tiantian Zhao
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Liangyan Lin
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Xiaoyan Yao
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Yaqin Teng
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Dongdong Zhang
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China
| | - Yongjun Jin
- Department of Endocrinology and Metabolism, Yantai Affiliated Hospital of Binzhou Medical University, No. 717, Mouping District, Binzhou, 264100, Shandong Province, People's Republic of China.
| | - Meizi Yang
- Department of Pharmacology, School of Basic Medical Sciences, Binzhou Medical University, No. 522, Huanghe Third Road, Binzhou, 264003, People's Republic of China.
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6
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Gusev E, Sarapultsev A. Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes. Int J Mol Sci 2023; 24:ijms24097910. [PMID: 37175617 PMCID: PMC10178362 DOI: 10.3390/ijms24097910] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).
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Affiliation(s)
- Evgenii Gusev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
| | - Alexey Sarapultsev
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Science, 620049 Ekaterinburg, Russia
- Russian-Chinese Education and Research Center of System Pathology, South Ural State University, 454080 Chelyabinsk, Russia
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7
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Govatati S, Pichavaram P, Kumar R, Rao GN. Blockade of CD47 function attenuates restenosis by promoting smooth muscle cell efferocytosis and inhibiting their migration and proliferation. J Biol Chem 2023; 299:104594. [PMID: 36898577 PMCID: PMC10124914 DOI: 10.1016/j.jbc.2023.104594] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 03/10/2023] Open
Abstract
Cluster of differentiation 47 (CD47) plays an important role in the pathophysiology of various diseases including atherosclerosis, but its role in neointimal hyperplasia which contributes to restenosis, has not been studied. Using molecular approaches in combination with a mouse vascular endothelial denudation model, we studied the role of CD47 in injury-induced neointimal hyperplasia. We determined that thrombin induced CD47 expression both in human and mouse aortic smooth muscle cells (HASMCs and MASMCs). In exploring the mechanisms, we found that the protease-activated receptor 1 (PAR1)-Gα protein q/11 (Gαq/11)-phospholipase Cβ3 (PLCβ3)-nuclear factor of activated T cells c1 (NFATc1) signaling axis regulates thrombin-induced CD47 expression in HASMCs. Depletion of CD47 levels using its siRNA or interference of its function by its blocking antibody (bAb) blunted thrombin-induced migration and proliferation of HASMCs and MASMCs. In addition, we found that thrombin-induced HASMC migration requires CD47 interaction with integrin β3. On the other hand, thrombin-induced HASMC proliferation was dependent on CD47's role in nuclear export and degradation of CDK-interacting protein 1 (p21Cip1). In addition, suppression of CD47 function by its bAb rescued HASMC efferocytosis from inhibition by thrombin. We also found that vascular injury induces CD47 expression in intimal SMCs and that inhibition of CD47 function by its bAb, while alleviating injury-induced inhibition of SMC efferocytosis, attenuated SMC migration and proliferation resulting in reduced neointima formation. Thus, these findings reveal a pathological role for CD47 in neointimal hyperplasia.
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Affiliation(s)
- Suresh Govatati
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Prahalathan Pichavaram
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Raj Kumar
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Gadiparthi N Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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8
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Gao L, He Z, Wu Y. Advances in Anti-metabolic Disease Treatments Targeting CD47. Curr Pharm Des 2022; 28:3720-3728. [PMID: 36201266 DOI: 10.2174/1381612828666221006123144] [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: 05/26/2022] [Revised: 08/15/2022] [Accepted: 08/21/2022] [Indexed: 01/28/2023]
Abstract
Metabolic disorders include a cluster of conditions that result from hyperglycemia, hyperlipidemia, insulin resistance, obesity, and hepatic steatosis, which cause the dysfunction of immune cells and innate cells, such as macrophages, natural killer cells, vascular endothelial cells, hepatocytes, and human kidney tubular epithelial cells. Besides targeting the derangements in lipid metabolism, therapeutic modulations to regulate abnormal responses in the immune system and innate cell dysfunctions may prove to be promising strategies in the management of metabolic diseases. In recent years, several targets have been explored for the CD47 molecule (CD47), a glycosylated protein, which was originally reported to transmit an anti-phagocytic signal known as "don't eat me" in the atherosclerotic environment, hindering the efferocytosis of immune cells and promoting arterial plaque accumulation. Subsequently, the role of CD47 has been explored in obesity, fatty liver, and lipotoxic nephropathy, and its utility as a therapeutic target has been investigated using anti-CD47 antibodies or inhibitors of the THBS1/CD47 axis and the CD47/SIRPα signaling pathway. This review summarizes the mechanisms of action of CD47 in different cell types during metabolic diseases and the clinical research progress to date, providing a reference for the comprehensive targeting of CD47 to treat metabolic diseases and the devising of potential improvements to possible side effects.
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Affiliation(s)
- Li Gao
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.,Center for Scientific Research of Anhui Medical University, Hefei 230022, China
| | - Zhe He
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Yonggui Wu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.,Center for Scientific Research of Anhui Medical University, Hefei 230022, China
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9
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Cai Y, Zang GY, Huang Y, Sun Z, Zhang LL, Qian YJ, Yuan W, Wang ZQ. Advances in neovascularization after diabetic ischemia. World J Diabetes 2022; 13:926-939. [PMID: 36437864 PMCID: PMC9693741 DOI: 10.4239/wjd.v13.i11.926] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/09/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
With the high incidence of diabetes around the world, ischemic complications cause a serious influence on people's production and living. Neovascularization plays a significant role in its development. Therefore, neovascularization after diabetic ischemia has aroused attention and has become a hot spot in recent years. Neovascularization is divided into angiogenesis represented by atherosclerosis and arteriogenesis characterized by coronary collateral circulation. When mononuclear macrophages successively migrate to the ischemia anoxic zone after ischemia or hypoxia, they induce the secretion of cytokines, such as vascular endothelial growth factor and hypoxia-inducible factor, activate signaling pathways such as classic Wnt and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathways, trigger oxidative stress response, activate endothelial progenitor cells or enter the glycolysis or lactic acid process and promote the formation of new blood vessels, remodeling them into mature blood vessels and restoring blood supply. However, the hypoglycemic condition has different impacts on neovascularization. Consequently, this review aimed to introduce the mechanisms of neovascularization after diabetic ischemia, increase our un-derstanding of diabetic ischemic complications and their therapies and provide more treatment options for clinical practice and effectively relieve patients' pain. It is believed that in the near future, neovascularization will bring more benefits and hope to patients with diabetes.
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Affiliation(s)
- Yue Cai
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Guang-Yao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yan Huang
- Department of Ophthalmology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Li-Li Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Yong-Jiang Qian
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
| | - Zhong-Qun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, Jiangsu Province, China
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10
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Hetherington I, Totary-Jain H. Anti-atherosclerotic therapies: Milestones, challenges, and emerging innovations. Mol Ther 2022; 30:3106-3117. [PMID: 36065464 PMCID: PMC9552812 DOI: 10.1016/j.ymthe.2022.08.024] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/22/2022] Open
Abstract
Atherosclerosis is the main underlying pathology for many cardiovascular diseases (CVDs), which are the leading cause of death globally and represent a serious health crisis. Atherosclerosis is a chronic condition that can lead to myocardial infarction, ischemic cardiomyopathy, stroke, and peripheral arterial disease. Elevated plasma lipids, hypertension, and high glucose are the major risk factors for developing atherosclerotic plaques. To date, most pharmacological therapies aim to control these risk factors, but they do not target the plaque-causing cells themselves. In patients with acute coronary syndromes, surgical revascularization with percutaneous coronary intervention has greatly reduced mortality rates. However, stent thrombosis and neo-atherosclerosis have emerged as major safety concerns of drug eluting stents due to delayed re-endothelialization. This review summarizes the major milestones, strengths, and limitations of current anti-atherosclerotic therapies. It provides an overview of the recent discoveries and emerging game-changing technologies in the fields of nanomedicine, mRNA therapeutics, and gene editing that have the potential to revolutionize CVD clinical practice by steering it toward precision medicine.
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Affiliation(s)
- Isabella Hetherington
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC08, 2170, Tampa, FL 33612, USA
| | - Hana Totary-Jain
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC08, 2170, Tampa, FL 33612, USA.
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11
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Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL). DISEASE MARKERS 2021; 2021:4894022. [PMID: 34567285 PMCID: PMC8463246 DOI: 10.1155/2021/4894022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022]
Abstract
At present, the use of the common chemotherapy regimen CHOP/R-CHOP for diffuse large B-cell lymphoma (DLBCL) has some shortcomings, especially for relapsed and refractory DLBCL. CD47 is now considered as a prominent target in cancer therapies, and CD47 blockade mainly inhibits the CD47-SIRPα axis to prevent tumor immune escape. Here, we evaluated the effects of the latest CD47 antibodies reported and the correlations of closely related genes with CD47 in this disease. In the future, therapeutic strategies for DLBCL will focus on multitarget antibody combined treatment and multigene joint attacks.
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12
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Kong XY, Huse C, Yang K, Øgaard J, Berges N, Vik ES, Nawaz MS, Quiles-Jiménez A, Abbas A, Gregersen I, Holm S, Bjerkli V, Rashidi A, Fladeby C, Suganthan R, Sagen EL, Skjelland M, Lång A, Bøe SO, Bjørås M, Aukrust P, Alseth I, Halvorsen B, Dahl TB. Endonuclease V Regulates Atherosclerosis Through C-C Motif Chemokine Ligand 2-Mediated Monocyte Infiltration. J Am Heart Assoc 2021; 10:e020656. [PMID: 34259011 PMCID: PMC8483470 DOI: 10.1161/jaha.120.020656] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Background In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine‐to‐inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine‐to‐inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine‐ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E‐deficient (ApoE−/−) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE−/− mice. Conclusions ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.
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Affiliation(s)
- Xiang Yi Kong
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Camilla Huse
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway
| | - Kuan Yang
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Jonas Øgaard
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Natalia Berges
- Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway.,Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Erik Sebastian Vik
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Meh Sameen Nawaz
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Ana Quiles-Jiménez
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway
| | | | - Ida Gregersen
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway
| | - Sverre Holm
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Vigdis Bjerkli
- Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway
| | - Azita Rashidi
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Cathrine Fladeby
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Rajikala Suganthan
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Ellen Lund Sagen
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Mona Skjelland
- Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway.,Department of Neurology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Anna Lång
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Stig Ove Bøe
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Magnar Bjørås
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway.,Department of Clinical and Molecular Medicine Norwegian University of Science and Technology Trondheim Norway
| | - Pål Aukrust
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway.,Section of Clinical Immunology and Infectious Diseases Oslo University Hospital, Rikshospitalet Oslo Norway.,K.G. Jebsen, The Faculty of Health Sciences The Arctic University of Tromsø Tromsø Norway
| | - Ingrun Alseth
- Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
| | - Bente Halvorsen
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway
| | - Tuva Børresdatter Dahl
- Research Institute for Internal Medicine Oslo University Hospital, Rikshospitalet Oslo Norway.,Department of Microbiology Oslo University Hospital, Rikshospitalet Oslo Norway
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