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Gu Y, Lin X, Dong Y, Wood G, Seidah NG, Werstuck G, Major P, Bonert M, Kapoor A, Tang D. PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2023; 42:2. [PMID: 36588164 PMCID: PMC9806914 DOI: 10.1186/s13046-022-02584-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. METHODS PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9-/- mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. RESULTS PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9-/- mice. CONCLUSIONS Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.
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Affiliation(s)
- Yan Gu
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Xiaozeng Lin
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Ying Dong
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Geoffrey Wood
- grid.34429.380000 0004 1936 8198Department of Pathology, University of Guelph, Guelph, ON N1G 2W1 Canada
| | - Nabil G. Seidah
- grid.511547.30000 0001 2106 1695Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, University of Montreal, Montreal, QC H2W 1R7 Canada
| | - Geoff Werstuck
- grid.25073.330000 0004 1936 8227Department of Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Pierre Major
- grid.25073.330000 0004 1936 8227Department of Oncology, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Michael Bonert
- grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Anil Kapoor
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Damu Tang
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
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Sipido KR, Nagyova I. Health research and knowledge translation for achieving the sustainable development goals: tackling the hurdles. Eur J Public Health 2021; 30:i36-i40. [PMID: 32391902 PMCID: PMC7213555 DOI: 10.1093/eurpub/ckaa032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We are far from reaching the sustainable development goals (SDGs) for health despite a wealth of novel insights in disease mechanisms and possible solutions. Why have we failed in knowledge translation and implementation? Starting from the case of cardiovascular diseases as one of the most prevalent non-communicable diseases, we examine barriers and hurdles, and perspectives for future health research. Health has multiple links with other SDGs. To accelerate the progress towards a healthy society, health research needs to take a broader view and become more cross-disciplinary and cross-sectoral. As one example, behavioural studies will underpin better prevention and treatment adherence. The next generation workforce in health and research needs an adapted education and training to implement more effective health approaches. As well, only effective dialogue and communication between researchers, practitioners, society and policymakers can lead to translation of evidence into policies, addressing the complexity of socioeconomic factors and commercial interests. Within Europe, health research needs a comprehensive vision and strategy that connects to achieving better health, as one of the interconnected SDGs.
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Affiliation(s)
- Karin R Sipido
- Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Iveta Nagyova
- Department of Social and Behavioural Medicine, Faculty of Medicine, PJ Safarik University, Kosice, Slovakia
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Christ A, Lauterbach M, Latz E. Western Diet and the Immune System: An Inflammatory Connection. Immunity 2020; 51:794-811. [PMID: 31747581 DOI: 10.1016/j.immuni.2019.09.020] [Citation(s) in RCA: 468] [Impact Index Per Article: 93.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/24/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023]
Abstract
The consumption of Western-type calorically rich diets combined with chronic overnutrition and a sedentary lifestyle in Western societies evokes a state of chronic metabolic inflammation, termed metaflammation. Metaflammation contributes to the development of many prevalent non-communicable diseases (NCDs), and these lifestyle-associated pathologies represent a rising public health problem with global epidemic dimensions. A better understanding of how modern lifestyle and Western diet (WD) activate immune cells is essential for the development of efficient preventive and therapeutic strategies for common NCDs. Here, we review the current mechanistic understanding of how the Western lifestyle can induce metaflammation, and we discuss how this knowledge can be translated to protect the public from the health burden associated with their selected lifestyle.
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Affiliation(s)
- Anette Christ
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA
| | - Mario Lauterbach
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim 7491, Norway; German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
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Wong HSC, Lin YJ, Lu HF, Liao WL, Chen CH, Wu JY, Chang WC, Tsai FJ. Genomic interrogation of familial short stature contributes to the discovery of the pathophysiological mechanisms and pharmaceutical drug repositioning. J Biomed Sci 2019; 26:91. [PMID: 31699087 PMCID: PMC6836357 DOI: 10.1186/s12929-019-0581-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 10/09/2019] [Indexed: 01/06/2023] Open
Abstract
Background Genetic factors, dysregulation in the endocrine system, cytokine and paracrine factors are implicated in the pathogenesis of familial short stature (FSS). Nowadays, the treatment choice for FSS is limited, with only recombinant human growth hormone (rhGH) being available. Methods Herein, starting from the identification of 122 genetic loci related to FSS, we adopted a genetic-driven drug discovery bioinformatics pipeline based on functional annotation to prioritize crucial biological FSS-related genes. These genes were suggested to be potential targets for therapeutics. Results We discovered five druggable subnetworks, which contained seven FSS-related genes and 17 druggable targerts. Conclusions This study provides a valuable drug repositioning accompanied by corresponding targetable gene clusters for FSS therapy.
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Affiliation(s)
- Henry Sung-Ching Wong
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ying-Ju Lin
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Hsing-Fang Lu
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.,Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
| | - Wen-Ling Liao
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.,Center for Personalized Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jer-Yuarn Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. .,Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. .,Department of Medical Research, Shuang Ho Hospital, Taipei Medical University , New Taipei City, Taiwan. .,Pain Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
| | - Fuu-Jen Tsai
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. .,School of Chinese Medicine, China Medical University, Taichung, Taiwan. .,Children's Hospital of China Medical University, Taichung, Taiwan. .,Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan.
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Grazioso G, Bollati C, Sgrignani J, Arnoldi A, Lammi C. First Food-Derived Peptide Inhibitor of the Protein-Protein Interaction between Gain-of-Function PCSK9 D374Y and the Low-Density Lipoprotein Receptor. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:10552-10557. [PMID: 30226051 DOI: 10.1021/acs.jafc.8b03233] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, because it induces the low-density lipoprotein receptor (LDLR) degradation. This protein may carry some positive or negative mutations: PCSK9D374Y is one of the most dangerous gain-of-function mutations. This paper reports the identification of the first food-derived peptide able to inhibit the protein-protein interaction (PPI) between PCSK9D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin β-conglutin, is able to impair the PPI between PCSK9D374Y and the LDLR, with an IC50 value equal to 285.6 ± 2.46 μM. The consequence of this inhibition is an increase of the protein level of the LDLR located on hepatic cell membranes up to 74.3 ± 4.4% and the restoration of the functional capability of HepG2 cells to uptake extracellular low-density lipoprotein up to 83.1 ± 1.6%. Finally, the putative binding mode of T9 to the LDLR binding site located on PCSK9D374Y was postulated by in silico tools.
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Affiliation(s)
- Giovanni Grazioso
- Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Via Luigi Mangiagalli 25 , 20133 Milan , Italy
| | - Carlotta Bollati
- Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Via Luigi Mangiagalli 25 , 20133 Milan , Italy
| | - Jacopo Sgrignani
- Istituto di Ricerca in Biomedicina (IRB) , Università della Svizzera Italiana (USI) , Via Vincenzo Vela 6 , CH-6500 Bellinzona , Switzerland
| | - Anna Arnoldi
- Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Via Luigi Mangiagalli 25 , 20133 Milan , Italy
| | - Carmen Lammi
- Dipartimento di Scienze Farmaceutiche , Università degli Studi di Milano , Via Luigi Mangiagalli 25 , 20133 Milan , Italy
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Bergauer T, Ruppert T, Essioux L, Spleiss O. Drug Target Identification and Validation: Global Pharmaceutical Industry Experts on Challenges, Best Strategies, Innovative Precompetitive Collaboration Concepts, and Future Areas of Industry Precompetitive Research and Development. Ther Innov Regul Sci 2016; 50:769-776. [PMID: 30231745 DOI: 10.1177/2168479016651298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Focused interviews were conducted with global pharmaceutical company representatives in order to derive a consistent view on drug target identification/validation challenges, collaborative strategies, and future developments in a precompetitive space. Analysis revealed translation into clinical utility as a major hurdle of novel drug target validation, originating from lack of biological understanding, irreproducibility of published results, and lack of valid animal models. Direct and close collaborations with academia are the preferred model to tackle basic research on novel drug targets in high-risk projects. Efforts to conduct target identification in large precompetitive consortia are acknowledged with some doubts about the pace of progress and data-sharing policies, while concept to extend the precompetitive space to target validation in phase II trials was curtailed to niche indications together with a revision of current intellectual property (IP) practice. Public-private partnerships in established areas are forecasted to increase. Novel emerging themes are toxicology data sharing, joint genetic patient data analysis, and reimbursement concepts.
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Affiliation(s)
- Tobias Bergauer
- 1 Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Thorsten Ruppert
- 2 Association of Research-Based Pharmaceutical Companies (vfa), Berlin, Germany
| | - Laurent Essioux
- 1 Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Olivia Spleiss
- 1 Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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7
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Sung YK, Yuan K, de Jesus Perez VA. Novel approaches to pulmonary arterial hypertension drug discovery. Expert Opin Drug Discov 2016; 11:407-14. [PMID: 26901465 PMCID: PMC4933595 DOI: 10.1517/17460441.2016.1153625] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Pulmonary arterial hypertension (PAH) is a rare disorder associated with abnormally elevated pulmonary pressures that, if untreated, leads to right heart failure and premature death. The goal of drug development for PAH is to develop effective therapies that halt, or ideally, reverse the obliterative vasculopathy that results in vessel loss and obstruction of blood flow to the lungs. AREAS COVERED This review summarizes the current approach to candidate discovery in PAH and discusses the currently available drug discovery methods that should be implemented to prioritize targets and obtain a comprehensive pharmacological profile of promising compounds with well-defined mechanisms. EXPERT OPINION To improve the successful identification of leading drug candidates, it is necessary that traditional pre-clinical studies are combined with drug screening strategies that maximize the characterization of biological activity and identify relevant off-target effects that could hinder the clinical efficacy of the compound when tested in human subjects. A successful drug discovery strategy in PAH will require collaboration of clinician scientists with medicinal chemists and pharmacologists who can identify compounds with an adequate safety profile and biological activity against relevant disease mechanisms.
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Affiliation(s)
- Yon K. Sung
- Division of Pulmonary and Critical Care Medicine, The Vera Moulton Wall Center for Pulmonary Vascular Medicine, Stanford Cardiovascular Institute, Stanford, California
| | - Ke Yuan
- Division of Pulmonary and Critical Care Medicine, The Vera Moulton Wall Center for Pulmonary Vascular Medicine, Stanford Cardiovascular Institute, Stanford, California
| | - Vinicio A. de Jesus Perez
- Division of Pulmonary and Critical Care Medicine, The Vera Moulton Wall Center for Pulmonary Vascular Medicine, Stanford Cardiovascular Institute, Stanford, California
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Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Grüntzig Lecture ESC 2014. Eur Heart J 2015; 36:3320-31. [PMID: 26417060 PMCID: PMC4677274 DOI: 10.1093/eurheartj/ehv511] [Citation(s) in RCA: 408] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 09/07/2015] [Indexed: 12/18/2022] Open
Abstract
Modern-day stenting procedures leverage advances in pharmacotherapy and device innovation. Patients treated with contemporary antiplatelet agents, peri-procedural antithrombin therapy and new-generation drug-eluting stents (DES) have excellent outcomes over the short to medium term. Indeed, coupled with the reducing costs of these devices in most countries there remain very few indications where patients should be denied treatment with standard-of-care DES therapy. The two major causes of stent failure are stent thrombosis (ST) and in-stent restenosis (ISR). The incidence of both has reduced considerably in recent years. Current clinical registries and randomized trials with broad inclusion criteria show rates of ST at or <1% after 1 year and ∼0.2-0.4% per year thereafter; rates of clinical ISR are 5% respectively. Angiographic surveillance studies in large cohorts show rates of angiographic ISR of ∼10% with new-generation DES. The advent of high-resolution intracoronary imaging has shown that in many cases of late stent failure neoatherosclerotic change within the stented segment represents a final common pathway for both thrombotic and restenotic events. In future, a better understanding of the pathogenesis of this process may translate into improved late outcomes. Moreover, the predominance of non-stent-related disease as a cause of subsequent myocardial infarction during follow-up highlights the importance of lifestyle and pharmacological interventions targeted at modification of the underlying disease process. Finally, although recent developments focus on strategies which circumvent the need for chronically indwelling stents--such as drug-coated balloons or fully bioresorbable stents-more data are needed before the wider use of these therapies can be advocated.
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Affiliation(s)
- Robert A Byrne
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, Munich, Germany
| | - Michael Joner
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, Munich, Germany
| | - Adnan Kastrati
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, Munich, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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PCSK9 and lipid lowering drugs. Clin Chim Acta 2014; 437:66-71. [PMID: 25036764 DOI: 10.1016/j.cca.2014.07.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 07/02/2014] [Accepted: 07/03/2014] [Indexed: 02/05/2023]
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10
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Okada Y. From the era of genome analysis to the era of genomic drug discovery: a pioneering example of rheumatoid arthritis. Clin Genet 2014; 86:432-40. [PMID: 25060537 DOI: 10.1111/cge.12465] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 07/19/2014] [Accepted: 07/21/2014] [Indexed: 01/18/2023]
Abstract
Although we have obtained comprehensive catalogs of genetic risk loci that are linked to human diseases, little is known regarding how to devise a systematic strategy to integrate genetic study results with diverse biological resources. Such strategies will be crucial for providing novel insights into disease biology and for aiding drug discovery as an ultimate goal. Here we describe the current progress in this field using a pioneering example of large-scale genetic association studies on rheumatoid arthritis (RA), an autoimmune disease characterized by inflammation and destruction of joints. Through functional and bioinformatic annotations of risk single nucleotide polymorphisms (SNPs) and genes from >100 RA risk loci identified by genome-wide association study (GWAS) meta-analysis, we found novel biological insights into RA pathogenicity. Further, by integrating RA genetic findings with the complete catalog of approved drugs for RA and other diseases, we provide empirical data to indicate that human genetic-based approaches may be useful for supporting 'genetics-driven genomic drug discovery' efforts in complex human traits and suggest that further development of integrative approaches should be undertaken.
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Affiliation(s)
- Y Okada
- Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Tran-Dinh A, Levoye A, Lambert G, Louedec L, Journé C, Meilhac O, Amarenco P. Low levels of low-density lipoprotein-C associated with proprotein convertase subtilisin kexin 9 inhibition do not increase the risk of hemorrhagic transformation. Stroke 2014; 45:3086-8. [PMID: 25123222 DOI: 10.1161/strokeaha.114.005958] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency. METHODS PCSK9-/- and PCSK9+/+ mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9-/- and PCSK9+/+ mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood-brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions. RESULTS PCSK9-/- mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9+/+ mice before and after 1 month on the high-fat/high-cholesterol diet. Hemoglobin concentration in ischemic cerebral tissue was not different between PCSK9-/- and PCSK9+/+ mice (31.5 [18.9-60.1] and 32.8 [14.7-69.9] ng/mg protein, respectively; P=0.81). Infarct volume was also similar in both groups (P=0.66). Incubation of human cerebral endothelial cells with decreasing concentrations of LDL-C under ischemia/reperfusion conditions did not alter blood-brain barrier permeability. CONCLUSIONS Low levels of LDL-C did not increase the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice. Our observations suggest that PCSK9 inhibition, leading to LDL-C lowering, should not increase hemorrhagic complications after acute ischemic stroke.
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Affiliation(s)
- Alexy Tran-Dinh
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Angélique Levoye
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Gilles Lambert
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Liliane Louedec
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Clément Journé
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Olivier Meilhac
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
| | - Pierre Amarenco
- From the Inserm UMR1148, Paris7 University, Xavier Bichat Hospital, Paris, France (A.T.-D., A.L., L.L., C.J., O.M., P.A.); Paris 7 University, Université Paris Diderot, Paris, France (A.T.-D., P.A.); CHU Bichat Stroke Center, Paris, France (P.A.); CHU de La Réunion, Saint-Pierre, France (O.M.); Paris 13 University, Villetaneuse, France (A.L.); UMR PhAN Laboratory, Nantes, France (G.L.); and University of Nantes Medical School, Nantes, France (G.L.)
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Hancock-Cerutti W, Rader DJ. Opposing effects of ABCG5/8 function on myocardial infarction and gallstone disease. J Am Coll Cardiol 2014; 63:2129-2130. [PMID: 24657684 DOI: 10.1016/j.jacc.2014.02.553] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 02/12/2014] [Accepted: 02/17/2014] [Indexed: 11/26/2022]
Affiliation(s)
- William Hancock-Cerutti
- Department of Medicine and Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Daniel J Rader
- Department of Medicine and Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
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Trapani L, Segatto M, Pallottini V. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people? World J Hepatol 2013; 5:676-684. [PMID: 24432184 PMCID: PMC3879689 DOI: 10.4254/wjh.v5.i12.676] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.
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