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Das UN, Hacimüftüoglu A, Akpinar E, Gul M, Abd El-Aty AM. Crosstalk between renin and arachidonic acid (and its metabolites). Lipids Health Dis 2025; 24:52. [PMID: 39962508 PMCID: PMC11831833 DOI: 10.1186/s12944-025-02463-3] [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: 11/18/2024] [Accepted: 02/02/2025] [Indexed: 02/21/2025] Open
Abstract
Renin plays a significant role in the regulation of blood pressure and fluid volume by modulating the renin‒angiotensin‒aldosterone (RAAS) system. Renin suppression reduces serum aldosterone levels and lowers blood pressure in addition to preserving renal function. However, exactly how renin synthesis and action are regulated and how renin suppression preserves renal function are not clear. We propose that arachidonic acid (AA) and its metabolites control renin synthesis, secretion, and action by virtue of its (AA) anti-inflammatory, cytoprotective actions and ability to regulate the secretion of renin. These findings suggest that direct renin suppression results in changes in AA metabolism. This proposal implies that AA and its metabolites may be developed as potential drugs to prevent and manage hypertension and preserve renal function.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle ground, WA, 98604, USA.
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Ahmet Hacimüftüoglu
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Erol Akpinar
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Mustafa Gul
- Department of Physiology, Faculty of Medicine, Ataturk University, Erzurum, 25240, Turkey
| | - A M Abd El-Aty
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
- Department of Pharmacology, Cairo University, Giza, 12211, Egypt
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2
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Yan M, Wang Z, Qiu Z, Cui Y, Xiang Q. Platelet signaling in immune landscape: comprehensive mechanism and clinical therapy. Biomark Res 2024; 12:164. [PMID: 39736771 DOI: 10.1186/s40364-024-00700-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/28/2024] [Indexed: 01/01/2025] Open
Abstract
Platelets are essential for blood clotting and maintaining normal hemostasis. In pathological conditions, platelets are increasingly recognized as crucial regulatory factors in various immune-mediated inflammatory diseases. Resting platelets are induced by various factors such as immune complexes through Fc receptors, platelet-targeting autoantibodies and other platelet-activating stimuli. Platelet activation in immunological processes involves the release of immune activation stimuli, antigen presentation and interaction with immune cells. Platelets participate in both the innate immune system (neutrophils, monocytes/macrophages, dendritic cells (DCs) and Natural Killer (NK) cells and the adaptive immune system (T and B cells). Clinical therapeutic strategies include targeting platelet activation, platelet-immune cell interaction and platelet-endothelial cell interaction, which display positive development prospects. Understanding the mechanisms of platelets in immunity is important, and developing targeted modulations of these mechanisms will pave the way for promising therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Zhe Wang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Zhiwei Qiu
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
| | - Qian Xiang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
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Visagie JL, Aruwajoye GS, van der Sluis R. Pharmacokinetics of aspirin: evaluating shortcomings in the literature. Expert Opin Drug Metab Toxicol 2024:1-14. [PMID: 39092921 DOI: 10.1080/17425255.2024.2386368] [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: 04/10/2024] [Accepted: 07/26/2024] [Indexed: 08/04/2024]
Abstract
INTRODUCTION Aspirin is known for its therapeutic benefits in preventing strokes and relieving pain. However, it is toxic to some individuals, and the biological mechanisms causing toxicity are unknown. Limited literature is available on the role of glycine conjugation as the principal pathway in aspirin detoxification. Previous studies have quantified this two-step enzyme reaction as a singular enzymatic process. Consequently, the individual contributions of these enzymes to the kinetics remain unclear. AREAS COVERED This review summarized the available information on the pharmacokinetics and detoxification of aspirin by the glycine conjugation pathway. Literature searches were conducted using Google Scholar and the academic journal databases accessible through the North-West University Library. Furthermore, the factors affecting interindividual variation in aspirin metabolism and what is known regarding aspirin toxicity were discussed. EXPERT OPINION The greatest drawback in understanding the pharmacokinetics of aspirin is the limited information available on the substrate preference of the xenobiotic ligase (ACSM) responsible for activating salicylate to salicyl-CoA. Furthermore, previous pharmacokinetic studies did not consider the contribution of other substrates from the diet or genetic variants, to the detoxification rate of glycine conjugation. Impaired glycine conjugation might contribute to adverse health effects seen in Reye's syndrome and cancer.
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Affiliation(s)
- Jacobus Lukas Visagie
- Focus Area for Human Metabolomics, North-West University, Potchefstroom, South Africa
| | | | - Rencia van der Sluis
- Focus Area for Human Metabolomics, North-West University, Potchefstroom, South Africa
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Simon CG, Bozenhardt EH, Celluzzi CM, Dobnik D, Grant ML, Lakshmipathy U, Nebel T, Peltier L, Ratcliffe A, Sherley JL, Stacey GN, Taghizadeh RR, Tan EHP, Vessillier S. Mechanism of action, potency and efficacy: considerations for cell therapies. J Transl Med 2024; 22:416. [PMID: 38698408 PMCID: PMC11067168 DOI: 10.1186/s12967-024-05179-7] [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: 03/15/2024] [Accepted: 04/05/2024] [Indexed: 05/05/2024] Open
Abstract
One of the most challenging aspects of developing advanced cell therapy products (CTPs) is defining the mechanism of action (MOA), potency and efficacy of the product. This perspective examines these concepts and presents helpful ways to think about them through the lens of metrology. A logical framework for thinking about MOA, potency and efficacy is presented that is consistent with the existing regulatory guidelines, but also accommodates what has been learned from the 27 US FDA-approved CTPs. Available information regarding MOA, potency and efficacy for the 27 FDA-approved CTPs is reviewed to provide background and perspective. Potency process and efficacy process charts are introduced to clarify and illustrate the relationships between six key concepts: MOA, potency, potency test, efficacy, efficacy endpoint and efficacy endpoint test. Careful consideration of the meaning of these terms makes it easier to discuss the challenges of correlating potency test results with clinical outcomes and to understand how the relationships between the concepts can be misunderstood during development and clinical trials. Examples of how a product can be "potent but not efficacious" or "not potent but efficacious" are presented. Two example applications of the framework compare how MOA is assessed in cell cultures, animal models and human clinical trials and reveals the challenge of establishing MOA in humans. Lastly, important considerations for the development of potency tests for a CTP are discussed. These perspectives can help product developers set appropriate expectations for understanding a product's MOA and potency, avoid unrealistic assumptions and improve communication among team members during the development of CTPs.
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Affiliation(s)
- Carl G Simon
- Biosystems and Biomaterials Division, National Institute of Standards and Technology (NIST), Gaithersburg, MD, USA.
| | - Erich H Bozenhardt
- United Therapeutics Corporation, Regenerative Medicine Operations, Research Triangle Park, NC, USA
| | - Christina M Celluzzi
- Association for the Advancement of Blood and Biotherapies (AABB), Bethesda, MD, USA
| | - David Dobnik
- Niba Labs, Ljubljana, Slovenia
- National Institute of Biology, Ljubljana, Slovenia
| | - Melanie L Grant
- Department of Pediatrics, Children's Healthcare of Atlanta, Marcus Center for Cellular and Gene Therapies, Correlative Studies Laboratory, Emory University School of Medicine, Atlanta, GA, USA
| | - Uma Lakshmipathy
- Pharma Services, Science and Technology, Thermo Fisher Scientific, San Diego, CA, USA
| | - Thiana Nebel
- Medical Education, Sports Medicine and Orthobiologics, Medical Sales Institute, San Diego, CA, USA
| | - Linda Peltier
- Cellular Therapy Lab, Research Institute of McGill University Health Center, Montreal, QC, Canada
| | | | | | - Glyn N Stacey
- International Stem Cell Banking Initiative, Barley, Herts, UK
- National Stem Cell Resource Centre, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cells and Regenerative Medicine, Chinese Academy of Sciences, Beijing, China
| | | | - Eddie H P Tan
- Cell and Gene Therapy Facility, Health Sciences Authority, Singapore, Singapore
| | - Sandrine Vessillier
- Science, Research and Innovation Group, Biotherapeutics and Advanced Therapies Division, Medicines and Healthcare Products Regulatory Agency, South Mimms, Hertfordshire, UK
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Gonzalez AL, Dungan MM, Smart CD, Madhur MS, Doran AC. Inflammation Resolution in the Cardiovascular System: Arterial Hypertension, Atherosclerosis, and Ischemic Heart Disease. Antioxid Redox Signal 2024; 40:292-316. [PMID: 37125445 PMCID: PMC11071112 DOI: 10.1089/ars.2023.0284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 05/02/2023]
Abstract
Significance: Chronic inflammation has emerged as a major underlying cause of many prevalent conditions in the Western world, including cardiovascular diseases. Although targeting inflammation has emerged as a promising avenue by which to treat cardiovascular disease, it is also associated with increased risk of infection. Recent Advances: Though previously assumed to be passive, resolution has now been identified as an active process, mediated by unique immunoresolving mediators and mechanisms designed to terminate acute inflammation and promote tissue repair. Recent work has determined that failures of resolution contribute to chronic inflammation and the progression of human disease. Specifically, failure to produce pro-resolving mediators and the impaired clearance of dead cells from inflamed tissue have been identified as major mechanisms by which resolution fails in disease. Critical Issues: Drawing from a rapidly expanding body of experimental and clinical studies, we review here what is known about the role of inflammation resolution in arterial hypertension, atherosclerosis, myocardial infarction, and ischemic heart disease. For each, we discuss the involvement of specialized pro-resolving mediators and pro-reparative cell types, including T regulatory cells, myeloid-derived suppressor cells, and macrophages. Future Directions: Pro-resolving therapies offer the promise of limiting chronic inflammation without impairing host defense. Therefore, it is imperative to better understand the mechanisms underlying resolution to identify therapeutic targets. Antioxid. Redox Signal. 40, 292-316.
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Affiliation(s)
- Azuah L. Gonzalez
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Matthew M. Dungan
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - C. Duncan Smart
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Meena S. Madhur
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Amanda C. Doran
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Sykes EME, White D, McLaughlin S, Kumar A. Salicylic acids and pathogenic bacteria: new perspectives on an old compound. Can J Microbiol 2024; 70:1-14. [PMID: 37699258 DOI: 10.1139/cjm-2023-0123] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
Salicylic acids have been used in human and veterinary medicine for their anti-pyretic, anti-inflammatory, and analgesic properties for centuries. A key role of salicylic acid-immune modulation in response to microbial infection-was first recognized during studies of their botanical origin. The effects of salicylic acid on bacterial physiology are diverse. In many cases, they impose selective pressures leading to development of cross-resistance to antimicrobial compounds. Initial characterization of these interactions was in Escherichia coli, where salicylic acid activates the multiple antibiotic resistance (mar) operon, resulting in decreased antibiotic susceptibility. Studies suggest that stimulation of the mar phenotype presents similarly in closely related Enterobacteriaceae. Salicylic acids also affect virulence in many opportunistic pathogens by decreasing their ability to form biofilms and increasing persister cell populations. It is imperative to understand the effects of salicylic acid on bacteria of various origins to illuminate potential links between environmental microbes and their clinically relevant antimicrobial-resistant counterparts. This review provides an update on known effects of salicylic acid and key derivatives on a variety of bacterial pathogens, offers insights to possible potentiation of current treatment options, and highlights cellular regulatory networks that have been established during the study of this important class of medicines.
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Affiliation(s)
- Ellen M E Sykes
- Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada
| | - Dawn White
- Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada
| | - Sydney McLaughlin
- Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada
| | - Ayush Kumar
- Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada
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Meng Y, Lin Y, Zhang JW, Zou WL, Liu YM, Shen XG, Shen QQ, Wang MM, Shao LN, Feng HY, Zhu Y, Yu JT, Lin B, Zhu B. Aspirin intervention before ICU admission reduced the mortality in critically ill patients with acute kidney injury: results from the MIMIC-IV. Front Pharmacol 2023; 14:1292745. [PMID: 38034989 PMCID: PMC10682711 DOI: 10.3389/fphar.2023.1292745] [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: 09/14/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Background: Aspirin, with its pleiotropic effects such as anti-inflammatory and anti-platelet aggregation, has been widely used for anti-inflammatory, analgesic, and cardiovascular diseases. However, the association between the use of aspirin before the intensive care unit (ICU) and clinical outcomes in critically ill patients with acute kidney injury (AKI) is unknown. Methods: Patients with AKI in this retrospective observational study were selected from the Marketplace for Medical Information in Intensive Care IV (MIMIC-IV). The association between aspirin intervention and 30-day mortality was assessed using Cox proportional hazards model. Logistic regression models were used to assess the association of aspirin intervention with the risks of intracranial hemorrhage, gastrointestinal bleeding and blood transfusion. The propensity score matching (PSM) method was adopted to balance the baseline variables. Sensitivity analysis was performed to validate the results by multiple interpolations for the missing data. Results: The study included 4237 pre-ICU aspirin users and 9745 non-users. In multivariate models, we found a decreased risk of mortality in those who received aspirin before ICU compared to those who did not (30-day:hazard ratio [HR], 0.70; 95% CI, 0.62-0.79; p < 0.001; 90-day:HR, 0.70; 95% CI, 0.63-0.77, p < 0.001; 180-day:HR, 0.72; 95%CI,0.65-0.79, p < 0.001). This benefit was consistent in the post-PSM analyses, sensitivity analyses, and subgroup analyses. Moreover, aspirin intervention was associated with a reduced risk of intracranial hemorrhage and gastrointestinal bleeding (HR, 0.16; 95% CI, 0.10-0.25; p < 0.001; HR, 0.59; 95% CI, 0.38-0.88, p = 0.012) after being adjusted by relating covariates, whereas with a increased risk of blood transfusion (HR, 1.28; 95% CI, 1.16-1.46; p < 0.001). Conclusion: Patients with AKI treated with aspirin before ICU admission might have reduced 30-day, 90-day and 180-day mortality without increasing the risk of intracranial hemorrhage (ICH) or gastrointestinal bleeding, but may increase the risk of transfusion.
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Affiliation(s)
- Yao Meng
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
- Hangzhou Hospital of Traditional Chinese Medicine, Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Yi Lin
- Hangzhou Hospital of Traditional Chinese Medicine, Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Jia-Wei Zhang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wen-Li Zou
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yue-Ming Liu
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiao-Gang Shen
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Quan-Quan Shen
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Min-Min Wang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Li-Na Shao
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hong-Yuan Feng
- Hangzhou Hospital of Traditional Chinese Medicine, Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Zhu
- Hangzhou Hospital of Traditional Chinese Medicine, Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Jing-Ting Yu
- Hangzhou Hospital of Traditional Chinese Medicine, Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Lin
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Bin Zhu
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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Irún P, Carrera-Lasfuentes P, Sánchez-Luengo M, Belio Ú, Domper-Arnal MJ, Higuera GA, Hawkins M, de la Rosa X, Lanas A. Pharmacokinetics and Changes in Lipid Mediator Profiling after Consumption of Specialized Pro-Resolving Lipid-Mediator-Enriched Marine Oil in Healthy Subjects. Int J Mol Sci 2023; 24:16143. [PMID: 38003333 PMCID: PMC10671020 DOI: 10.3390/ijms242216143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) play a vital role in human health, well-being, and the management of inflammatory diseases. Insufficient intake of omega-3 is linked to disease development. Specialized pro-resolving mediators (SPMs) are derived from omega-3 PUFAs and expedite the resolution of inflammation. They fall into categories known as resolvins, maresins, protectins, and lipoxins. The actions of SPMs in the resolution of inflammation involve restricting neutrophil infiltration, facilitating the removal of apoptotic cells and cellular debris, promoting efferocytosis and phagocytosis, counteracting the production of pro-inflammatory molecules like chemokines and cytokines, and encouraging a pro-resolving macrophage phenotype. This is an experimental pilot study in which ten healthy subjects were enrolled and received a single dose of 6 g of an oral SPM-enriched marine oil emulsion. Peripheral blood was collected at baseline, 3, 6, 9, 12, and 24 h post-administration. Temporal increases in plasma and serum SPM levels were found by using LC-MS/MS lipid profiling. Additionally, we characterized the temporal increases in omega-3 levels and established fundamental pharmacokinetics in both aforementioned matrices. These findings provide substantial evidence of the time-dependent elevation of SPMs, reinforcing the notion that oral supplementation with SPM-enriched products represents a valuable source of essential bioactive SPMs.
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Affiliation(s)
- Pilar Irún
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
| | - Patricia Carrera-Lasfuentes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Faculty of Health Sciences, Campus Universitario Villanueva de Gállego, Universidad San Jorge, Villanueva de Gállego, 50830 Zaragoza, Spain
| | - Marta Sánchez-Luengo
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Úrsula Belio
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - María José Domper-Arnal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Gustavo A. Higuera
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Malena Hawkins
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Xavier de la Rosa
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- SOLUTEX GC, SL., 50180 Zaragoza, Spain
| | - Angel Lanas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 50009 Zaragoza, Spain; (P.C.-L.); (M.J.D.-A.); (A.L.)
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain;
- Centro Mixto de Investigación con Empresas (CEMINEM), Campus Rio Ebro, Universidad de Zaragoza, 50018 Zaragoza, Spain; (Ú.B.); (G.A.H.); (M.H.)
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
- Departamento de Medicina, Psiquiatría y Dermatología, Facultad de Medicina, Campus Plaza San Francisco, Universidad de Zaragoza, 50009 Zaragoza, Spain
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Chen R, Huang M, Xu P. Polyphosphate as an antithrombotic target and hemostatic agent. J Mater Chem B 2023; 11:7855-7872. [PMID: 37534776 DOI: 10.1039/d3tb01152f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
Abstract
Polyphosphate (PolyP) is a polymer comprised of linear phosphate units connected by phosphate anhydride bonds. PolyP exists in a diverse range of eukaryotes and prokaryotes with varied chain lengths ranging from six to thousands of phosphate units. Upon activation, human platelets and neutrophils release short-chain PolyP, along with other components, to initiate the coagulation pathway. Long-chain PolyP derived from cellular or bacterial organelles exhibits higher proinflammatory and procoagulant effects compared to short-chain PolyP. Notably, PolyP has been identified as a low-hemorrhagic antithrombotic target since neutralizing plasma PolyP suppresses the thrombotic process without impairing the hemostatic functions. As an inorganic polymer without uniform steric configuration, PolyP is typically targeted by cationic polymers or recombinant polyphosphatases rather than conventional antibodies, small-molecule compounds, or peptides. Additionally, because of its procoagulant property, PolyP has been incorporated in wound-dressing materials to facilitate blood hemostasis. This review summarizes current studies on PolyP as a low-hemorrhagic antithrombotic target and the development of hemostatic materials based on PolyP.
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Affiliation(s)
- Ruoyu Chen
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, P. R. China.
| | - Mingdong Huang
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, P. R. China.
- College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350108, P. R. China
| | - Peng Xu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian, 350108, P. R. China.
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10
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Granada-Gómez M, Velásquez-Berrío M, Molina CR, Martín SS, Escudero C, Alvarez AM, Cadavid AP. Modulation of the activation of endothelial nitric oxide synthase and nitrosative stress biomarkers by aspirin triggered lipoxins: A possible mechanism of action of aspirin in the antiphospholipid syndrome. Am J Reprod Immunol 2023; 90:e13753. [PMID: 37491919 DOI: 10.1111/aji.13753] [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: 04/09/2022] [Revised: 06/20/2023] [Accepted: 07/04/2023] [Indexed: 07/27/2023] Open
Abstract
PROBLEM Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. METHODS We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. RESULTS Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. CONCLUSIONS Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.
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Affiliation(s)
- Manuel Granada-Gómez
- Grupo Reproducción, Facultad de Medicina, Dpto. Microbiología y Parasitología, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Manuela Velásquez-Berrío
- Grupo Reproducción, Facultad de Medicina, Dpto. Microbiología y Parasitología, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Carolina Rúa Molina
- Grupo de Investigación en Trombosis, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Sebastián San Martín
- Biomedical Research Center School of Medicine, Universidad de Valparaiso, Valparaiso, Chile
- Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillan, Chile
| | - Carlos Escudero
- Vascular Physiology Laboratory, Basic Sciences Department, Faculty of Sciences, Universidad del Bio-Bio, Chillán, Chile
- Group of Research and Innovation in Vascular Health (GRIVAS Health), Chillan, Chile
- Red Iberoamericana de Alteraciones Vasculares Asociadas a TRanstornos del EMbarazo (RIVATREM)
| | - Angela M Alvarez
- Grupo Reproducción, Facultad de Medicina, Dpto. Microbiología y Parasitología, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Angela P Cadavid
- Grupo Reproducción, Facultad de Medicina, Dpto. Microbiología y Parasitología, Universidad de Antioquia UdeA, Medellín, Colombia
- Grupo de Investigación en Trombosis, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
- Red Iberoamericana de Alteraciones Vasculares Asociadas a TRanstornos del EMbarazo (RIVATREM)
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11
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Lipoxin and glycation in SREBP signaling: Insight into diabetic cardiomyopathy and associated lipotoxicity. Prostaglandins Other Lipid Mediat 2023; 164:106698. [PMID: 36379414 DOI: 10.1016/j.prostaglandins.2022.106698] [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: 09/26/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/15/2022]
Abstract
Diabetes and cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Diabetes increases cardiovascular risk through hyperglycemia and atherosclerosis. Chronic hyperglycemia accelerates glycation reaction, which forms advanced glycation end products (AGEs). Additionally, hyperglycemia with enhanced levels of cholesterol, native and oxidized low-density lipoproteins, free fatty acids, and oxidative stress induces lipotoxicity. Accelerated glycation and disturbed lipid metabolism are characteristic features of diabetic heart failure. SREBP signaling plays a significant role in lipid and glucose homeostasis. AGEs increase lipotoxicity in diabetic cardiomyopathy by inhibiting SREBP signaling. While anti-inflammatory lipid mediators, lipoxins resolve inflammation caused by lipotoxicity by upregulating the PPARγ expression and regulating CD36. PPARγ connects the bridge between glycation and lipoxin in SREBP signaling. A summary of treatment modalities against diabetic cardiomyopathy is given in brief. This review indicates the novel therapeutic approach in the crosstalk between glycation and lipoxin in SREBP signaling.
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12
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Schrör K, Verheugt FWA, Trenk D. Drug-Drug Interaction between Antiplatelet Therapy and Lipid-Lowering Agents (Statins and PCSK9 Inhibitors). Thromb Haemost 2023; 123:166-176. [PMID: 36522182 DOI: 10.1055/s-0042-1758654] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Lipid-lowering agents and antiplatelet drugs are guideline-recommended standard treatment for secondary prevention of acute thrombotic events in patients with increased cardiovascular risk. Aspirin is the most frequently used antiplatelet drug, either alone or in combination with other antiplatelet agents (P2Y12 inhibitors), while statins are first-line treatment of hypercholesterolemia. The well-established mode of action of aspirin is inhibition of platelet-dependent thromboxane formation. In addition, aspirin also improves endothelial oxygen defense via enhanced NO formation and inhibits thrombin formation. Low-dose aspirin exerts in addition anti-inflammatory effects, mainly via inhibition of platelet-initiated activation of white cells.Statins inhibit platelet function via reduction of circulating low-density lipoprotein-cholesterol (LDL-C) levels and a more direct inhibition of platelet function. This comprises inhibition of thromboxane formation via inhibition of platelet phospholipase A2 and inhibition of (ox)LDL-C-mediated increases in platelet reactivity via the (ox)LDL-C receptor (CD36). Furthermore, statins upregulate endothelial NO-synthase and improve endothelial oxygen defense by inhibition of NADPH-oxidase. PCSK9 antibodies target a serine protease (PCSK9), which promotes the degradation of the LDL-C receptor impacting on LDL-C plasma levels and (ox)LDL-C-receptor-mediated signaling in platelets similar to but more potent than statins.These functionally synergistic actions are the basis for numerous interactions between antiplatelet and these lipid-lowering drugs, which may, in summary, reduce the incidence of atherothrombotic vascular events.
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Affiliation(s)
- Karsten Schrör
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, Düsseldorf, Germany
| | - Freek W A Verheugt
- Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands
| | - Dietmar Trenk
- Department Universitäts-Herzzentrum, Klinik für Kardiologie und Angiologie Bad Krozingen, Klinische Pharmakologie, Universitätsklinikum Freiburg, Bad Krozingen, Germany
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13
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Ani NI, Okolo KO, Offiah RO. Evaluation of antibacterial, antioxidant, and anti-inflammatory properties of GC/MS characterized methanol leaf extract of Terminalia superba (Combretaceae, Engl. & Diels). FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2023. [DOI: 10.1186/s43094-022-00455-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Abstract
Background
Terminalia superba is a well-known medicinal plant used in folk medicine for the management of various diseases and swelling. Validation of its efficacy in standardized scientific models is lacking. This gap needs to be filled as a way of enhancing modern drug discovery. The aim is to evaluate the antibacterial, antioxidant, and anti-inflammatory properties of T. superba in known and established models. Also, to establish and possibly correlate the established activity with the phytochemicals identified using GC/MS and qualitative methods.
Results
The result showed a dose-dependent percentage inhibition of DPPH, HO•, and Fe3+ reducing activity. The antibacterial activity showed dose-dependent significant (p < 0.05) inhibition against all the organisms used. The anti-inflammatory activity of METS was confirmed in the carrageenan model with significant (p < 0.05) inhibition of paw volume when compared to control while significantly decreasing (p < 0.05) weight of xylene-induced ear. For instance, after 6 h, there was a reduction of 42%, 33%, and 22% for diclofenac, 200 mg, and 100 mg, respectively, as against 4% in control. The significant (p < 0.05) increase in MDA was attenuated by the treatment with METS dose dependently. Phytochemical assay and GC/MS characterization showed that alkaloids, saponins, phenols, quinone, tannins, coumarins, proteins, flavonoids, and amino acids were dominant with fatty acids accounting for 53%. Others are esters (23%), organic compounds (12%), alkanes (9%), and carboxylic acids (3%).
Conclusions
T. superba possesses antioxidant, antibacterial, and anti-inflammatory properties which are believed to arise from the secondary metabolites observed in the GC–MS characterization.
Graphical Abstract
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14
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Hosseinzadeh S, Shams F, Fattahi R, Nuoroozi G, rostami E, Shahghasempour L, Salehi-Nik N, Bohlouli M, Khojasteh A, Ghasemi N, Peiravi H. Surface Coating of Polyurethane Films with Gelatin, Aspirin and Heparin to Increase the Hemocompatibility of Artificial Vascular Grafts. Adv Pharm Bull 2023; 13:123-133. [PMID: 36721809 PMCID: PMC9871267 DOI: 10.34172/apb.2023.013] [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: 05/03/2021] [Revised: 10/14/2021] [Accepted: 12/31/2021] [Indexed: 02/03/2023] Open
Abstract
Purpose: A hemocompatible substrate can offer a wonderful facility for nitric oxide (NO) production by vascular endothelial cells in reaction to the inflammation following injuries. NO inhibits platelet aggregation this is especially critical in small-diameter vessels. Methods: The substrate films were made of polyurethane (PU) in a casting process and after plasma treatments, their surface was chemically decorated with polyethylene glycol (PEG) 2000, gelatin, gelatin-aspirin, gelatin-heparin and gelatin-aspirin-heparin. The concentrations of these ingredients were optimized in order to achieve the biocompatible values and the resulting modifications were characterized by water contact angle and Fourier transform infra-red (FTIR) assays. The values of NO production and platelet adhesion were then examined. Results: The water contact angle of the modified surface was reduced to 26±4∘ and the newly developed hydrophilic chemical groups were confirmed by FTIR. The respective concentrations of 0.05 mg/ml and 100 mg/mL were found to be the IC50 values for aspirin and heparin. However, after the surface modification with aspirin, the bioactivity of the substrate increased in compared to the other experimental groups. In addition, there was a synergistic effect between these reagents for NO synthesis. While, heparin inhibited platelet adhesion more than aspirin. Conclusion: Because of the highly hydrophilic nature of heparin, this reagent was hydrolyzed faster than aspirin and therefore its influence on platelet aggregation and cell growth was greater. Taken together, the results give the biocompatible concentrations of both biomolecules that are required for endothelial cell proliferation, NO synthesis and platelet adhesion.
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Affiliation(s)
- Simzar Hosseinzadeh
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Corresponding Authors: Simzar Hosseinzadeh and Nasim Salehi-Nik, ,
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roya Fattahi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghader Nuoroozi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elnaz rostami
- Department of Animal Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - lida Shahghasempour
- Department of Microbiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Nasim Salehi-Nik
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Corresponding Authors: Simzar Hosseinzadeh and Nasim Salehi-Nik, ,
| | - Mahboubeh Bohlouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Khojasteh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nazanin Ghasemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Habibollah Peiravi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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15
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Batiha GES, Al-Gareeb AI, Elekhnawy E, Al-kuraishy HM. Potential role of lipoxin in the management of COVID-19: a narrative review. Inflammopharmacology 2022; 30:1993-2001. [PMID: 36114383 PMCID: PMC9483298 DOI: 10.1007/s10787-022-01070-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/20/2022] [Indexed: 01/18/2023]
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection leads to the development of coronavirus disease 2019 (COVID-19), which causes endothelial dysfunction (ED), oxidative stress (OS), and inflammatory disorders. These changes cause hypoxia and cytokine storm with the development of cardio-pulmonary complications. Bioactive lipids and other polyunsaturated fatty acids participate in a vital role in the SARS-CoV-2 infection process. One of these mediators is the anti-inflammatory compound, lipoxin (LX). LXs are produced from arachidonic acid (AA) by collaboration between 5-lipoxygenase (5-LO) and 12-15 LO during cell interactions. Thus, our goal was to review the probable role of LXs in COVID-19 regarding the effects of LXs on the inflammatory signaling pathways that are linked with COVID-19 pathogenesis and complications.
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Affiliation(s)
- Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511 AlBeheira Egypt
| | - Ali I. Al-Gareeb
- Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, 14132 Iraq
| | - Engy Elekhnawy
- Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt
| | - Hayder M. Al-kuraishy
- Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, 14132 Iraq
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Kotlyarov S, Kotlyarova A. Clinical significance of polyunsaturated fatty acids in the prevention of cardiovascular diseases. Front Nutr 2022; 9:998291. [PMID: 36276836 PMCID: PMC9582942 DOI: 10.3389/fnut.2022.998291] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular diseases are one of the most important problems of modern medicine. They are associated with a large number of health care visits, hospitalizations and mortality. Prevention of atherosclerosis is one of the most effective strategies and should start as early as possible. Correction of lipid metabolism disorders is associated with definite clinical successes, both in primary prevention and in the prevention of complications of many cardiovascular diseases. A growing body of evidence suggests a multifaceted role for polyunsaturated fatty acids. They demonstrate a variety of functions in inflammation, both participating directly in a number of cellular processes and acting as a precursor for subsequent biosynthesis of lipid mediators. Extensive clinical data also support the importance of polyunsaturated fatty acids, but all questions have not been answered to date, indicating the need for further research.
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Affiliation(s)
| | - Anna Kotlyarova
- Department of Pharmacy Management and Economics, Ryazan State Medical University, Ryazan, Russia
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17
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Pindjakova D, Pilarova E, Pauk K, Michnova H, Hosek J, Magar P, Cizek A, Imramovsky A, Jampilek J. Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics. Int J Mol Sci 2022; 23:ijms231911648. [PMID: 36232947 PMCID: PMC9569995 DOI: 10.3390/ijms231911648] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/22/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity.
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Affiliation(s)
- Dominika Pindjakova
- Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
| | - Eliska Pilarova
- Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 530 09 Pardubice, Czech Republic
| | - Karel Pauk
- Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 530 09 Pardubice, Czech Republic
| | - Hana Michnova
- Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Palackeho tr. 1946/1, 612 42 Brno, Czech Republic
| | - Jan Hosek
- Department of Pharmacology and Toxicology, Veterinary Research Institute, Hudcova 296/70, 621 00 Brno, Czech Republic
| | - Pratibha Magar
- Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 530 09 Pardubice, Czech Republic
| | - Alois Cizek
- Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Palackeho tr. 1946/1, 612 42 Brno, Czech Republic
| | - Ales Imramovsky
- Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 95, 530 09 Pardubice, Czech Republic
- Correspondence:
| | - Josef Jampilek
- Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia
- Department of Chemical Biology, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, 783 71 Olomouc, Czech Republic
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18
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Ghati N, Bhatnagar S, Mahendran M, Thakur A, Prasad K, Kumar D, Dwivedi T, Mani K, Tiwari P, Gupta R, Mohan A, Saxena A, Guleria R, Deepti S. Statin and aspirin as adjuvant therapy in hospitalised patients with SARS-CoV-2 infection: a randomised clinical trial (RESIST trial). BMC Infect Dis 2022; 22:606. [PMID: 35810307 PMCID: PMC9270743 DOI: 10.1186/s12879-022-07570-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/27/2022] [Indexed: 01/21/2023] Open
Abstract
Background Statins and aspirin have been proposed for treatment of COVID-19 because of their anti-inflammatory and anti-thrombotic properties. Several observational studies have shown favourable results. There is a need for a randomised controlled trial. Methods In this single-center, open-label, randomised controlled trial, 900 RT-PCR positive COVID-19 patients requiring hospitalisation, were randomly assigned to receive either atorvastatin 40 mg (Group A, n = 224), aspirin 75 mg (Group B, n = 225), or both (Group C, n = 225) in addition to standard of care for 10 days or until discharge whichever was earlier or only standard of care (Group D, n = 226). The primary outcome variable was clinical deterioration to WHO Ordinal Scale for Clinical Improvement ≥ 6. The secondary outcome was change in serum C-reactive protein, interleukin-6, and troponin I. Results The primary outcome occurred in 25 (2.8%) patients: 7 (3.2%) in Group A, 3 (1.4%) in Group B, 8 (3.6%) in Group C, and 7 (3.2%) in Group D. There was no difference in primary outcome across the study groups (P = 0.463). Comparison of all patients who received atorvastatin or aspirin with the control group (Group D) also did not show any benefit [Atorvastatin: HR 1.0 (95% CI 0.41–2.46) P = 0.99; Aspirin: HR 0.7 (95% CI 0.27–1.81) P = 0.46]. The secondary outcomes revealed lower serum interleukin-6 levels among patients in Groups B and C. There was no excess of adverse events. Conclusions Among patients admitted with mild to moderate COVID-19 infection, additional treatment with aspirin, atorvastatin, or a combination of the two does not prevent clinical deterioration. Trial Registry Number CTRI/2020/07/026791 (http://ctri.nic.in; registered on 25/07/2020) Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07570-5.
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Affiliation(s)
- Nirmal Ghati
- Department of Cardiology, Jai Prakash Narayan Apex Trauma Center, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Sushma Bhatnagar
- Department of Onco-Anaesthesia, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Manjit Mahendran
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Abhishek Thakur
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Kshitij Prasad
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Devesh Kumar
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Tanima Dwivedi
- Department of Laboratory Medicine, National Cancer Institute (Jhajjar, Haryana), All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Kalaivani Mani
- Department of Biostatistics, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Pawan Tiwari
- Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Ritu Gupta
- Department of Laboratory Oncology, Dr. B.R.A Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Anant Mohan
- Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Anita Saxena
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Randeep Guleria
- Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Siddharthan Deepti
- Department of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India. .,Department of Cardiology, Cardiothoracic Sciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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19
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Liotti F, Marotta M, Melillo RM, Prevete N. The Impact of Resolution of Inflammation on Tumor Microenvironment: Exploring New Ways to Control Cancer Progression. Cancers (Basel) 2022; 14:3333. [PMID: 35884394 PMCID: PMC9316558 DOI: 10.3390/cancers14143333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 12/23/2022] Open
Abstract
Non-resolving inflammation is an enabling feature of cancer. A novel super-family of lipid mediators termed Specialized Pro-resolving Mediators (SPMs) have a role as bioactive molecules mediating the resolution of inflammation in cancer biology. SPMs are derived from ω-3 and ω-6 polyunsaturated fatty acids through the activity of lipoxygenases. SPMs have been described to directly modulate cancer progression by interfering with the epithelial to mesenchymal transition and invasion of cancer cells. SPMs have also been demonstrated to act on several components of the tumor microenvironment (TME). Consistently with their natural immunomodulatory and anti-inflammatory properties, SPMs are able to reprogram macrophages to favor phagocytosis of cell debris, which are an important source of pro-inflammatory and pro-angiogenic signals; sustain a direct cytotoxic immune response against cancer cells; stimulate neutrophils anti-tumor activities; and inhibit the development of regulatory T and B cells, thus indirectly leading to enhanced anti-tumor immunity. Furthermore, the resolution pathways exert crucial anti-angiogenic functions in lung, liver, and gastrointestinal cancers, and inhibit cancer-associated fibroblast differentiation and functions in hepatocellular carcinoma and pancreatic cancer. The present review will be focused on the potential protective effects of resolution pathways against cancer, exerted by modulating different components of the TME.
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Affiliation(s)
- Federica Liotti
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
| | - Maria Marotta
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
| | - Rosa Marina Melillo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (F.L.); (M.M.)
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
| | - Nella Prevete
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, 80131 Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
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Kotlyarov S, Kotlyarova A. Molecular Pharmacology of Inflammation Resolution in Atherosclerosis. Int J Mol Sci 2022; 23:4808. [PMID: 35563200 PMCID: PMC9104781 DOI: 10.3390/ijms23094808] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Atherosclerosis is one of the most important problems of modern medicine as it is the leading cause of hospitalizations, disability, and mortality. The key role in the development and progression of atherosclerosis is the imbalance between the activation of inflammation in the vascular wall and the mechanisms of its control. The resolution of inflammation is the most important physiological mechanism that is impaired in atherosclerosis. The resolution of inflammation has complex, not fully known mechanisms, in which lipid mediators derived from polyunsaturated fatty acids (PUFAs) play an important role. Specialized pro-resolving mediators (SPMs) represent a group of substances that carry out inflammation resolution and may play an important role in the pathogenesis of atherosclerosis. SPMs include lipoxins, resolvins, maresins, and protectins, which are formed from PUFAs and regulate many processes related to the active resolution of inflammation. Given the physiological importance of these substances, studies examining the possibility of pharmacological effects on inflammation resolution are of interest.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
| | - Anna Kotlyarova
- Department of Pharmacology and Pharmacy, Ryazan State Medical University, 390026 Ryazan, Russia;
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21
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Specialized Pro-Resolving Lipid Mediators: New Therapeutic Approaches for Vascular Remodeling. Int J Mol Sci 2022; 23:ijms23073592. [PMID: 35408952 PMCID: PMC8998739 DOI: 10.3390/ijms23073592] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/16/2022] [Accepted: 03/19/2022] [Indexed: 12/13/2022] Open
Abstract
Vascular remodeling is a typical feature of vascular diseases, such as atherosclerosis, aneurysms or restenosis. Excessive inflammation is a key mechanism underlying vascular remodeling via the modulation of vascular fibrosis, phenotype and function. Recent evidence suggests that not only augmented inflammation but unresolved inflammation might also contribute to different aspects of vascular diseases. Resolution of inflammation is mediated by a family of specialized pro-resolving mediators (SPMs) that limit immune cell infiltration and initiate tissue repair mechanisms. SPMs (lipoxins, resolvins, protectins, maresins) are generated from essential polyunsaturated fatty acids. Synthases and receptors for SPMs were initially described in immune cells, but they are also present in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), where they regulate processes important for vascular physiology, such as EC activation and VSMC phenotype. Evidence from genetic models targeting SPM pathways and pharmacological supplementation with SPMs have demonstrated that these mediators may play a protective role against the development of vascular remodeling in atherosclerosis, aneurysms and restenosis. This review focuses on the latest advances in understanding the role of SPMs in vascular cells and their therapeutic effects in the vascular remodeling associated with different cardiovascular diseases.
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22
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Cecconello C, Clària Ribas P, Norling LV. Resolving acute inflammation; what happens when inflammation goes haywire? How can it get back in line? DIET, INFLAMMATION, AND HEALTH 2022:113-162. [DOI: 10.1016/b978-0-12-822130-3.00018-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Tantry US, Schror K, Navarese EP, Jeong YH, Kubica J, Bliden KP, Gurbel PA. Aspirin as an Adjunctive Pharmacologic Therapy Option for COVID-19: Anti-Inflammatory, Antithrombotic, and Antiviral Effects All in One Agent. J Exp Pharmacol 2021; 13:957-970. [PMID: 34908882 PMCID: PMC8665864 DOI: 10.2147/jep.s330776] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022] Open
Abstract
Introduction Pharmacologic therapy options for COVID-19 should include antiviral, anti-inflammatory, and anticoagulant agents. With the limited effectiveness, currently available virus-directed therapies may have a substantial impact on global health due to continued reports of mutant variants affecting repeated waves of COVID-19 around the world. Methods We searched articles pertaining to aspirin, COVID-19, acute lung injury and pharmacology in PubMed and provide a comprehensive appraisal of potential use of aspirin in the management of patients with COVID-19. The scope of this article is to provide an overview of the rationale and currently available clinical evidence that supports aspirin as an effective therapeutic option in COVID-19. Results Experimental and clinical evidence are available for the potential use of aspirin in patients with COVID-19. Discussion Aspirin targets the intracellular signaling pathway that is essential for viral replication, and resultant inflammatory responses, hypercoagulability, and platelet activation. With these multiple benefits, aspirin can be a credible adjunctive therapeutic option for the treatment of COVID-19. In addition, inhaled formulation with its rapid effects may enhance direct delivery to the lung, which is the key organ damaged in COVID-19 during the critical initial course of the disease, whereas the 150-325 mg/day can be used for long-term treatment to prevent thrombotic event occurrences. Being economical and widely available, aspirin can be exploited globally, particularly in underserved communities and remote areas of the world to combat the ongoing COVID-19 pandemic.
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Affiliation(s)
- Udaya S Tantry
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, USA
| | - Karsten Schror
- Department of Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Eliano Pio Navarese
- Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Young-Hoon Jeong
- Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, South Korea
| | - Jacek Kubica
- Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Kevin P Bliden
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, USA
| | - Paul A Gurbel
- Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, LifeBridge Health, Baltimore, MD, USA
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24
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Usmani J, Khan T, Ahmad R, Sharma M. Potential role of herbal medicines as a novel approach in sepsis treatment. Biomed Pharmacother 2021; 144:112337. [PMID: 34688080 DOI: 10.1016/j.biopha.2021.112337] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 09/09/2021] [Accepted: 10/11/2021] [Indexed: 12/17/2022] Open
Abstract
The growing number of deaths related to sepsis has become a major concern for past few years. Sepsis is a complex pathological reactions that is explained by series of host response to microbial insult. The resulted systemic reactions are manifested by early appearance of proinflammatory cytokines leading to hyperinflammatory phase which is followed by septic shock and death of the patient. The present study has revealed that antibiotics are not self-sufficient to control the complex mechanism of sepsis. Moreover prolonged and unnecessary administration of antibiotics may lead to antibiotic resistance to pathogens. In addition to this, immunosuppressive medications are selective and have targeted approach to certain study population. Drugs from herbal origin have shown to possess a mammoth of immunomodulatory potential by suppressing proinflammatory and anti-inflammatory cytokines exhibiting no or minimal unwanted secondary responses. Concomitantly, herbal plants tend to modulate oxidative stress level and haematological imbalance during inflammatory diseased conditions. Natural compounds have gained much attention for the treatment of several clinical complications. Considering the promising responses of medicinal plants with less/no side effects and easy procurement, comprehensive research on herbal plants to treat sepsis should be contemplated.
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Affiliation(s)
- Juveria Usmani
- Department of Pharmacology, School of Pharmaceutical Sciences & Research, Jamia Hamdard, New Delhi, India
| | - Tahira Khan
- Department of Pharmacology, School of Pharmaceutical Sciences & Research, Jamia Hamdard, New Delhi, India
| | - Razi Ahmad
- Department of Pharmacology, Hamdard Institute of Medical Sciences & Research, Jamia Hamdard, New Delhi 110019, India.
| | - Manju Sharma
- Department of Pharmacology, School of Pharmaceutical Sciences & Research, Jamia Hamdard, New Delhi, India
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25
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Brox R, Hackstein H. Physiologically relevant aspirin concentrations trigger immunostimulatory cytokine production by human leukocytes. PLoS One 2021; 16:e0254606. [PMID: 34428217 PMCID: PMC8384208 DOI: 10.1371/journal.pone.0254606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 06/29/2021] [Indexed: 01/04/2023] Open
Abstract
Acetylsalicylic acid is a globally used non-steroidal anti-inflammatory drug (NSAID) with diverse pharmacological properties, although its mechanism of immune regulation during inflammation (especially at in vivo relevant doses) remains largely speculative. Given the increase in clinical perspective of Acetylsalicylic acid in various diseases and cancer prevention, this study aimed to investigate the immunomodulatory role of physiological Acetylsalicylic acid concentrations (0.005, 0.02 and 0.2 mg/ml) in a human whole blood of infection-induced inflammation. We describe a simple, highly reliable whole blood assay using an array of toll-like receptor (TLR) ligands 1–9 in order to systematically explore the immunomodulatory activity of Acetylsalicylic acid plasma concentrations in physiologically relevant conditions. Release of inflammatory cytokines and production of prostaglandin E2 (PGE2) were determined directly in plasma supernatant. Experiments demonstrate for the first time that plasma concentrations of Acetylsalicylic acid significantly increased TLR ligand-triggered IL-1β, IL-10, and IL-6 production in a dose-dependent manner. In contrast, indomethacin did not exhibit this capacity, whereas cyclooxygenase (COX)-2 selective NSAID, celecoxib, induced a similar pattern like Acetylsalicylic acid, suggesting a possible relevance of COX-2. Accordingly, we found that exogenous addition of COX downstream product, PGE2, attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro-inflammatory cytokines. Low PGE2 levels were at least involved in the enhanced IL-1β production by Acetylsalicylic acid.
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Affiliation(s)
- Regine Brox
- Department of Transfusion Medicine and Hemostaseology, University Hospital, Erlangen, Germany
- * E-mail:
| | - Holger Hackstein
- Department of Transfusion Medicine and Hemostaseology, University Hospital, Erlangen, Germany
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26
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Mylonas KS, Iliopoulos D, Nikiteas N, Schizas D. Looking for the Achilles heel of atheromatosis: could it be immunotherapy? Immunotherapy 2021; 13:557-560. [PMID: 33757293 DOI: 10.2217/imt-2021-0015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Affiliation(s)
- Konstantinos S Mylonas
- First Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | | | - Nikolaos Nikiteas
- Second Propaedeutic Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Laiko General Hospital, National & Kapodistrian University of Athens, Athens, Greece
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27
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Abstract
Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.
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28
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Recchiuti A, Patruno S, Plebani R, Romano M. The Resolution Approach to Cystic Fibrosis Inflammation. Front Pharmacol 2020; 11:1129. [PMID: 32848748 PMCID: PMC7403222 DOI: 10.3389/fphar.2020.01129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/10/2020] [Indexed: 01/11/2023] Open
Abstract
Despite the high expectations associated with the recent introduction of CFTR modulators, airway inflammation still remains a relevant clinical issue in cystic fibrosis (CF). The classical anti-inflammatory drugs have shown very limited efficacy, when not being harmful, raising the question of whether alternative approaches should be undertaken. Thus, a better knowledge of the mechanisms underlying the aberrant inflammation observed in CF is pivotal to develop more efficacious pharmacology. In this respect, the observation that endogenous proresolving pathways are defective in CF and that proresolving mediators, physiologically generated during an acute inflammatory reaction, do not completely suppress inflammation, but promote resolution, tissue healing and microbial clearance, without compromising immune host defense mechanisms, opens interesting therapeutic scenarios for CF. In this mini-review, we present the current knowledge and perspectives of proresolving pharmacology in CF, focusing on the specialized proresolving lipid mediators and selected peptides.
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Affiliation(s)
- Antonio Recchiuti
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Sara Patruno
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Roberto Plebani
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Mario Romano
- Laboratory of Molecular Medicine, Center on Advanced Studies and Technology (CAST), Department of Medical, Oral e Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
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29
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Alqahtani S, Kobos LM, Xia L, Ferreira C, Franco J, Du X, Shannahan JH. Exacerbation of Nanoparticle-Induced Acute Pulmonary Inflammation in a Mouse Model of Metabolic Syndrome. Front Immunol 2020; 11:818. [PMID: 32457752 PMCID: PMC7221136 DOI: 10.3389/fimmu.2020.00818] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/09/2020] [Indexed: 12/15/2022] Open
Abstract
Nanotechnology has the capacity to revolutionize numerous fields and processes, however, exposure-induced health effects are of concern. The majority of nanoparticle (NP) safety evaluations have been performed utilizing healthy models and have demonstrated the potential for pulmonary toxicity. A growing proportion of individuals suffer diseases that may enhance their susceptibility to exposures. Specifically, metabolic syndrome (MetS) is increasingly prevalent and is a risk factor for the development of chronic diseases including type-2 diabetes, cardiovascular disease, and cancer. MetS is a combination of conditions which includes dyslipidemia, obesity, hypertension, and insulin resistance. Due to the role of lipids in inflammatory signaling, we hypothesize that MetS-associated dyslipidemia may modulate NP-induced immune responses. To examine this hypothesis, mice were fed either a control diet or a high-fat western diet (HFWD) for 14-weeks. A subset of mice were treated with atorvastatin for the final 7-weeks to modulate lipids. Mice were exposed to silver NPs (AgNPs) via oropharyngeal aspiration and acute toxicity endpoints were evaluated 24-h post-exposure. Mice on the HFWD demonstrated MetS-associated alterations such as increased body weight and cholesterol compared to control-diet mice. Cytometry analysis of bronchoalveolar lavage fluid (BALF) demonstrated exacerbation of AgNP-induced neutrophilic influx in MetS mice compared to healthy. Additionally, enhanced proinflammatory mRNA expression and protein levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and interleukin-6 were observed in MetS mice compared to healthy following exposure. AgNP exposure reduced mRNA expression of enzymes involved in lipid metabolism, such as arachidonate 5-lipoxygenase and arachidonate 15-lipoxygenase in both mouse models. Exposure to AgNPs decreased inducible nitric oxide synthase gene expression in MetS mice. An exploratory lipidomic profiling approach was utilized to screen lipid mediators involved in pulmonary inflammation. This assessment indicates the potential for reduced levels of lipids mediators of inflammatory resolution (LMIR) in the MetS model compared to healthy mice following AgNP exposure. Statin treatment inhibited enhanced inflammatory responses as well as alterations in LMIR observed in the MetS model due to AgNP exposure. Taken together our data suggests that MetS exacerbates the acute toxicity induced by AgNPs exposure possibly via a disruption of LMIR leading to enhanced pulmonary inflammation.
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Affiliation(s)
- Saeed Alqahtani
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States.,National Center for Pharmaceuticals, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Lisa M Kobos
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
| | - Li Xia
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
| | - Christina Ferreira
- Purdue Metabolite Profiling Facility, Purdue University, West Lafayette, IN, United States
| | - Jackeline Franco
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Xuqin Du
- Department of Occupational Medicine and Toxicology, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China
| | - Jonathan H Shannahan
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
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30
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Ge Y, Zhang S, Wang J, Xia F, Wan JB, Lu J, Ye RD. Dual modulation of formyl peptide receptor 2 by aspirin-triggered lipoxin contributes to its anti-inflammatory activity. FASEB J 2020; 34:6920-6933. [PMID: 32239559 DOI: 10.1096/fj.201903206r] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/15/2020] [Accepted: 03/17/2020] [Indexed: 12/28/2024]
Abstract
The eicosanoid lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 (ATL) are potent anti-inflammatory agents. How their anti-inflammatory effects are mediated by receptors such as the formyl peptide receptor 2 (FPR2/ALX) remains incompletely understood. In the present study, fluorescent biosensors of FPR2/ALX were prepared and ATL-induced conformational changes were recorded. A biphasic dose curve consisting of a descending phase and an ascending phase was observed, with the descending phase corresponding to diminished FPR2 response such as Ca2+ mobilization induced by the potent synthetic agonist WKYMVm. Preincubation of FPR2-expressing cells with 100 pM of ATL also lowered the threshold for WKYMVm to induce β-arrestin-2 membrane translocation, and inhibited WKYMVm-induced interleukin 8 secretion, suggesting signaling bias favoring anti-inflammatory activities. At 100 pM and above, ATL-induced receptor conformational changes resembling that of the WKYMVm along with a weak but measurable inhibition of forskolin-induced cAMP accumulation. However, no Ca2+ mobilization was induced by ATL until its concentration reached 1 µM. Taken together, these results suggest a dual regulatory mechanism by which ATL exerts anti-inflammatory effects through FPR2/ALX.
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Affiliation(s)
- Yunjun Ge
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
| | - Shuo Zhang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Junlin Wang
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
| | - Fangbo Xia
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
| | - Jian-Bo Wan
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
| | - Jinjian Lu
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
| | - Richard D Ye
- State Key Laboratory for Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau Special Administrative Region, China
- Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China
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31
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Fu T, Mohan M, Brennan EP, Woodman OL, Godson C, Kantharidis P, Ritchie RH, Qin CX. Therapeutic Potential of Lipoxin A 4 in Chronic Inflammation: Focus on Cardiometabolic Disease. ACS Pharmacol Transl Sci 2020; 3:43-55. [PMID: 32259087 DOI: 10.1021/acsptsci.9b00097] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Indexed: 02/07/2023]
Abstract
Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation. Biological actions of LXs include inhibition of neutrophil infiltration, promotion of macrophage polarization, increase of macrophage efferocytosis, and restoration of tissue homeostasis. Recently, several studies have demonstrated that LXs and synthetic analogues protect tissues from acute and chronic inflammation. The mechanism includes down-regulation of pro-inflammatory cytokines and chemokines (e.g., interleukin-1β and tumor necrosis factor-α), inhibition of the activation of the master pro-inflammatory pathway (e.g., nuclear factor κ-light-chain-enhancer of activated B cells pathway) and increased release of the pro-resolving cytokines (e.g., interleukin-10). Three generations of LXs analogues are well described in the literature, and more recently a fourth generation has been generated that appears to show enhanced potency. In this review, we will briefly discuss the potential therapeutic opportunity provided by lipoxin A4 as a novel approach to treat chronic inflammatory disorders, focusing on cardiometabolic disease and the current drug development in this area.
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Affiliation(s)
- Ting Fu
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Eoin P Brennan
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Owen L Woodman
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Phillip Kantharidis
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Rebecca H Ritchie
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Cheng Xue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
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32
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Xie Y, Pan M, Gao Y, Zhang L, Ge W, Tang P. Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration. Cell Biosci 2019; 9:103. [PMID: 31890152 PMCID: PMC6929289 DOI: 10.1186/s13578-019-0369-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 12/20/2019] [Indexed: 01/10/2023] Open
Abstract
The failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (< 100 μg/mL), which is widely recommended for prevention of thrombosis, is very likely to be benefit for maintaining bone mass and qualities by activation of osteoblastic bone formation and inhibition of osteoclast activities via cyclooxygenase-independent manner. While, the roles of high-dose aspirin (150-300 μg/mL) and other NSAIDs in bone self-regeneration and fracture-healing process are difficult to elucidate owing to their dual effects on osteoclast activity and bone formation of osteoblast. In conclusion, this study highlighted the potential clinical applications of low-dose aspirin in abnormal bone remodeling as well as the risks of high-dose aspirin and other NSAIDs for relieving pain and anti-inflammation in fractures and orthopedic operations.
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Affiliation(s)
- Yong Xie
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
| | - Meng Pan
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Yanpan Gao
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Licheng Zhang
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
| | - Wei Ge
- 2State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100005 China
| | - Peifu Tang
- 1Department of Orthopedics, Chinese PLA General Hospital, Beijing, 100853 China
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33
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Gil‐Villa AM, Alvarez AM, Velásquez‐Berrío M, Rojas‐López M, Cadavid J AP. Role of aspirin‐triggered lipoxin A4, aspirin, and salicylic acid in the modulation of the oxidative and inflammatory responses induced by plasma from women with pre‐eclampsia. Am J Reprod Immunol 2019; 83:e13207. [DOI: 10.1111/aji.13207] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 10/19/2019] [Accepted: 10/30/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Aura María Gil‐Villa
- Grupo Reproducción Departamento de Microbiología y Parasitología Facultad de Medicina Universidad de Antioquia Medellín Colombia
| | - Angela M. Alvarez
- Grupo Reproducción Departamento de Microbiología y Parasitología Facultad de Medicina Universidad de Antioquia Medellín Colombia
- Red Iberoamericana de Alteraciones Vasculares Asociadas a Transtornos del Embarazo (RIVA‐TREM) Chillán Chile
| | - Manuela Velásquez‐Berrío
- Grupo Reproducción Departamento de Microbiología y Parasitología Facultad de Medicina Universidad de Antioquia Medellín Colombia
| | - Mauricio Rojas‐López
- Grupo de Inmunología Celular e Inmunogenética – Unidad de Citometría de Flujo Sede de Investigación Universitaria (SIU) Universidad de Antioquia Medellín Colombia
| | - Angela P. Cadavid J
- Grupo Reproducción Departamento de Microbiología y Parasitología Facultad de Medicina Universidad de Antioquia Medellín Colombia
- Red Iberoamericana de Alteraciones Vasculares Asociadas a Transtornos del Embarazo (RIVA‐TREM) Chillán Chile
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Zhang T, Hao H, Zhou XY. The role of lipoxin in regulating tumor immune microenvironments. Prostaglandins Other Lipid Mediat 2019; 144:106341. [PMID: 31152809 DOI: 10.1016/j.prostaglandins.2019.106341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/21/2019] [Accepted: 05/28/2019] [Indexed: 12/31/2022]
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Proresolving Lipid Mediators: Endogenous Modulators of Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8107265. [PMID: 31316721 PMCID: PMC6604337 DOI: 10.1155/2019/8107265] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/28/2019] [Indexed: 02/06/2023]
Abstract
Specialized proresolving mediators (SPMs) are a novel class of endogenous lipids, derived by ω-6 and ω-3 essential polyunsaturated fatty acids such as arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) that trigger and orchestrate the resolution of inflammation, which is the series of cellular and molecular events that leads to spontaneous regression of inflammatory processes and restoring of tissue homeostasis. These lipids are emerging as highly effective therapeutic agents that exert their immunoregulatory activity by activating the proresolving pathway, as reported by a consistent bulk of evidences gathered in the last two decades since their discovery. The production of reactive oxygen (ROS) and nitrogen (RNS) species by immune cells plays indeed an important role in the inflammatory mechanisms of host defence, and it is now clear that oxidative stress, viewed as an imbalance between such species and their elimination, can lead to many chronic inflammatory diseases. This review, the first of its kind, is aimed at exploring the manifold effects of SPMs on modulation of reactive species production, along with the mechanisms through which they either inhibit molecular signalling pathways that are activated by oxidative stress or induce the expression of endogenous antioxidant systems. Furthermore, the possible role of SPMs in oxidative stress-mediated chronic disorders is also summarized, suggesting not only that their anti-inflammatory and proresolving properties are strictly associated with their antioxidant role but also that these endogenous lipids might be exploited in the treatment of several pathologies in which uncontrolled production of ROS and RNS or impairment of the antioxidant machinery represents a main pathogenetic mechanism.
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Recchiuti A, Mattoscio D, Isopi E. Roles, Actions, and Therapeutic Potential of Specialized Pro-resolving Lipid Mediators for the Treatment of Inflammation in Cystic Fibrosis. Front Pharmacol 2019; 10:252. [PMID: 31001110 PMCID: PMC6454233 DOI: 10.3389/fphar.2019.00252] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 02/28/2019] [Indexed: 01/07/2023] Open
Abstract
Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF.
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Affiliation(s)
- Antonio Recchiuti
- Department of Medical, Oral and Biotechnological Science, Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
- Centro di Scienze dell’Invecchiamento e Medicina Traslazionale (CeSI-MeT), Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
| | - Domenico Mattoscio
- Department of Medical, Oral and Biotechnological Science, Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
- Centro di Scienze dell’Invecchiamento e Medicina Traslazionale (CeSI-MeT), Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
| | - Elisa Isopi
- Department of Medical, Oral and Biotechnological Science, Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
- Centro di Scienze dell’Invecchiamento e Medicina Traslazionale (CeSI-MeT), Università “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
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Zhao TX, Mallat Z. Targeting the Immune System in Atherosclerosis. J Am Coll Cardiol 2019; 73:1691-1706. [DOI: 10.1016/j.jacc.2018.12.083] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/20/2018] [Accepted: 12/30/2018] [Indexed: 02/08/2023]
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Ramirez JL, Zahner GJ, Spaulding KA, Khetani SA, Hills NK, Gasper WJ, Harris WS, Cohen BE, Grenon SM. Peripheral Artery Disease Is Associated with a Deficiency of Erythrocyte Membrane n-3 Polyunsaturated Fatty Acids. Lipids 2019; 54:211-219. [PMID: 30883776 DOI: 10.1002/lipd.12140] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 02/07/2019] [Accepted: 02/09/2019] [Indexed: 12/31/2022]
Abstract
Population-based data suggest that individuals who consume large dietary amounts of n-3 polyunsaturated fatty acids (PUFA) have lower odds of peripheral artery disease (PAD); however, clinical studies examining n-3 PUFA levels in patients with PAD are sparse. The objective of this study is to compare erythrocyte membrane fatty acid (FA) content between patients with PAD and controls. We conducted a cross-sectional study of 179 vascular surgery outpatients (controls, 34; PAD, 145). A blood sample was drawn and the erythrocyte FA content was assayed using capillary gas chromatography. We calculated the ratio of the n-3 PUFA eicosapentaenoic acid (EPA) to the n-6 PUFA arachidonic acid (ARA) as well as the omega-3 index (O3I), a measure of erythrocyte content of the n-3 PUFA, EPA, and docosahexaenoic acid (DHA), expressed as a percentage of total erythrocyte FA. Compared with controls, patients with PAD smoked more and were more likely to have hypertension and hyperlipidemia (p < 0.05). Patients with PAD had a lower mean O3I (5.0 ± 1.7% vs 6.0 ± 1.6%, p < 0.001) and EPA:ARA ratio (0.04 ± 0.02 vs 0.05 ± 0.05, p < 0.001), but greater mean total saturated fats (39.5 ± 2.5% vs 38.5 ± 2.6%, p = 0.01). After adjusting for several patient characteristics, comorbidities, and medications, an absolute decrease of 1% in the O3I was associated with 39% greater odds of PAD (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03-1.86, and p = 0.03). PAD was associated with a deficiency of erythrocyte n-3 PUFA, a lower EPA:ARA ratio, and greater mean total saturated fats. These alterations in FA content may be involved in the pathogenesis or development of poor outcomes in PAD.
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Affiliation(s)
- Joel L Ramirez
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA
| | - Greg J Zahner
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA
| | - Kimberly A Spaulding
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA.,Vascular Surgery Section, Veterans Affairs Medical Center, Mail Code 112G, 4150 Clement St, San Francisco, CA 94121, USA
| | - Sukaynah A Khetani
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA.,Vascular Surgery Section, Veterans Affairs Medical Center, Mail Code 112G, 4150 Clement St, San Francisco, CA 94121, USA
| | - Nancy K Hills
- Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, 2nd Floor, San Francisco, CA 94158-2549, USA
| | - Warren J Gasper
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA.,Vascular Surgery Section, Veterans Affairs Medical Center, Mail Code 112G, 4150 Clement St, San Francisco, CA 94121, USA
| | - William S Harris
- OmegaQuant Analytics, LLC, 5009 W. 12th Street, Suite 8, Sioux Falls, SD 57106, USA.,Department of Medicine, Sanford School of Medicine, University of South Dakota, 1400 W. 22nd St, Sioux Falls, SD 57105, USA
| | - Beth E Cohen
- Department of Medicine, University of California, San Francisco, Box 1211, San Francisco, CA 94143-1211, USA.,Department of Medicine, Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121, USA
| | - S Marlene Grenon
- Department of Surgery, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA
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Gilroy DW, Bishop-Bailey D. Lipid mediators in immune regulation and resolution. Br J Pharmacol 2019; 176:1009-1023. [PMID: 30674066 DOI: 10.1111/bph.14587] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 12/05/2018] [Accepted: 12/08/2018] [Indexed: 12/31/2022] Open
Abstract
We are all too familiar with the events that follow a bee sting-heat, redness, swelling, and pain. These are Celsus' four cardinal signs of inflammation that are driven by very well-defined signals and hormones. In fact, targeting the factors that drive this onset phase is the basis upon which most current anti-inflammatory therapies were developed. We are also very well aware that within a few hours, these cardinal signs normally disappear. In other words, inflammation resolves. When it does not, inflammation persists, resulting in damaging chronic conditions. While inflammatory onset is actively driven, so also is its resolution-years of research have identified novel internal counter-regulatory signals that work together to switch off inflammation. Among these signals, lipids are potent signalling molecules that regulate an array of immune responses including vascular hyper reactivity and pain, as well as leukocyte trafficking and clearance, so-called resolution. Here, we collate bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and their role in inflammation, as well as resolution. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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Affiliation(s)
- Derek W Gilroy
- Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK
| | - David Bishop-Bailey
- Comparative Biological Sciences, Royal Veterinary College, University of London, London, UK
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Ramirez JL, Gasper WJ, Khetani SA, Zahner GJ, Hills NK, Mitchell PT, Sansbury BE, Conte MS, Spite M, Grenon SM. Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial). J Surg Res 2019; 238:164-174. [PMID: 30771686 DOI: 10.1016/j.jss.2019.01.038] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/14/2018] [Accepted: 01/11/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.
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Affiliation(s)
- Joel L Ramirez
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California
| | - Warren J Gasper
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California; Vascular Surgery Section, Veterans Affairs Medical Center, San Francisco, California
| | - Sukaynah A Khetani
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California; Vascular Surgery Section, Veterans Affairs Medical Center, San Francisco, California
| | - Greg J Zahner
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California
| | - Nancy K Hills
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California
| | - Pete T Mitchell
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Building for Transformative Medicine, Boston, Massachusetts
| | - Brian E Sansbury
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Building for Transformative Medicine, Boston, Massachusetts
| | - Michael S Conte
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California
| | - Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Building for Transformative Medicine, Boston, Massachusetts
| | - S Marlene Grenon
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of California, San Francisco, California.
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41
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Das UN. Arachidonic acid in health and disease with focus on hypertension and diabetes mellitus: A review. J Adv Res 2018; 11:43-55. [PMID: 30034875 PMCID: PMC6052660 DOI: 10.1016/j.jare.2018.01.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 01/01/2018] [Accepted: 01/02/2018] [Indexed: 02/06/2023] Open
Abstract
Arachidonic acid (AA 20:4n-6) is an essential component of cell membranes and modulates cell membrane fluidity. AA is metabolized by cyclo-oxygenase (COX), lipoxygenase (LOX) and cytochrome P450 enzymes to form several metabolites that have important biological actions. Of all the actions, role of AA in the regulation of blood pressure and its ability to prevent both type 1 and type 2 diabetes mellitus seems to be interesting. Studies showed that AA and its metabolites especially, lipoxin A4 (LXA4) and epoxyeicosatrienoic acids (EETs), potent anti-inflammatory metabolites, have a crucial role in the pathobiology of hypertension and diabetes mellitus. AA, LXA4 and EETs regulate smooth muscle function and proliferation, voltage gated ion channels, cell membrane fluidity, membrane receptors, G-coupled receptors, PPARs, free radical generation, nitric oxide formation, inflammation, and immune responses that, in turn, participate in the regulation blood pressure and pathogenesis of diabetes mellitus. In this review, role of AA and its metabolites LXA4 and EETs in the pathobiology of hypertension, pre-eclampsia and diabetes mellitus are discussed. Based on several lines of evidences, it is proposed that a combination of aspirin and AA could be of benefit in the prevention and management of hypertension, pre-eclampsia and diabetes mellitus.
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Abstract
The once-popular approach of using natural products as a prime source for medicinal chemistry and drug discovery has waned considerably in the past two decades due to the advent of high-throughput screening of small molecule mega libraries. However, the growing appreciation of network pharmacology as the next drug-discovery paradigm suggests that natural products and their unique polypharmacology offer significant advantages for finding novel therapeutics particularly for the treatment of complex and multifactorial diseases. Drug discovery process is awaiting the revitalization of interest in natural products and their derivatives. The current challenge is how to decipher this natural chemical diversity.
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Hsu J, Donnelly JP, Chaudhary NS, Moore JX, Safford MM, Kim J, Wang HE. Aspirin use and long-term rates of sepsis: A population-based cohort study. PLoS One 2018; 13:e0194829. [PMID: 29668690 PMCID: PMC5905958 DOI: 10.1371/journal.pone.0194829] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 03/09/2018] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Sepsis is the syndrome of life-threatening organ dysfunction resulting from dysregulated host response to infection. Aspirin, an anti-inflammatory agent, may play a role in attenuating the inflammatory response during infection. We evaluated the association between aspirin use and long-term rates of sepsis as well as sepsis outcomes. METHODS We analyzed data from 30,239 adults ≥45 years old in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The primary exposure was aspirin use, identified via patient interview. The primary outcome was sepsis hospitalization, defined as admission for infection with two or more systemic inflammatory response syndrome criteria. We fit Cox proportional hazards models assessing the association between aspirin use and rates of sepsis, adjusted for participant demographics, health behaviors, chronic medical conditions, medication adherence, and biomarkers. We used a propensity-matched analysis and a series of sensitivity analyses to assess the robustness of our results. We also examined risk of organ dysfunction and hospital mortality during hospitalization for sepsis. RESULTS Among 29,690 REGARDS participants with follow-up data available, 43% reported aspirin use (n = 12,869). Aspirin users had higher sepsis rates (hazard ratio 1.35; 95% CI: 1.22-1.49) but this association was attenuated following adjustment for potential confounders (adjusted HR 0.99; 95% CI: 0.88-1.12). We obtained similar results in propensity-matched and sensitivity analyses. Among sepsis hospitalizations, aspirin use was not associated with organ dysfunction or hospital death. CONCLUSIONS In the REGARDS cohort, baseline aspirin use was not associated with long-term rates of sepsis.
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Affiliation(s)
- Joann Hsu
- University of Alabama School of Medicine, Birmingham, Alabama, United States of America
| | - John P. Donnelly
- Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America
- Division of Preventive Medicine, Department of Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Ninad S. Chaudhary
- Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Justin X. Moore
- Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Monika M. Safford
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States of America
| | - Junghyun Kim
- Department of Emergency Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Henry E. Wang
- Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama, United States of America
- Department of Emergency Medicine, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
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[Antipyretics in intensive care patients]. Anaesthesist 2018; 66:511-517. [PMID: 28364306 DOI: 10.1007/s00101-017-0301-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND Antipyretics are among the most widely prescribed drugs in German hospitals. Despite this widespread use, their role for treatment of critically ill patients still remains unclear. In particular, the questionable positive effects of reducing fever are discussed. OBJECTIVES In this review we aimed to summarize and discuss current study results covering the use of antipyretics in critically ill patients. Suspected effects with regard to fever reduction and lethality should be considered. MATERIALS AND METHODS A selective literature search was carried out in the PubMed database. We reviewed the bibliographies of all work considered relevant. RESULTS There are only a few studies on the use of antipyretics in intensive care patients, which are difficult to compare systematically due to different designs, protocols and endpoints. All in all, the decrease in temperature was very low (0.3 °C) and showed even adverse effects on 28-days mortality in sepsis. In patients with sepsis and ASS medication, a decreased mortality has been shown in retrospective analysis. CONCLUSIONS The benefit of fever control using antipyretics in intensive care patients with regard to endpoints like lethality remains unclear. Randomized controlled trials with suitable protocols and endpoints are needed to provide a solid base for development of guidelines.
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Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching. Crit Care Med 2017; 45:1871-1879. [PMID: 28799949 DOI: 10.1097/ccm.0000000000002654] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.
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Fredman G, Tabas I. Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1211-1221. [PMID: 28527709 DOI: 10.1016/j.ajpath.2017.01.018] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 01/30/2017] [Indexed: 02/08/2023]
Abstract
Defective inflammation resolution is the underlying cause of prevalent chronic inflammatory diseases, such as arthritis, asthma, cancer, and neurodegenerative and cardiovascular diseases. Inflammation resolution is governed by several endogenous factors, including fatty acid-derived specialized proresolving mediators and proteins, such as annexin A1. Specifically, specialized proresolving mediators comprise a family of mediators that include arachidonic acid-derived lipoxins, omega-3 fatty acid eicosapentaenoic acid-derived resolvins, docosahexaenoic acid-derived resolvins, protectins, and maresins. Emerging evidence indicates that imbalances between specialized proresolving mediators and proinflammatory mediators are associated with several prevalent human diseases, including atherosclerosis. Mechanisms that drive this imbalance remain largely unknown and will be discussed in this review. Furthermore, the concept of dysregulated inflammation resolution in atherosclerosis has been known for several decades. Recently, there has been an explosion of new work with regard to the therapeutic application of proresolving ligands in experimental atherosclerosis. Therefore, this review will highlight recent advances in our understanding of how inflammation resolution may become defective in atherosclerosis and the potential for proresolving therapeutics in atherosclerosis. Last, we offer insight for future implications of the field.
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Affiliation(s)
- Gabrielle Fredman
- Department of Molecular and Cellular Physiology, Center for Cardiovascular Sciences, Albany Medical College, Albany, New York.
| | - Ira Tabas
- Departments of Medicine, Pathology and Cell Biology, and Physiology, Columbia University Medical Center, New York, New York
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Wu B, Mottola G, Schaller M, Upchurch GR, Conte MS. Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications. Mol Aspects Med 2017; 58:72-82. [PMID: 28765077 DOI: 10.1016/j.mam.2017.07.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 07/05/2017] [Accepted: 07/05/2017] [Indexed: 12/25/2022]
Abstract
Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized pro-resolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.
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Affiliation(s)
- Bian Wu
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Giorgio Mottola
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Melinda Schaller
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States
| | - Gilbert R Upchurch
- Department of Surgery, University of Virginia, Charlottesville, VA, United States
| | - Michael S Conte
- Division of Vascular and Endovascular Surgery, Department of Surgery, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, United States.
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Abstract
Lipids are potent signaling molecules that regulate a multitude of cellular responses, including cell growth and death and inflammation/infection, via receptor-mediated pathways. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. This diversity arises from their synthesis, which occurs via discrete enzymatic pathways and because they elicit responses via different receptors. This review will collate the bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and role in inflammation. Specifically, lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins, and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins, and maresins) will be discussed herein.
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Sansbury BE, Spite M. Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology. Circ Res 2017; 119:113-30. [PMID: 27340271 DOI: 10.1161/circresaha.116.307308] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 05/26/2016] [Indexed: 12/11/2022]
Abstract
Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved proresolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while also promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related proresolving mediators in immunity, thrombosis, and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host disruptive.
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Affiliation(s)
- Brian E Sansbury
- From the Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Matthew Spite
- From the Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
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Mackenzie AE, Milligan G. The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 2017; 113:661-671. [DOI: 10.1016/j.neuropharm.2015.07.035] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/20/2015] [Accepted: 07/27/2015] [Indexed: 02/07/2023]
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