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Koniari E, Hatziagapiou K, Nikola AO, Georgoulia K, Marinakis N, Bakakos P, Athanasopoulou A, Koromilias A, Rovina N, Efthymiou V, Papakonstantinou E, Vlachakis D, Mavrikou S, Koutsoukou A, Traeger-Synodinos J, Chrousos GP. ENaC gene variants and their involvement in Covid‑19 severity. Biomed Rep 2024; 21:176. [PMID: 39355526 PMCID: PMC11443493 DOI: 10.3892/br.2024.1864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/05/2024] [Indexed: 10/03/2024] Open
Abstract
Epidemiological studies report the association of diverse cardiovascular conditions with coronavirus disease 2019 (COVID-19), but the causality has remained to be established. Specific genetic factors and the extent to which they can explain variation in susceptibility or severity are largely elusive. The present study aimed to evaluate the link between 32 cardio-metabolic traits and COVID-19. A total of 60 participants were enrolled, who were categorized into the following 4 groups: A control group with no COVID-19 or any other underlying pathologies, a group of patients with a certain form of dyslipidemia and predisposition to atherosclerotic disease, a COVID-19 group with mild or no symptoms and a COVID-19 group with severe symptomatology hospitalized at the Intensive Care Unit of Sotiria Hospital (Athens, Greece). Demographic, clinical and laboratory data were recorded and genetic material was isolated, followed by simultaneous analysis of the genes related to dyslipidemia using a custom-made next-generation sequencing panel. In the COVID-19 group with mild or absent symptoms, the variant c.112C>T:p.P38S was detected in the sodium channel epithelial 1 subunit α (SCNN1A) gene, with a major allele frequency (Maf) of <0.01. In the COVID-19 group with severe symptoms, the variant c.786G>A:p.T262T was detected in the SCNN1B gene, which encodes for the β-subunit of the epithelial sodium channel ENaC, with a Maf <0.01. None of the two rare variants were detected in the control or dyslipidemia groups. In conclusion, the current study suggests that ENaC variants are likely associated with genetic susceptibility to COVID-19, supporting the rationale for the risk and protective genetic factors for the morbidity and mortality of COVID-19.
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Affiliation(s)
- Eleni Koniari
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Kyriaki Hatziagapiou
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 11527 Athens, Greece
- First Department of Pediatrics, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece
| | - Alexandra Olti Nikola
- First Department of Pediatrics, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece
| | - Konstantina Georgoulia
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Marinakis
- Laboratory of Medical Genetics, St. Sophia's Children's Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Petros Bakakos
- Intensive Care Unit, First Department of Pulmonary Medicine, National and Kapodistrian University of Athens and Sotiria Hospital, 11527 Athens, Greece
| | - Athanasia Athanasopoulou
- Intensive Care Unit, First Department of Pulmonary Medicine, National and Kapodistrian University of Athens and Sotiria Hospital, 11527 Athens, Greece
| | - Athanasios Koromilias
- Intensive Care Unit, First Department of Pulmonary Medicine, National and Kapodistrian University of Athens and Sotiria Hospital, 11527 Athens, Greece
| | - Nikoletta Rovina
- Intensive Care Unit, First Department of Pulmonary Medicine, National and Kapodistrian University of Athens and Sotiria Hospital, 11527 Athens, Greece
| | - Vasiliki Efthymiou
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni Papakonstantinou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 10447 Athens, Greece
| | - Dimitrios Vlachakis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 10447 Athens, Greece
| | - Sophia Mavrikou
- Faculty of Applied Biology and Biotechnology, Department of Biotechnology, Agricultural University of Athens, 10447 Athens, Greece
| | - Antonia Koutsoukou
- Intensive Care Unit, First Department of Pulmonary Medicine, National and Kapodistrian University of Athens and Sotiria Hospital, 11527 Athens, Greece
| | - Joanne Traeger-Synodinos
- Laboratory of Medical Genetics, St. Sophia's Children's Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - George P Chrousos
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Izuegbuna OO, Olawumi HO, Agodirin OS, Olatoke SA. Lipid Profile and Atherogenic Risk Assessment in Nigerian Breast Cancer Patients - A Cross-Sectional Study. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2024; 43:582-591. [PMID: 38805002 DOI: 10.1080/27697061.2024.2353289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 03/30/2024] [Accepted: 05/04/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND The lipid profile and atherogenic risk indices in Nigerian breast cancer patients are largely unknown. This study evaluated the lipid profile and atherogenic risk indices of breast cancer patients in Nigeria. METHODS This study involved 45 primarily diagnosed breast cancer patients and 50 normal control subjects. Total cholesterol, triglyceride, and High-density lipoprotein cholesterol (HDL-C) were measured. Low-density lipoprotein cholesterol (LDL-C) was calculated according to Friedewald formula. Atherogenic index of plasma (AIP), Atherogenic coefficient (AC), TC/HDL-C (Castelli I) and LDL-C/HDL-C (Castelli II) risk indices were all calculated. The Framingham risk assessment was calculated and categorized. RESULTS The study group had significantly higher triglycerides (TG), and atherogenic indices than the control group (p < 0.001), while HDL-Cholesterol (HDL-C) was significantly lower in the study group (p < 0.001). Total cholesterol and LDL-Cholesterol (LDL-C) had a significant positive correlation with age (r = 0.283, p < 0.018; r = 0.272, p < 0.023); TG was significantly positively correlated with systolic and diastolic blood pressure (r = 0.320. p < 0.007; r = 0.334, p < 0.005); HDL-C had a significant negative correlation with BMI, systolic and diastolic blood pressure (r = -0.252, p < 0.035; r = -0.29, p < 0.015; r = -0.329, p < 0.005). The lipid ratios (TC/HDL-C, LDL-C/HDL-C) were significantly positively correlated with body mass index (BMI), systolic and diastolic blood pressure. The Framingham Risk Score showed that only 2 subjects in the study group (4.4%) were at a high risk of having a cardiovascular event. CONCLUSION Breast cancer patients have a higher prevalence of dyslipidaemia, and cardiovascular risk than the normal population.
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Affiliation(s)
- Ogochukwu O Izuegbuna
- Department of Haematology and Blood Transfusion, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Hannah O Olawumi
- Department of Haematology and Blood Transfusion, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Olayide S Agodirin
- Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Samuel A Olatoke
- Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria
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Kolahi Ahari R, Akbari N, Babaeepoor N, Fallahi Z, Saffar Soflaei S, Ferns G, Ebrahimi M, Moohebati M, Esmaily H, Ghayour‐Mobarhan M. Association of Three Novel Inflammatory Markers: Lymphocyte to HDL-C Ratio, High-Sensitivity C-Reactive Protein to HDL-C Ratio and High-Sensitivity C-Reactive Protein to Lymphocyte Ratio With Metabolic Syndrome. Endocrinol Diabetes Metab 2024; 7:e00479. [PMID: 38590230 PMCID: PMC11002532 DOI: 10.1002/edm2.479] [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: 01/08/2024] [Revised: 02/13/2024] [Accepted: 02/23/2024] [Indexed: 04/10/2024] Open
Abstract
OBJECTIVE We aimed to compare the association of three novel inflammatory indicators with metabolic syndrome (MetS) among Mashhad stroke and heart atherosclerotic disorder (MASHAD) cohort participants. METHODS According to the International Diabetes Federation (IDF) criteria, the cohort participants were divided into the MetS(+) and MetS(-) groups. The lymphocyte to high-density lipoprotein cholesterol (HDL-C) ratio (LHR), high-sensitivity C-reactive protein (hs-CRP) to HDL-C ratio (HCHR) and hs-CRP to lymphocyte ratio (HCLR) were calculated and were compared between the groups. Binary logistic regression (LR) analysis was performed to find the association of the indices with the presence of MetS among men and women. Receiver-operating characteristic (ROC) curve analysis was used to establish cut-off values in predicting MetS for men and women. p-Values <0.05 were considered as statistically significant. RESULTS Among a total of 8890 participants (5500 MetS(-) and 3390 MetS(+)), LHR, HCHR and HCLR were significantly higher in the MetS(+) group than in MetS(-) group (p < 0.001). In LR analysis, after adjusting for multiple cofounders, LHR remained an independent factor for the presence of MetS among men (OR: 1.254; 95% CI: 1.202-1.308; p < 0.001) and women (OR: 1.393; 95% CI: 1.340-1.448; p < 0.001). HCHR also remained an independent factor for the presence of MetS only in women (OR: 1.058; 95% CI: 1.043-1.073; p < 0.001). ROC curve analysis showed that LHR had the higher AUC for predicting MetS in both men (AUC: 0.627; 95% CI: 0.611-0.643; p < 0.001) and women (AUC: 0.683; 95% CI: 0.670, 0.696; p < 0.001). CONCLUSION This suggests that among both genders, the LHR as an inexpensive and easy-to-access marker has a better diagnostic performance and could be a promising alternative to the traditional expensive inflammatory markers such as hs-CRP for the evaluation of inflammation in patients with MetS.
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Affiliation(s)
- Rana Kolahi Ahari
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashadIran
- Applied Biomedical Research CenterMashhad University of Medical SciencesMashadIran
| | - Nazanin Akbari
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashadIran
| | - Negin Babaeepoor
- School of Nursing and MidwiferyMashhad University of Medical SciencesMashadIran
| | - Zahra Fallahi
- School of Nursing and MidwiferyMashhad University of Medical SciencesMashadIran
| | - Sara Saffar Soflaei
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashadIran
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashadIran
| | - Gordon Ferns
- Division of Medical EducationBrighton and Sussex Medical SchoolBrightonUK
| | - Mahmoud Ebrahimi
- Faculty of Medicine, Vascular and Endovascular Research CenterMashhad University of Medical SciencesMashadIran
| | - Mohsen Moohebati
- Department of Cardiology, Faculty of MedicineMashhad University of Medical SciencesMashadIran
| | - Habibollah Esmaily
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashadIran
- Department of Biostatistics, School of Health, Social Determinants of Health Research CenterMashhad University of Medical SciencesMashadIran
| | - Majid Ghayour‐Mobarhan
- International UNESCO Center for Health‐Related Basic Sciences and Human NutritionMashhad University of Medical SciencesMashadIran
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashadIran
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Al-Zadjali J, Al-Lawati A, Al Riyami N, Al Farsi K, Al Jarradi N, Boudaka A, Al Barhoumi A, Al Lawati M, Al Khaifi A, Musleh A, Gebrayel P, Vaulont S, Peyssonnaux C, Edeas M, Saleh J. Reduced HDL-cholesterol in long COVID-19: A key metabolic risk factor tied to disease severity. Clinics (Sao Paulo) 2024; 79:100344. [PMID: 38552385 PMCID: PMC10998035 DOI: 10.1016/j.clinsp.2024.100344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 01/17/2024] [Accepted: 03/03/2024] [Indexed: 04/09/2024] Open
Abstract
This controlled study investigated metabolic changes in non-vaccinated individuals with Long-COVID-19, along with their connection to the severity of the disease. The study involved 88 patients who experienced varying levels of initial disease severity (mild, moderate, and severe), and a control group of 29 healthy individuals. Metabolic risk markers from fasting blood samples were analyzed, and data regarding disease severity indicators were collected. Findings indicated significant metabolic shifts in severe Long-COVID-19 cases, mainly a marked drop in HDL-C levels and a doubled increase in ferritin levels and insulin resistance compared to the mild cases and controls. HDL-C and ferritin were identified as the leading factors predicted by disease severity. In conclusion, the decline in HDL-C levels and rise in ferritin levels seen in Long-COVID-19 individuals, largely influenced by the severity of the initial infection, could potentially play a role in the persistence and progression of Long-COVID-19. Hence, these markers could be considered as possible therapeutic targets, and help shape preventive strategies to reduce the long-term impacts of the disease.
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Affiliation(s)
| | | | - Nafila Al Riyami
- Biochemistry Department, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Koukab Al Farsi
- Biochemistry Department, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Najwa Al Jarradi
- Biochemistry Department, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Ammar Boudaka
- Sultan Qaboos University, Muscat, Oman; Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | | | | | | | | | | | - Sophie Vaulont
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014, Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Carole Peyssonnaux
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014, Paris, France; Laboratory of Excellence GR-Ex, Paris, France
| | - Marvin Edeas
- Université de Paris, Institut Cochin, INSERM, CNRS, F-75014, Paris, France; Laboratory of Excellence GR-Ex, Paris, France.
| | - Jumana Saleh
- Biochemistry Department, College of Medicine, Sultan Qaboos University, Muscat, Oman.
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Bhargav A, Ramanathan V, Ramadoss R, Kavadichanda C, Mariaselvam CM, Negi VS, Thabah MM. Outcome of critically ill patients with systemic lupus erythematosus from a medical intensive care unit in Southern India. Lupus 2023; 32:1462-1470. [PMID: 37769791 DOI: 10.1177/09612033231204074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
OBJECTIVE Systemic lupus erythematosus (SLE) has become the most prevalent autoimmune condition requiring admission in the intensive care units (ICU) in the last two decades. Here we analysed the clinical outcomes of SLE patients admitted to our ICU between 2011 and 2021, and studied the prognostic role of high-density lipoprotein (HDL) and procalcitonin in those enrolled after August 2019. METHODS Systemic lupus erythematosus (ACR/SLICC 2012) were enrolled, 72 retrospectively and 30 prospectively. Data on indications for ICU admission, complications, infections, and disease activity were recorded. Outcome was mortality at 90 days (prospective) whereas in the retrospective analysis outcome was hospital discharge or death in hospital. Serum HDL and procalcitonin (PCT) was estimated in the prospectively enrolled 30 patients and compared with 30 non ICU-SLE patients. RESULTS Indications for ICU admissions were respiratory causes in 78/102 (76.5%) patients; for haemodynamic monitoring and for invasive procedures in the remaining. Pneumonia was the primary reason for mechanical ventilation, followed by diffuse alveolar haemorrhage (DAH). Eighty-three (81.3%) patients died; infections (n = 54) and SLE related causes (n = 29). APACHE-II >16 (p = .026), lymphopenia (p = .021), infection (p = .002), creatinine >1.3 mg/dL (p = .023), and hypotension requiring vasopressor support (p = .006) emerged as significant predictors of non-survival on multivariable analysis. HDL (mg/dL) day 1 was significantly lower in SLE-ICU patients compared to non ICU-SLE (31.8 ± 14.3 vs 38.8 ± 11.4 mg/dl); p = .045. On day 1, PCT (ng/mL) in SLE-ICU was significantly higher when compared to non-ICU SLE; median (IQR): 0.53 (0.26-5.27) versus 0.13 (0.05-0.47), p < .001), respectively. It was also significantly higher on day 5 in SLE-ICU than non-ICU SLE (median (IQR): 4.18 (0.20-14.67) versus 0.10 (0.08-0.46), p = .004. CONCLUSION The mortality of SLE patients admitted to the ICU in this study is high, and infections were the principal reason for death. Baseline low HDL and higher procalcitonin are potential biomarkers to identify critically ill SLE patients.
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Affiliation(s)
- Arvind Bhargav
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Venkateswaran Ramanathan
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Ramu Ramadoss
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Chengappa Kavadichanda
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Christina M Mariaselvam
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Vir S Negi
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Molly M Thabah
- Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
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Dossou AS, Mantsch ME, Kapic A, Burnett WL, Sabnis N, Coffer JL, Berg RE, Fudala R, Lacko AG. Mannose-Coated Reconstituted Lipoprotein Nanoparticles for the Targeting of Tumor-Associated Macrophages: Optimization, Characterization, and In Vitro Evaluation of Effectiveness. Pharmaceutics 2023; 15:1685. [PMID: 37376134 DOI: 10.3390/pharmaceutics15061685] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/29/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been utilized as delivery vehicles to a variety of targets, including cancer cells. However, the modification of rHDL NPs for the targeting of the pro-tumoral tumor-associated macrophages (TAMs) remains largely unexplored. The presence of mannose on nanoparticles can facilitate the targeting of TAMs which highly express the mannose receptor at their surface. Here, we optimized and characterized mannose-coated rHDL NPs loaded with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an immunomodulatory drug. Lipids, recombinant apolipoprotein A-I, DMXAA, and different amounts of DSPE-PEG-mannose (DPM) were combined to assemble rHDL-DPM-DMXAA NPs. The introduction of DPM in the nanoparticle assembly altered the particle size, zeta potential, elution pattern, and DMXAA entrapment efficiency of the rHDL NPs. Collectively, the changes in physicochemical characteristics of rHDL NPs upon the addition of the mannose moiety DPM indicated that the rHDL-DPM-DMXAA NPs were successfully assembled. The rHDL-DPM-DMXAA NPs induced an immunostimulatory phenotype in macrophages pre-exposed to cancer cell-conditioned media. Furthermore, rHDL-DPM NPs delivered their payload more readily to macrophages than cancer cells. Considering the effects of the rHDL-DPM-DMXAA NPs on macrophages, the rHDL-DPM NPs have the potential to serve as a drug delivery platform for the selective targeting of TAMs.
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Affiliation(s)
- Akpedje S Dossou
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
| | - Morgan E Mantsch
- College of Natural Sciences, University of Texas at Austin, Austin, TX 78705, USA
| | - Ammar Kapic
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
| | - William L Burnett
- College of Science and Engineering, Texas Christian University (TCU), Fort Worth, TX 76129, USA
| | - Nirupama Sabnis
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
| | - Jeffery L Coffer
- College of Science and Engineering, Texas Christian University (TCU), Fort Worth, TX 76129, USA
| | - Rance E Berg
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
| | - Rafal Fudala
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
| | - Andras G Lacko
- Department of Microbiology, Immunology and Genetics, UNT Health Science Center (UNTHSC), Fort Worth, TX 76107, USA
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Wrona M, Skrypnik D. New-Onset Diabetes Mellitus, Hypertension, Dyslipidaemia as Sequelae of COVID-19 Infection-Systematic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph192013280. [PMID: 36293857 PMCID: PMC9602450 DOI: 10.3390/ijerph192013280] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 10/06/2022] [Accepted: 10/13/2022] [Indexed: 06/05/2023]
Abstract
As the population recovers from the coronavirus disease 2019 (COVID-19) pandemic, a subset of individuals is emerging as post-coronavirus disease (post-COVID) patients who experience multifactorial long-term symptoms several weeks after the initial recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aim of this systematic review is to present the latest scientific reports that evaluate changes in glucose levels, blood pressure readings and lipid profiles after recovery from COVID-19 to verify the hypothesis that new-onset diabetes mellitus, arterial hypertension and dyslipidaemia are a possible sequela of a COVID-19 infection. The open access databases PubMed and Google Scholar were searched. Articles investigating patients with residual clinical signs and biochemical alteration indicating diabetes, hypertension and dyslipidaemia at least a month after recovering from COVID-19 were included. It has been shown that a select number of patients were diagnosed with new-onset diabetes, arterial hypertension and dyslipidaemia after COVID-19 infection. Alterations in glucose levels, blood pressure and lipid profiles months after initial infection shows the importance of considering diabetes mellitus, arterial hypertension and dyslipidaemia as part of the multifactorial diagnostic criteria post-COVID to better provide evidence-based clinical care.
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Affiliation(s)
- Marysia Wrona
- Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Damian Skrypnik
- Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences, 60-569 Poznan, Poland
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Relationship between Metabolic Syndrome Components and COVID-19 Disease Severity in Hospitalized Patients: A Pilot Study. CANADIAN JOURNAL OF INFECTIOUS DISEASES AND MEDICAL MICROBIOLOGY 2022; 2022:9682032. [PMID: 36061633 PMCID: PMC9433267 DOI: 10.1155/2022/9682032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/23/2022] [Accepted: 07/22/2022] [Indexed: 01/08/2023]
Abstract
Background Preliminary data suggest that patients with comorbidities are more susceptible to severe COVID-19 infection. However, data regarding the presence of metabolic syndrome (MetS) in patients with COVID-19 are scarce. Aim In the present study, we aim to investigate the association between MetS components and disease severity in hospitalized COVID-19 patients. Methods We conducted a prospective observational study of 90 hospitalized patients with COVID-19 pneumonia at a tertiary hospital. The study population consisted of inpatients who tested positive by the reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2. Patients with critical COVID-19 disease on admission were excluded. Adult Treatment Panel III of the National Cholesterol Education Program (NCEP-ATP III) criteria were used to define MetS. Laboratory analysis and thorax CT were performed on admission. Results 90 patients, 60 moderate and 30 severe COVID-19 patients, included in the study. The percentage of MetS cases was higher among severe COVID-19 patients (p=0.018). Of the MetS criteria fasting blood glucose (p=0.004), triglycerides (p=0.007) were significantly higher in patients with severe COVID-19 disease with no statistical significance found in waist circumference (WC) (p=0.348), systolic blood pressure (p=0.429), and HDL-C levels (p=0.263) between two groups. Body mass index (BMI) values were similar in both severe and moderate cases (p=0.854). In logistic regression analysis, serum triglycerides (p=0.024), HDL-C (p=0.006), and WC (p=0.004) were found as independent prognostic factor for severe COVID-19 infection. Conclusion Severe COVID-19 patients have higher rates of MetS. Serum triglycerides, HDL-C, and WC have an impact on disease severity in COVID-19.
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Makhoul E, Aklinski JL, Miller J, Leonard C, Backer S, Kahar P, Parmar MS, Khanna D. A Review of COVID-19 in Relation to Metabolic Syndrome: Obesity, Hypertension, Diabetes, and Dyslipidemia. Cureus 2022; 14:e27438. [PMID: 36051728 PMCID: PMC9420458 DOI: 10.7759/cureus.27438] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/29/2022] [Indexed: 11/05/2022] Open
Abstract
Although severe cases and mortality of coronavirus disease 2019 (COVID-19) are proportionally infrequent, these cases are strongly linked to patients with conditions of metabolic syndrome (obesity, hypertension, diabetes, and dyslipidemia). However, the pathophysiology of COVID-19 in relation to metabolic syndrome is not well understood. Thus, the goal of this secondary literature review was to examine the relationship between severe acute respiratory syndrome (SARS-CoV-2) infection and the individual conditions of metabolic syndrome. The objective of this secondary literature review was achieved by examining primary studies, case studies, and other secondary studies, to obtain a comprehensive perspective of theories and observations of COVID-19 etiology with metabolic syndrome. The most extensive research was available on the topics of diabetes, hypertension, and obesity, which yielded multiple (and sometimes conflicting) hypothetical pathophysiology. The sources on dyslipidemia and COVID-19 were scarcer and failed to provide an equally comprehensive image, highlighting the need for further research. It was concluded that hypertension had the strongest correlation with COVID-19 incidence (followed by obesity), yet the causative pathophysiology was ambiguous; most likely related to cardiovascular, angiotensin-converting enzyme 2 (ACE-2)-related complications from renin-angiotensin-aldosterone system (RAAS) imbalance. Obesity was also positively correlated to the severity of COVID-19 cases and was believed to contribute to mechanical difficulties with respiration, in addition to hypothetical connections with the expression of ACE-2 on abundant adipose tissue. Diabetes was believed to contribute to COVID-19 severity by producing a chronic inflammatory state and interfering with neutrophil and T-cell function. Furthermore, there were indications that COVID-19 may induce acute-onset diabetes and diabetic ketoacidosis. Lastly, dyslipidemia was concluded to potentially facilitate SARS-CoV-2 infection by enhancing lipid rafts and immunosuppressive functions. There were also indications that cholesterol levels may have prognostic indications and that statins may have therapeutic benefits.
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Kotlyarov S. High-Density Lipoproteins: A Role in Inflammation in COPD. Int J Mol Sci 2022; 23:8128. [PMID: 35897703 PMCID: PMC9331387 DOI: 10.3390/ijms23158128] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high rates of disability and mortality. COPD is characterized by chronic inflammation in the bronchi as well as systemic inflammation, which contributes significantly to the clinically heterogeneous course of the disease. Lipid metabolism disorders are common in COPD, being a part of its pathogenesis. High-density lipoproteins (HDLs) are not only involved in lipid metabolism, but are also part of the organism's immune and antioxidant defense. In addition, HDL is a versatile transport system for endogenous regulatory agents and is also involved in the removal of exogenous substances such as lipopolysaccharide. These functions, as well as information about lipoprotein metabolism disorders in COPD, allow a broader assessment of their role in the pathogenesis of heterogeneous and comorbid course of the disease.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
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11
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Effect of COVID-19 on lipid profile parameters and its correlation with acute phase reactants: A single-center retrospective analysis. Ann Med Surg (Lond) 2022; 78:103856. [PMID: 35637852 PMCID: PMC9134795 DOI: 10.1016/j.amsu.2022.103856] [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: 04/03/2022] [Revised: 05/22/2022] [Accepted: 05/22/2022] [Indexed: 01/09/2023] Open
Abstract
Background and objective The development and correlation of dyslipidemia is unknown in COVID-19. This investigation was performed to assess the pathological alterations in lipid profile and their association in COVID-19. Methods This was a retrospective study performed on real-world patients to assess serum levels of LDL-C, HDL, TG, TC on COVID-19 patients (mild: 319; moderate: 391; critical: 357). Age- and gender-matched controls who had their lipid profiles in the same period were included as the control group. Results LDL-C, HDL, TG, and TC levels were significantly lower in COVID-19 patients when compared with the control group (P < 0.001, 0.047, 0.045, <0.001, respectively). All parameters decreased gradually with COVID-19 disease severity (LDL-C: median (IQR), mild: 98 (91,134); moderate: 97 (81,113); critical: 68 (68,83); HDL: mild: 45 (37,50); moderate: 46 (41,50); critical: 40 (37,46); TG: mild: 186 (150,245); moderate: 156 (109,198); critical: 111 (98,154); TC: mild: 224 (212,238); moderate: 212 (203,213); critical: 154 (125,187)). Logistic regression demonstrated lipid profile as predictor of severity of COVID-19 disease. Conclusion Hypolipidemia develops in increasing frequency with severe COVID-19 disease. It inversely correlates with levels of acute-phase reactants, indicating SARS-COV-2 as the causative agent for alteration in lipid and thyroid levels.
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12
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Jeon WH, Seon JY, Park SY, Oh IH. Association of Metabolic Syndrome with COVID-19 in the Republic of Korea. Diabetes Metab J 2022; 46:427-438. [PMID: 34837934 PMCID: PMC9171168 DOI: 10.4093/dmj.2021.0105] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/26/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is reportedly a crucial risk factor for coronavirus disease 2019 (COVID-19). Since the epidemiological studies that examine this association are few and include small samples, we investigated the relationship between MetS and COVID-19 severity and death using a larger sample in the Republic of Korea. METHODS We analyzed 66,321 patients, 4,066 of whom had COVID-19. We used chi-square tests to examine patients' characteristics. We performed logistic regression analysis to analyze differences in COVID-19 infection and clinical outcomes according to the presence of MetS. RESULTS Although MetS was not significantly associated with COVID-19 risk, acquiring MetS was significantly associated with the risk of severe COVID-19 outcomes (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.34 to 2.91; P=0.001). The mortality risk was significantly higher in COVID-19 patients with MetS (OR, 1.74; 95% CI, 1.17 to 2.59; P=0.006). Patients with abnormal waist circumference were approximately 2.07 times more likely to develop severe COVID-19 (P<0.001), and high-density lipoprotein cholesterol (HDL-C) levels were significantly associated with COVID-19; the mortality risk due to COVID-19 was 1.74 times higher in men with an HDL-C level of <40 mg/dL and in women with an HDL-C level of <50 mg/dL (P=0.012). CONCLUSION COVID-19 is likely associated with severity and death in patients with MetS or in patients with MetS risk factors. Therefore, patients with MetS or those with abnormal waist circumference and HDL-C levels need to be treated with caution.
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Affiliation(s)
- Woo-Hwi Jeon
- Department of Preventive Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Jeong-Yeon Seon
- Department of Preventive Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
| | - So-Youn Park
- Department of Medical Education and Humanities, College of Medicine, Kyung Hee University, Seoul, Korea
- Corresponding authors: So-Youn Park https://orcid.org/0000-0003-0553-5381 Department of Medical Education and Humanities, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea E-mail:
| | - In-Hwan Oh
- Department of Preventive Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
- In-Hwan Oh https://orcid.org/0000-0002-5450-9887 Department of Preventive Medicine, College of Medicine, Kyung Hee University, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea E-mail:
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13
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Li M, Feng S, Zhan X, Peng F, Feng X, Zhou Q, Wu X, Wang X, Su N, Tang X, Wang Z, Zhang Y, Zeng Y, Zhu L, Xie Y, Liang J, Liu L, Wen Y. Neutrophil to high-density lipoprotein ratio associates with higher all-cause mortality and new onset cardiovascular events in peritoneal dialysis patients. Int Urol Nephrol 2022; 54:2745-2754. [PMID: 35411415 DOI: 10.1007/s11255-022-03202-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 03/15/2022] [Indexed: 01/02/2023]
Abstract
BACKGROUND Neutrophil to high-density lipoprotein ratio (NHR), a new inflammatory marker, is associated with poor clinical prognosis. However, the correlation of NHR and adverse outcomes in peritoneal dialysis (PD) patients remains unclear. METHODS In this retrospective cohort study, a total of 1051 PD patients were recruited from three centers during Jan 1, 2009 to Dec 31, 2017. Eligible patients were distributed according to quartiles of the NHR. Kaplan-Meier cumulative incidence curves, multivariate COX regression, competitive risk analysis and restricted cubic spline (RCS) were applied to analyze the relationship between NHR and all-cause mortality as well as cardiovascular events (CVE). In addition, forest plots were used to calculate the interaction between different subgroups. RESULTS During follow-up, a total of 240 all-cause mortality and 157 new-onset CVE were recorded. The all-cause mortality in the highest quartile of NHR (> 5.43) were higher than those in the other groups. RCS showed a non-linear relationship between NHR and adverse outcomes. Multivariate COX regression indicated elevated NHR was an independent risk factor for all-cause mortality. Compared to the highest quartile, hazard ratio (HR) of new-onset CVE equals to 0.522 (95% CI 0.321-0.849) in the secondary quartile (2.43 < NHR ≤ 3.57), and the HR of all-cause mortality analysis is 0.551 (95% CI 0.378-0.803) in the third quartile (3.57 < NHR ≤ 5.43). Kaplan-Meier analysis suggested there were significant differences in all-cause mortality and new-onset CVE among four NHR groups. CONCLUSIONS NHR was a new independent risk factor for all-cause mortality in PD patients.
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Affiliation(s)
- Mengmeng Li
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shaozhen Feng
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaojiang Zhan
- Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fenfen Peng
- Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoran Feng
- Department of Nephrology, Jiujiang NO.1 people's Hospital, Jiangxi, China
| | - Qian Zhou
- Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xianfeng Wu
- Department of Nephrology, Affiliated Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoyang Wang
- Department of Nephrology, The First Affiliated Hospital, Zhengzhou University, ZhengZhou, Henan, China
| | - Ning Su
- Department of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xingming Tang
- Department of Nephrology, Affiliated Tungwah Hospital, Sun Yet-Sen University, Dongguan, Guangdong, China
| | - Zebin Wang
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yujing Zhang
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yingsi Zeng
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Liya Zhu
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yuxin Xie
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianbo Liang
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Lingling Liu
- Department of General Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yueqiang Wen
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
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14
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Tang H, Xiang Z, Li L, Shao X, Zhou Q, You X, Xiong C, Ning J, Chen T, Deng D, Zou H. Potential role of anti-inflammatory HDL subclasses in metabolic unhealth/obesity. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2021; 49:565-575. [PMID: 34402692 DOI: 10.1080/21691401.2021.1961798] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/19/2021] [Indexed: 01/29/2023]
Abstract
High-density lipoprotein (HDL) particles comprising heterogeneous subclasses of different functions exert anti-inflammatory effects by interacting with immune-response cells. However, the relationship of HDL subclasses with immune-response cells in metabolic unhealth/obesity has not been defined clearly. The purpose of this study was to delineate the relational changes of HDL subclasses with immune cells and inflammatory markers in metabolic unhealth/obesity to understand the role of anti-inflammatory HDL subclasses. A total of 316 participants were classified by metabolic health. HDL subclasses were detected by microfluidic chip electrophoresis. White blood cell (WBC) counts and lymphocytes were assessed using automatic haematology analyser. Levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) were measured. In our study, not only the distribution of HDL subclasses, but also HDL-related structural proteins changed with the deterioration of metabolic disease. Moreover, lymphocytes and inflammation factors significantly gradually increased. The level of HDL2b was negatively associated with WBC, lymphocytes and hs-CRP in multivariable linear regression analysis. In multinomial logistic regression analysis, high levels of HDL3 and low levels of HDL2b increased the probability of having an unfavourable metabolic unhealth/obesity status. We supposed that HDL2b particles may play anti-inflammation by negatively regulating lymphocytes activation. HDL2b may be a therapeutic target for future metabolic disease due to the anti-inflammatory effects.
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Affiliation(s)
- Hongjuan Tang
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Department of Nephrology, Maoming People's Hospital, Maoming, China
| | - Zhicong Xiang
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Longyu Li
- Guangdong Ardent Biomed Co. Ltd & Ardent BioMed LLC (California), Guangzhou, CA, USA
| | - Xiaofei Shao
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qin Zhou
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Xu You
- Department of Clinical Lab, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Chongxiang Xiong
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Jing Ning
- Department of Nephrology, Pinghu Hospital, Health Science Center, South China Hospital of Shenzhen University, Shenzhen, P.R. China
| | - Tong Chen
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - David Deng
- Guangdong Ardent Biomed Co. Ltd & Ardent BioMed LLC (California), Guangzhou, CA, USA
| | - Hequn Zou
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Department of Nephrology, Pinghu Hospital, Health Science Center, South China Hospital of Shenzhen University, Shenzhen, P.R. China
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15
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Sharifi Y, Payab M, Mohammadi-Vajari E, Aghili SMM, Sharifi F, Mehrdad N, Kashani E, Shadman Z, Larijani B, Ebrahimpur M. Association between cardiometabolic risk factors and COVID-19 susceptibility, severity and mortality: a review. J Diabetes Metab Disord 2021; 20:1743-1765. [PMID: 34222055 PMCID: PMC8233632 DOI: 10.1007/s40200-021-00822-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/23/2021] [Indexed: 02/08/2023]
Abstract
The novel coronavirus, which began spreading from China Wuhan and gradually spreaded to most countries, led to the announcement by the World Health Organization on March 11, 2020, as a new pandemic. The most important point presented by the World Health Organization about this disease is to better understand the risk factors that exacerbate the course of the disease and worsen its prognosis. Due to the high majority of cardio metabolic risk factors like obesity, hypertension, diabetes, and dyslipidemia among the population over 60 years old and higher, these cardio metabolic risk factors along with the age of these people could worsen the prognosis of the coronavirus disease of 2019 (COVID-19) and its mortality. In this study, we aimed to review the articles from the beginning of the pandemic on the impression of cardio metabolic risk factors on COVID-19 and the effectiveness of COVID-19 on how to manage these diseases. All the factors studied in this article, including hypertension, diabetes mellitus, dyslipidemia, and obesity exacerbate the course of Covid-19 disease by different mechanisms, and the inflammatory process caused by coronavirus can also create a vicious cycle in controlling these diseases for patients.
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Affiliation(s)
- Yasaman Sharifi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Yaas Diabetes and Metabolic Diseases Research Center, Indiana University School of Medicine, Indianapolis, IN 46202 US
| | - Moloud Payab
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Mohammadi-Vajari
- Student of Medicine, School of Medicine, Gilan University of Medical Sciences, Rasht, Iran
| | - Seyed Morsal Mosallami Aghili
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshad Sharifi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Mehrdad
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Nursing Care Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Kashani
- Department of Obstetrics and Gynecology, Golestan University of Medical Sciences, Golestan, Iran
| | - Zhaleh Shadman
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahbube Ebrahimpur
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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16
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Xue YH, Feng LS, Xu ZY, Zhao FY, Wen XL, Jin T, Sun ZX. The time-dependent variations of zebrafish intestine and gill after polyethylene microplastics exposure. ECOTOXICOLOGY (LONDON, ENGLAND) 2021; 30:1997-2010. [PMID: 34529203 DOI: 10.1007/s10646-021-02469-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/17/2021] [Indexed: 06/13/2023]
Abstract
Microplastics (MPs) are common environmental contaminants that present a growing health concern due to their increasing presence in aquatic and human systems. However, the mechanisms behind MP effects on organisms are unclear. In this study, zebrafish (Danio rerio) were used as an in vivo model to investigate the potential risks and molecular mechanisms of the toxic effects of polyethylene MPs (45-53 μm). In the zebrafish intestine, 6, 5, and 186 genes showed differential expression after MP treatment for 1, 5, and 10 days, respectively. In the gills, 318, 92, and 484 genes showed differential expression after MP treatment for 1, 5, and 10 days, respectively. In both the intestine and the gills, Gene Ontology (GO) annotation showed that the main enriched terms were biological regulation, cellular process, metabolic process, cellular anatomical entity, and binding. KEGG enrichment analysis on DEGs revealed that the dominant pathways were carbohydrate metabolism and lipid metabolism, which were strongly influenced by MPs in the intestine. The dominant pathways in the gills were immune and lipid metabolism. The respiratory rate of gills, the activity of SOD and GSH in the intestine significantly increased after exposure to MPs compared with the control (p < 0.05), while the activity of SOD did not change in the gills. GSH activity was only significantly increased after MP exposure for 5 days. Also, the MDA content was not changed in the intestine but was significantly decreased in the gills after MP exposure. The activity of AChE significantly decreased only after MPs exposure for 5 days. Overall, these results indicated that MPs pollution significantly induced oxidative stress and neurotoxicity, increased respiratory rate, disturbed energy metabolism and stimulated immune function in fish, displaying an environmental risk of MPs to aquatic ecosystems.
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Affiliation(s)
- Ying-Hao Xue
- College of Land and Environment, Shenyang Agricultural University, Shenyang, 110866, PR China
- Rural Energy and Environment Agency, Ministry of Agriculture and Rural Affairs, Beijing, 100125, PR China
| | - Liang-Shan Feng
- Liaoning Academy of Agricultural Sciences, Shenyang, 110161, PR China
| | - Zhi-Yu Xu
- Rural Energy and Environment Agency, Ministry of Agriculture and Rural Affairs, Beijing, 100125, PR China
| | - Feng-Yan Zhao
- Liaoning Academy of Agricultural Sciences, Shenyang, 110161, PR China
| | - Xin-Li Wen
- School of Ecology and Environment, Anhui Normal University, Wuhu, 241000, PR China
| | - Tuo Jin
- Rural Energy and Environment Agency, Ministry of Agriculture and Rural Affairs, Beijing, 100125, PR China
| | - Zhan-Xiang Sun
- Liaoning Academy of Agricultural Sciences, Shenyang, 110161, PR China.
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17
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Teunissen AJP, Burnett ME, Prévot G, Klein ED, Bivona D, Mulder WJM. Embracing nanomaterials' interactions with the innate immune system. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2021; 13:e1719. [PMID: 33847441 PMCID: PMC8511354 DOI: 10.1002/wnan.1719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/12/2021] [Accepted: 03/21/2021] [Indexed: 12/17/2022]
Abstract
Immunotherapy has firmly established itself as a compelling avenue for treating disease. Although many clinically approved immunotherapeutics engage the adaptive immune system, therapeutically targeting the innate immune system remains much less explored. Nanomedicine offers a compelling opportunity for innate immune system engagement, as many nanomaterials inherently interact with myeloid cells (e.g., monocytes, macrophages, neutrophils, and dendritic cells) or can be functionalized to target their cell-surface receptors. Here, we provide a perspective on exploiting nanomaterials for innate immune system regulation. We focus on specific nanomaterial design parameters, including size, form, rigidity, charge, and surface decoration. Furthermore, we examine the potential of high-throughput screening and machine learning, while also providing recommendations for advancing the field. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Abraham J. P. Teunissen
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marianne E. Burnett
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Geoffrey Prévot
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Emma D. Klein
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daniel Bivona
- Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Willem J. M. Mulder
- Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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18
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Morris G, Berk M, Walder K, O'Neil A, Maes M, Puri BK. The lipid paradox in neuroprogressive disorders: Causes and consequences. Neurosci Biobehav Rev 2021; 128:35-57. [PMID: 34118292 DOI: 10.1016/j.neubiorev.2021.06.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 04/27/2021] [Accepted: 06/06/2021] [Indexed: 02/07/2023]
Abstract
Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A2 activation; cytosolic phospholipase A2 activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Michael Berk
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, CMMR Strategic Research Centre, School of Medicine, Geelong, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Ken Walder
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Adrienne O'Neil
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Michael Maes
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand
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19
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Syed S, Nissilä E, Ruhanen H, Fudo S, Gaytán MO, Sihvo SP, Lorey MB, Metso J, Öörni K, King SJ, Oommen OP, Jauhiainen M, Meri S, Käkelä R, Haapasalo K. Streptococcus pneumoniae pneumolysin and neuraminidase A convert high-density lipoproteins into pro-atherogenic particles. iScience 2021; 24:102535. [PMID: 34124613 PMCID: PMC8175417 DOI: 10.1016/j.isci.2021.102535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 04/19/2021] [Accepted: 05/10/2021] [Indexed: 11/19/2022] Open
Abstract
High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLs may lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger for complement activation, inflammatory response, and thereby promote atherogenic disease progression.
S. pneumoniae molecules PLY and NanA target human high-density lipoprotein (HDL). These interactions result in major modifications in the HDL proteome and lipidome. Microbially modified HDL activates humoral and cell-mediated innate immune responses. The activated immune response mediates formation of pro-atherogenic epitopes on HDL.
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Affiliation(s)
- Shahan Syed
- Department of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland
| | - Eija Nissilä
- Department of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland
| | - Hanna Ruhanen
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
- Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute for Life Science (HiLIFE) and Biocenter Finland, Helsinki 00014, Finland
| | - Satoshi Fudo
- Department of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland
| | - Meztlli O. Gaytán
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Sanna P. Sihvo
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
- Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute for Life Science (HiLIFE) and Biocenter Finland, Helsinki 00014, Finland
| | | | - Jari Metso
- Minerva Foundation Institute for Medical Research, Biomedicum, 00290 Helsinki, Finland
- Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland
| | | | - Samantha J. King
- Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA
| | - Oommen P. Oommen
- Bioengineering and Nanomedicine Lab, Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33720 Tampere, Finland
| | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research, Biomedicum, 00290 Helsinki, Finland
- Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland
| | - Reijo Käkelä
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
- Helsinki University Lipidomics Unit (HiLIPID), Helsinki Institute for Life Science (HiLIFE) and Biocenter Finland, Helsinki 00014, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, University of Helsinki, 00014 Helsinki, Finland
- Corresponding author
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20
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Jayawardena I, Wilson K, Plebanski M, Grøndahl L, Corrie S. Morphology and Composition of Immunodiffusion Precipitin Complexes Evaluated via Microscopy and Proteomics. J Proteome Res 2021; 20:2618-2627. [PMID: 33823594 DOI: 10.1021/acs.jproteome.0c01042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
New approaches to rapid, simple, in vitro diagnostic immunoassays that do not rely on centralized laboratory facilities are urgently needed for disease diagnosis and to inform treatment strategies. The recent and ongoing COVID-19 pandemic has emphasized that rapid diagnostics are needed to help guide government policies on quarantines, social distancing measures, and community lockdowns. A common approach to developing new immunoassays is to modify existing platforms (e.g., automated ELISA and lateral flow assays) for the new analyte, even though this does not address the drawbacks of existing platforms. An alternate approach is to search for robust assays that have been superseded but could in fact solve important challenges using modern technologies. Immunodiffusion is one such platform based on unique "precipitin ring" patterns formed in gels or paper following interactions between proteins and cognate antibodies in diffusion/reaction systems. Herein, we investigate the microstructure of these precipitin rings using a combination of fluorescence and electron microscopy and also perform a mass spectrometry investigation to determine the proteomic composition of the rings. We observed that the rings were composed of microparticles, which we termed "precipitin complexes", and that these complexes were composed of at least 19 key proteins, including immunoglobulins and complement factors along with a range of plasma proteins, possibly related to immune complexes and/or high-density lipoprotein particles. This information will be useful in developing new in vitro diagnostics using reaction/diffusion systems-techniques that require a single assay step and that only require calibrated length measurements for target protein quantification.
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Affiliation(s)
- Imanda Jayawardena
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
| | - Kirsty Wilson
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Magdalena Plebanski
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - Lisbeth Grøndahl
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia
| | - Simon Corrie
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia.,Department of Chemical Engineering, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Clayton, VIC 3800, Australia
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21
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Morris G, Puri BK, Bortolasci CC, Carvalho A, Berk M, Walder K, Moreira EG, Maes M. The role of high-density lipoprotein cholesterol, apolipoprotein A and paraoxonase-1 in the pathophysiology of neuroprogressive disorders. Neurosci Biobehav Rev 2021; 125:244-263. [PMID: 33657433 DOI: 10.1016/j.neubiorev.2021.02.037] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 01/29/2021] [Accepted: 02/23/2021] [Indexed: 12/11/2022]
Abstract
Lowered high-density lipoprotein (HDL) cholesterol has been reported in major depressive disorder, bipolar disorder, first episode of psychosis, and schizophrenia. HDL, its major apolipoprotein component, ApoA1, and the antioxidant enzyme paraoxonase (PON)1 (which is normally bound to ApoA1) all have anti-atherogenic, antioxidant, anti-inflammatory, and immunomodulatory roles, which are discussed in this paper. The paper details the pathways mediating the anti-inflammatory effects of HDL, ApoA1 and PON1 and describes the mechanisms leading to compromised HDL and PON1 levels and function in an environment of chronic inflammation. The molecular mechanisms by which changes in HDL, ApoA1 and PON1 might contribute to the pathophysiology of the neuroprogressive disorders are explained. Moreover, the anti-inflammatory actions of ApoM-mediated sphingosine 1-phosphate (S1P) signalling are reviewed as well as the deleterious effects of chronic inflammation and oxidative stress on ApoM/S1P signalling. Finally, therapeutic interventions specifically aimed at improving the levels and function of HDL and PON1 while reducing levels of inflammation and oxidative stress are considered. These include the so-called Mediterranean diet, extra virgin olive oil, polyphenols, flavonoids, isoflavones, pomegranate juice, melatonin and the Mediterranean diet combined with the ketogenic diet.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | | | - Chiara C Bortolasci
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, CMMR Strategic Research Centre, School of Medicine, Geelong, Victoria, Australia.
| | - Andre Carvalho
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - Michael Berk
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry and The Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Ken Walder
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, CMMR Strategic Research Centre, School of Medicine, Geelong, Victoria, Australia
| | - Estefania G Moreira
- Post-Graduation Program in Health Sciences, State University of Londrina, Londrina, PR, Brazil
| | - Michael Maes
- Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, King Chulalongkorn University Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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22
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Lodge S, Nitschke P, Kimhofer T, Coudert JD, Begum S, Bong SH, Richards T, Edgar D, Raby E, Spraul M, Schaefer H, Lindon JC, Loo RL, Holmes E, Nicholson JK. NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines. J Proteome Res 2021; 20:1382-1396. [PMID: 33426894 PMCID: PMC7805607 DOI: 10.1021/acs.jproteome.0c00876] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Indexed: 02/08/2023]
Abstract
To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed 1H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz 1H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-positive patients (n = 15, with multiple sampling timepoints) and age-matched healthy controls (n = 34, confirmed rRT-PCR negative), together with patients with COVID-19/influenza-like clinical symptoms who tested SARS-CoV-2 negative (n = 35). We compared the single-pulse NMR spectral data with in vitro diagnostic research (IVDr) information on quantitative lipoprotein profiles (112 parameters) extracted from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 positive patients from controls and SARS-CoV-2 negative patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory analysis in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We observed four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1β, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong positive correlations with LDL1-4 subfractions and negative correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune response to SARS CoV-2 infection interacting with the plasma lipoproteome giving a strong and characteristic immunometabolic phenotype of the disease. We observed that some patients in the respiratory recovery phase and testing virus-free were still metabolically highly abnormal, which indicates a new role for these technologies in assessing full systemic recovery.
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Affiliation(s)
- Samantha Lodge
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Centre for Computational and Systems Medicine, Health
Futures Institute, Murdoch University, Murdoch, Western
Australia 6150, Australia
| | - Philipp Nitschke
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
| | - Torben Kimhofer
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Centre for Computational and Systems Medicine, Health
Futures Institute, Murdoch University, Murdoch, Western
Australia 6150, Australia
| | - Jerome D. Coudert
- Centre for Molecular Medicine and Innovative
Therapeutics, Murdoch University, Harry Perkins Building,
Perth, Western Australia 6150, Australia
- Perron Institute for Neurological and
Translational Science, Nedlands, Western Australia 6009,
Australia
- School of Medicine, University of Notre
Dame, Fremantle, Western Australia 6160,
Australia
| | - Sofina Begum
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Section of Nutrition Research , Department of Metabolism,
Nutrition and Reproduction, Faculty of Medicine, Sir Alexander Fleming Building,
Imperial College London, London SW7 2AZ,
U.K.
| | - Sze-How Bong
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
| | - Toby Richards
- Division of Surgery, Medical School, Faculty of Health
and Medical Sciences, University of Western Australia, Harry
Perkins Building, Robert Warren Drive, Murdoch, Perth, Western Australia 6150,
Australia
| | - Dale Edgar
- Faculty of Health and Medical Sciences,
University of Western Australia, Harry Perkins Building,
Robert Warren Drive, Murdoch, Perth, Western Australia 6150,
Australia
| | - Edward Raby
- Department of Clinical Microbiology,
PathWest Laboratory Medicine WA, Murdoch, Perth, Western
Australia 6150, Australia
| | | | | | - John C. Lindon
- Division of Systems Medicine, Department of
Metabolism, Nutrition and Reproduction, Faculty of Medicine, Sir Alexander Fleming
Building, Imperial College London, London SW7 2AZ,
U.K.
| | - Ruey Leng Loo
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Centre for Computational and Systems Medicine, Health
Futures Institute, Murdoch University, Murdoch, Western
Australia 6150, Australia
| | - Elaine Holmes
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Centre for Computational and Systems Medicine, Health
Futures Institute, Murdoch University, Murdoch, Western
Australia 6150, Australia
- Section of Nutrition Research , Department of Metabolism,
Nutrition and Reproduction, Faculty of Medicine, Sir Alexander Fleming Building,
Imperial College London, London SW7 2AZ,
U.K.
| | - Jeremy K. Nicholson
- Australian National Phenome Centre, Health Futures
Institute, Murdoch University, Harry Perkins Building, Perth,
Western Australia 6150, Australia
- Centre for Computational and Systems Medicine, Health
Futures Institute, Murdoch University, Murdoch, Western
Australia 6150, Australia
- Division of Surgery, Medical School, Faculty of Health
and Medical Sciences, University of Western Australia, Harry
Perkins Building, Robert Warren Drive, Murdoch, Perth, Western Australia 6150,
Australia
- Institute of Global Health Innovation,
Imperial College London, Level 1, Faculty Building South
Kensington Campus, London SW7 2NA, U.K.
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23
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Basu MK, Massicano F, Yu L, Halkidis K, Pillai V, Cao W, Zheng L, Zheng XL. Exome Sequencing Identifies Abnormalities in Glycosylation and ANKRD36C in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura. Thromb Haemost 2020; 121:506-517. [PMID: 33184803 DOI: 10.1055/s-0040-1719030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). However, the mechanism underlying anti-ADAMTS13 autoantibody formation is not known, nor it is known how genetic aberrations contribute to the pathogenesis of iTTP. METHODS Here we performed whole exome sequencing (WES) of DNA samples from 40 adult patients with iTTP and 15 local healthy subjects with no history of iTTP and other hematological disorders. RESULTS WES revealed variations in the genes involved in protein glycosylation, including O-linked glycosylation, to be a major pathway affected in patients with iTTP. Moreover, variations in the ANKRD gene family, particularly ANKRD36C and its paralogs, were also more prevalent in patients with iTTP than in the healthy controls. The ANKRD36 family of proteins have been implicated in inflammation. Mass spectrometry revealed a dramatic alternation in plasma glycoprotein profile in patients with iTTP compared with the healthy controls. CONCLUSION Altered glycosylation may affect the disease onset and progression in various ways: it may predispose patients to produce ADAMTS13 autoantibodies or affect their binding properties; it may also alter clearance kinetics of hemostatic and inflammatory proteins. Together, our findings provide novel insights into plausible mechanisms underlying the pathogenesis of iTTP.
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Affiliation(s)
- Malay Kumar Basu
- Division of Genomic Diagnostics and Bioinformatics, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Felipe Massicano
- Division of Genomic Diagnostics and Bioinformatics, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Lijia Yu
- Division of Genomic Diagnostics and Bioinformatics, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Konstantine Halkidis
- Division of Hematology/Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States
| | - Vikram Pillai
- Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Wenjing Cao
- Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Liang Zheng
- Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States
| | - X Long Zheng
- Department of Pathology & Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, United States
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24
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Bakke FK, Monte MM, Stead DA, Causey DR, Douglas A, Macqueen DJ, Dooley H. Plasma Proteome Responses in Salmonid Fish Following Immunization. Front Immunol 2020; 11:581070. [PMID: 33133099 PMCID: PMC7579410 DOI: 10.3389/fimmu.2020.581070] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/21/2020] [Indexed: 12/18/2022] Open
Abstract
Vaccination plays a critical role in the protection of humans and other animals from infectious diseases. However, the same vaccine often confers different protection levels among individuals due to variation in genetics and/or immunological histories. While this represents a well-recognized issue in humans, it has received little attention in fish. Here we address this knowledge gap in a proteomic study of rainbow trout (Oncorhynchus mykiss, Walbaum), using non-lethal repeated blood sampling to establish the plasma protein response of individual fish following immunization. Six trout were immunized with adjuvanted hen egg-white lysozyme (HEL) and peripheral blood sampled at ten time points from day 0 to day 84 post-injection. We confirm that an antigen-specific antibody response to HEL was raised, showing differences in timing and magnitude among individuals. Using label-free liquid chromatography-mass spectrometry, we quantified the abundance of 278 plasma proteins across the timecourse. As part of the analysis, we show that this approach can distinguish many (but not all) duplicated plasma proteins encoded by paralogous genes retained from the salmonid-specific whole genome duplication event. Global variation in the plasma proteome was predominantly explained by individual differences among fish. However, sampling day explained a major component of variation in abundance for a statistically defined subset of 41 proteins, representing 15% of those detected. These proteins clustered into five groups showing distinct temporal responses to HEL immunization at the population level, and include classical immune (e.g. complement system members) and acute phase molecules (e.g. apolipoproteins, haptoglobins), several enzymes and other proteins supporting the immune response, in addition to evolutionarily conserved molecules that are as yet uncharacterized. Overall, this study improves our understanding of the fish plasma proteome, provides valuable marker proteins for different phases of the immune response, and has implications for vaccine development and the design of immune challenge experiments.
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Affiliation(s)
- Fiona K Bakke
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Milena M Monte
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - David A Stead
- Aberdeen Proteomics, The Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom
| | - Dwight R Causey
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Alex Douglas
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Daniel J Macqueen
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom
| | - Helen Dooley
- Department of Microbiology and Immunology, Institute of Marine and Environmental Technology (IMET), University of Maryland School of Medicine, Baltimore, MD, United States
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25
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Ahn SS, Yoon T, Song JJ, Park YB, Lee SW. Lipid Profiles in Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis: A Cross-sectional Analysis. JOURNAL OF RHEUMATIC DISEASES 2020. [DOI: 10.4078/jrd.2020.27.4.261] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Sung Soo Ahn
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Taejun Yoon
- Department of Medical Science, BK21 Plus Project, Yonsei University College of Medicine, Seoul, Korea
| | - Jason Jungsik Song
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Yong-Beom Park
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Sang-Won Lee
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
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26
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Hariyanto TI, Kurniawan A. Dyslipidemia is associated with severe coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndr 2020; 14:1463-1465. [PMID: 32771919 PMCID: PMC7395301 DOI: 10.1016/j.dsx.2020.07.054] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND AIMS The number of positive and death cases from coronavirus disease 2019 (COVID-19) is still increasing. The identification of risk factors for severe outcomes is important. Dyslipidemia has been shown as a long-known risk factor for cardiovascular disease. The aim of this study is to analyze the potential association between dyslipidemia and the severity of COVID-19 infection. METHODS We systematically searched the PubMed database using specific keywords related to our aims until July 9th, 2020. All articles published on COVID-19 and dyslipidemia were retrieved. Statistical analysis was done using Review Manager 5.4 software. RESULTS A total of 7 studies with a total of 6922 patients were included in our analysis. Our meta-analysis showed that dyslipidemia is associated with severe COVID-19 infections [RR 1.39 (95% CI 1.03-1.87), p = 0.03, I2 = 57%, random-effect modelling]. CONCLUSION Dyslipidemia increases the risk of the development of severe outcomes from COVID-19 infections. Patients with dyslipidemia should be monitored closely to minimize the risk of COVID-19.
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Affiliation(s)
- Timotius Ivan Hariyanto
- Faculty of Medicine, Pelita Harapan University, Boulevard Jendral Sudirman Street, Karawaci, Tangerang, 15811, Indonesia
| | - Andree Kurniawan
- Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Boulevard Jendral Sudirman Street, Karawaci, Tangerang, 15811, Indonesia.
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27
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Sugahara G, Ishida Y, Sun J, Tateno C, Saito T. Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice. Semin Liver Dis 2020; 40:189-212. [PMID: 32074631 PMCID: PMC8629128 DOI: 10.1055/s-0040-1701444] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Hence, it has been increasingly employed for a variety of applications including, but not limited to, the investigation of drug metabolism and pharmacokinetics and stem cell biology. To date, more than a dozen distinctive HLCM systems have been established, and each model system has similarities as well as unique characteristics, which are often perplexing for end-users. Thus, this review aims to summarize the history, evolution, advantages, and pitfalls of each model system with the goal of providing comprehensive information that is necessary for researchers to implement the ideal HLCM system for their purposes. Furthermore, this review article summarizes the contribution of HLCM and its derivatives to our mechanistic understanding of various human liver diseases, its potential for novel applications, and its current limitations.
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Affiliation(s)
- Go Sugahara
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California,Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan
| | - Yuji Ishida
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California,Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan
| | - Jeffrey Sun
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Chise Tateno
- Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan
| | - Takeshi Saito
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California,USC Research Center for Liver Diseases, Los Angeles, California
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28
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Parra S, Heras M, Herrero P, Amigó N, Garcés E, Girona J, Correig X, Canela N, Castro A. Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c. Rheumatology (Oxford) 2020; 59:650-661. [PMID: 31504936 DOI: 10.1093/rheumatology/kez293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 05/28/2019] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVES To identify potential biomarkers of disease activity analysing the proteome of high-density lipoprotein (HDL) particles from SLE patients in clinical remission and when they develop a flare compared with a healthy control group. METHODS Quantitative proteomic analyses of purified HDL were performed using Tandem Mass Tag isobaric tag-labelling and nanoLC-Orbitrap (nLC-MS/MS) from nine SLE patients in clinical remission when they developed a flare and from nine healthy controls (9-9-9). We verified the identified proteins by Western blot and ELISA in a cohort of 104 SLE women patients, 46 healthy women and 14 SLE patients when a flare developed. RESULTS We found 17 proteins with a significant fold-change (>1.1) compared with the control group. In lupus patients experiencing a flare compared with those in remission, we identified four proteins with a significant fold-change (C4, Indian Hedgehog protein, S100A8 and gelsolin). Plasma gelsolin (pGSN) levels were decreased in the 104 SLE patients (176.02(74.9) mcg/l) compared with the control group (217.13(86.7) mcg/l); P=0.005 and when they developed a clinical flare (104.84(41.7) mcg/l); P=0.002). pGSN levels were associated with HDL cholesterol levels (r = 0.316, P<0.001). Antimalarial treated patients showed significant higher levels of pGSN (214.56(88.94) mcg/l regarding 170.35(66.36) mcg/l); P = 0.017. CONCLUSION Decreased pGSN are associated with clinical disease activity in SLE patients. Antimalarial treatment and HDL cholesterol are associated with higher levels of pGSN.
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Affiliation(s)
- Sandra Parra
- Autoimmune Diseases Unit, Internal Medicine Department, 'Sant Joan' University Hospital (Reus, Spain), Spain.,Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), Reus, Spain
| | - Mercedes Heras
- Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), Reus, Spain.,Unitat de Recerca de Lipids i Arteriosclerosis (URLA), 'Sant Joan' University Hospital (Reus-Spain), Spain
| | - Pol Herrero
- Centre for Omic Science, Joint Unit Universitat Rovira i Virgili-Eurecat, Spain
| | - Nuria Amigó
- Department of Electronic Engineering, Universitat Rovira i Virgili (URV), Reus, Spain, Rovira i Virgili University, IISPV, Spain
| | - Esperanza Garcés
- Autoimmune Diseases Unit, Internal Medicine Department, 'Sant Joan' University Hospital (Reus, Spain), Spain
| | - Josefa Girona
- Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), Reus, Spain.,Unitat de Recerca de Lipids i Arteriosclerosis (URLA), 'Sant Joan' University Hospital (Reus-Spain), Spain
| | - Xavier Correig
- Department of Electronic Engineering, Universitat Rovira i Virgili (URV), Reus, Spain, Rovira i Virgili University, IISPV, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Nuria Canela
- Centre for Omic Science, Joint Unit Universitat Rovira i Virgili-Eurecat, Spain
| | - Antoni Castro
- Autoimmune Diseases Unit, Internal Medicine Department, 'Sant Joan' University Hospital (Reus, Spain), Spain.,Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), Reus, Spain
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Copenhaver MM, Yu CY, Zhou D, Hoffman RP. Relationships of complement components C3 and C4 and their genetics to cardiometabolic risk in healthy, non-Hispanic white adolescents. Pediatr Res 2020; 87:88-94. [PMID: 31404919 PMCID: PMC6962538 DOI: 10.1038/s41390-019-0534-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 07/18/2019] [Accepted: 07/25/2019] [Indexed: 12/01/2022]
Abstract
BACKGROUND Complement promotes inflammatory and immune responses and may affect cardiometabolic risk. This study was designed to investigate the effect of complement components C3 and C4 on cardiometabolic risk in healthy non-Hispanic white adolescents. METHODS Body mass index (BMI), BMI percentile, waist circumference, and percent body fat were assessed in 75 adolescents. Arterial stiffness was assessed using arterial tomography and endothelial function using reactive hyperemia. Fasting lipids, inflammatory markers, and complement levels were measured and oral glucose tolerance test was performed. A single C3 polymorphism and C4 gene copy number variations were assessed. RESULTS C3 plasma levels increased with measures of obesity. Endothelial function worsened with increased C3 and C4 levels. Triglycerides and low-density lipoprotein increased and high-density lipoprotein (HDL) and insulin sensitivity decreased with increasing C3 levels, but the relationships were lost when body habitus was included in the model. C4 negatively related to HDL and positively to inflammatory markers. Subjects with at least one C3F allele had increased BMI and fat mass index. HDL was significantly related to C4L, C4S, C4A, and C4B gene copy number variation. CONCLUSIONS C3 levels increase with increasing body mass and increased C4 levels and copy number are associated with increased cardiometabolic risk in healthy adolescents.
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Affiliation(s)
- Melanie M Copenhaver
- Department of Pediatrics, Division of Emergency Medicine, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Chack-Yung Yu
- Department of Pediatrics, Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Danlei Zhou
- Department of Pediatrics, Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Robert P Hoffman
- Department of Pediatrics, Division of Endocrinology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.
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Limonta G, Mancia A, Benkhalqui A, Bertolucci C, Abelli L, Fossi MC, Panti C. Microplastics induce transcriptional changes, immune response and behavioral alterations in adult zebrafish. Sci Rep 2019; 9:15775. [PMID: 31673028 PMCID: PMC6823372 DOI: 10.1038/s41598-019-52292-5] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 10/10/2019] [Indexed: 12/03/2022] Open
Abstract
Microplastics have become pervasive environmental pollutants in both freshwater and marine ecosystems. The presence of microplastics have been recorded in the tissues of many wild fish species, and laboratory studies have demonstrated that microplastics can exert adverse health effects. To further investigate the biological mechanisms underlying microplastics toxicity we applied an integrated approach, analyzing the effects of microplastics at transcriptomic, histological and behavioral level. Adult zebrafish have been exposed to two concentrations of high-density polyethylene and polystyrene microplastics for twenty days. Transcriptomic results indicate alterations in the expression of immune system genes and the down-regulation of genes correlated with epithelium integrity and lipid metabolism. The transcriptomic findings are supported by tissue alterations and higher occurrence of neutrophils observed in gills and intestinal epithelium. Even the daily rhythm of activity of zebrafish appears to be affected, although the regular pattern of activity is recovered over time. Considering the transcriptomic and histological findings reported, we hypothesize that the effects on mucosal epithelium integrity and immune response could potentially reduce the organism defense against pathogens, and lead to a different utilization of energy stores.
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Affiliation(s)
- Giacomo Limonta
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, 53100, Italy.
| | - Annalaura Mancia
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 44121, Italy
| | - Assja Benkhalqui
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 44121, Italy
| | - Cristiano Bertolucci
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 44121, Italy
| | - Luigi Abelli
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, 44121, Italy
| | - Maria Cristina Fossi
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, 53100, Italy
| | - Cristina Panti
- Department of Physical, Earth and Environmental Sciences, University of Siena, Siena, 53100, Italy
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Rojo C, Zhang Q, Keleş S. iFunMed: Integrative functional mediation analysis of GWAS and eQTL studies. Genet Epidemiol 2019; 43:742-760. [PMID: 31328826 DOI: 10.1002/gepi.22217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/17/2019] [Accepted: 05/07/2019] [Indexed: 11/08/2022]
Abstract
Genome-wide association studies (GWAS) have successfully identified thousands of genetic variants contributing to disease and other phenotypes. However, significant obstacles hamper our ability to elucidate causal variants, identify genes affected by causal variants, and characterize the mechanisms by which genotypes influence phenotypes. The increasing availability of genome-wide functional annotation data is providing unique opportunities to incorporate prior information into the analysis of GWAS to better understand the impact of variants on disease etiology. Although there have been many advances in incorporating prior information into prioritization of trait-associated variants in GWAS, functional annotation data have played a secondary role in the joint analysis of GWAS and molecular (i.e., expression) quantitative trait loci (eQTL) data in assessing evidence for association. To address this, we develop a novel mediation framework, iFunMed, to integrate GWAS and eQTL data with the utilization of publicly available functional annotation data. iFunMed extends the scope of standard mediation analysis by incorporating information from multiple genetic variants at a time and leveraging variant-level summary statistics. Data-driven computational experiments convey how informative annotations improve single-nucleotide polymorphism (SNP) selection performance while emphasizing robustness of iFunMed to noninformative annotations. Application to Framingham Heart Study data indicates that iFunMed is able to boost detection of SNPs with mediation effects that can be attributed to regulatory mechanisms.
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Affiliation(s)
- Constanza Rojo
- Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin
| | - Qi Zhang
- Department of Statistics, University of Nebraska-Lincoln, Lincoln, Nebraska
| | - Sündüz Keleş
- Department of Statistics, University of Wisconsin-Madison, Madison, Wisconsin.,Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin
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Abstract
The systematic study of nanoparticle-biological interactions requires particles to be reproducibly dispersed in relevant fluids along with further development in the identification of biologically relevant structural details at the materials-biology interface. Here, we develop a biocompatible long-term colloidally stable water dispersion of few-layered graphene nanoflakes in the biological exposure medium in which it will be studied. We also report the study of the orientation and functionality of key proteins of interest in the biolayer (corona) that are believed to mediate most of the early biological interactions. The evidence accumulated shows that graphene nanoflakes are rich in effective apolipoprotein A-I presentation, and we are able to map specific functional epitopes located in the C-terminal portion that are known to mediate the binding of high-density lipoprotein to binding sites in receptors that are abundant in the liver. This could suggest a way of connecting the materials' properties to the biological outcomes.
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Gray DW, Welsh MD, Mansoor F, Doherty S, Chevallier OP, Elliott CT, Mooney MH. DIVA metabolomics: Differentiating vaccination status following viral challenge using metabolomic profiles. PLoS One 2018; 13:e0194488. [PMID: 29621258 PMCID: PMC5886402 DOI: 10.1371/journal.pone.0194488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 03/05/2018] [Indexed: 12/20/2022] Open
Abstract
Bovine Respiratory Disease (BRD) is a major source of economic loss within the agricultural industry. Vaccination against BRD-associated viruses does not offer complete immune protection and vaccine failure animals present potential routes for disease spread. Serological differentiation of infected from vaccinated animals (DIVA) is possible using antigen-deleted vaccines, but during virus outbreaks DIVA responses are masked by wild-type virus preventing accurate serodiagnosis. Previous work by the authors has established the potential for metabolomic profiling to reveal metabolites associated with systemic immune responses to vaccination. The current study builds on this work by demonstrating for the first time the potential to use plasma metabolite profiling to differentiate between vaccinated and non-vaccinated animals following infection-challenge. Male Holstein Friesian calves were intranasally vaccinated (Pfizer RISPOVAL®PI3+RSV) and subsequently challenged with Bovine Parainfluenza Virus type-3 (BPI3V) via nasal inoculation. Metabolomic plasma profiling revealed that viral challenge led to a shift in acquired plasma metabolite profiles from day 2 to 20 p.i., with 26 metabolites identified whose peak intensities were significantly different following viral challenge depending on vaccination status. Elevated levels of biliverdin and bilirubin and decreased 3-indolepropionic acid in non-vaccinated animals at day 6 p.i. may be associated with increased oxidative stress and reactive oxygen scavenging at periods of peak virus titre. During latter stages of infection, increased levels of N-[(3α,5β,12α)-3,12-dihydroxy-7,24-dioxocholan-24-yl]glycine and lysophosphatidycholine and decreased enterolactone in non-vaccinated animals may reflect suppression of innate immune response mechanisms and progression to adaptive immune responses. Levels of hexahydrohippurate were also shown to be significantly elevated in non-vaccinated animals from days 6 to 20 p.i. These findings demonstrate the potential of metabolomic profiling to identify plasma markers that can be employed in disease diagnostic applications to both differentially identify infected non-vaccinated animals during disease outbreaks and provide greater information on the health status of infected animals.
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Affiliation(s)
- Darren W. Gray
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
- * E-mail:
| | - Michael D. Welsh
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Fawad Mansoor
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Simon Doherty
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Olivier P. Chevallier
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
| | - Christopher T. Elliott
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
| | - Mark H. Mooney
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
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Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome. DISEASE MARKERS 2017; 2017:7909407. [PMID: 29259350 PMCID: PMC5702395 DOI: 10.1155/2017/7909407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/29/2017] [Accepted: 09/07/2017] [Indexed: 12/26/2022]
Abstract
Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.
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Jurynczyk M, Probert F, Yeo T, Tackley G, Claridge TDW, Cavey A, Woodhall MR, Arora S, Winkler T, Schiffer E, Vincent A, DeLuca G, Sibson NR, Isabel Leite M, Waters P, Anthony DC, Palace J. Metabolomics reveals distinct, antibody-independent, molecular signatures of MS, AQP4-antibody and MOG-antibody disease. Acta Neuropathol Commun 2017; 5:95. [PMID: 29208041 PMCID: PMC5718082 DOI: 10.1186/s40478-017-0495-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 11/11/2022] Open
Abstract
The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not prognostic and may become undetectable after treatment or during remission. Therefore, there is still a need to discover antibody-independent biomarkers. We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre. Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling. Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases. In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease. In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%. The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease. RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol. Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level. The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis.
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Affiliation(s)
- Maciej Jurynczyk
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
- Department of Neurology, Medical University of Lodz, Lodz, Poland
| | - Fay Probert
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
| | - Tianrong Yeo
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
- Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore
| | - George Tackley
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Tim D W Claridge
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
| | - Ana Cavey
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Mark R Woodhall
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Siddharth Arora
- Mathematical Institute, University of Oxford, Woodstock Rd, Oxford, OX2 6GC, UK
| | | | - Eric Schiffer
- Numares AG, Am Biopark 9, 93053, Regensburg, Germany
| | - Angela Vincent
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Gabriele DeLuca
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Nicola R Sibson
- Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, OX37DQ, Oxford, UK
| | - M Isabel Leite
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Patrick Waters
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK
| | - Daniel C Anthony
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
| | - Jacqueline Palace
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Level 3, West Wing, Headley Way, Oxford, OX3 9DU, UK.
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Prada-Medina CA, Fukutani KF, Pavan Kumar N, Gil-Santana L, Babu S, Lichtenstein F, West K, Sivakumar S, Menon PA, Viswanathan V, Andrade BB, Nakaya HI, Kornfeld H. Systems Immunology of Diabetes-Tuberculosis Comorbidity Reveals Signatures of Disease Complications. Sci Rep 2017; 7:1999. [PMID: 28515464 PMCID: PMC5435727 DOI: 10.1038/s41598-017-01767-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 04/10/2017] [Indexed: 12/13/2022] Open
Abstract
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM. Neutrophil count correlated with the molecular degree of perturbation, especially in TBDM patients. Body mass index and HDL cholesterol were negatively correlated with molecular degree of perturbation. Diabetic complication pathways including several pathways linked to epigenetic reprogramming were activated in TBDM above levels observed with DM alone. Our data provide a rationale for trials of host-directed therapies in TBDM, targeting neutrophilic inflammation and diabetic complication pathways to address the greater morbidity and mortality associated with this increasingly prevalent dual burden of communicable and non-communicable diseases.
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Affiliation(s)
- Cesar A Prada-Medina
- Department of Pathophysiology and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, 05508, São Paulo, Brazil
| | - Kiyoshi F Fukutani
- Laboratório de Imunoparasitologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil
| | - Nathella Pavan Kumar
- National Institutes of Health- NIRT - International Center for Excellence in Research, Chennai, India
| | - Leonardo Gil-Santana
- Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research, Instituto Brasileiro para a Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil
- Curso de Medicina, Faculdade de Tecnologia e Ciências, Salvador, Brazil
| | - Subash Babu
- National Institutes of Health- NIRT - International Center for Excellence in Research, Chennai, India
| | - Flávio Lichtenstein
- Department of Pathophysiology and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, 05508, São Paulo, Brazil
| | - Kim West
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | | | - Pradeep A Menon
- National Institute for Research in Tuberculosis, Chennai, India
| | | | - Bruno B Andrade
- Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil
- Multinational Organization Network Sponsoring Translational and Epidemiological Research, Instituto Brasileiro para a Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil
- Curso de Medicina, Faculdade de Tecnologia e Ciências, Salvador, Brazil
- Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, USA
| | - Helder I Nakaya
- Department of Pathophysiology and Toxicology, School of Pharmaceutical Sciences, University of São Paulo, 05508, São Paulo, Brazil.
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
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Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection. AIDS 2016; 30:2625-2633. [PMID: 27603288 DOI: 10.1097/qad.0000000000001238] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The pathogenesis of immune dysfunction in chronic HIV-1 infection is unclear, and a potential role for oxidized lipids has been suggested. We hypothesize that both oxidized HDL and LDL (HDLox and LDLox) contribute to HIV-1-related immune dysfunction. STUDY In the AIDS Clinical Trials Group A5260, 234 HIV-infected antiretroviral therapy (ART)-naive participants were randomized to receive tenofovir-emtricitabine and protease inhibitors or raltegravir and had HIV-1 RNA less than 50 copies/ml by week 24 and thereafter. METHODS Associations between biomarkers of inflammation (IL-6, high-sensitivity C-reactive protein and D-dimer), immune activation (sCD163, sCD14, soluble IL-2 receptor, CD38 and HLA-DR), inflammatory monocytes (CD14CD16), T-cell senescence (CD28 and CD57) and exhaustion (PD1), and HDLox, LDLox were assessed at entry and after ART (week 96) with Spearman (partial) correlations. RESULTS HDLox declined and LDLox increased over 96 weeks of ART. Positive associations were observed at baseline and over time between HDLox (but not consistently for LDLox) and most markers of inflammation and immune activation (but not senescence/exhaustion), even after adjustment for multiple comparisons, demographics, entry CD4 cell count and HIV-1 RNA. HDLox was positively associated with IL-6 (r = 0.19 - 0.29, P < 0.01) and sCD163 (r = 0.14 - 0.41, P ≤ 0.04) at all time points. CONCLUSION These prospective longitudinal data suggest that oxidized lipoproteins may contribute to persistent immune activation on ART.
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Saballs M, Parra S, Sahun P, Pellejà J, Feliu M, Vasco C, Gumà J, Borràs JL, Masana L, Castro A. HDL-c levels predict the presence of pleural effusion and the clinical outcome of community-acquired pneumonia. SPRINGERPLUS 2016; 5:1491. [PMID: 27652064 PMCID: PMC5011465 DOI: 10.1186/s40064-016-3145-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/24/2016] [Indexed: 01/02/2023]
Abstract
Objectives To investigate if HDL cholesterol (HDL-c) could be a biomarker of the degree of severity according to prognostic prediction scores in community-acquired pneumonia (CAP) or the development of clinical complications such as pleural effusion. Methods We included in a retrospective study 107 patients admitted to the hospital that fulfilled diagnostic criteria for CAP between the 30th October 2011 and 1st September 2012. HDL-c levels at admission, CAP prognosis scores (PSI and CURB65) and clinical outcomes were recorded for the study. Results Basal HDL-c levels were not statistically different according to prognostics scores neither PSI nor CURB-65. Significantly lower levels of HDL-c were also associated to the development of septic shock and admission to the intensive care unit. HDL-c were inversely correlated with acute phase reactants CRP (r = −0.585, P < 0.001), ESR (r = −0.477, P < 0.001), and leukocytes cell count (r = −0.254, P < 0.009). Patients with pleural effusion showed significant lower levels of HDL-c [28.9 (15.5) mg/dl vs. 44.6 (21.1) mg/dl]; P = 0.007. HDL-c is a good predictor of the presence of pleural effusion in multivariate analyses and using ROC analyses [AUC = 0.712 (0.591–0.834), P = 0.006]. HDL-c levels of 10 mg/dl showed a sensitivity of 97.6 % and a specificity of 82.4 % for the presence of pleural effusion. Conclusion Monitoring HDL-c in CAP is an useful serum marker of acute phase response, clinical outcome and the presence of pleural effusion.
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Affiliation(s)
- M Saballs
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain ; Oncology Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - S Parra
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
| | - P Sahun
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
| | - J Pellejà
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
| | - M Feliu
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
| | - C Vasco
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
| | - J Gumà
- Oncology Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - J L Borràs
- Oncology Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Reus, Spain
| | - L Masana
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain ; URLA, CIBERDEM, "Sant Joan" University Hospital (Reus-Spain), IISPV, Universitat Rovira i Virgili, Reus, Spain ; Unitat de Medicina Vascular i Metabolisme (UVASMET), Unitat de Recerca de Lipids i Arteriosclerosis (URLA), "Sant Joan" University Hospital (Reus-Spain), Internal Medicine, IISPV, Universitat Rovira i Virgili, Reus, Spain
| | - A Castro
- Internal Medicine Department, "Sant Joan" University Hospital (Reus-Spain), Institut Investigació Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Av/Josep Laporte, 1, 43206 Reus, Spain
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Uslu AU, Aydin B, Icagasıoğlu IS, Balta S, Deveci K, Alkan F, Yıldız G, Sahin A. The Relationship Among the Level of Serum Amyloid A, High-Density Lipoprotein and Microalbuminuria in Patients With Familial Mediterranean Fever. J Clin Lab Anal 2016; 30:1003-1008. [PMID: 27094695 DOI: 10.1002/jcla.21971] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/14/2016] [Accepted: 02/27/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Serum amyloid A (SAA), which is produced in the liver, acts as an apoprotein of high-density lipoprotein (HDL) accumulation in extracellular matrix of tissues and organs. SAA elevations play a significant role in the development of amyloidosis. Microalbuminuria (MAU) is the early period of amyloidosis in patients with familial Mediterranean fever (FMF). We assessed the association between SAA as an important factor for the development of amyloidosis in patients with FMF and cytokines, HDL, and MAU. METHODS A total of 40 FMF patients diagnosed with Tel-Hashomer criteria and making regular follow-up visits at the tertiary referral center from 2012 to 2013 were included in this study, besides 40 age- and sex-matched individuals as controls. RESULTS Compared with controls, FMF patients had higher SAA (25.20 ± 45.78 vs. 1.68 ± 0.63 ng/ml; P = 0.002). Also, FMF patients had higher MAU than controls (23.20 ± 39.86 vs. 9.40 ± 5.32 mg/day; P = 0.036). HDL was significantly lower in the patient group than in controls (39.35 ± 10.45 vs. 47.82 ± 15.31 mg/dl; P = 0.023). Interleukin-1 beta (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) levels were higher in the FMF group than in controls (P < 0.0001, P = 0.009, P = 0.003, respectively). CONCLUSIONS Our results suggest that IL-1, IL-6, TNF-α, SAA, and HDL may serve as markers of subclinical inflammation in FMF patients. Due to increased plasma HDL levels, antiinflammatory and antioxidant effects may elevate in FMF patients.
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Affiliation(s)
- Ali Ugur Uslu
- Department of Internal Medicine, Eskisehir Military Hospital, Eskisehir, Turkey.
| | - Bahattin Aydin
- Department of Internal Medicine, Etimesgut Military Hospital, Ankara, Turkey
| | | | - Sevket Balta
- Department of Cardiology, Gulhane Medical Faculty, Ankara, Turkey
| | - Köksal Deveci
- Department of Internal Medicine, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
| | - Filiz Alkan
- Department of Internal Medicine, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
| | - Gürsel Yıldız
- Department of Nephrology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
| | - Ali Sahin
- Department of Rheumatology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey
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Flote VG, Vettukattil R, Bathen TF, Egeland T, McTiernan A, Frydenberg H, Husøy A, Finstad SE, Lømo J, Garred Ø, Schlichting E, Wist EA, Thune I. Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer. Lipids Health Dis 2016; 15:56. [PMID: 26970778 PMCID: PMC4789271 DOI: 10.1186/s12944-016-0225-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/08/2016] [Indexed: 12/25/2022] Open
Abstract
Background High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. Methods Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35–75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. Results The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m2; total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5 %. Most (93 %) of the patients had estrogen receptor (ER) positive tumors (≥1 % ER+), and 82 % had progesterone receptor (PgR) positive tumors (≥10 % PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (β 0.46, CI 0.22–0.69, p < 0.001), HDL cholesterol (β 0.95, CI 0.51–1.39, p < 0.001), HDL free cholesterol (β 2.88, CI 1.28–4.48, p = 0.001), HDL phospholipids (β 0.70, CI 0.36–1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (β -0.25, p = 0.008), and in particular between HDL1’s contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. Conclusion Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies. Electronic supplementary material The online version of this article (doi:10.1186/s12944-016-0225-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Vidar G Flote
- The Cancer Centre, Oslo University Hospital HF, N-0424, Oslo, Norway.
| | - Riyas Vettukattil
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Tone F Bathen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Thore Egeland
- Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, N-1432, Aas, Norway
| | - Anne McTiernan
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hanne Frydenberg
- The Cancer Centre, Oslo University Hospital HF, N-0424, Oslo, Norway
| | - Anders Husøy
- The Cancer Centre, Oslo University Hospital HF, N-0424, Oslo, Norway
| | - Sissi E Finstad
- Norwegian Directorate of Health, PO Box 7000, St. Olavs plass, N-0130, Oslo, Norway
| | - Jon Lømo
- Department of Pathology, Oslo University Hospital, N-0424, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Oslo University Hospital, N-0424, Oslo, Norway
| | - Ellen Schlichting
- Department of Breast and Endocrine Surgery, Oslo University Hospital, N-0424, Oslo, Norway
| | - Erik A Wist
- The Cancer Centre, Oslo University Hospital HF, N-0424, Oslo, Norway
| | - Inger Thune
- The Cancer Centre, Oslo University Hospital HF, N-0424, Oslo, Norway.,Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, N-9037, Tromsø, Norway
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Oberbach A, Adams V, Schlichting N, Heinrich M, Kullnick Y, Lehmann S, Lehmann S, Feder S, Correia JC, Mohr FW, Völker U, Jehmlich N. Proteome profiles of HDL particles of patients with chronic heart failure are associated with immune response and also include bacteria proteins. Clin Chim Acta 2015; 453:114-22. [PMID: 26688386 DOI: 10.1016/j.cca.2015.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 12/02/2015] [Accepted: 12/04/2015] [Indexed: 01/29/2023]
Abstract
Besides modulation of reverse cholesterol transport, high density lipoprotein (HDL) is able to modulate vascular function by stimulating endothelial nitric oxide synthase. Recently, it could be documented that this function of HDL was significantly impaired in patients with chronic heart failure (CHF). We investigated alterations in the HDL proteome in CHF patients. Therefore, HDL was isolated from 5 controls (HDLhealthy) and 5 CHF patients of NYHA-class IIIb (HDLCHF). Proteome analysis of HDL particles was performed by two-dimensional liquid chromatography-mass spectrometry (SCX/RP LC-MS/MS). In total, we identified 494 distinct proteins, of which 107 proteins were commonly found in both groups (HDLCHF and HDLhealthy) indicating a high inter-subject variability across HDL particles. Several important proteins (e.g. ITGA2, APBA1 or A2M) varied in level. Functional analysis revealed regulated pathways. A minor proportion of bacteria-derived proteins were also identified in the HDL-particles. The extension of the list of HDL-associated proteins allows besides their mere description new insights into alterations in HDL function in diseases. In addition, the detection of bacterial proteins bound to HDL will broaden our view of HDL not only as a cholesterol carrier but also as a carrier of proteins.
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Affiliation(s)
- Andreas Oberbach
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany; Division of Diagnostics, Experimental Surgery/CardiOMICs, Fraunhofer-Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Volker Adams
- Department of Cardiology, University of Leipzig, Heart Center Leipzig, Germany
| | - Nadine Schlichting
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany; Department of Pediatric Surgery, University of Leipzig, Germany
| | - Marco Heinrich
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | - Yvonne Kullnick
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | - Stefanie Lehmann
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | - Sven Lehmann
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | - Stefan Feder
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | - Joao Carlos Correia
- Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Germany
| | | | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany; DZHK (German Center for Cardiovascular Research) Partner Site Greifswald, Germany
| | - Nico Jehmlich
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.
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Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics. CHOLESTEROL 2015; 2015:296417. [PMID: 26634153 PMCID: PMC4655037 DOI: 10.1155/2015/296417] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 10/12/2015] [Accepted: 10/12/2015] [Indexed: 02/02/2023]
Abstract
High-Density Lipoprotein-Cholesterol (HDL-C) is regarded as an important protective factor against cardiovascular disease, with abundant evidence of an inverse relationship between its serum levels and risk of cardiovascular disease, as well as various antiatherogenic, antioxidant, and anti-inflammatory properties. Nevertheless, observations of hereditary syndromes featuring scant HDL-C concentration in absence of premature atherosclerotic disease suggest HDL-C levels may not be the best predictor of cardiovascular disease. Indeed, the beneficial effects of HDL may not depend solely on their concentration, but also on their quality. Distinct subfractions of this lipoprotein appear to be constituted by specific protein-lipid conglomerates necessary for different physiologic and pathophysiologic functions. However, in a chronic inflammatory microenvironment, diverse components of the HDL proteome and lipid core suffer alterations, which propel a shift towards a dysfunctional state, where HDL-C becomes proatherogenic, prooxidant, and proinflammatory. This heterogeneity highlights the need for further specialized molecular studies in this aspect, in order to achieve a better understanding of this dysfunctional state; with an emphasis on the potential role for proteomics and lipidomics as valuable methods in the search of novel therapeutic approaches for cardiovascular disease.
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43
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Gutierrez-Achury J, Zorro MM, Ricaño-Ponce I, Zhernakova DV, Diogo D, Raychaudhuri S, Franke L, Trynka G, Wijmenga C, Zhernakova A. Functional implications of disease-specific variants in loci jointly associated with coeliac disease and rheumatoid arthritis. Hum Mol Genet 2015; 25:180-90. [PMID: 26546613 DOI: 10.1093/hmg/ddv455] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 10/27/2015] [Indexed: 02/06/2023] Open
Abstract
Hundreds of genomic loci have been associated with a significant number of immune-mediated diseases, and a large proportion of these associated loci are shared among traits. Both the molecular mechanisms by which these loci confer disease susceptibility and the extent to which shared loci are implicated in a common pathogenesis are unknown. We therefore sought to dissect the functional components at loci shared between two autoimmune diseases: coeliac disease (CeD) and rheumatoid arthritis (RA). We used a cohort of 12 381 CeD cases and 7827 controls, and another cohort of 13 819 RA cases and 12 897 controls, all genotyped with the Immunochip platform. In the joint analysis, we replicated 19 previously identified loci shared by CeD and RA and discovered five new non-HLA loci shared by CeD and RA. Our fine-mapping results indicate that in nine of 24 shared loci the associated variants are distinct in the two diseases. Using cell-type-specific histone markers, we observed that loci which pointed to the same variants in both diseases were enriched for marks of promoters active in CD14+ and CD34+ immune cells (P < 0.001), while loci pointing to distinct variants in one of the two diseases showed enrichment for marks of more specialized cell types, like CD4+ regulatory T cells in CeD (P < 0.0001) compared with Th17 and CD15+ in RA (P = 0.0029).
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Affiliation(s)
- Javier Gutierrez-Achury
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Maria Magdalena Zorro
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Isis Ricaño-Ponce
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Daria V Zhernakova
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Dorothée Diogo
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA and
| | - Soumya Raychaudhuri
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Lude Franke
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Gosia Trynka
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
| | - Cisca Wijmenga
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra Zhernakova
- Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands,
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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45
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Liu L, Zhou L, Li Y, Bai W, Liu N, Li W, Gao Y, Liu Z, Han R. High-density lipoprotein acts as an opsonin to enhance phagocytosis of group A streptococcus by U937 cells. Microbiol Immunol 2015; 59:419-25. [DOI: 10.1111/1348-0421.12270] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 05/20/2015] [Accepted: 06/04/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Ling Liu
- Research Center of Plasma Lipoprotein Immunology
| | - Lulei Zhou
- Research Center of Plasma Lipoprotein Immunology
| | - Yuxin Li
- Research Center of Plasma Lipoprotein Immunology
| | - Wencheng Bai
- Research Center of Plasma Lipoprotein Immunology
- Key Laboratory of Animal Clinic Diagnosis and Treatment (Ministry of Agriculture of China); Inner Mongolia Agricultural University; Huhhot China
| | - Na Liu
- Research Center of Plasma Lipoprotein Immunology
| | - Wenlong Li
- Research Center of Plasma Lipoprotein Immunology
| | - Yumin Gao
- Research Center of Plasma Lipoprotein Immunology
| | - Zhi Liu
- Research Center of Plasma Lipoprotein Immunology
| | - Runlin Han
- Research Center of Plasma Lipoprotein Immunology
- Key Laboratory of Animal Clinic Diagnosis and Treatment (Ministry of Agriculture of China); Inner Mongolia Agricultural University; Huhhot China
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46
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Madi A, Bransburg-Zabary S, Maayan-Metzger A, Dar G, Ben-Jacob E, Cohen IR. Tumor-associated and disease-associated autoantibody repertoires in healthy colostrum and maternal and newborn cord sera. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2015; 194:5272-81. [PMID: 25917091 PMCID: PMC4432729 DOI: 10.4049/jimmunol.1402771] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/31/2015] [Indexed: 02/07/2023]
Abstract
In this work, we studied autoantibody repertoires and Ig isotypes in 71 mothers and their 104 healthy newborns (including twins and triplets delivered term or premature). Newborns receive maternal IgG Abs via the placenta before birth, but developing infants must produce their own IgM and IgA Abs. We used an Ag microarray analysis to detect binding to a selection of 295 self-Ags, compared with 27 standard foreign Ags. The magnitude of binding to specific self-Ags was found to be not less than that to the foreign Ags. As expected, each newborn shared with its mother a similar IgG repertoire-manifest as early as the 24th week of gestation. IgM and IgA autoantibody repertoires in cord sera were highly correlated among the newborns and differed from their mothers' repertoires; the latter differed in sera and milk. The autoantibodies bound to self-Ags known to be associated with tumors and to autoimmune diseases. Thus, autoantibody repertoires in healthy humans--the immunological homunculus--arise congenitally, differ in maternal milk and sera, and mark the potential of the immune system to attack tumors, beneficially, or healthy tissues, harmfully; regulation of the tissue site, the dynamics, and the response phenotype of homuncular autoimmunity very likely affects health.
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Affiliation(s)
- Asaf Madi
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel; Department of Neonatology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 5262100 Ramat Gan, Israel
| | - Sharron Bransburg-Zabary
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel
| | - Ayala Maayan-Metzger
- Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Department of Neonatology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 5262100 Ramat Gan, Israel
| | - Gittit Dar
- School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel
| | - Eshel Ben-Jacob
- School of Physics and Astronomy, Tel Aviv University, 69978 Tel Aviv, Israel; Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; and
| | - Irun R Cohen
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
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47
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Altered lipid subfraction profile and impaired antioxidant defense of high-density lipoprotein in Smith-Lemli-Opitz syndrome. Pediatr Res 2015; 77:703-9. [PMID: 25668223 DOI: 10.1038/pr.2015.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 11/07/2014] [Indexed: 11/09/2022]
Abstract
BACKGROUND Smith-Lemli-Opitz syndrome (SLOS) is a rare disease caused by biallelic mutation in the 7-dehydrocholesterol (7DHC) reductase gene. High oxidizability of 7DHC and the appearance of small-sized low-density lipoprotein (LDL) subfractions indicate increased endogenous oxidative stress that is counterbalanced by natural antioxidant defense mechanisms including the high-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) enzyme. PON1 prevents lipoproteins from oxidative modifications; however, PON1 activity and the distribution of lipoprotein subfractions have not been studied in SLOS. METHODS 7DHC levels and PON1 arylesterase activities were measured spectrophotometrically in 11 SLOS patients and 10 healthy children. Lipoprotein subfractions were detected by polyacrylamide gel electrophoresis. RESULTS Compared to controls, there was a shift towards the small-dense LDL subfraction and the large HDL subfraction in SLOS. PON1 arylesterase activity was significantly decreased in SLOS patients and correlated negatively with the proportion of small-dense LDL subfraction and the proportion of large HDL subfraction. Significant positive correlations were detected between PON1 arylesterase activity and the ratios of intermediate and small HDL subfractions. CONCLUSIONS Decreased PON1 activity and the deleterious shift in the distribution of lipoprotein subfractions may contribute to the impaired antioxidant status observed in SLOS. Monitoring of serum PON1 arylesterase activity may be a complementary biomarker in SLOS.
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48
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Flote VG, Frydenberg H, Ursin G, Iversen A, Fagerland MW, Ellison PT, Wist EA, Egeland T, Wilsgaard T, McTiernan A, Furberg AS, Thune I. High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women. Cancer Prev Res (Phila) 2015; 8:535-44. [PMID: 25804612 DOI: 10.1158/1940-6207.capr-14-0267] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 03/18/2015] [Indexed: 11/16/2022]
Abstract
High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17β-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17β-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies.
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Affiliation(s)
- Vidar G Flote
- The Cancer Centre, Oslo University Hospital, Oslo, Norway.
| | | | - Giske Ursin
- Cancer Registry of Norway, Majorstuen, Oslo, Norway
| | - Anita Iversen
- Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Morten W Fagerland
- Unit of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | - Peter T Ellison
- Department of Anthropology, Harvard University, Cambridge, Massachusetts
| | - Erik A Wist
- The Cancer Centre, Oslo University Hospital, Oslo, Norway
| | - Thore Egeland
- Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Aas, Norway
| | - Tom Wilsgaard
- Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Anne McTiernan
- Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, Washington
| | - Anne-Sofie Furberg
- Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Inger Thune
- The Cancer Centre, Oslo University Hospital, Oslo, Norway. Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø, Norway
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Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals. J Immunol Res 2015; 2015:762506. [PMID: 25759848 PMCID: PMC4352479 DOI: 10.1155/2015/762506] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 02/08/2015] [Indexed: 12/22/2022] Open
Abstract
Statins have been shown to modulate the number and the suppressive function of CD4+FOXP3+ T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating
Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4+ T cells.
We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values;
however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67
expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c),
suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects.
Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.
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50
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Karlsson H, Kontush A, James RW. Functionality of HDL: antioxidation and detoxifying effects. Handb Exp Pharmacol 2015; 224:207-228. [PMID: 25522989 DOI: 10.1007/978-3-319-09665-0_5] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
High-density lipoproteins (HDL) are complexes of multiple talents, some of which have only recently been recognised but all of which are under active investigation. Clinical interest initially arose from their amply demonstrated role in atherosclerotic disease with their consequent designation as a major cardiovascular disease (CVD) risk factor. However, interest is no longer confined to vascular tissues, with the reports of impacts of the lipoprotein on pancreatic, renal and nervous tissues, amongst other possible targets. The ever-widening scope of HDL talents also encompasses environmental hazards, including infectious agents and environmental toxins. In almost all cases, HDL would appear to have a beneficial impact on health. It raises the intriguing question of whether these various talents emanate from a basic ancestral function to protect the cell.The following chapter will illustrate and review our current understanding of some of the functions attributed to HDL. The first section will look at the antioxidative functions of HDL and possible mechanisms that are involved. The second section will focus specifically on paraoxonase-1 (PON1), which appears to bridge the divide between the two HDL functions discussed herein. This will lead into the final section dealing with HDL as a detoxifying agent protecting against exposure to environmental pathogens and other toxins.
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Affiliation(s)
- Helen Karlsson
- Occupational and Environmental Medicine, Heart Medical Centre, County Council of Ostergotland, Linkoping University, SE-58185, Linkoping, Sweden,
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