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Birner C, Mester P, Liebisch G, Höring M, Schmid S, Müller M, Pavel V, Buechler C. Lipid Metabolism Disorders as Diagnostic Biosignatures in Sepsis. Infect Dis Rep 2024; 16:806-819. [PMID: 39311203 PMCID: PMC11417812 DOI: 10.3390/idr16050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/26/2024] Open
Abstract
Critical illness causes disturbances in lipid metabolism. Here, we investigated the levels of apolipoprotein A-IV (apoA-IV), a regulator of triglyceride and cholesterol metabolism, in human sepsis. ApoA-IV (analyzed in 156 patients with systemic inflammatory response syndrome (SIRS)/sepsis) and cholesteryl ester (CE) (analyzed in 121 of these patients) were lower in patients compared to 43 healthy controls. In contrast, triglyceride (TG) levels were elevated in patients. ApoA-IV levels in plasma of the patients did not correlate with these lipids. Patients with SIRS, sepsis or septic shock had comparable apoA-IV, TG, CE and free cholesterol (FC) levels. Patients on dialysis had significantly lower CE levels, whereas apoA-IV levels did not change much. CE levels were elevated in patients with viral sepsis due to SARS-CoV-2 infection in comparison to SIRS/sepsis patients not infected by this virus. CE levels correlated negatively with procalcitonin, interleukin-6 and bilirubin, while TGs were positively associated with bilirubin and C-reactive protein. ApoA-IV, TG, CE and FC levels were not associated with bacterial infection or survival. In conclusion, this analysis suggests that CE levels decline in sepsis-related renal failure and also shows that plasma apoA-IV and CE levels are early biomarkers of sepsis.
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Affiliation(s)
- Charlotte Birner
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
| | - Patricia Mester
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93053 Regensburg, Germany; (G.L.); (M.H.)
| | - Marcus Höring
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, 93053 Regensburg, Germany; (G.L.); (M.H.)
| | - Stephan Schmid
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
| | - Martina Müller
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
| | - Vlad Pavel
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
| | - Christa Buechler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany; (C.B.); (P.M.); (S.S.); (M.M.); (V.P.)
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Santana MDFM, Sawada MIBAC, Junior DRS, Giacaglia MB, Reis M, Xavier J, Côrrea-Giannella ML, Soriano FG, Gebrim LH, Ronsein GE, Passarelli M. Proteomic Profiling of HDL in Newly Diagnosed Breast Cancer Based on Tumor Molecular Classification and Clinical Stage of Disease. Cells 2024; 13:1327. [PMID: 39195217 PMCID: PMC11352958 DOI: 10.3390/cells13161327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.
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Affiliation(s)
- Monique de Fatima Mello Santana
- Laboratório de Lípides (LIM10), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil
| | - Maria Isabela Bloise Alves Caldas Sawada
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil; (M.I.B.A.C.S.); (M.R.)
- Grupo de Saúde de Curitiba (GSAU-CT), CINDACTA II, Brazilian Air Force, Curitiba 82510-901, Brazil
| | - Douglas Ricardo Souza Junior
- Laboratório de Proteômica Aplicada à Processos Inflamatórios, Instituto de Química, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil (G.E.R.)
| | - Marcia Benacchio Giacaglia
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil; (M.I.B.A.C.S.); (M.R.)
| | - Mozania Reis
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil; (M.I.B.A.C.S.); (M.R.)
- Unidade Básica de Saúde Dra. Ilza Weltman Hutzler, Sao Paulo 02472-180, Brazil
| | - Jacira Xavier
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil; (M.I.B.A.C.S.); (M.R.)
- Unidade Básica de Saúde Dra. Ilza Weltman Hutzler, Sao Paulo 02472-180, Brazil
| | - Maria Lucia Côrrea-Giannella
- Laboratório de Carboidratos e Radioimunoensaio (LIM18), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil;
| | - Francisco Garcia Soriano
- Laboratório de Emergências Clínicas (LIM51), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil
| | - Luiz Henrique Gebrim
- Centro de Referência da Saúde, Mulher-Hospital Pérola Byington, Sao Paulo 01215-000, Brazil
| | - Graziella Eliza Ronsein
- Laboratório de Proteômica Aplicada à Processos Inflamatórios, Instituto de Química, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil (G.E.R.)
| | - Marisa Passarelli
- Laboratório de Lípides (LIM10), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil
- Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, Sao Paulo 01525-000, Brazil; (M.I.B.A.C.S.); (M.R.)
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Kollerits B, Gruber S, Steinbrenner I, Schwaiger JP, Weissensteiner H, Schönherr S, Forer L, Kotsis F, Schultheiss UT, Meiselbach H, Wanner C, Eckardt KU, Kronenberg F. Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study. BMC Cancer 2024; 24:320. [PMID: 38454416 PMCID: PMC10921727 DOI: 10.1186/s12885-024-12053-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 02/26/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case-control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study. METHODS These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30-60 mL/min/1.73m2 or an eGFR > 60 mL/min/1.73m2 in the presence of overt proteinuria. RESULTS Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFRcreatinine). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57-0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44-0.88, P = 0.007). CONCLUSIONS Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD.
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Affiliation(s)
- Barbara Kollerits
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Simon Gruber
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Inga Steinbrenner
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Johannes P Schwaiger
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Hansi Weissensteiner
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Sebastian Schönherr
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Lukas Forer
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria
| | - Fruzsina Kotsis
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Ulla T Schultheiss
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Heike Meiselbach
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- German Chronic Kidney Disease Study, Erlangen, Germany
| | - Christoph Wanner
- Division of Nephrology, Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- German Chronic Kidney Disease Study, Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, Innsbruck, 6020, Austria.
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Nyangahu DD, Happel AU, Wendoh J, Kiravu A, Wang Y, Feng C, Plumlee C, Cohen S, Brown BP, Djukovic D, Ganief T, Gasper M, Raftery D, Blackburn JM, Allbritton NL, Gray CM, Paik J, Urdahl KB, Jaspan HB. Bifidobacterium infantis associates with T cell immunity in human infants and is sufficient to enhance antigen-specific T cells in mice. SCIENCE ADVANCES 2023; 9:eade1370. [PMID: 38064556 PMCID: PMC10708209 DOI: 10.1126/sciadv.ade1370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 11/09/2023] [Indexed: 12/18/2023]
Abstract
Bacille Calmette-Guerin (BCG) vaccine can elicit good TH1 responses in neonates. We hypothesized that the pioneer gut microbiota affects vaccine T cell responses. Infants who are HIV exposed but uninfected (iHEU) display an altered immunity to vaccination. BCG-specific immune responses were analyzed at 7 weeks of age in iHEU, and responses were categorized as high or low. Bifidobacterium longum subsp. infantis was enriched in the stools of high responders, while Bacteroides thetaiotaomicron was enriched in low responders at time of BCG vaccination. Neonatal germ-free or SPF mice orally gavaged with live B. infantis exhibited significantly higher BCG-specific T cells compared with pups gavaged with B. thetaiotaomicron. B. infantis and B. thetaiotaomicron differentially affected stool metabolome and colonic transcriptome. Human colonic epithelial cells stimulated with B. infantis induced a unique gene expression profile versus B. thetaiotaomicron. We thus identified a causal role of B. infantis in early-life antigen-specific immunity.
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Affiliation(s)
- Donald D. Nyangahu
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Anna-Ursula Happel
- Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Division of Immunology, University of Cape Town, Cape Town, South Africa
| | - Jerome Wendoh
- Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Division of Immunology, University of Cape Town, Cape Town, South Africa
| | - Agano Kiravu
- Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Division of Immunology, University of Cape Town, Cape Town, South Africa
| | - Yuli Wang
- Department of Bioengineering, University of Washington, Seattle, WA, USA
| | - Colin Feng
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Courtney Plumlee
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Sara Cohen
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Bryan P. Brown
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Danijel Djukovic
- Northwest Metabolomics Research Center, University of Washington, Seattle, WA, USA
| | - Tariq Ganief
- Institute of Infectious Diseases and Molecular Medicine, Department of Integrative Biomedical Sciences, Division of Chemical and Systems Biology, University of Cape Town, Cape Town, South Africa
| | - Melanie Gasper
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
| | - Daniel Raftery
- Northwest Metabolomics Research Center, University of Washington, Seattle, WA, USA
| | - Jonathan M. Blackburn
- Institute of Infectious Diseases and Molecular Medicine, Department of Integrative Biomedical Sciences, Division of Chemical and Systems Biology, University of Cape Town, Cape Town, South Africa
| | | | - Clive M. Gray
- Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Division of Immunology, University of Cape Town, Cape Town, South Africa
- Biomedical Research Institute, Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa
| | - Jisun Paik
- Department of Comparative Medicine, University of Washington, Seattle, WA, USA
| | - Kevin B. Urdahl
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
- Department of Pediatrics, School of Medicine, University of Washington, Seattle WA, USA
| | - Heather B. Jaspan
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA
- Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Division of Immunology, University of Cape Town, Cape Town, South Africa
- Department of Pediatrics, School of Medicine, University of Washington, Seattle WA, USA
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5
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Liu J, Chang X, Ding X, He X, Wang J, Wang G. Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes. Diabetol Metab Syndr 2023; 15:251. [PMID: 38044448 PMCID: PMC10694884 DOI: 10.1186/s13098-023-01229-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 11/24/2023] [Indexed: 12/05/2023] Open
Abstract
BACKGROUND Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduced the risk of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D), but the underlying mechanism has not been well elucidated. The circulating levels of proteins and metabolites reflect the overall state of the human body. This study aimed to evaluate the effect of dapagliflozin on the proteome and metabolome in patients with newly diagnosed T2D. METHODS A total of 57 newly diagnosed T2D patients were enrolled, and received 12 weeks of dapagliflozin treatment (10 mg/d, AstraZeneca). Serum proteome and metabolome were investigated at the baseline and after dapagliflozin treatment. RESULTS Dapagliflozin significantly decreased HbA1c, BMI, and HOMA-IR in T2D patients (all p < 0.01). Multivariate models indicated clear separations of proteomics and metabolomics data between the baseline and after dapagliflozin treatment. A total of 38 differentially abundant proteins including 23 increased and 15 decreased proteins, and 35 differentially abundant metabolites including 17 increased and 18 decreased metabolites, were identified. In addition to influencing glucose metabolism (glycolysis/gluconeogenesis and pentose phosphate pathway), dapagliflozin significantly increased sex hormone-binding globulin, transferrin receptor protein 1, disintegrin, and metalloprotease-like decysin-1 and apolipoprotein A-IV levels, and decreased complement C3, fibronectin, afamin, attractin, xanthine, and uric acid levels. CONCLUSIONS The circulating proteome and metabolome in newly diagnosed T2D patients were significantly changed after dapagliflozin treatment. These changes in proteins and metabolites might be associated with the beneficial effect of dapagliflozin on cardiovascular and renal outcomes.
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Affiliation(s)
- Jia Liu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xiaona Chang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xiaoyu Ding
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xueqing He
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Jiaxuan Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China.
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de Azúa-López ZR, Pezzotti MR, González-Díaz Á, Meilhac O, Ureña J, Amaya-Villar R, Castellano A, Varela LM. HDL anti-inflammatory function is impaired and associated with high SAA1 and low APOA4 levels in aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2023; 43:1919-1930. [PMID: 37357772 PMCID: PMC10676137 DOI: 10.1177/0271678x231184806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 05/07/2023] [Accepted: 06/02/2023] [Indexed: 06/27/2023]
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease with high morbidity and mortality rates. Within 24 hours after aSAH, monocytes are recruited and enter the subarachnoid space, where they mature into macrophages, increasing the inflammatory response and contributing, along with other factors, to delayed neurological dysfunction and poor outcomes. High-density lipoproteins (HDL) are lipid-protein complexes that exert anti-inflammatory effects but under pathological conditions undergo structural alterations that have been associated with loss of functionality. Plasma HDL were isolated from patients with aSAH and analyzed for their anti-inflammatory activity and protein composition. HDL isolated from patients lost the ability to prevent VCAM-1 expression in endothelial cells (HUVEC) and subsequent adhesion of THP-1 monocytes to the endothelium. Proteomic analysis showed that HDL particles from patients had an altered composition compared to those of healthy subjects. We confirmed by western blot that low levels of apolipoprotein A4 (APOA4) and high of serum amyloid A1 (SAA1) in HDL were associated with the lack of anti-inflammatory function observed in aSAH. Our results indicate that the study of HDL in the pathophysiology of aSAH is needed, and functional HDL supplementation could be considered a novel therapeutic approach to the treatment of the inflammatory response after aSAH.
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Affiliation(s)
- Zaida Ruiz de Azúa-López
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Unidad de Cuidados Intensivos, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - M Rosa Pezzotti
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - Ángela González-Díaz
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Olivier Meilhac
- Université de La Réunion, INSERM, UMR 1188 Diabète athérothombose Réunion Océan Indien (DéTROI), Saint-Pierre de La Réunion, France
- CHU de La Réunion, Saint-Pierre de la Réunion, France
| | - Juan Ureña
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - Rosario Amaya-Villar
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Unidad de Cuidados Intensivos, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Antonio Castellano
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - Lourdes M Varela
- Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
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7
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Andraski AB, Singh SA, Higashi H, Lee LH, Aikawa M, Sacks FM. The distinct metabolism between large and small HDL indicates unique origins of human apolipoprotein A4. JCI Insight 2023; 8:162481. [PMID: 37092549 DOI: 10.1172/jci.insight.162481] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 03/01/2023] [Indexed: 04/25/2023] Open
Abstract
Apolipoprotein A4's (APOA4's) functions on HDL in humans are not well understood. A unique feature of APOA4 is that it is an intestinal apolipoprotein secreted on HDL and chylomicrons. The goal of this study was to gain a better understanding of the origin and function of APOA4 on HDL by studying its metabolism across 6 HDL sizes. Twelve participants completed a metabolic tracer study. HDL was isolated by APOA1 immunopurification and separated by size. Tracer enrichments for APOA4 and APOA1 were determined by targeted mass spectrometry, and metabolic rates were derived by compartmental modeling. APOA4 metabolism on small HDL (alpha3, prebeta, and very small prebeta) was distinct from that of APOA4 on large HDL (alpha0, 1, 2). APOA4 on small HDL appeared in circulation by 30 minutes and was relatively rapidly catabolized. In contrast, APOA4 on large HDL appeared in circulation later (1-2 hours) and had a much slower catabolism. The unique metabolic profiles of APOA4 on small and large HDL likely indicate that each has a distinct origin and function in humans. This evidence supports the notion that APOA4 on small HDL originates directly from the small intestine while APOA4 on large HDL originates from chylomicron transfer.
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Affiliation(s)
- Allison B Andraski
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Sasha A Singh
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, and
| | - Hideyuki Higashi
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, and
| | - Lang Ho Lee
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, and
| | - Masanori Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, and
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Frank M Sacks
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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8
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Ji J, Zhao X, Huang J, Wu X, Xie F, Li L, Wang T, Mi S. Apolipoprotein A-IV of diabetic-foot patients upregulates tumor necrosis factor α expression in microfluidic arterial models. Exp Biol Med (Maywood) 2023; 248:691-701. [PMID: 36775868 PMCID: PMC10408548 DOI: 10.1177/15353702221147562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/21/2022] [Indexed: 02/14/2023] Open
Abstract
Diabetic peripheral arterial atherosclerosis is one of the important characteristics of diabetic foot syndrome. Apolipoprotein (Apo A-IV) participates in various physiological processes, and animal studies have shown that it has roles of anti-atherosclerosis, prevention of platelet aggregation and thrombosis. Apo A-IV glycosylation is closely related to the occurrence and development of diabetic peripheral atherosclerosis. This study aimed to explore the mechanism of diabetic peripheral arterial lesions caused by glycosylated Apo A-IV. Type 2 diabetes mellitus (T2DM) and T2DM with diabetic foot patients (T2DM-F; n = 45, 30) were enrolled in this study, and individuals without diabetes (n = 35) served as normal controls (NC). In T2DM group, serum Apo A-IV content was higher than those in NC and T2DM-F group, as carboxymethyl lysine (CML) glycosylation of Apo A-IV in mixed serum from T2DM-F group was identified to be more significant than those in two other groups. Within a microfluidic arterial chip model, Apo A-IV from T2DM and T2DM-F group significantly increased transcription and protein levels of tumor necrosis factor alpha (TNF-α) in chip arteries, and CML expression was observed in T2DM-F group, which were associated with increased nuclear receptor subfamily 4 group A member 3 (NR4A3) expression. Recombinant human Apo A-IV could reverse the stimulating effect of serum Apo A-IV from T2DM-F group on TNF-α expression, and NR4A3 blocking peptide downregulated TNF-α expression by inhibiting NR4A3 expression. In the chip arteries, Apo A-IV from T2DM and T2DM-F increased TNF-α expression and turn them into a pre-atherosclerotic state, which might be one of the important mechanisms of glycosylated Apo A-IV to induce diabetic peripheral arterial lesions and eventually lead to diabetic foot.
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Affiliation(s)
- Jun Ji
- Department of Cardiovascular Surgery, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen 518027, China
| | - Xiaoyu Zhao
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055 China
| | - Jiajun Huang
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055 China
| | - Xuanqin Wu
- Department of Cardiovascular Surgery, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen 518027, China
| | - Fang Xie
- Department of Endocrinology, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen 518027, China
| | - Liang Li
- Department of Cardiovascular Surgery, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen 518027, China
| | - Tao Wang
- Department of Cardiovascular Surgery, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen 518027, China
| | - Shengli Mi
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055 China
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9
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Allogenic Adipose-Derived Stem Cells in Diabetic Foot Ulcer Treatment: Clinical Effectiveness, Safety, Survival in the Wound Site, and Proteomic Impact. Int J Mol Sci 2023; 24:ijms24021472. [PMID: 36674989 PMCID: PMC9864558 DOI: 10.3390/ijms24021472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023] Open
Abstract
Although encouraging results of adipose-derived stem cell (ADSC) use in wound healing are available, the mechanism of action has been studied mainly in vitro and in animals. This work aimed to examine the safety and efficacy of allogenic ADSCs in human diabetic foot ulcer treatment, in combination with the analyses of the wound. Equal groups of 23 participants each received fibrin gel with ADSCs or fibrin gel alone. The clinical effects were assessed at four time points: days 7, 14, 21 and 49. Material collected during debridement from a subset of each group was analyzed for the presence of ADSC donor DNA and proteomic changes. The reduction in wound size was greater at all subsequent visits, significantly on day 21 and 49, and the time to 50% reduction in the wound size was significantly shorter in patients who received ADSCs. Complete healing was achieved at the end of the study in seven patients treated with ADSCs vs. one treated without ADSCs. One week after ADSC application, 34 proteins significantly differentiated the material from both groups, seven of which, i.e., GAPDH, CAT, ACTN1, KRT1, KRT9, SCL4A1, and TPI, positively correlated with the healing rate. We detected ADSC donor DNA up to 21 days after administration. We confirmed ADSC-related improvement in wound healing that correlated with the molecular background, which provides insights into the role of ADSCs in wound healing-a step toward the development of cell-based therapies.
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10
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Li WH, Zhang L, Li YY, Wang XY, Li JL, Zhao SN, Ni MQ, Li Q, Sun H. Apolipoprotein A-IV Has Bi-Functional Actions in Alcoholic Hepatitis by Regulating Hepatocyte Injury and Immune Cell Infiltration. Int J Mol Sci 2022; 24:ijms24010670. [PMID: 36614113 PMCID: PMC9820766 DOI: 10.3390/ijms24010670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Alcohol abuse can lead to alcoholic hepatitis (AH), a worldwide public health issue with high morbidity and mortality. Here, we identified apolipoprotein A-IV (APOA4) as a biomarker and potential therapeutic target for AH. APOA4 expression was detected by Gene Expression Omnibus (GEO) databases, Immunohistochemistry, and qRT-PCR in AH. Bioinformatics Methods (protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Set Enrichment Analysis (GSEA) were used to show down-stream gene and pathways of APOA4 in AH. AML-12 cells were used to evaluate the biological function of APOA4 using an ELISA kit (AST, ALT, and IL-1β) and flow cytometry (ROS activity). Both in vivo and in vitro, APOA4 expression was significantly elevated in the AH model induced by alcohol (ETOH). AML-12 cell damage was specifically repaired by APOA4 deficiency, while AST, ALT, and IL-1β activity that was increased by ETOH (200 µmol, 12 h) were suppressed. APOA4 inhibition increased intracellular ROS induced by ETOH, which was detected by flow cytometry. Functional and PPI network analyses showed Fcgamma receptor (FCGR) and platelet activation signaling were potential downstream pathways. We identified CIDEC as a downstream gene of APOA4. The CIDEC AUC values for the ROC curves were 0.861. At the same time, APOA4 silencing downregulated the expression of CIDEC, whereas the knockdown of CIDEC did not influence the expression of APOA4 in AML-12 cells. Collectively, APOA4 regulates CIDEC expression and immune cell infiltration and may hold great potential as a biomarker and therapeutic target for AH.
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Affiliation(s)
- Wan-Hong Li
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Li Zhang
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yue-Ying Li
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Xin-Yue Wang
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jin-Liang Li
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Shu-Ning Zhao
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Ming-Qi Ni
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Qian Li
- Pharmaceutical Analysis and Analytical Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Correspondence: (Q.L.); (H.S.); Tel./Fax: +86-451-86699347 (Q.L.)
| | - Hui Sun
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Correspondence: (Q.L.); (H.S.); Tel./Fax: +86-451-86699347 (Q.L.)
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11
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Vyletelová V, Nováková M, Pašková Ľ. Alterations of HDL's to piHDL's Proteome in Patients with Chronic Inflammatory Diseases, and HDL-Targeted Therapies. Pharmaceuticals (Basel) 2022; 15:1278. [PMID: 36297390 PMCID: PMC9611871 DOI: 10.3390/ph15101278] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/03/2022] [Accepted: 10/14/2022] [Indexed: 09/10/2023] Open
Abstract
Chronic inflammatory diseases, such as rheumatoid arthritis, steatohepatitis, periodontitis, chronic kidney disease, and others are associated with an increased risk of atherosclerotic cardiovascular disease, which persists even after accounting for traditional cardiac risk factors. The common factor linking these diseases to accelerated atherosclerosis is chronic systemic low-grade inflammation triggering changes in lipoprotein structure and metabolism. HDL, an independent marker of cardiovascular risk, is a lipoprotein particle with numerous important anti-atherogenic properties. Besides the essential role in reverse cholesterol transport, HDL possesses antioxidative, anti-inflammatory, antiapoptotic, and antithrombotic properties. Inflammation and inflammation-associated pathologies can cause modifications in HDL's proteome and lipidome, transforming HDL from atheroprotective into a pro-atherosclerotic lipoprotein. Therefore, a simple increase in HDL concentration in patients with inflammatory diseases has not led to the desired anti-atherogenic outcome. In this review, the functions of individual protein components of HDL, rendering them either anti-inflammatory or pro-inflammatory are described in detail. Alterations of HDL proteome (such as replacing atheroprotective proteins by pro-inflammatory proteins, or posttranslational modifications) in patients with chronic inflammatory diseases and their impact on cardiovascular health are discussed. Finally, molecular, and clinical aspects of HDL-targeted therapies, including those used in therapeutical practice, drugs in clinical trials, and experimental drugs are comprehensively summarised.
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Affiliation(s)
| | | | - Ľudmila Pašková
- Department of Cell and Molecular Biology of Drugs, Faculty of Pharmacy, Comenius University, 83232 Bratislava, Slovakia
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12
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Thomas SR, Zhang Y, Rye KA. The pleiotropic effects of high-density lipoproteins and apolipoprotein A-I. Best Pract Res Clin Endocrinol Metab 2022; 37:101689. [PMID: 36008277 DOI: 10.1016/j.beem.2022.101689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The high density lipoprotein (HDL) fraction of human plasma consists of multiple subpopulations of spherical particles that are structurally uniform, but heterogeneous in terms of size, composition and function. Numerous epidemiological studies have established that an elevated high density lipoprotein cholesterol (HDL-C) level is associated with decreased cardiovascular risk. However, with several recent randomised clinical trials of HDL-C raising agents failing to reduce cardiovascular events, contemporary research is transitioning towards clinical development of the cardioprotective functions of HDLs and the identification of functions that can be exploited for treatment of other diseases. This review describes the origins of HDLs and the causes of their compositional and functional heterogeneity. It then summarises current knowledge of how cardioprotective and other functions of HDLs are regulated. The final section of the review summarises recent advances in the clinical development of HDL-targeted therapies.
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Affiliation(s)
- Shane R Thomas
- Cardiometabolic Disease Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
| | - Yunjia Zhang
- Cardiometabolic Disease Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
| | - Kerry-Anne Rye
- Cardiometabolic Disease Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
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13
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Shearston K, Tan JTM, Cochran BJ, Rye KA. Inhibition of Vascular Inflammation by Apolipoprotein A-IV. Front Cardiovasc Med 2022; 9:901408. [PMID: 35845068 PMCID: PMC9279673 DOI: 10.3389/fcvm.2022.901408] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/25/2022] [Indexed: 11/18/2022] Open
Abstract
Background Apolipoprotein (apo) A-IV, the third most abundant apolipoprotein in human high density lipoproteins (HDLs), inhibits intestinal and systemic inflammation. This study asks if apoA-IV also inhibits acute vascular inflammation. Methods Inflammation was induced in New Zealand White rabbits by placing a non-occlusive silastic collar around the common carotid artery. A single 1 mg/kg intravenous infusion of lipid-free apoA-IV or saline (control) was administered to the animals 24 h before collar insertion. The animals were euthanised 24 h post-collar insertion. Human coronary artery cells (HCAECs) were pre-incubated with reconstituted HDLs containing apoA-IV complexed with phosphatidylcholine, (A-IV)rHDLs, then activated by incubation with tumour necrosis factor (TNF)-α. Cell surface vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in the TNF-α-activated HCAECs was quantified by flow cytometry. VCAM-1, ICAM-1 and 3β-hydroxysteroid-Δ24 reductase (DHCR24) mRNA levels were quantified by real time PCR. Results Apolipoprotein ApoA-IV treatment significantly decreased collar-induced endothelial expression of VCAM-1, ICAM-1 and neutrophil infiltration into the arterial intima by 67.6 ± 9.9% (p < 0.01), 75.4 ± 6.9% (p < 0.01) and 74.4 ± 8.5% (p < 0.05), respectively. It also increased endothelial expression of DHCR24 by 2.6-fold (p < 0.05). Pre-incubation of HCAECs with (A-IV)rHDLs prior to stimulation with TNF-α inhibited VCAM-1 and ICAM-1 protein levels by 62.2 ± 12.1% and 33.7 ± 5.7%, respectively. VCAM-1 and ICAM-1 mRNA levels were decreased by 55.8 ± 7.2% and 49.6 ± 7.9%, respectively, while DHCR24 mRNA expression increased by threefold. Transfection of HCAECs with DHCR24 siRNA attenuated the anti-inflammatory effects of (A-IV)rHDLs. Pre-incubation of TNF-α-activated HCAECs with (A-IV)rHDLs also inhibited nuclear translocation of the p65 subunit of nuclear factor-κB (NF-κB), and decreased IκBα phosphorylation. Conclusion These results indicate that apoA-IV inhibits vascular inflammation in vitro and in vivo by inhibiting NF-κB activation in a DHCR24-dependent manner.
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Affiliation(s)
- Kate Shearston
- Lipid Research Group, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Joanne T. M. Tan
- Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Blake J. Cochran
- Lipid Research Group, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Kerry-Anne Rye
- Lipid Research Group, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
- *Correspondence: Kerry-Anne Rye,
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14
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Schwaiger JP, Kollerits B, Steinbrenner I, Weissensteiner H, Schönherr S, Forer L, Kotsis F, Lamina C, Schneider MP, Schultheiss UT, Wanner C, Köttgen A, Eckardt KU, Kronenberg F. Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: Results from the GCKD study. J Intern Med 2022; 291:622-636. [PMID: 34914850 PMCID: PMC9305919 DOI: 10.1111/joim.13437] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD. OBJECTIVES We aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study. METHODS This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m2 or an eGFR >60 ml/min/1.73m2 in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders. RESULTS Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01). CONCLUSIONS These data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
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Affiliation(s)
- Johannes P Schwaiger
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.,Department of Internal Medicine, Landeskrankenhaus Hall i.T., Hall in Tirol, Austria
| | - Barbara Kollerits
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Inga Steinbrenner
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Hansi Weissensteiner
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Sebastian Schönherr
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas Forer
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Fruzsina Kotsis
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.,Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Claudia Lamina
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus P Schneider
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ulla T Schultheiss
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.,Department of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Christoph Wanner
- Division of Nephrology, Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.,Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
| | -
- Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria
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15
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KAÇAR Y, BAYKAL AT, AYDIN L, BATMAZ H. Evaluation of the efficacy of cow colostrum in the treatment and its effect on serum proteomes in calves with cryptosporidiosis. Vet Immunol Immunopathol 2022; 248:110429. [DOI: 10.1016/j.vetimm.2022.110429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/16/2022] [Accepted: 04/21/2022] [Indexed: 11/26/2022]
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16
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Kiron V, Kathiresan P, Fernandes JM, Sørensen M, Vasanth GK, Qingsong L, Lin Q, Kwang LT, Dahle D, Dias J, Trichet VV. Clues from the intestinal mucus proteome of Atlantic salmon to counter inflammation. J Proteomics 2022; 255:104487. [DOI: 10.1016/j.jprot.2022.104487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 10/19/2022]
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17
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Ghanemi A, Yoshioka M, St-Amand J. Trefoil Factor Family Member 2: From a High-Fat-Induced Gene to a Potential Obesity Therapy Target. Metabolites 2021; 11:metabo11080536. [PMID: 34436477 PMCID: PMC8401738 DOI: 10.3390/metabo11080536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 12/11/2022] Open
Abstract
Obesity has its epidemiological patterns continuously increasing. With controlling both diet and exercise being the main approaches to manage the energy metabolism balance, a high-fat (HF) diet is of particular importance. Indeed, lipids have a low satiety potential but a high caloric density. Thus, focusing on pharmacologically targetable pathways remains an approach with promising therapeutic potential. Within this context, trefoil factor family member 2 (Tff2) has been characterized as specifically induced by HF diet rather than low-fat diet. TFF2 has also been linked to diverse neurological mechanisms and metabolic patterns suggesting its role in energy balance. The hypothesis is that TFF2 would be a HF diet-induced signal that regulates metabolism with a focus on lipids. Within this review, we put the spotlight on key findings highlighting this line of thought. Importantly, the hypothetical mechanisms pointed highlight TFF2 as an important contributor to obesity development via increasing lipids intestinal absorption and anabolism. Therefore, an outlook for future experimental activities and evaluation of the therapeutic potential of TFF2 inhibition is given. Indeed, its knockdown or downregulation would contribute to an antiobesity phenotype. We believe this work represents an addition to our understanding of the lipidic molecular implications in obesity, which will contribute to develop therapies aiming to manage the lipidic metabolic pathways including the absorption, storage and metabolism via targeting TFF2-related pathways. We briefly discuss important relevant concepts for both basic and clinical researchers.
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Affiliation(s)
- Abdelaziz Ghanemi
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Quebec, QC G1V 4G2, Canada; (A.G.); (M.Y.)
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada
| | - Mayumi Yoshioka
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Quebec, QC G1V 4G2, Canada; (A.G.); (M.Y.)
| | - Jonny St-Amand
- Functional Genomics Laboratory, CREMI, Québec Genome Center, CHUL-CHU de Québec Research Center, Quebec, QC G1V 4G2, Canada; (A.G.); (M.Y.)
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada
- Correspondence:
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18
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Taavela J, Viiri K, Välimäki A, Sarin J, Salonoja K, Mäki M, Isola J. Apolipoprotein A4 Defines the Villus-Crypt Border in Duodenal Specimens for Celiac Disease Morphometry. Front Immunol 2021; 12:713854. [PMID: 34394117 PMCID: PMC8358775 DOI: 10.3389/fimmu.2021.713854] [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] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 12/18/2022] Open
Abstract
Histological evaluation of the small intestinal mucosa is the cornerstone of celiac disease diagnostics and an important outcome in scientific studies. Gluten-dependent injury can be evaluated either with quantitative morphometry or grouped classifications. A drawback of mucosal readings is the subjective assessment of the border where the crypt epithelium changes to the differentiated villus epithelium. We studied potential immunohistochemical markers for the detection of the villus-crypt border: apolipoprotein A4 (APOA4), Ki-67, glucose transporter 2, keratin 20, cytochrome P450 3A4 and intestinal fatty-acid binding protein. Among these, villus-specific APOA4 was chosen as the best candidate for further studies. Hematoxylin-eosin (H&E)- and APOA4 stained duodenal biopsy specimens from 74 adult patients were evaluated by five observers to determine the villus-to-crypt ratio (VH : CrD). APOA4 delineated the villus to crypt epithelium transition clearly, and the correlation coefficient of VH : CrD values between APOA4 and H&E was excellent (r=0.962). The VH : CrD values were lower in APOA4 staining (p<0.001) and a conversion factor of 0.2 in VH : CrD measurements was observed to make the two methods comparable to each other. In the intraobserver analysis, the doubled standard deviations, representing the error ranges, were 0.528 for H&E and 0.388 for APOA4 staining, and the ICCs were 0.980 and 0.971, respectively. In the interobserver analysis, the average error ranges were 1.017 for H&E and 0.847 for APOA4 staining, and the ICCs were better for APOA4 than for H&E staining in all analyses. In conclusion, the reliability and reproducibility of morphometrical VH : CrD readings are improved with the use of APOA4 staining.
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Affiliation(s)
- Juha Taavela
- Central Finland Central Hospital, Jyväskylä, Finland.,Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Keijo Viiri
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anna Välimäki
- Fimlab Laboratories Inc, Tampere, Finland.,Jilab Inc, Tampere, Finland
| | | | | | - Markku Mäki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Tampere University Hospital, Tampere, Finland
| | - Jorma Isola
- Jilab Inc, Tampere, Finland.,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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19
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McCormack M, Talbot A, Dillon E, O’Connor I, MacCarthy E. Host Response of Atlantic Salmon ( Salmo salar) Re-Inoculated with Paramoeba perurans. Microorganisms 2021; 9:microorganisms9050993. [PMID: 34062978 PMCID: PMC8147987 DOI: 10.3390/microorganisms9050993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/26/2021] [Accepted: 05/03/2021] [Indexed: 11/28/2022] Open
Abstract
In aquaculture, recurrence rates of amoebic gill disease (AGD) caused by the ectoparasite Paramoeba perurans are high and no prophylactic strategies exist for disease prevention. In this study, Atlantic salmon (Salmo salar) were initially inoculated with P. perurans and following the development of amoebic gill disease were treated with freshwater immersion on day 21 and day 35 post inoculation. Fish were re-inoculated following a negative qPCR analysis for the presence of P. perurans. The gill host immune response was investigated at 7, 14, and 18 days post re-inoculation. Differential proteome expression of immune related proteins was assessed by comparison of each time point against naïve controls. In the gill, some proteins of the innate immune system were expressed in response to gill re-colonization by P. perurans, while no features of adaptive immunity were found to be differentially expressed. Many of the proteins identified are novel in the context of AGD and their expression profiles suggest that their roles in the response to disease development and progression in single or multiple infections warrant further investigation.
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Affiliation(s)
- Michelle McCormack
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (A.T.); (I.O.); (E.M.)
- Correspondence:
| | - Anita Talbot
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (A.T.); (I.O.); (E.M.)
| | - Eugene Dillon
- Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland;
| | - Ian O’Connor
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (A.T.); (I.O.); (E.M.)
| | - Eugene MacCarthy
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (A.T.); (I.O.); (E.M.)
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20
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Hojo M, Yamamoto Y, Sakamoto Y, Maeno A, Ohnuki A, Suzuki J, Inomata A, Moriyasu T, Taquahashi Y, Kanno J, Hirose A, Nakae D. Histological sequence of the development of rat mesothelioma by MWCNT, with the involvement of apolipoproteins. Cancer Sci 2021; 112:2185-2198. [PMID: 33665882 PMCID: PMC8177772 DOI: 10.1111/cas.14873] [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] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/11/2021] [Accepted: 03/03/2021] [Indexed: 01/07/2023] Open
Abstract
A rat model of mesothelioma development by peritoneal injection of multiwalled carbon nanotube (MWCNT) has been established and found to be useful to understand the mechanisms underlying fibrous particles‐associated carcinogenesis. Its detailed histological sequence, however, remains largely obscure. We therefore aimed to assess the time‐course of mesothelioma development by MWCNT and evaluate a set of lipoprotein‐related molecules as potential mechanism‐based biomarkers for the phenomenon. Male Fischer 344 rats were injected intraperitoneally (ip) with MWCNT (MWNT‐7) at 1 mg/kg body weight, and necropsied at 8, 16, 24, 32, or 42 wk after injection. For biochemical analyses of the lipoprotein‐related molecules, more samples, including severe mesothelioma cases, were obtained from 2 other carcinogenicity tests. Histologically, in association with chronic inflammation, mesothelial proliferative lesions appeared at c. Wk‐24. Before and at the beginning of the tumor development, a prominent infiltration of CD163‐positive cells was seen near mesothelial cells. The histological pattern of early mesothelioma was not a papillary structure, but was a characteristic structure with a spherical appearance, composed of the mesothelioma cells in the surface area that were underlain by connective tissue‐like cells. Along with the progression, mesotheliomas started to show versatile histological subtypes. Serum levels of apolipoprotein A‐I and A‐IV, and a ratio of HDL cholesterol to total cholesterol were inversely correlated with mesothelioma severity. Overall, the detailed histological sequence of mesotheliomagenesis by MWCNT is demonstrated, and indicated that the altered profile of apolipoproteins may be involved in its underlying mechanisms.
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Affiliation(s)
- Motoki Hojo
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Yukio Yamamoto
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Yoshimitsu Sakamoto
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Ai Maeno
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Aya Ohnuki
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Jin Suzuki
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Akiko Inomata
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Takako Moriyasu
- Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan
| | - Yuhji Taquahashi
- Center for Biological Safety and Research, National Institute of Health Sciences, Kanagawa, Japan
| | - Jun Kanno
- Center for Biological Safety and Research, National Institute of Health Sciences, Kanagawa, Japan
| | - Akihiko Hirose
- Center for Biological Safety and Research, National Institute of Health Sciences, Kanagawa, Japan
| | - Dai Nakae
- Department of Nutritional Science and Food Safety, Faculty of Applied Biosciences, Tokyo University of Agriculture, Tokyo, Japan
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Role of Short Chain Fatty Acids and Apolipoproteins in the Regulation of Eosinophilia-Associated Diseases. Int J Mol Sci 2021; 22:ijms22094377. [PMID: 33922158 PMCID: PMC8122716 DOI: 10.3390/ijms22094377] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are key components of our host defense and potent effectors in allergic and inflammatory diseases. Once recruited to the inflammatory site, eosinophils release their cytotoxic granule proteins as well as cytokines and lipid mediators, contributing to parasite clearance but also to exacerbation of inflammation and tissue damage. However, eosinophils have recently been shown to play an important homeostatic role in different tissues under steady state. Despite the tremendous progress in the treatment of eosinophilic disorders with the implementation of biologics, there is an unmet need for novel therapies that specifically target the cytotoxic effector functions of eosinophils without completely depleting this multifunctional immune cell type. Recent studies have uncovered several endogenous molecules that decrease eosinophil migration and activation. These include short chain fatty acids (SCFAs) such as butyrate, which are produced in large quantities in the gastrointestinal tract by commensal bacteria and enter the systemic circulation. In addition, high-density lipoprotein-associated anti-inflammatory apolipoproteins have recently been shown to attenuate eosinophil migration and activation. Here, we focus on the anti-pathogenic properties of SCFAs and apolipoproteins on eosinophil effector function and provide insights into the potential use of SCFAs and apolipoproteins (and their mimetics) as effective agents to combat eosinophilic inflammation.
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McCormack M, Dillon E, O’Connor I, MacCarthy E. Investigation of the Initial Host Response of Naïve Atlantic Salmon ( Salmo salar) Inoculated with Paramoeba perurans. Microorganisms 2021; 9:microorganisms9040746. [PMID: 33918228 PMCID: PMC8066739 DOI: 10.3390/microorganisms9040746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/23/2021] [Accepted: 03/31/2021] [Indexed: 01/15/2023] Open
Abstract
Amoebic Gill Disease (AGD), caused by the ectoparasite Paramoeba perurans is characterised by hyperplasia of the gill epithelium and lamellar fusion. In this study, the initial host response of naïve Atlantic salmon (Salmo salar) inoculated with P. perurans was investigated. Using gel-free proteomic techniques and mass spectrometry gill and serum samples were analysed at 7 timepoints (2, 3, 4, 7, 9, 11 and 14 days) post-inoculation with P. perurans. Differential expression of immune related proteins was assessed by comparison of protein expression from each time point against naïve controls. Few host immune molecules associated with innate immunity showed increased expression in response to gill colonisation by amoebae. Furthermore, many proteins with roles in immune signalling, phagocytosis and T-cell proliferation were found to be inhibited upon disease progression. Initially, various immune factors demonstrated the anticipated increase in expression in response to infection in the serum while some immune inhibition became apparent at the later stages of disease progression. Taken together, the pro-immune trend observed in serum, the lack of a robust early immune response in the gill and the diversity of those proteins in the gill whose altered expression negatively impact the immune response, support the concept of a pathogen-derived suppression of the host response.
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Affiliation(s)
- Michelle McCormack
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (I.O.); (E.M.)
- Correspondence:
| | - Eugene Dillon
- Conway Institute of Biomolecular & Biomedical Research, University College Dublin, D04 V1W8 Dublin, Ireland;
| | - Ian O’Connor
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (I.O.); (E.M.)
| | - Eugene MacCarthy
- Marine and Freshwater Research Centre, Galway Mayo Institute of Technology, Dublin Road, H91 TRNW Galway, Ireland; (I.O.); (E.M.)
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Hsu TY, Tsai KW, Lan KC, Hung HN, Lai YJ, Cheng HH, Tsai CC, Li SC. Identifying the potential protein biomarkers of preterm birth in amniotic fluid. Taiwan J Obstet Gynecol 2021; 59:366-371. [PMID: 32416881 DOI: 10.1016/j.tjog.2020.03.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2020] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Preterm birth severely threatens neonatal health and life. Although the detailed mechanism of preterm birth is not well understood, accurately predicting preterm birth can help people make preparations in advance, greatly reducing the subsequent health risk of neonates. Therefore, in this study, we aimed to identify potential protein biomarkers of preterm birth in amniotic fluid (AF). MATERIALS AND METHODS We first enrolled pregnant subjects and collected their AF samples when they underwent amniocentesis at the second trimester of gestation. After delivery, the collected AF samples were classified into a full-term birth (sample size n = 21) set or preterm birth (n = 36) set, followed by 2-D DIGE and MS/MS assays. RESULTS By doing so, we identified seven potential protein biomarkers of preterm birth, three of which were further validated in all samples with ELISA, including Apolipoprotein A-IV (Apoa4), Lumican (Lum) and Kininogen-1 (Kng1). As a result, all three potential biomarkers were significantly differently expressed between preterm and full-term birth AF samples. Furthermore, without prior classification, we found that these three biomarkers were positively correlated with gestation age (correlation coefficient ranging from 0.25 to 0.38) and were able to predict the occurrence of preterm birth. CONCLUSION In this study, by examining amniotic fluid, we identified three biomarker proteins that may facilitate the identification of preterm birth. There three proteins were never reported to be related to preterm birth. Their pathogenesis roles in preterm birth deserve further investigations by using in vitro cell model or in vivo animal model assays.
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Affiliation(s)
- Te-Yao Hsu
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan.
| | - Kuo-Chung Lan
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Hsuan-Ning Hung
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Yun-Ju Lai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Hsin-Hsin Cheng
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Chih-Chang Tsai
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Sung-Chou Li
- Genomics and Proteomics Core Laboratory, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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24
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Tang B, Zhu G, Chen C, Zheng S, Pu Y, Xu Y, Huang H, Wang G, Huang D, Liu Y, Zhang X. Hepatitis C Virus RNA Transcript Associates with Prognosis in Non-human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma. Laryngoscope 2021; 131:1774-1781. [PMID: 33592124 DOI: 10.1002/lary.29422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/11/2020] [Accepted: 01/08/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE/HYPOTHESIS Hepatitis C virus (HCV) was reported to associate with head and neck squamous cell carcinoma (HNSCC) in many studies. However, its correlation with prognosis of non-human papillomavirus (HPV) associated HNSCC remains unknown. Here, we sought to investigate clinical significance of HCV RNA transcript in non-HPV associated HNSCC by analyzing corresponding RNA-seq data. STUDY DESIGN A retrospective cohort study. METHODS Four hundred and forty-eight non-HPV associated HNSCC patients with aligned RNA-seq and clinical follow-up data were included and divided into two groups: low-HCV and high-HCV. Means of continuous variables and proportions of categorical variables were compared using independent sample t-test and chi-square test, respectively. Survival data were compared using Cox regression analysis, Kaplan-Meier curves, and log-rank test. Expression of genome-wide mRNAs and abundance of immune cells were compared using volcano plot and cell signature estimated score analysis. RESULTS HCV RNA transcript negatively correlates with pathologic (P = .028) and clinical-stage (P = .023), clinical N stage (P = .025), and nodal extracapsular spread (P = .042) and is an independent prognosis factor in non-HPV associated HNSCC (HR = 1.488; 95% CI: 1.004-2.206; P = .048). Elevated expression of HCV improved 5-year overall survival (43.6% vs. 53.2%; P = .035) in all non-HPV associated HNSCC patients, the same as in male (46.6% vs. 58.7%; P = .049), clinical M0 stage (42.8% vs. 52.9%; P = .036), white (42.9% vs. 55.9%; P = .010), and histologic grade 1 to 2 subgroups (42.1% vs. 57.2%; P = .043). The expression of several immune-related genes and abundance of some immune cells significantly changed with the increase of HCV RNA transcript, while HCV-related oncogenes and tumor suppressor gene did not. CONCLUSIONS HCV RNA transcript is an independent favorable factor for prognosis of non-HPV associated HNSCC. LEVELS OF EVIDENCE 4 Laryngoscope, 131:1774-1781, 2021.
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Affiliation(s)
- Bin Tang
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Gangcai Zhu
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Changhan Chen
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Siyuan Zheng
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Yuting Pu
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Yimin Xu
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Huimei Huang
- Department of Otolaryngology-Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Gang Wang
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China
| | - Donghai Huang
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China.,National Clinical Research Center for Geriatric Disorders, XiangYa Hospital, Changsha, China
| | - Yong Liu
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China.,National Clinical Research Center for Geriatric Disorders, XiangYa Hospital, Changsha, China
| | - Xin Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Xiangya Hospital, Central South University, Changsha, China.,Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, China.,Clinical Research Center for Pharyngolaryngeal Diseases and Voice Disorders in Hunan Province, Changsha, China.,National Clinical Research Center for Geriatric Disorders, XiangYa Hospital, Changsha, China
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25
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Wang Y, Yang Z, Wei Y, Li X, Li S. Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice. Int Immunopharmacol 2021; 90:107222. [PMID: 33276196 DOI: 10.1016/j.intimp.2020.107222] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/02/2020] [Accepted: 11/16/2020] [Indexed: 12/19/2022]
Abstract
This article explores the role of ApoA4 in a CCl4-induced chronic liver injury (CLI) mouse model. C57BL/6J mice (WT) and ApoA4 knock-out (KO) mice were divided into CCl4 CLI (WT-CCl4 and KO-CCl4) and olive oil solvent control groups (WT-Veh and KO-Veh). Some of the KO-CCl4 mice were additionally treated with recombinant mouse ApoA4 and primary mouse T lymphocyte injections. After 6 weeks, histological analyses, biochemical and superoxide dismutase (SOD) and malondialdehyde (MDA) assays, flow cytometry of immune cells and qRT-PCR analyses were performed. KO mice after treatment with CCl4 showed reduced hepatic SOD and enhanced serum MDA activities leading to worsening liver injury and fibrosis compared with WT-CCl4, accompanied by enhanced hepatic alpha smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type I alpha 1 chain (COL1A1) transcriptions, elevated macrophage M1 levels, enhanced tumor necrosis factor-alpha (TNF-α), Interleukin 6 (IL-6) and C-C Motif Chemokine Ligand 5 (CCL5), but reduced Interleukin 10 (IL-10), monocyte chemotactic protein 1 (MCP-1), C-C Motif Chemokine Receptor 2 (CCR2), C-X3-C Motif Chemokine Receptor 1 (CX3CR1) and C-X-C Motif Chemokine Ligand 9 (CXCL9) transcription, as well as reduced CD3+, CD4+ and CD8+ T cell percentages in hepatic tissue, blood cells and spleen. In addition, CD11b+CD115+, CD11b+/Ly6Chigh, CD11b+/LyC6- and CD11b+/Ly6Cint cells were enhanced, which partly reversed by ApoA4 protein and T cell injections. In conclusion, we propose that ApoA4 might be involved in liver protection via inhibiting fibrotic mediators and inflammatory cytokines, suppression of pro-inflammatory hepatic M1 cell invasion and regulation of CD8+ T and CD4+ T lymphocytes.
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Affiliation(s)
- Yinan Wang
- Bio-evidence Science Academy (BSA), Xi'an Jiaotong University (XJTU), No. 205 Zhuque Street, Xi'an 710061, China; Key laboratory of Ministry of Public Health for Forensic Sciences, No. 205 Zhuque Street, Xi'an 710061, China
| | - Ziyu Yang
- Bio-evidence Science Academy (BSA), Xi'an Jiaotong University (XJTU), No. 205 Zhuque Street, Xi'an 710061, China; Key laboratory of Ministry of Public Health for Forensic Sciences, No. 205 Zhuque Street, Xi'an 710061, China
| | - Yang Wei
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medical Institute, Institute of Digestive Diseases. The Second Affiliated Hospital, Xi'an Jiaotong University, No. 157 West 5th Road, Xi'an 710004, China
| | - Xiaoming Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medical Institute, Institute of Digestive Diseases. The Second Affiliated Hospital, Xi'an Jiaotong University, No. 157 West 5th Road, Xi'an 710004, China.
| | - Shengbin Li
- Bio-evidence Science Academy (BSA), Xi'an Jiaotong University (XJTU), No. 205 Zhuque Street, Xi'an 710061, China; Key laboratory of Ministry of Public Health for Forensic Sciences, No. 205 Zhuque Street, Xi'an 710061, China.
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Maternal dietary linoleic acid altered intestinal barrier function in domestic pigeons ( Columba livia). Br J Nutr 2020; 126:1003-1016. [PMID: 33298208 DOI: 10.1017/s0007114520004973] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Linoleic acid (LA) is predominantly essential for poultry. Poultry lacking LA show retarded growth and reduced disease resistance. Intestinal barrier function plays an important role in pigeon squab growth, whereas research on the effects of LA on intestinal health in altrices is scant. Considering that squabs are fed by their parents, the study aimed to explore the effects of maternal dietary LA on intestinal morphology, tight junction proteins, immune cytokines and microbial flora in squabs. A completely randomised design with a control group, 1 % LA supplementation group, 2 % LA supplementation group and 4 % LA supplementation group was used. Six squabs from each treatment were randomly sampled at 21 d post-hatching. The results indicated that LA supplementation improved intestinal morphology, as reflected by increased villus height, villus area and the ratio of villi to crypts. Also, 1 % LA supplementation elevated the density of goblet cells in the intestine and strengthened tight junctions by up-regulating claudin-3 and occludin gene expression but down-regulating claudin-2 gene expression. Moreover, 1 % LA supplementation reduced the secretion of proinflammatory cytokines and partly increased anti-inflammatory cytokines. The intestinal microbial diversity in the 1 % LA supplementation group was higher than that in the other groups. As beneficial bacteria, Butyrivibrio was the biomarker of 1 % LA supplementation. However, excessive (4 %) LA supplementation led to adverse impacts on intestinal immunity and microbiota. In conclusion, maternal dietary LA might alter intestinal barrier function in pigeon squabs in a dose-dependent manner. Supplementation with 1 % LA was suggested in parental pigeons.
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27
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Kao SST, Bassiouni A, Ramezanpour M, Finnie J, Chegeni N, Colella AD, Chataway TK, Wormald PJ, Vreugde S, Psaltis AJ. Proteomic analysis of nasal mucus samples of healthy patients and patients with chronic rhinosinusitis. J Allergy Clin Immunol 2020; 147:168-178. [PMID: 32750382 DOI: 10.1016/j.jaci.2020.06.037] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/08/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) has a complex and multifactorial pathogenesis with a heterogeneous inflammatory profile. Proteomic analysis of nasal mucus may enable further understanding of protein abundances and biologic processes present in CRS and its endotypes compared with in healthy patients. OBJECTIVE Our aim was to determine differences in the nasal mucus proteome of healthy patients and patients with CRS. METHODS Nasal mucus was obtained from healthy patients, patients with CRS without nasal polyps (CRSsNP), and patients with CRS with nasal polyps (CRSwNP) before surgery. Gel electrophoresis was performed to fractionate the complex protein extracts before mass spectrometry analysis. Gene set enrichment analysis was performed on differentially expressed proteins. RESULTS A total of 33 patients were included in this study (12 healthy, 10 with CRSsNP, and 11 with CRSwNP). In all, 1142 proteins were identified in mucus samples from healthy patients, 761 in mucus samples from patients with CRSsNP, and 998 in mucus samples from patients with CRSwNP. Dysfunction in immunologic pathways, reduced cellular signaling, and increased cellular metabolism with associated tissue remodeling pathways were present in patients with CRS compared with in healthy patients. CONCLUSION Significant downregulation of mucosal immunity and antioxidant pathways with increased tissue modeling processes may account for the clinical manifestations of CRS. Ultimately, the differing proteome and biologic processes provide further insight into CRS pathogenesis and its endotypes.
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Affiliation(s)
- Stephen Shih-Teng Kao
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia
| | - Ahmed Bassiouni
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia
| | - Mahnaz Ramezanpour
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia
| | - John Finnie
- Discipline of Anatomy and Pathology, Adelaide Medical School, The University of Adelaide and South Australia Pathology, Adelaide, Australia
| | - Nusha Chegeni
- Discipline of Anatomy and Pathology, Adelaide Medical School, The University of Adelaide and South Australia Pathology, Adelaide, Australia; Flinders Proteomic Facility, Department of Human Physiology, Flinders University, Bedford Park, Australia
| | - Alex D Colella
- Discipline of Anatomy and Pathology, Adelaide Medical School, The University of Adelaide and South Australia Pathology, Adelaide, Australia; Flinders Proteomic Facility, Department of Human Physiology, Flinders University, Bedford Park, Australia
| | - Timothy K Chataway
- Discipline of Anatomy and Pathology, Adelaide Medical School, The University of Adelaide and South Australia Pathology, Adelaide, Australia; Flinders Proteomic Facility, Department of Human Physiology, Flinders University, Bedford Park, Australia
| | - Peter-John Wormald
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia
| | - Sarah Vreugde
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia
| | - Alkis James Psaltis
- Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide, Woodville South, Australia.
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28
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Ko CW, Qu J, Black DD, Tso P. Regulation of intestinal lipid metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol 2020; 17:169-183. [PMID: 32015520 DOI: 10.1038/s41575-019-0250-7] [Citation(s) in RCA: 284] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/02/2019] [Indexed: 12/21/2022]
Abstract
Lipids entering the gastrointestinal tract include dietary lipids (triacylglycerols, cholesteryl esters and phospholipids) and endogenous lipids from bile (phospholipids and cholesterol) and from shed intestinal epithelial cells (enterocytes). Here, we comprehensively review the digestion, uptake and intracellular re-synthesis of intestinal lipids as well as their packaging into pre-chylomicrons in the endoplasmic reticulum, their modification in the Golgi apparatus and the exocytosis of the chylomicrons into the lamina propria and subsequently to lymph. We also discuss other fates of intestinal lipids, including intestinal HDL and VLDL secretion, cytosolic lipid droplets and fatty acid oxidation. In addition, we highlight the applicability of these findings to human disease and the development of therapeutics targeting lipid metabolism. Finally, we explore the emerging role of the gut microbiota in modulating intestinal lipid metabolism and outline key questions for future research.
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Affiliation(s)
- Chih-Wei Ko
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Jie Qu
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Dennis D Black
- Children's Foundation Research Institute at Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA.
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Roula D, Theiler A, Luschnig P, Sturm GJ, Tomazic PV, Marsche G, Heinemann A, Sturm EM. Apolipoprotein A-IV acts as an endogenous anti-inflammatory protein and is reduced in treatment-naïve allergic patients and allergen-challenged mice. Allergy 2020; 75:392-402. [PMID: 31408538 PMCID: PMC7065107 DOI: 10.1111/all.14022] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/07/2019] [Accepted: 06/26/2019] [Indexed: 12/15/2022]
Abstract
Background Recent studies pointed to a crucial role for apolipoproteins in the pathogenesis of inflammatory diseases. However, the role of apolipoprotein‐IV (ApoA‐IV) in allergic inflammation has not been addressed thoroughly thus far. Objective Here, we explored the anti‐inflammatory effects and underlying signaling pathways of ApoA‐IV on eosinophil effector function in vitro and in vivo. Methods Migratory responsiveness, Ca2+‐flux and apoptosis of human peripheral blood eosinophils were assessed in vitro. Allergen‐driven airway inflammation was assessed in a mouse model of acute house dust mite‐induced asthma. ApoA‐IV serum levels were determined by ELISA. Results Recombinant ApoA‐IV potently inhibited eosinophil responsiveness in vitro as measured by Ca2+‐flux, shape change, integrin (CD11b) expression, and chemotaxis. The underlying molecular mechanism involved the activation of Rev‐ErbA‐α and induced a PI3K/PDK1/PKA‐dependent signaling cascade. Systemic application of ApoA‐IV prevented airway hyperresponsiveness (AHR) and airway eosinophilia in mice following allergen challenge. ApoA‐IV levels were decreased in serum from allergic patients compared to healthy controls. Conclusion Our data suggest that ApoA‐IV is an endogenous anti‐inflammatory protein that potently suppresses effector cell functions in eosinophils. Thus, exogenously applied ApoA‐IV may represent a novel pharmacological approach for the treatment of allergic inflammation and other eosinophil‐driven disorders.
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Affiliation(s)
- David Roula
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
| | - Anna Theiler
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
| | - Petra Luschnig
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
| | - Gunter J. Sturm
- Department of Dermatology and Venerology Medical University of Graz Graz Austria
- Allergy Outpatient Clinic Reumannplatz Vienna Austria
| | | | - Gunther Marsche
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
| | - Eva M. Sturm
- Division of Pharmacology, Otto‐Loewi Research Center for Vascular Biology, Immunology and Inflammation Medical University of Graz Graz Austria
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30
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The Role and Function of HDL in Patients with Chronic Kidney Disease and the Risk of Cardiovascular Disease. Int J Mol Sci 2020; 21:ijms21020601. [PMID: 31963445 PMCID: PMC7014265 DOI: 10.3390/ijms21020601] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is a worldwide health problem with steadily increasing occurrence. Significantly elevated cardiovascular morbidity and mortality have been observed in CKD. Cardiovascular diseases are the most important and frequent cause of death of CKD patients globally. The presence of CKD is related to disturbances in lipoprotein metabolism whose consequences are dyslipidemia and the accumulation of atherogenic particles. CKD not only fuels the reduction of high-density lipoprotein (HDL) cholesterol concentration, but also it modifies the composition of this lipoprotein. The key role of HDL is the participation in reverse cholesterol transport from peripheral tissues to the liver. Moreover, HDL prevents the oxidation of low-density lipoprotein (LDL) cholesterol by reactive oxygen species (ROS) and protects against the adverse effects of oxidized LDL (ox-LDL) on the endothelium. Numerous studies have demonstrated the ability of HDL to promote the production of nitric oxide (NO) by endothelial cells (ECs) and to exert antiapoptotic and anti-inflammatory effects. Increasing evidence suggests that in patients with chronic inflammatory disorders, HDLs may lose important antiatherosclerotic properties and become dysfunctional. So far, no therapeutic strategy to raise HDL, or alter the ratio of HDL subfractions, has been successful in slowing the progression of CKD or reducing cardiovascular disease in patients either with or without CKD.
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Obinata H, Kuo A, Wada Y, Swendeman S, Liu CH, Blaho VA, Nagumo R, Satoh K, Izumi T, Hla T. Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice. J Lipid Res 2019; 60:1912-1921. [PMID: 31462513 DOI: 10.1194/jlr.ra119000277] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/15/2019] [Indexed: 11/20/2022] Open
Abstract
HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM- and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The Apom:Alb DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, Apom:Alb DKO mice had reduced levels (∼25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.
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Affiliation(s)
- Hideru Obinata
- Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Andrew Kuo
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115
| | - Yukata Wada
- Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Steven Swendeman
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115
| | - Catherine H Liu
- Weill Cornell Medical College, Cornell University, New York, NY 10065
| | - Victoria A Blaho
- Weill Cornell Medical College, Cornell University, New York, NY 10065
| | - Rieko Nagumo
- Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | | | - Takashi Izumi
- Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02115
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32
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Wang Z, Wang L, Zhang Z, Feng L, Song X, Wu J. Apolipoprotein A-IV involves in glucose and lipid metabolism of rat. Nutr Metab (Lond) 2019; 16:41. [PMID: 31303888 PMCID: PMC6604154 DOI: 10.1186/s12986-019-0367-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/06/2019] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Apolipoprotein A-IV (ApoA-IV) exists in relatively high levels in the circulation systems of animals, but its roles are not fully elucidated. It is known that the Apoa4 gene resides in the cluster Apoa1/Apoc3/Apoa4. Because of a short intergenic sequence between Apoc3 and Apoa4, a previous ApoA-IV knockout mouse model by gene targeting had an accompanying deficiency in ApoC-III expression, which limited its application in investigating the precise roles of ApoA-IV. To solve this problem, we created a specific knockout of ApoA-IV in Sprague-Dawlay rats by TALEN approach. METHODS Age-matched knockout rats and their wild-type littermate controls maintained on a standard rodent diet were studied and blood metabolic parameters were measured. Glucose, insulin, olive oil, and intralipid tolerance tests were performed to study the glucose and lipid metabolism of rats. Quantitative real-time PCR and RNA-seq analysis in liver and inguinal white adipose tissue (iWAT) of rats at three ages (18 weeks, 45 weeks and 90 weeks) were performed to identify the genes altered by ApoA-IV knockout. RESULTS ApoA-IV knockout rats were apparently normal and fertile, but exhibited improved glucose clearance when challenged with glucose tolerance test. In addition, fasting-induced hepatic steatosis was more pronounced in ApoA-IV knockout rats. Further analysis identified that a set of hepatic genes involved in glycolysis, gluconeogenesis and de novo lipogenesis were altered in the absence of ApoA-IV, which induced enhanced glycolysis, attenuated gluconeogenesis and elevated de novo lipogenesis. And the RNA-seq results also confirmed that almost all the genes mentioned in the phenotyping section were highly consistent throughout the three studied ages. CONCLUSIONS ApoA-IV functions in an age-independent manner in the modulation of glucose and lipid metabolism of rats, and may serve as a potential linker between hepatic glucose and lipid metabolism.
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Affiliation(s)
- Zhenguo Wang
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Lu Wang
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Zhuzhen Zhang
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Li Feng
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Xue Song
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
- School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210 China
| | - Jiarui Wu
- Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
- School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210 China
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33
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Qu J, Ko CW, Tso P, Bhargava A. Apolipoprotein A-IV: A Multifunctional Protein Involved in Protection against Atherosclerosis and Diabetes. Cells 2019; 8:E319. [PMID: 30959835 PMCID: PMC6523623 DOI: 10.3390/cells8040319] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 03/31/2019] [Accepted: 04/02/2019] [Indexed: 12/19/2022] Open
Abstract
Apolipoprotein A-IV (apoA-IV) is a lipid-binding protein, which is primarily synthesized in the small intestine, packaged into chylomicrons, and secreted into intestinal lymph during fat absorption. In the circulation, apoA-IV is present on chylomicron remnants, high-density lipoproteins, and also in lipid-free form. ApoA-IV is involved in a myriad of physiological processes such as lipid absorption and metabolism, anti-atherosclerosis, platelet aggregation and thrombosis, glucose homeostasis, and food intake. ApoA-IV deficiency is associated with atherosclerosis and diabetes, which renders it as a potential therapeutic target for treatment of these diseases. While much has been learned about the physiological functions of apoA-IV using rodent models, the action of apoA-IV at the cellular and molecular levels is less understood, let alone apoA-IV-interacting partners. In this review, we will summarize the findings on the molecular function of apoA-IV and apoA-IV-interacting proteins. The information will shed light on the discovery of apoA-IV receptors and the understanding of the molecular mechanism underlying its mode of action.
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Affiliation(s)
- Jie Qu
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237-0507, USA.
| | - Chih-Wei Ko
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237-0507, USA.
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, 2180 E Galbraith Road, Cincinnati, OH 45237-0507, USA.
| | - Aditi Bhargava
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0556, USA.
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34
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Peng J, Li XP. Apolipoprotein A-IV: A potential therapeutic target for atherosclerosis. Prostaglandins Other Lipid Mediat 2018; 139:87-92. [PMID: 30352313 DOI: 10.1016/j.prostaglandins.2018.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/05/2018] [Accepted: 10/10/2018] [Indexed: 12/13/2022]
Abstract
Apolipoprotein A-IV is lipid-binding protein, which is synthesized by the intestine and secreted into mesenteric lymph. ApoA-IV is correlated with chylomicrons and high density lipoprotein, but a large portion is free-lipoprotein, in circulation. Studies showed that apoA-IV has anti-inflammatory and anti-oxidative properties, and is able to mediate reverse cholesterol transport, which suggest that it may has anti-atherosclerotic effects and be related to protection from atherosclerotic cardiovascular disease. This article focus on current studies and the possible anti-atherogenic mechanism related to apoA-IV, in order to provide a new therapeutic target for atherosclerotic cardiovascular diseases.
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Affiliation(s)
- Jia Peng
- Department of Cardiovascular Diseases, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China
| | - Xiang-Ping Li
- Department of Cardiovascular Diseases, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, China.
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35
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Saadane A, Petrov A, Mast N, El-Darzi N, Dao T, Alnemri A, Song Y, Dunaief JL, Pikuleva IA. Mechanisms that minimize retinal impact of apolipoprotein E absence. J Lipid Res 2018; 59:2368-2382. [PMID: 30333155 DOI: 10.1194/jlr.m090043] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/17/2018] [Indexed: 01/28/2023] Open
Abstract
Apolipoprotein E (APOE) is a component of lipid-transporting particles and a recognition ligand for receptors, which bind these particles. The APOE isoform ε2 is a risk factor for age-related macular degeneration; nevertheless, APOE absence in humans and mice does not significantly affect the retina. We found that retinal cholesterol biosynthesis and the levels of retinal cholesterol were increased in Apoe-/- mice, whereas cholesterol elimination by metabolism was decreased. No focal cholesterol deposits were observed in the Apoe-/- retina. Retinal proteomics identified the most abundant cholesterol-related proteins in WT mice and revealed that, of these cholesterol-related proteins, only APOA4 had increased expression in the Apoe-/- retina. In addition, there were changes in retinal abundance of proteins involved in proinflammatory and antiinflammatory responses, cellular cytoskeleton maintenance, vesicular traffic, and retinal iron homeostasis. The data obtained indicate that when APOE is absent, particles containing APOA1, APOA4, and APOJ still transport cholesterol in the intraretinal space, but these particles are not taken up by retinal cells. Therefore, cholesterol biosynthesis inside retinal cells increase, whereas metabolism to oxysterols decreases to prevent cells from cholesterol depletion. These and other compensatory changes underlie only a minor retinal phenotype in Apoe-/- mice.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
| | - Alexey Petrov
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
| | - Natalia Mast
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
| | - Nicole El-Darzi
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
| | - Tung Dao
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
| | - Ahab Alnemri
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ying Song
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Joshua L Dunaief
- F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Irina A Pikuleva
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH
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36
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Xu XR, Wang Y, Adili R, Ju L, Spring CM, Jin JW, Yang H, Neves MAD, Chen P, Yang Y, Lei X, Chen Y, Gallant RC, Xu M, Zhang H, Song J, Ke P, Zhang D, Carrim N, Yu SY, Zhu G, She YM, Cyr T, Fu W, Liu G, Connelly PW, Rand ML, Adeli K, Freedman J, Lee JE, Tso P, Marchese P, Davidson WS, Jackson SP, Zhu C, Ruggeri ZM, Ni H. Apolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis. Nat Commun 2018; 9:3608. [PMID: 30190457 PMCID: PMC6127106 DOI: 10.1038/s41467-018-05806-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 07/19/2018] [Indexed: 12/29/2022] Open
Abstract
Platelet αIIbβ3 integrin and its ligands are essential for thrombosis and hemostasis, and play key roles in myocardial infarction and stroke. Here we show that apolipoprotein A-IV (apoA-IV) can be isolated from human blood plasma using platelet β3 integrin-coated beads. Binding of apoA-IV to platelets requires activation of αIIbβ3 integrin, and the direct apoA-IV-αIIbβ3 interaction can be detected using a single-molecule Biomembrane Force Probe. We identify that aspartic acids 5 and 13 at the N-terminus of apoA-IV are required for binding to αIIbβ3 integrin, which is additionally modulated by apoA-IV C-terminus via intra-molecular interactions. ApoA-IV inhibits platelet aggregation and postprandial platelet hyperactivity. Human apoA-IV plasma levels show a circadian rhythm that negatively correlates with platelet aggregation and cardiovascular events. Thus, we identify apoA-IV as a novel ligand of αIIbβ3 integrin and an endogenous inhibitor of thrombosis, establishing a link between lipoprotein metabolism and cardiovascular diseases. Activation of integrin αIIbβ3 at the surface of platelets is required for their aggregation and for thrombus formation. Here Xu et al. identify apolipoprotein A-IV as a novel ligand for platelet αIIbβ3 integrin, and find it inhibits platelet aggregation and thrombosis.
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Affiliation(s)
- Xiaohong Ruby Xu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510120.,Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510000
| | - Yiming Wang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Reheman Adili
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Lining Ju
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA, 30332.,Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA, 30332.,Heart Research Institute, and Charles Perkins Centre, The University of Sydney, Camperdown, Australia, 2006
| | - Christopher M Spring
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Joseph Wuxun Jin
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Hong Yang
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Miguel A D Neves
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Pingguo Chen
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Yan Yang
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Xi Lei
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Yunfeng Chen
- Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA, 30332.,Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA, 30332
| | - Reid C Gallant
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Miao Xu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Hailong Zhang
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Jina Song
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Peifeng Ke
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510000.,Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510120
| | - Dan Zhang
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510000
| | - Naadiya Carrim
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1
| | - Si-Yang Yu
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, P.R. China, 410011
| | - Guangheng Zhu
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Yi-Min She
- Centre for Biologics Research, Biologics and Genetic Therapies Directorate, HPFB, Health Canada, Ottawa, ON, Canada, K1A 0M2
| | - Terry Cyr
- Centre for Biologics Research, Biologics and Genetic Therapies Directorate, HPFB, Health Canada, Ottawa, ON, Canada, K1A 0M2
| | - Wenbin Fu
- Department of Acupuncture and Moxibustion, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510120.,Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China, 510000
| | - Guoqing Liu
- Institute of Cardiovascular Science, Peking University Health Science Center, Beijing, P.R. China, 100083
| | - Philip W Connelly
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8
| | - Margaret L Rand
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8
| | - Khosrow Adeli
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Program in Molecular Structure & Function, The Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8
| | - John Freedman
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8.,Department of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A1
| | - Jeffrey E Lee
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA, 45219
| | - Patrizia Marchese
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA, 92037
| | - W Sean Davidson
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA, 45219
| | - Shaun P Jackson
- Heart Research Institute, and Charles Perkins Centre, The University of Sydney, Camperdown, Australia, 2006.,Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA, 92037
| | - Cheng Zhu
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA, 30332.,Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA, 30332.,Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA, 30332
| | - Zaverio M Ruggeri
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA, 92037
| | - Heyu Ni
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1. .,Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, Canada, M5B 1W8. .,Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, M5G 2M1. .,Department of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A1. .,Department of Physiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.
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Zanoni P, Velagapudi S, Yalcinkaya M, Rohrer L, von Eckardstein A. Endocytosis of lipoproteins. Atherosclerosis 2018; 275:273-295. [PMID: 29980055 DOI: 10.1016/j.atherosclerosis.2018.06.881] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/04/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023]
Abstract
During their metabolism, all lipoproteins undergo endocytosis, either to be degraded intracellularly, for example in hepatocytes or macrophages, or to be re-secreted, for example in the course of transcytosis by endothelial cells. Moreover, there are several examples of internalized lipoproteins sequestered intracellularly, possibly to exert intracellular functions, for example the cytolysis of trypanosoma. Endocytosis and the subsequent intracellular itinerary of lipoproteins hence are key areas for understanding the regulation of plasma lipid levels as well as the biological functions of lipoproteins. Indeed, the identification of the low-density lipoprotein (LDL)-receptor and the unraveling of its transcriptional regulation led to the elucidation of familial hypercholesterolemia as well as to the development of statins, the most successful therapeutics for lowering of cholesterol levels and risk of atherosclerotic cardiovascular diseases. Novel limiting factors of intracellular trafficking of LDL and the LDL receptor continue to be discovered and to provide drug targets such as PCSK9. Surprisingly, the receptors mediating endocytosis of high-density lipoproteins or lipoprotein(a) are still a matter of controversy or even new discovery. Finally, the receptors and mechanisms, which mediate the uptake of lipoproteins into non-degrading intracellular itineraries for re-secretion (transcytosis, retroendocytosis), storage, or execution of intracellular functions, are largely unknown.
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Affiliation(s)
- Paolo Zanoni
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Srividya Velagapudi
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Mustafa Yalcinkaya
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Lucia Rohrer
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Arnold von Eckardstein
- Institute for Clinical Chemistry, University and University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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38
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Packard AEB, Zhang J, Myers B, Ko CW, Wang F, Tso P, Ulrich-Lai YM. Apolipoprotein A-IV constrains HPA and behavioral stress responsivity in a strain-dependent manner. Psychoneuroendocrinology 2017; 86:34-44. [PMID: 28910603 PMCID: PMC5659927 DOI: 10.1016/j.psyneuen.2017.08.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 07/28/2017] [Accepted: 08/30/2017] [Indexed: 12/21/2022]
Abstract
There is a critical gap in our knowledge of the mechanisms that govern interactions between daily life experiences (e.g., stress) and metabolic diseases, despite evidence that stress can have profound effects on cardiometabolic health. Apolipoprotein A-IV (apoA-IV) is a protein found in chylomicrons (lipoprotein particles that transport lipids throughout the body) where it participates in lipid handling and the regulation of peripheral metabolism. Moreover, apoA-IV is expressed in brain regions that regulate energy balance including the arcuate nucleus. Given that both peripheral and central metabolic processes are important modulators of hypothalamic-pituitary-adrenocortical (HPA) axis activity, the present work tests the hypothesis that apoA-IV activity affects stress responses. As emerging data suggests that apoA-IV actions can vary with background strain, we also explore the strain-dependence of apoA-IV stress regulation. These studies assess HPA axis, metabolic (hyperglycemia), and anxiety-related behavioral responses to psychogenic stress in control (wildtype) and apoA-IV-deficient (KO) mice on either the C57Bl/6J (C57) or 129×1/SvJ (129) background strain. The results indicate that apoA-IV KO increases post-stress corticosterone and anxiety-related behavior specifically in the 129 strain, and increases stress-induced hyperglycemia exclusively in the C57 strain. These data support the hypothesis that apoA-IV is a novel factor that limits stress reactivity in a manner that depends on genetic background. An improved understanding of the complex relationship among lipid homeostasis, stress sensitivity, and genetics is needed to optimize the development of personalized treatments for stress- and metabolism-related diseases.
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Affiliation(s)
- Amy E B Packard
- Dept. of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Jintao Zhang
- Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Brent Myers
- Dept. of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Chih-Wei Ko
- Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Fei Wang
- Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Patrick Tso
- Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
| | - Yvonne M Ulrich-Lai
- Dept. of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2120 E. Galbraith Road, Cincinnati, OH, USA.
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Lee HJ, Kim JH, Kim SW, Joo HA, Lee HW, Kim YS, Park SJ, Hong SP, Kim TI, Kim WH, Kim YH, Cheon JH. Proteomic Analysis of Serum Amyloid A as a Potential Marker in Intestinal Behçet's Disease. Dig Dis Sci 2017; 62:1953-1962. [PMID: 28523576 DOI: 10.1007/s10620-017-4606-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 05/04/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND/AIMS Data regarding biomarkers to understand disease pathogenesis and to assess disease activity of intestinal Behçet's disease (BD) are limited. Therefore, we aimed to investigate the differentially expressed proteins in sera from patients with intestinal BD and to search for biomarkers using mass spectrometry-based proteomic analysis. METHODS Serum samples were pooled for the screening study, and two-dimensional electrophoresis (2-DE) was performed to characterize the proteins present in intestinal BD patients. Candidate protein spots were identified using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and bioinformatic analysis. To validate the proteomic results, serum samples from an independent cohort were assessed by enzyme-linked immunosorbent assay. RESULTS Pooled serum samples were used for 2-DE, and approximately 400 protein spots were detected in the sera of intestinal BD patients. Of the 22 differentially expressed proteins, 3 were successfully identified using MALDI-TOF/TOF MS. The three up-regulated proteins identified in the intestinal BD group included fibrin, apolipoprotein A-IV, and serum amyloid A (SAA). Serum SAA in intestinal BD patients (2.76 ± 2.50 ng/ml) was significantly higher than that in controls (1.68 ± 0.90 ng/ml, p = 0.007), which is consistent with the proteomic results. In addition, the level of IL-1β in patients with intestinal BD (8.96 ± 1.23 pg/ml) was higher than that in controls (5.40 ± 0.15 pg/ml, p = 0.009). SAA released by HT-29 cells was markedly increased by tumor necrosis factor-α (TNF-α) and lipopolysaccharides stimulation. CONCLUSIONS Our proteomic analysis revealed that SAA was up-regulated in intestinal BD patients.
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Affiliation(s)
- Hyun Jung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Jae Hyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Won Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Ah Joo
- Department of Biochemistry, Yonsei University, Seoul, Korea
| | - Hye Won Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - You Sun Kim
- Department of Internal Medicine, Inje University College of Medicine, Seoul, Korea
| | - Soo Jung Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Sung Pil Hong
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Tae Il Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Won Ho Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, 135-710, Republic of Korea.
| | - Jae Hee Cheon
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea. .,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. .,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
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40
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Sugihara K, Masuda M, Nakao M, Abuduli M, Imi Y, Oda N, Okahisa T, Yamamoto H, Takeda E, Taketani Y. Dietary phosphate exacerbates intestinal inflammation in experimental colitis. J Clin Biochem Nutr 2017; 61:91-99. [PMID: 28955125 PMCID: PMC5612814 DOI: 10.3164/jcbn.16-117] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 12/26/2016] [Indexed: 12/31/2022] Open
Abstract
The recent widespread consumption of Western diets and food additives worldwide is associated with excessive inorganic phosphate intake. However, researchers have known little about the impact of dietary phosphate intake on the development of inflammatory bowel disease to date. In this study, we investigated the effects of dietary phosphate on intestinal inflammation in experimental colitis. Sprague-Dawley rats were fed different phosphate diets (0.5%, 1.0% and 1.5% phosphate) with or without dextran sulfate sodium. For in vitro study, the effects of phosphate on proinflammatory cytokine induction and reactive oxygen species production in RAW264.7 macrophage were examined. Dietary phosphate exacerbated intestinal inflammation in experimental colitis in a dose-dependent manner, as assessed by the clinical disease activity score, colon length, and histology. Furthermore, the high phosphate diet increased myeloperoxidase activity and proinflammatory cytokine mRNA expression through the activation of nuclear factor κB in the inflamed colon. In addition, high phosphate loading in RAW264.7 cells directly enhanced reactive oxygen species production and proinflammatory cytokine gene expression. Our results demonstrated that the high phosphate diet exacerbated intestinal inflammation in experimental colitis. These findings have important therapeutic implications for inflammatory bowel disease patients.
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Affiliation(s)
- Kohei Sugihara
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Masashi Masuda
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Mari Nakao
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Maerjianghan Abuduli
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yukiko Imi
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Naoko Oda
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Toshiya Okahisa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Hironori Yamamoto
- Department of Health and Nutrition, Faculty of Human Life, Jin-ai University, Fukui 915-8586, Japan
| | - Eiji Takeda
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yutaka Taketani
- Departments of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
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Zhang Y, He J, Zhao J, Xu M, Lou D, Tso P, Li Z, Li X. Effect of ApoA4 on SERPINA3 mediated by nuclear receptors NR4A1 and NR1D1 in hepatocytes. Biochem Biophys Res Commun 2017; 487:327-332. [PMID: 28412351 DOI: 10.1016/j.bbrc.2017.04.058] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 04/12/2017] [Indexed: 12/29/2022]
Abstract
ApoA4 exerts anti-inflammatory effects, but the mechanism remains unclear. SERPINA3 is a member of the serine proteinase inhibitor gene family, and has been shown to be involved in anti-inflammation and associated with a number of human diseases. In this study, we revealed that ApoA4 stimulates the gene expression of SERPINA3 in mouse hepatocytes both in vivo and in vitro, in a dose- and time-dependent manner. The transcriptional response of SERPINA3 to ApoA4 is regulated through the binding of ApoA4 with nuclear receptors NR4A1 and NR1D1 on the SERPINA3 promoter, which was verified with ChIP, Luciferase activity assay and RNA interference-mediated NR4A1 or NR1D1 gene knockdown. These data suggests that ApoA4 transcriptionally induced SERPINA3 expression via NR1D1 and NR4A1. Our findings may throw light on the function of ApoA4 in inflammatory responses and acute-phase reactions, as well as the development of SERPINA3 relative diseases.
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Affiliation(s)
- Yupeng Zhang
- National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Jing He
- College of Medicine and Forensic Science, Xi'an Jiaotong University, Xi'an, China
| | - Jing Zhao
- College of Medicine and Forensic Science, Xi'an Jiaotong University, Xi'an, China
| | - Min Xu
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, USA
| | - Danwen Lou
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, USA
| | - Zongfang Li
- National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Xiaoming Li
- National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.
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42
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Islam J, Sato S, Watanabe K, Watanabe T, Ardiansyah, Hirahara K, Aoyama Y, Tomita S, Aso H, Komai M, Shirakawa H. Dietary tryptophan alleviates dextran sodium sulfate-induced colitis through aryl hydrocarbon receptor in mice. J Nutr Biochem 2017; 42:43-50. [PMID: 28113104 DOI: 10.1016/j.jnutbio.2016.12.019] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 12/27/2016] [Accepted: 12/28/2016] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis is the typical progression of chronic inflammatory bowel disease. Amino acids, particularly tryptophan, have been reported to exert a protective effect against colitis induced by dextran sodium sulfate (DSS), but the precise underlying mechanisms remain incompletely clarified. Tryptophan metabolites are recognized to function as endogenous ligands for aryl hydrocarbon receptor (Ahr), which is a critical regulator of inflammation and immunity. Thus, we conducted this study to investigate whether dietary tryptophan supplementation protects against DSS-induced colitis by acting through Ahr. Female wild-type (WT) and Ahr-deficient (knockout; KO) mice (10-12 weeks old) were divided into four groups and fed either a control or 0.5% tryptophan diet. The tryptophan diet ameliorated DSS-induced colitis symptoms and severity in WT mice but not in KO mice, and the diet reduced the mRNA expression of Il-6, Tnfα, Il-1β and the chemokines Ccl2, Cxcl1 and Cxcl2 in the WT groups. Furthermore, Il-22 and Stat3 mRNA expression in the colon was elevated in WT mice fed with the tryptophan diet, which mainly protected epithelial layer integrity, and Ahr also modulated immune homeostasis by regulating Foxp3 and Il-17 mRNA expression. These data suggest that tryptophan-containing diet might ameliorate DSS-induced acute colitis and regulate epithelial homeostasis through Ahr. Thus, tryptophan could serve as a promising preventive agent in the treatment of ulcerative colitis.
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Affiliation(s)
- Jahidul Islam
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Shoko Sato
- Department of Biological Science and Technology, Tokyo University of Science, Tokyo, Japan
| | - Kouichi Watanabe
- Cellular Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Takaya Watanabe
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Ardiansyah
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; Department of Food Science and Technology, Universitas Bakrie, Jakarta, Indonesia
| | - Keisuke Hirahara
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Yukihide Aoyama
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Shuhei Tomita
- Department of Pharmacology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hisashi Aso
- Cellular Biology Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
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Downregulation of CX 3CR1 ameliorates experimental colitis: evidence for CX 3CL1-CX 3CR1-mediated immune cell recruitment. Int J Colorectal Dis 2017; 32:315-324. [PMID: 27942903 DOI: 10.1007/s00384-016-2735-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/05/2016] [Indexed: 02/04/2023]
Abstract
PURPOSE Inflammatory conditions like inflammatory bowel diseases (IBD) are characterized by increased immune cell infiltration. The chemokine ligand CX3CL1 and its receptor CX3CR1 have been shown to be involved in leukocyte adhesion, transendothelial recruitment, and chemotaxis. Therefore, the objective of this study was to describe CX3CL1-CX3CR1-mediated signaling in the induction of immune cell recruitment during experimental murine colitis. METHODS Acute colitis was induced by dextran sodium sulfate (DSS), and sepsis was induced by injection of lipopolysaccharide (LPS). Serum concentrations of CX3CR1 and CX3CL1 were measured by ELISA. Wild-type and CX3CR1-/- mice were challenged with DSS, and on day 6, intravital microscopy was performed to monitor colonic leukocyte and platelet recruitment. Intestinal inflammation was assessed by disease activity, histopathology, and neutrophil infiltration. RESULTS CX3CR1 was upregulated in DSS colitis and LPS-induced sepsis. CX3CR1-/- mice were protected from disease severity and intestinal injury in DSS colitis, and CX3CR1 deficiency resulted in reduced rolling of leukocytes and platelets. CONCLUSIONS In the present study, we provide evidence for a crucial role of CX3CL1-CX3CR1 in experimental colitis, in particular for intestinal leukocyte recruitment during murine colitis. Our findings suggest that CX3CR1 blockade represents a potential therapeutic strategy for treatment of IBD.
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Sanderlin EJ, Leffler NR, Lertpiriyapong K, Cai Q, Hong H, Bakthavatchalu V, Fox JG, Oswald JZ, Justus CR, Krewson EA, O'Rourke D, Yang LV. GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochim Biophys Acta Mol Basis Dis 2016; 1863:569-584. [PMID: 27940273 DOI: 10.1016/j.bbadis.2016.12.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/13/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023]
Abstract
GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.
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Affiliation(s)
- Edward J Sanderlin
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Nancy R Leffler
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA
| | - Qi Cai
- Department of Pathology, Brody School of Medicine, East Carolina University, USA
| | - Heng Hong
- Department of Pathology, Brody School of Medicine, East Carolina University, USA
| | | | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, USA
| | - Joani Zary Oswald
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA
| | - Calvin R Justus
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA
| | - Elizabeth A Krewson
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA
| | - Dorcas O'Rourke
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, USA
| | - Li V Yang
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, USA; Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, USA.
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Yan H, Fei N, Wu G, Zhang C, Zhao L, Zhang M. Regulated Inflammation and Lipid Metabolism in Colon mRNA Expressions of Obese Germfree Mice Responding to Enterobacter cloacae B29 Combined with the High Fat Diet. Front Microbiol 2016; 7:1786. [PMID: 27877172 PMCID: PMC5099522 DOI: 10.3389/fmicb.2016.01786] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/24/2016] [Indexed: 01/07/2023] Open
Abstract
Increased evidences have demonstrated that gut microbiota targeted diet intervention can alleviate obesity and related metabolic disorders. The underlying mechanism of interactions among diet, microbiota, and host still remains unclear. Enterobacter cloacae B29, an endotoxin-producing strain dominated in the gut of a morbidly obese volunteer (weight 174.8 kg, BMI 58.8 kg m-2) was isolated and transplanted to germfree mice (inoculated 1010 cells of B29 per day for 1 week). Using deep mRNA sequencing technology, we compared different gene expression profiles in the colon samples of the germfree mice treated with/without B29 and/or high fat diet (HFD) for 16 weeks and identified 279 differential expressed genes in total, including up-regulated genes Apoa4 (fold change, 2.77), Ido1 (2.66), Cyp4a10 (7.01), and down-regulated genes Cyp2e1 (0.11), Cyp26b1 (0.34), Akr1b7 (0.42), Adipoq (0.36), Cyp1a1 (0.11), Apoa1 (0.44), Npc1l1 (0.37), Tff2 (0.13), Apoc1 (0.30), Ctla2a (0.34), Mttp (0.49), Lpl (0.48). Fifty-nine GO biological processes and five KEGG pathways, particularly the peroxisome proliferator-activated receptors signaling pathway, were significantly enriched in response to HFD+B29, which were mainly relevant to inflammation and the metabolism of lipid, lipoprotein, and sterols. These functional changes were consistent with the developed obesity, insulin-resistance, and aggravated inflammatory conditions of the HFD+B29 mice. This work provides insight into the gene expression changes in response to HFD+B29, helping to understand the mechanism of the interactions among HFD, B29 and the germfree mice.
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Affiliation(s)
- Huiying Yan
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Na Fei
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Guojun Wu
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Liping Zhao
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Menghui Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
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Leung JM, Chen V, Hollander Z, Dai D, Tebbutt SJ, Aaron SD, Vandemheen KL, Rennard SI, FitzGerald JM, Woodruff PG, Lazarus SC, Connett JE, Coxson HO, Miller B, Borchers C, McManus BM, Ng RT, Sin DD. COPD Exacerbation Biomarkers Validated Using Multiple Reaction Monitoring Mass Spectrometry. PLoS One 2016; 11:e0161129. [PMID: 27525416 PMCID: PMC4985129 DOI: 10.1371/journal.pone.0161129] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 07/30/2016] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) result in considerable morbidity and mortality. However, there are no objective biomarkers to diagnose AECOPD. METHODS We used multiple reaction monitoring mass spectrometry to quantify 129 distinct proteins in plasma samples from patients with COPD. This analytical approach was first performed in a biomarker cohort of patients hospitalized with AECOPD (Cohort A, n = 72). Proteins differentially expressed between AECOPD and convalescent states were chosen using a false discovery rate <0.01 and fold change >1.2. Protein selection and classifier building were performed using an elastic net logistic regression model. The performance of the biomarker panel was then tested in two independent AECOPD cohorts (Cohort B, n = 37, and Cohort C, n = 109) using leave-pair-out cross-validation methods. RESULTS Five proteins were identified distinguishing AECOPD and convalescent states in Cohort A. Biomarker scores derived from this model were significantly higher during AECOPD than in the convalescent state in the discovery cohort (p<0.001). The receiver operating characteristic cross-validation area under the curve (CV-AUC) statistic was 0.73 in Cohort A, while in the replication cohorts the CV-AUC was 0.77 for Cohort B and 0.79 for Cohort C. CONCLUSIONS A panel of five biomarkers shows promise in distinguishing AECOPD from convalescence and may provide the basis for a clinical blood test to diagnose AECOPD. Further validation in larger cohorts is necessary for future clinical translation.
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Affiliation(s)
- Janice M. Leung
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- Division of Respiratory Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Virginia Chen
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Zsuzsanna Hollander
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Darlene Dai
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Scott J. Tebbutt
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- Division of Respiratory Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Shawn D. Aaron
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Kathy L. Vandemheen
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Stephen I. Rennard
- Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- AstraZeneca, Cambridge, United Kingdom
| | - J. Mark FitzGerald
- Division of Respiratory Medicine, Department of Medicine, Vancouver General Hospital and the Institute for Heart and Lung Health, Vancouver, British Columbia, Canada
| | - Prescott G. Woodruff
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America
| | - Stephen C. Lazarus
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America
| | - John E. Connett
- University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Harvey O. Coxson
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Bruce Miller
- GlaxoSmithKline Research and Development, King of Prussia, Pennsylvania, United States of America
| | - Christoph Borchers
- University of Victoria-Genome British Columbia Proteomics Centre, Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
| | - Bruce M. McManus
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Raymond T. Ng
- PROOF Center of Excellence, St. Paul’s Hospital, Vancouver, British Columbia, Canada
| | - Don D. Sin
- Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- Division of Respiratory Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, British Columbia, Canada
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Nowacki TM, Remaley AT, Bettenworth D, Eisenblätter M, Vowinkel T, Becker F, Vogl T, Roth J, Tietge UJ, Lügering A, Heidemann J, Nofer JR. The 5A apolipoprotein A-I (apoA-I) mimetic peptide ameliorates experimental colitis by regulating monocyte infiltration. Br J Pharmacol 2016; 173:2780-92. [PMID: 27425846 DOI: 10.1111/bph.13556] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 06/15/2016] [Accepted: 07/05/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND PURPOSE New therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A-I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis. EXPERIMENTAL APPROACH Daily injections of 5A peptide, a synthetic bihelical apoA-I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v(-1) ) dextran sodium sulfate (DSS) in drinking water or healthy controls. KEY RESULTS Daily treatment with 5A peptide potently restricted DSS-induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNFα and IL-6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein-1 and the monocyte expression of adhesion-mediating molecule CD11b were down-regulated, pro-inflammatory CD11b(+) /Ly6c(high) monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide-treated animals as determined by intravital macrophage-related peptide-8/14-directed fluorescence-mediated tomography and post-mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM-1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNFα-stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS-induced inflammation was noted in apoA-I(-/-) mice. CONCLUSIONS AND IMPLICATIONS The 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA-I mimetics as a potential treatment approach for IBD.
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Affiliation(s)
- Tobias M Nowacki
- Department of Medicine B, University Hospital Münster, Münster, Germany
| | - Alan T Remaley
- National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Michel Eisenblätter
- Translational Research Imaging Center, Department of Clinical Radiology, University Hospital Münster, Münster, Germany
| | - Thorsten Vowinkel
- Department of General and Visceral Surgery, University Hospital Münster, Münster, Germany
| | - Felix Becker
- Department of General and Visceral Surgery, University Hospital Münster, Münster, Germany
| | - Thomas Vogl
- Institute of Immunology, University Hospital Münster, Münster, Germany
| | - Johannes Roth
- Institute of Immunology, University Hospital Münster, Münster, Germany
| | - Uwe J Tietge
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, GZ Groningen, The Netherlands
| | | | - Jan Heidemann
- Department of Medicine B, University Hospital Münster, Münster, Germany.,Department of Gastroenterology, Klinikum Bielefeld, Bielefeld, Germany
| | - Jerzy-Roch Nofer
- Center for Laboratory Medicine, University Hospital Münster, Münster, Germany
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Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, Faicchia D, Marone G, Tramontano D, Corona M, Alviggi C, Porcellini A, La Cava A, Mauri P, Matarese G. The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements. Immunity 2016; 44:406-21. [PMID: 26885861 PMCID: PMC4760097 DOI: 10.1016/j.immuni.2016.01.028] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 07/29/2015] [Accepted: 11/13/2015] [Indexed: 11/23/2022]
Abstract
Human CD4+CD25hiFoxp3+CD127− Treg and CD4+CD25−Foxp3− Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.
Ex vivo human Treg cells are highly glycolytic and proliferating Ex vivo human Tconv cells use fatty-acid oxidation (FAO) and are non-proliferating In vitro proliferation of human Treg cells requires both glycolysis and FAO In vitro proliferation of human Tconv cells relies mainly on glycolysis
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Affiliation(s)
- Claudio Procaccini
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy
| | - Fortunata Carbone
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy
| | - Dario Di Silvestre
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), 20090 Segrate, Milano, Italy
| | - Francesca Brambilla
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), 20090 Segrate, Milano, Italy
| | - Veronica De Rosa
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Unità di NeuroImmunologia, IRCCS Fondazione Santa Lucia, 00143 Roma, Italy
| | - Mario Galgani
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy
| | - Deriggio Faicchia
- Dipartimento di Scienze Mediche Traslazionali e Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base Cliniche (CISI), Università di Napoli "Federico II," 80131 Napoli, Italy
| | - Gianni Marone
- Dipartimento di Scienze Mediche Traslazionali e Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base Cliniche (CISI), Università di Napoli "Federico II," 80131 Napoli, Italy
| | - Donatella Tramontano
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Napoli, Italy
| | - Marco Corona
- Istituto di Genetica e Biofisica "A. Buzzati-Traverso" Consiglio Nazionale delle Ricerche (IGB-CNR), 80131 Napoli, Italy
| | - Carlo Alviggi
- Dipartimento di Neuroscienze e Scienze Riproduttive e Odontostomatologiche, Università di Napoli "Federico II," 80131 Napoli, Italy
| | - Antonio Porcellini
- Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli 80126, Italy
| | - Antonio La Cava
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Pierluigi Mauri
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), 20090 Segrate, Milano, Italy; Istituto di Scienze della Vita, Scuola Superiore Sant'Anna, 56127 Pisa, Italy
| | - Giuseppe Matarese
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Napoli, Italy.
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Geronimo FRB, Barter PJ, Rye KA, Heather AK, Shearston KD, Rodgers KJ. Plaque stabilizing effects of apolipoprotein A-IV. Atherosclerosis 2016; 251:39-46. [PMID: 27240254 DOI: 10.1016/j.atherosclerosis.2016.04.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 03/20/2016] [Accepted: 04/24/2016] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS Apolipoprotein (apo) A-IV, the third most abundant HDL-associated protein, is atheroprotective and shares similar properties as apoA-I. We have reported previously that apoA-I, the most abundant apolipoprotein in HDL, inhibits plaque disruption in a mouse model. We aimed at examining the effects of apoA-IV on markers of plaque stability in vivo. METHODS Plaques within brachiocephalic arteries of 16-week old apoE-knockout C57BL/6 mice were examined for changes in composition after 10 weeks on a high-fat diet (HFD). The animals received twice-weekly injections of human lipid-free apoA-IV (1 mg/kg, n = 31) or PBS (n = 32) during the 9th and 10th weeks of the HFD. RESULTS In the apoA-IV treated mice, there were significantly fewer hemorrhagic plaque disruptions (9/31 vs. 18/32, p < 0.05), thicker fibrous caps, smaller lipid cores, a lower macrophage:SMC ratio, less MMP-9 protein, more collagen, and fewer proliferating cells. In the plaques of mice given apoA-IV, MCP-1, VCAM-1, and inducible NOS were also significantly lower. Based on the percentage of cleaved PARP-positive and TUNEL-positive plaque nuclei, apoA-IV reduced apoptosis. in HMDMs, apoA-IV reduced MMP-9 mRNA expression by half, doubled mRNA levels of TIMP1 and decreased MMP-9 activity. CONCLUSIONS ApoA-IV treatment is associated with a more stable plaque phenotype and a reduced incidence of acute disruptions in this mouse model.
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Affiliation(s)
| | - P J Barter
- School of Medical Sciences, University of New South Wales, Australia.
| | - K A Rye
- School of Medical Sciences, University of New South Wales, Australia.
| | - A K Heather
- The Heart Research Institute, Sydney, Australia; School of Medical Sciences, University of Otago, Dunedin, New Zealand.
| | - K D Shearston
- School of Dentistry, University of Western Australia, Australia.
| | - K J Rodgers
- School of Life Sciences, Faculty of Science, University of Technology, Sydney, Australia.
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50
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Yu S, Li S, Henke A, Muse ED, Cheng B, Welzel G, Chatterjee AK, Wang D, Roland J, Glass CK, Tremblay M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. FASEB J 2016; 30:2570-9. [PMID: 27025962 DOI: 10.1096/fj.201600244r] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 03/21/2016] [Indexed: 12/26/2022]
Abstract
Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.
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Affiliation(s)
- Shan Yu
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Sijia Li
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Adam Henke
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Evan D Muse
- Department of Cellular and Molecular Medicine and Scripps Translational Science Institute, Scripps Health, La Jolla, California, USA and
| | - Bo Cheng
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Gustav Welzel
- California Institute for Biomedical Research, La Jolla, California, USA
| | | | - Danling Wang
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Jason Roland
- California Institute for Biomedical Research, La Jolla, California, USA
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine and Department of Medicine, University of California, San Diego, La Jolla, California, USA; and
| | - Matthew Tremblay
- California Institute for Biomedical Research, La Jolla, California, USA;
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