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Kume H, Kazama K, Sato R, Sato Y. Possible Involvement of Lysophospholipids in Severe Asthma as Novel Lipid Mediators. Biomolecules 2025; 15:182. [PMID: 40001485 PMCID: PMC11852450 DOI: 10.3390/biom15020182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/25/2024] [Accepted: 01/02/2025] [Indexed: 02/27/2025] Open
Abstract
In severe asthma, symptoms are unstable despite intensive treatment based on high doses of inhaled corticosteroids and on-demand use of oral corticosteroids. Although, recently, various biological agents related to Th2 cytokines have been added to intensive controller medications for severe asthma, a significant progress has not been observed in the management for symptoms (dyspnea, wheezing and cough). Medical treatment focused on Type 2 inflammation is probably insufficient to maintain good long-term management for severe asthma. Airway eosinophilia and decreased reversibility in forced expiratory volume in 1 second (FEV1) are listed as major predictors for exacerbation-prone asthma. However, it is generally considered that asthma is complex and heterogeneous. It is necessary to establish precision medicine using treatable traits based on a multidimensional approach related to asthma. Since phospholipids generate lysophospholipids and arachidonic acid by phospholipases, lysophospholipids can be associated with the pathogenesis of this disease via action on smooth muscle, endothelium, and epithelium in the airways. Lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosine 1-phosphate (S1P) are increased in bronchoalveolar fluid after allergen challenge. LPA, LPC, and S1P recruit eosinophils to the lungs and cause β2-adrenergic desensitization. LAP and S1P cause contraction and hyperresponsiveness in airway smooth muscle. Moreover, lysophosphatidylserine and S1P are associated with the allergic reaction related to IgE/FcεRI in mast cells. Lysophospholipid action is probably comprised of corticosteroid resistance and is independent of Type 2 inflammation, and may be corelated with oxidative stress. Lysophospholipids may be a novel molecular target in advancing the management and treatment of asthma. This review discusses the clinical relevance of lysophospholipids in asthma.
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Affiliation(s)
- Hiroaki Kume
- Department of Infectious Diseases and Respiratory Medicine, Fukushima Medical University Aizu Medical Center, 21-2 Maeda, Tanisawa, Kawahigashi, Aizuwakamatsu 969-3492, Japan; (K.K.); (R.S.); (Y.S.)
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Turpin J, Wadolowski S, Tambo W, Kim D, Al Abed Y, Sciubba DM, Becker LB, Ledoux D, Kim J, Powell K, Li C. Exploring Lysophosphatidylcholine as a Biomarker in Ischemic Stroke: The Plasma-Brain Disjunction. Int J Mol Sci 2024; 25:10649. [PMID: 39408978 PMCID: PMC11477326 DOI: 10.3390/ijms251910649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 09/27/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Lipids and their bioactive metabolites, notably lysophosphatidylcholine (LPC), are increasingly important in ischemic stroke research. Reduced plasma LPC levels have been linked to stroke occurrence and poor outcomes, positioning LPC as a potential prognostic or diagnostic marker. Nonetheless, the connection between plasma LPC levels and stroke severity remains unclear. This study aimed to elucidate this relationship by examining plasma LPC levels in conjunction with brain LPC levels to provide a deeper understanding of the underlying mechanisms. Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly assigned to different groups (sham-operated, vehicle, LPC supplementation, or LPC inhibition). We measured multiple LPC species in the plasma and brain, alongside assessing sensorimotor dysfunction, cerebral perfusion, lesion volume, and markers of BBB damage, inflammation, apoptosis, and oxidative stress. Among five LPC species, plasma LPC(16:0) and LPC(18:1) showed strong correlations with sensorimotor dysfunction, lesion severity, and mechanistic biomarkers in the rat stroke model. Despite notable discrepancies between plasma and brain LPC levels, both were strongly linked to functional outcomes and mechanistic biomarkers, suggesting that LPC's prognostic value is retained extracranially. This study advances the understanding of LPC as a blood marker in ischemic stroke and highlights directions for future research to further elucidate its association with stroke severity, particularly through investigations in more clinically representative models.
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Affiliation(s)
- Justin Turpin
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
| | - Steven Wadolowski
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
| | - Willians Tambo
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, New York, NY 11030, USA
| | - Daniel Kim
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Biology Department, Boston College, Chestnut Hill, MA 02467, USA
| | - Yousef Al Abed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, New York, NY 11030, USA
| | - Daniel M. Sciubba
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Lance B. Becker
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, New York, NY 11030, USA
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
| | - David Ledoux
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Junhwan Kim
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Laboratory for Critical Care Physiology, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
| | - Keren Powell
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
| | - Chunyan Li
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
- Translational Brain Research Laboratory, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, NY 11030, USA
- Elmezzi Graduate School of Molecular Medicine at Northwell Health, Manhasset, New York, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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Wang L, Li H, Zhang H, Song X, Jiang H, Wang D, Wang Y. Serum-based metabolomics reveals the mechanism of action of isorhynchophylline in the intervention of atherosclerosis in ApoE -/- mice. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2024; 16:1083-1092. [PMID: 38284158 DOI: 10.1039/d3ay01803b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease with disorders of lipid metabolism. Metabolic disorders, inflammation and lipid deposition are prominent pathological features of atherosclerosis. Isorhynchophylline (IRN) has pharmacological effects such as protection of vascular endothelial cells, anti-inflammatory, anti-thrombotic, and anti-smooth muscle cell proliferation. However, it is unclear whether IRN is efficacious in atherosclerosis. In the present study, we verified the pharmacological efficacy and hepatoprotective effects of IRN in intervening in AS. LC-MS-based serum untargeted metabolomics was performed to search for potential biomarkers and related pathways in IRN-treated AS in ApoE-/- mice. Fifty-eight biomarkers were metabolically disturbed in the model mice compared to controls. Thirteen biomarkers showed optimal recovery methods after IRN-40 mg ml-1 intervention. We identified three metabolic pathways involved in IRN: glycerophospholipid metabolism, linoleic acid metabolism, and alpha-linolenic acid metabolism. These findings provide a research basis for the intervention of IRN in atherosclerosis.
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Affiliation(s)
- Lihua Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Haichao Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Hao Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Xiayinan Song
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Haiqiang Jiang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
- Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Danyang Wang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
| | - Yu Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, China.
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Li X, Yin Z, Yan W, Wang M, Chang C, Guo C, Xue L, Zhou Q, Sun Y. Association between Changes in Plasma Metabolism and Clinical Outcomes of Sepsis. Emerg Med Int 2023; 2023:2590115. [PMID: 37346225 PMCID: PMC10281824 DOI: 10.1155/2023/2590115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 04/06/2023] [Accepted: 04/25/2023] [Indexed: 06/23/2023] Open
Abstract
Current prognostic biomarkers for sepsis have limited sensitivity and specificity. This study aimed to investigate dynamic lipid metabolomics and their association with septic immune response and clinical outcomes of sepsis. This prospective cohort study included patients with sepsis who met the Sepsis 3.0 criteria. On hospitalization days 1 (D1) and 7 (D7), plasma samples were collected, and patients underwent liquid chromatography with tandem mass spectrometry. A total of 40 patients were enrolled in the study, 24 (60%) of whom were men. The median age of the enrolled patients was 81 (68-84) years. Thirty-one (77.5%) patients had a primary infection site of the lung. Participants were allocated to the survivor (25 cases) and nonsurvivor (15 cases) groups based on their 28-day survival status. Ultimately, a total of 113 lipids were detected in plasma samples on D 1 and D 7, of which 42 lipids were most abundant in plasma samples. The nonsurvival group had significantly lower lipid expression levels in lysophosphatidylcholine (LysoPC) (16 : 0, 17 : 0,18 : 0) and 18 : 1 SM than those in the survival group (p < 0.05) on D7-D1. The correlation analysis showed that D7-D1 16 : 0 LysoPC (r = 0.367, p = 0.036),17 : 0 LysoPC (r = 0.389, p = 0.025) and 18 : 0 LysoPC(r = 0.472, p = 0.006) levels were positively correlated with the percentage of CD3+ T cell in the D7-D1. Plasma LysoPC and SM changes may serve as prognostic biomarkers for sepsis, and lipid metabolism may play a role in septic immune disturbances.
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Affiliation(s)
- Xin Li
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Zhongnan Yin
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Biobank, Peking University Third Hospital, Beijing 100191, China
| | - Wei Yan
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Meng Wang
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Chun Chang
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Chenglin Guo
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Lixiang Xue
- Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Biobank, Peking University Third Hospital, Beijing 100191, China
| | - Qingtao Zhou
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Yongchang Sun
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China
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Menanteau-Ledouble S, Skov J, Lukassen MB, Rolle-Kampczyk U, Haange SB, Dalsgaard I, von Bergen M, Nielsen JL. Modulation of gut microbiota, blood metabolites, and disease resistance by dietary β-glucan in rainbow trout (Oncorhynchus mykiss). Anim Microbiome 2022; 4:58. [PMID: 36404315 PMCID: PMC9677660 DOI: 10.1186/s42523-022-00209-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Prebiotics are known to have a positive impact on fish health and growth rate, and β-glucans are among the most used prebiotics on the market. In this study, rainbow trout (Oncorhynchus mykiss) were treated with a β-1,3;1,6-glucan dietary supplement (at a dose of 0 g, 1 g, 10 g, and 50 g β-glucan per kg of feed). After 6 weeks, the effect of the β-glucan was evaluated by determining the changes in the microbiota and the blood serum metabolites in the fish. The impact of β-glucan on the immune system was evaluated through a challenge experiment with the bacterial fish pathogen Yersinia ruckeri. RESULTS The microbiota showed a significant change in terms of composition following β-glucan treatment, notably an increase in the relative abundance of members of the genus Aurantimicrobium, associated with a decreased abundance of the genera Carnobacterium and Deefgea. Furthermore, analysis of more than 200 metabolites revealed that the relative levels of 53 metabolites, in particular compounds related to phosphatidylcholines, were up- or downregulated in response to the dietary supplementation, this included the amino acid alanine that was significantly upregulated in the fish that had received the highest dose of β-glucan. Meanwhile, no strong effect could be detected on the resistance of the fish to the bacterial infection. CONCLUSIONS The present study illustrates the ability of β-glucans to modify the gut microbiota of fish, resulting in alteration of the metabolome and affecting fish health through the lipidome of rainbow trout.
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Affiliation(s)
- Simon Menanteau-Ledouble
- grid.5117.20000 0001 0742 471XDepartment of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220 Aalborg East, Denmark
| | - Jakob Skov
- grid.5254.60000 0001 0674 042XDepartment of Veterinary and Animal Sciences, University of Copenhagen, Grønnegårdsvej 15, 1870 Frederiksberg C, Denmark ,grid.5170.30000 0001 2181 8870National Institute of Aquatic Resources, Technical University of Denmark, Kemitorvet, 2800 Kongens Lyngby, Denmark
| | - Mie Bech Lukassen
- grid.5117.20000 0001 0742 471XDepartment of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220 Aalborg East, Denmark
| | - Ulrike Rolle-Kampczyk
- grid.7492.80000 0004 0492 3830Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, UFZ, Permoserstr. 15, 04318 Leipzig, Germany
| | - Sven-Bastiaan Haange
- grid.7492.80000 0004 0492 3830Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, UFZ, Permoserstr. 15, 04318 Leipzig, Germany
| | - Inger Dalsgaard
- grid.5170.30000 0001 2181 8870National Institute of Aquatic Resources, Technical University of Denmark, Kemitorvet, 2800 Kongens Lyngby, Denmark
| | - Martin von Bergen
- grid.7492.80000 0004 0492 3830Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, UFZ, Permoserstr. 15, 04318 Leipzig, Germany ,grid.421064.50000 0004 7470 3956German Centre for Integrative Biodiversity Research, (iDiv) Halle-Jena-Leipzig, Puschstraße 4, 04103 Leipzig, Germany ,grid.9647.c0000 0004 7669 9786Institute of Biochemistry, Faculty of Life Sciences, University of Leipzig, Brüderstraße 34, 04103 Leipzig, Germany
| | - Jeppe Lund Nielsen
- grid.5117.20000 0001 0742 471XDepartment of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, 9220 Aalborg East, Denmark
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Fahrmann JF, Saini NY, Chia-Chi C, Irajizad E, Strati P, Nair R, Fayad LE, Ahmed S, Lee HJ, Iyer S, Steiner R, Vykoukal J, Wu R, Dennison JB, Nastoupil L, Jain P, Wang M, Green M, Westin J, Blumenberg V, Davila M, Champlin R, Shpall EJ, Kebriaei P, Flowers CR, Jain M, Jenq R, Stein-Thoeringer CK, Subklewe M, Neelapu SS, Hanash S. A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma. Cell Rep Med 2022; 3:100720. [PMID: 36384092 PMCID: PMC9729795 DOI: 10.1016/j.xcrm.2022.100720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 06/06/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022]
Abstract
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.
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Affiliation(s)
- Johannes F Fahrmann
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA
| | - Neeraj Y Saini
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Chang Chia-Chi
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Ehsan Irajizad
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA
| | - Paolo Strati
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Ranjit Nair
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Luis E Fayad
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Sairah Ahmed
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Hun Ju Lee
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Swaminathan Iyer
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Raphael Steiner
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Jody Vykoukal
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA
| | - Ranran Wu
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA
| | - Jennifer B Dennison
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA
| | - Loretta Nastoupil
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Preetesh Jain
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Michael Wang
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Michael Green
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Jason Westin
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Viktoria Blumenberg
- Department of Medicine III, University Hospital, LMU Munich, 81377 Munich, Germany; National Center for Tumor Diseases (NCT), Neuenheimer Feld 460, 69120 Heidelberg, Germany
| | - Marco Davila
- Department of Blood and Marrow Transplant and Cellular Therapy, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Richard Champlin
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Partow Kebriaei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Christopher R Flowers
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Michael Jain
- Department of Blood and Marrow Transplant and Cellular Therapy, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Robert Jenq
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Christoph K Stein-Thoeringer
- National Center for Tumor Diseases (NCT), Neuenheimer Feld 460, 69120 Heidelberg, Germany; German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany
| | - Marion Subklewe
- Department of Medicine III, University Hospital, LMU Munich, 81377 Munich, Germany; German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany; Laboratory for Translational Cancer Immunology, Gene Center of the LMU Munich, Munich, Germany.
| | - Sattva S Neelapu
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
| | - Sam Hanash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA.
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Dolgova EV, Kirikovich SS, Levites EV, Ruzanova VS, Proskurina AS, Ritter GS, Taranov OS, Varaksin NA, Ryabicheva TG, Leplina OY, Ostanin AA, Chernykh ER, Bogachev SS. Analysis of the Biological Properties of Blood Plasma Protein with GcMAF Functional Activity. Int J Mol Sci 2022; 23:8075. [PMID: 35897653 PMCID: PMC9330714 DOI: 10.3390/ijms23158075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
The main problem related to the studies focusing on group-specific component protein-derived macrophage-activating factor (GcMAF) is the lack of clarity about changes occurring in different types of macrophages and related changes in their properties under the effect of GcMAF in various clinical conditions. We analyzed the antitumor therapeutic properties of GcMAF in a Lewis carcinoma model in two clinical conditions: untreated tumor lesion and tumor resorption after exposure to Karanahan therapy. GcMAF is formed during site-specific deglycosylation of vitamin D3 binding protein (DBP). DBP was obtained from the blood of healthy donors using affinity chromatography on a column with covalently bound actin. GcMAF-related factor (GcMAF-RF) was converted in a mixture with induced lymphocytes through the cellular enzymatic pathway. The obtained GcMAF-RF activates murine peritoneal macrophages (p < 0.05), induces functional properties of dendritic cells (p < 0.05) and promotes in vitro polarization of human M0 macrophages to M1 macrophages (p < 0.01). Treatment of whole blood cells with GcMAF-RF results in active production of both pro- and anti-inflammatory cytokines. It is shown that macrophage activation by GcMAF-RF is inhibited by tumor-secreted factors. In order to identify the specific antitumor effect of GcMAF-RF-activated macrophages, an approach to primary reduction of humoral suppressor activity of the tumor using the Karanahan therapy followed by macrophage activation in the tumor-associated stroma (TAS) was proposed. A prominent additive effect of GcMAF-RF, which enhances the primary immune response activation by the Karanahan therapy, was shown in the model of murine Lewis carcinoma. Inhibition of the suppressive effect of TAS is the main condition required for the manifestation of the antitumor effect of GcMAF-RF. When properly applied in combination with any chemotherapy, significantly reducing the humoral immune response at the advanced tumor site, GcMAF-RF is a promising antitumor therapeutic agent that additively destroys the pro-tumor properties of macrophages of the tumor stroma.
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Affiliation(s)
- Evgeniya V. Dolgova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
| | - Svetlana S. Kirikovich
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
| | - Evgeniy V. Levites
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
| | - Vera S. Ruzanova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
- Department of Natural Sciences, Novosibirsk National Research State University, 630090 Novosibirsk, Russia
| | - Anastasia S. Proskurina
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
| | - Genrikh S. Ritter
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
| | - Oleg S. Taranov
- State Research Center of Virology and Biotechnology “Vector”, 630559 Koltsovo, Russia;
| | | | | | - Olga Yu. Leplina
- Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (O.Y.L.); (A.A.O.); (E.R.C.)
| | - Alexandr A. Ostanin
- Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (O.Y.L.); (A.A.O.); (E.R.C.)
| | - Elena R. Chernykh
- Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (O.Y.L.); (A.A.O.); (E.R.C.)
| | - Sergey S. Bogachev
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia; (E.V.D.); (S.S.K.); (E.V.L.); (V.S.R.); (A.S.P.); (G.S.R.)
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8
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Shan K, Feng N, Zhu D, Qu H, Fu G, Li J, Cui J, Chen H, Wang R, Qi Y, Chen YQ. Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells. Eur J Nutr 2022; 61:4059-4075. [PMID: 35804267 DOI: 10.1007/s00394-022-02940-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 06/15/2022] [Indexed: 02/07/2023]
Abstract
PURPOSE Ferroptosis is a form of regulated cell death that has the potential to be targeted as a cancer therapeutic strategy. But cancer cells have a wide range of sensitivities to ferroptosis, which limits its therapeutic potential. Accumulation of lipid peroxides determines the occurrence of ferroptosis. However, the type of lipid involved in peroxidation and the mechanism of lipid peroxide accumulation are less studied. METHODS The effects of fatty acids (10 μM) with different carbon chain length and unsaturation on ferroptosis were evaluated by MTT and LDH release assay in cell lines derived from prostate cancer (PC3, 22RV1, DU145 and LNCaP), colorectal cancer (HT-29), cervical cancer (HeLa) and liver cancer (HepG2). Inhibitors of apoptosis, necroptosis, autophagy and ferroptosis were used to determine the type of cell death. Then the regulation of reactive oxygen species (ROS) and lipid peroxidation by docosahexaenoic acid (DHA) was measured by HPLC-MS and flow cytometry. The avtive form of DHA was determined by siRNA mediated gene silencing. The role of lipoxygenases was checked by inhibitors and gene silencing. Finally, the effect of DHA on ferroptosis-mediated tumor killing was verified in xenografts. RESULTS The sensitivity of ferroptosis was positively correlated with the unsaturation of exogenously added fatty acid. DHA (22:6 n-3) sensitized cancer cells to ferroptosis-inducing reagents (FINs) at the highest level in vitro and in vivo. In this process, DHA increased ROS accumulation, lipid peroxidation and protein oxidation independent of its membrane receptor, GPR120. Inhibition of long chain fatty acid-CoA ligases and lysophosphatidylcholine acyltransferases didn't affect the role of DHA. DHA-involved ferroptosis can be induced in both arachidonate lipoxygenase 5 (ALOX5) negative and positive cells. Down regulation of ALOX5 inhibited ferroptosis, while overexpression of ALOX5 promoted ferroptosis. CONCLUSION DHA can effectively promote ferroptosis-mediated tumor killing by increasing intracellular lipid peroxidation. Both ALOX5 dependent and independent pathways are involved in DHA-FIN induced ferroptosis. And during this process, free DHA plays an important role.
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Affiliation(s)
- Kai Shan
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Ninghan Feng
- Department of Urology, Wuxi No. 2 People's Hospital, Wuxi, 214000, Jiangsu Province, China
| | - Doudou Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Hongyan Qu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Guoling Fu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Jiaqi Li
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Jing Cui
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Heyan Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Rong Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Yumin Qi
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China
| | - Yong Q Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China.
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu Province, China.
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9
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Yao Y, Du Jiang P, Chao BN, Cagdas D, Kubo S, Balasubramaniyam A, Zhang Y, Shadur B, NaserEddin A, Folio LR, Schwarz B, Bohrnsen E, Zheng L, Lynberg M, Gottlieb S, Leney-Greene MA, Park AY, Tezcan I, Akdogan A, Gocmen R, Onder S, Rosenberg A, Soilleux EJ, Johnson E, Jackson PK, Demeter J, Chauvin SD, Paul F, Selbach M, Bulut H, Clatworthy MR, Tuong ZK, Zhang H, Stewart BJ, Bosio CM, Stepensky P, Clare S, Ganesan S, Pascall JC, Daumke O, Butcher GW, McMichael AJ, Simon AK, Lenardo MJ. GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans. J Exp Med 2022; 219:213217. [PMID: 35551368 PMCID: PMC9111091 DOI: 10.1084/jem.20201405] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 01/18/2022] [Accepted: 03/16/2022] [Indexed: 11/26/2022] Open
Abstract
Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6−/− mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)–containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6−/− mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.
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Affiliation(s)
- Yikun Yao
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Ping Du Jiang
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Brittany N Chao
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD.,Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Deniz Cagdas
- Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.,Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey.,Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Satoshi Kubo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Arasu Balasubramaniyam
- Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 6, Berlin, Germany
| | - Yu Zhang
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Bella Shadur
- Hadassah University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Jerusalem, Israel.,The Garvan Institute of Medical Research, Immunology Division, Darlinghurst, Sydney, Australia.,St Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, Australia
| | - Adeeb NaserEddin
- Hadassah University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Jerusalem, Israel
| | - Les R Folio
- Clinical Center, National Institutes of Health, Bethesda, MD
| | - Benjamin Schwarz
- Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Eric Bohrnsen
- Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Lixin Zheng
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Matthew Lynberg
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Simone Gottlieb
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Michael A Leney-Greene
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Ann Y Park
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Ilhan Tezcan
- Division of Immunology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.,Department of Pediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Turkey.,Ihsan Dogramaci Childrens Hospital, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ali Akdogan
- Division of Rheumatology, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Rahsan Gocmen
- Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sevgen Onder
- Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Avi Rosenberg
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.,Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD
| | | | - Errin Johnson
- The Dunn School of Pathology, South Parks Road, Oxford, UK
| | - Peter K Jackson
- Baxter Laboratory, Departments of Microbiology & Immunology and Pathology Stanford University School of Medicine, Stanford, CA
| | - Janos Demeter
- Baxter Laboratory, Departments of Microbiology & Immunology and Pathology Stanford University School of Medicine, Stanford, CA
| | - Samuel D Chauvin
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
| | - Florian Paul
- Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Matthias Selbach
- Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Haydar Bulut
- Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 6, Berlin, Germany
| | - Menna R Clatworthy
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.,Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Zewen K Tuong
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.,Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Hanlin Zhang
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Benjamin J Stewart
- Molecular Immunity Unit, University of Cambridge Department of Medicine, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.,Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Catharine M Bosio
- Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - Polina Stepensky
- Hadassah University Medical Center, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Jerusalem, Israel
| | - Simon Clare
- Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK
| | - Sundar Ganesan
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, Rockville, MD
| | - John C Pascall
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, UK
| | - Oliver Daumke
- Crystallography, Max-Delbrück-Centrum for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 6, Berlin, Germany
| | - Geoffrey W Butcher
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, UK
| | - Andrew J McMichael
- Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Anna Katharina Simon
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford, UK
| | - Michael J Lenardo
- Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.,National Institute of Allergy and Infectious Diseases Clinical Genomics Program, Rockville, MD
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10
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Shen CL, Mo H, Dunn DM, Watkins BA. Tocotrienol Supplementation Led to Higher Serum Levels of Lysophospholipids but Lower Acylcarnitines in Postmenopausal Women: A Randomized Double-Blinded Placebo-Controlled Clinical Trial. Front Nutr 2022; 8:766711. [PMID: 35004805 PMCID: PMC8740329 DOI: 10.3389/fnut.2021.766711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/22/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis is a major health problem in postmenopausal women. Herein we evaluated the effects of 12-week tocotrienols (TT) supplementation on serum metabolites in postmenopausal, osteopenic women. Eighty-nine participants (59.7 ± 6.8 yr, BMI 28.7 ± 5.7 kg/m2) were assigned to 3 treatments: placebo (860 mg olive oil/day), 300mg TT (300 mg TT/day), and 600mg TT (600 mg TT/day) for 12 weeks. TT consisted of 90% δ-TT and 10% γ-TT. In this metabolomic study, we evaluated the placebo and 600mgTT at baseline and 12 weeks. As expected, TT and its metabolite levels were higher in the supplemented group after 12 weeks. At baseline, there were no differences in demographic parameters or comprehensive metabolic panels (CMP). Metabolomics analysis of serum samples revealed that 48 biochemicals were higher and 65 were lower in the 600mg TT group at 12 weeks, compared to baseline. The results confirmed higher serum levels of tocotrienols and lysophospholipids, but lower acylcarnitines and catabolites of tryptophan and steroids in subjects given 600mg TT. In summary, 12-week TT supplementation altered many serum metabolite levels in postmenopausal women. The present study supports our previous findings that TT supplementation helps reduce bone loss in postmenopausal osteopenic women by suppressing inflammation and oxidative stress. Furthermore, the body incorporates TT which restructures biomembranes and modifies phospholipid metabolism, a response potentially linked to reduced inflammation and oxidative stress.
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Affiliation(s)
- Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, United States.,Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, United States.,Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Huanbiao Mo
- Nutrition, Georgia State University, Atlanta, GA, United States
| | - Dale M Dunn
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Bruce A Watkins
- Department of Nutrition, University of California, Davis, Davis, CA, United States
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11
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Parra-Millán R, Jiménez-Mejías ME, Ayerbe-Algaba R, Domínguez-Herrera J, Díaz C, Pérez Del Palacio J, Pachón J, Smani Y. Impact of the immune response modification by lysophosphatidylcholine in the efficacy of antibiotic therapy of experimental models of peritoneal sepsis and pneumonia by Pseudomonas aeruginosa: LPC therapeutic effect in combined therapy. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2022; 40:14-21. [PMID: 34991848 DOI: 10.1016/j.eimce.2020.06.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/15/2020] [Indexed: 06/14/2023]
Abstract
INTRODUCTION Immune response stimulation may be an adjuvant to antimicrobial treatment. Here, we evaluated the impact of immune response modification by lysophosphatidylcholine (LPC), combined with imipenem or ceftazidime, in murine models of peritoneal sepsis (PS) and pneumonia induced by Pseudomonas aeruginosa. METHODS The imipenem and ceftazidime-susceptible strain (Pa39) and imipenem and ceftazidime-resistant strain (Pa238) were used. Ceftazidime pharmacokinetic and pharmacodynamic parameters were determined. The therapeutic efficacy and TNF-α and IL-10 levels were determined in murine models of PS and pneumonia induced by Pa39 and Pa238 and treated with LPC, imipenem or ceftazidime, alone or in combination. RESULTS In the PS model, LPC+ceftazidime reduced spleen and lung Pa238 concentrations (-3.45 and -3.56log10CFU/g; P<0.05) to a greater extent than ceftazidime monotherapy, while LPC+imipenem maintained the imipenem efficacy (-1.66 and -1.45log10CFU/g; P>0.05). In the pneumonia model, LPC+ceftazidime or LPC+imipenem reduced the lung Pa238 concentrations (-2.37log10CFU/g, P=0.1, or -1.35log10CFU/g, P=0.75). For Pa39, no statistically significant difference was observed in the PS and pneumonia models between combined therapy and monotherapy. Moreover, LPC+imipenem and LPC+ceftazidime significantly decreased and increased the TNF-α and IL-10 levels, respectively, in comparison with the untreated controls and monotherapies. CONCLUSIONS These results demonstrate the impact of immune response modification by LPC plus antibiotics on the prognosis of infections induced by ceftazidime-resistant P. aeruginosa.
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Affiliation(s)
- Raquel Parra-Millán
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Manuel E Jiménez-Mejías
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
| | - Rafael Ayerbe-Algaba
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Juan Domínguez-Herrera
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Caridad Díaz
- Fundación Centro De Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Fundación MEDINA, Granada, Spain
| | - José Pérez Del Palacio
- Fundación Centro De Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Fundación MEDINA, Granada, Spain
| | - Jerónimo Pachón
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Younes Smani
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
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12
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El-Katcha MI, Soltan MA, Shewita R, Abdo SE, Sanad AS, Tufarelli V, Alagawany M, El-Naggar K. Dietary Fiber and Lysolecithin Supplementation in Growing Ducks: Effect on Performance, Immune Response, Intestinal Morphology and Lipid Metabolism-Regulating Genes. Animals (Basel) 2021; 11:ani11102873. [PMID: 34679893 PMCID: PMC8532726 DOI: 10.3390/ani11102873] [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: 08/17/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary Searching for and introducing unconventional feeds in ducks’ diets has become a major concern. However, low-priced feed ingredients such as rice bran and seed hulls are generally low in energy with high dietary fiber content. Thus, this study focused on the effects of different dietary fiber levels (with or without lysolecithin) on the performance, immune response, expression of some lipid regulating genes, and intestinal morphology of ducks. From our results, increasing fiber level in the diet (with or without the addition of lysolecithin) altered duck performance and intestinal morphology, improved immunity, and lowered serum lipid profile with a modulatory effect on the expression of lipid metabolism-regulating genes. Abstract The impact of different dietary fiber (DF) levels (with or without lysolecithin supplementation) on growth performance, immune response, expression of some lipid regulating genes and intestinal morphology was assessed in 408 Pekin ducks for 2 months. Soybean hulls were added to the diet to provide four different levels of DF: 2.4 (control diet), 3.8, 5.3, and 6.7% for the first four groups, respectively, while groups 5 to 8 fed the same four levels of DF with lysolecithin addition. Increasing dietary DF non-significantly reduced (p > 0.05) the ducks’ body weight (BW). However, ducks fed on 3.8% DF showed higher BW and improved feed conversion ratio. Lysolecithin supplementation with different DF did not support growth performance. Increasing DF with or without lysolecithin had no effect on serum lipid profile (p > 0.05). However, serum high-density lipoproteins (HDL) concentration was significantly increased with increasing fiber level in diet (p ˂ 0.05). Increasing DF with or without lysolecithin addition increased serum antioxidant activities and improved the immune response in terms of phagocytic and lysozyme activities. The DF level reduced the duodenal villi length and mucosal layer thickness while increased the villi width (p ˂ 0.05). Lysolecithin supplementation to diets ameliorated adverse effects on intestinal morphology. Moreover, DF level in ducks’ diet with or without lysolecithin significantly upregulated the expression of fatty acid synthase and lipoprotein lipase (p ˂ 0.05). Thus, it could be concluded that ducks fed on soybean hulls containing a diet at the level of 4.5% and providing 3.8% fiber level with or without lysolecithin showed the best performance.
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Affiliation(s)
- Mohamed I. El-Katcha
- Nutrition and Veterinary Clinical Nutrition Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.I.E.-K.); (M.A.S.); (R.S.); (K.E.-N.)
| | - Mosaad A. Soltan
- Nutrition and Veterinary Clinical Nutrition Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.I.E.-K.); (M.A.S.); (R.S.); (K.E.-N.)
| | - Ramadan Shewita
- Nutrition and Veterinary Clinical Nutrition Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.I.E.-K.); (M.A.S.); (R.S.); (K.E.-N.)
| | - Safaa E. Abdo
- Genetics and Genetic Engineering, Department of Animal Wealth Development, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Amr S. Sanad
- Veterinarian, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Vincenzo Tufarelli
- Department of DETO, Section of Veterinary Science and Animal Production, University of Bari ‘Aldo Moro’, 70010 Valenzano, Italy
- Correspondence: (V.T.); (M.A.)
| | - Mahmoud Alagawany
- Department of Poultry, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
- Correspondence: (V.T.); (M.A.)
| | - Karima El-Naggar
- Nutrition and Veterinary Clinical Nutrition Department, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt; (M.I.E.-K.); (M.A.S.); (R.S.); (K.E.-N.)
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13
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Barberis E, Timo S, Amede E, Vanella VV, Puricelli C, Cappellano G, Raineri D, Cittone MG, Rizzi E, Pedrinelli AR, Vassia V, Casciaro FG, Priora S, Nerici I, Galbiati A, Hayden E, Falasca M, Vaschetto R, Sainaghi PP, Dianzani U, Rolla R, Chiocchetti A, Baldanzi G, Marengo E, Manfredi M. Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2. Int J Mol Sci 2020; 21:E8623. [PMID: 33207699 PMCID: PMC7696386 DOI: 10.3390/ijms21228623] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 01/08/2023] Open
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.
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Affiliation(s)
- Elettra Barberis
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
| | - Sara Timo
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
- Department of Sciences and Technological Innovation, University of Piemonte Orientale, 28100 Alessandria, Italy
| | - Elia Amede
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
| | - Virginia V. Vanella
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
| | - Chiara Puricelli
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Giuseppe Cappellano
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Davide Raineri
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Micol G. Cittone
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Eleonora Rizzi
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Anita R. Pedrinelli
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Veronica Vassia
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Francesco G. Casciaro
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Simona Priora
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Ilaria Nerici
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Alessandra Galbiati
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Eyal Hayden
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy & Biomedical Sciences, Curtin University, Perth 6102, Australia;
| | - Rosanna Vaschetto
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
| | - Pier Paolo Sainaghi
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (M.G.C.); (E.R.); (A.R.P.); (V.V.); (F.G.C.); (S.P.); (I.N.); (A.G.); (E.H.); (P.P.S.)
- Azienda Ospedaliero-Universitaria “Maggiore della Carità”, 28100 Novara, Italy
| | - Umberto Dianzani
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Roberta Rolla
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Annalisa Chiocchetti
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (C.P.); (U.D.); (R.R.)
| | - Gianluca Baldanzi
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
| | - Emilio Marengo
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
- Department of Sciences and Technological Innovation, University of Piemonte Orientale, 28100 Alessandria, Italy
| | - Marcello Manfredi
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; (E.B.); (E.A.); (V.V.V.); (R.V.); (G.B.)
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, 28100 Novara, Italy; (S.T.); (G.C.); (D.R.); (A.C.); (E.M.)
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Parra-Millán R, Jiménez-Mejías ME, Ayerbe-Algaba R, Domínguez-Herrera J, Díaz C, Pérez Del Palacio J, Pachón J, Smani Y. Impact of the immune response modification by lysophosphatidylcholine in the efficacy of antibiotic therapy of experimental models of peritoneal sepsis and pneumonia by Pseudomonas aeruginosa: LPC therapeutic effect in combined therapy. Enferm Infecc Microbiol Clin 2020; 40:S0213-005X(20)30233-0. [PMID: 32674904 DOI: 10.1016/j.eimc.2020.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Immune response stimulation may be an adjuvant to antimicrobial treatment. Here, we evaluated the impact of immune response modification by lysophosphatidylcholine (LPC), combined with imipenem or ceftazidime, in murine models of peritoneal sepsis (PS) and pneumonia induced by Pseudomonas aeruginosa. METHODS The imipenem and ceftazidime-susceptible strain (Pa39) and imipenem and ceftazidime-resistant strain (Pa238) were used. Ceftazidime pharmacokinetic and pharmacodynamic parameters were determined. The therapeutic efficacy and TNF-α and IL-10 levels were determined in murine models of PS and pneumonia induced by Pa39 and Pa238 and treated with LPC, imipenem or ceftazidime, alone or in combination. RESULTS In the PS model, LPC+ceftazidime reduced spleen and lung Pa238 concentrations (-3.45 and -3.56log10CFU/g; P<0.05) to a greater extent than ceftazidime monotherapy, while LPC+imipenem maintained the imipenem efficacy (-1.66 and -1.45log10CFU/g; P>0.05). In the pneumonia model, LPC+ceftazidime or LPC+imipenem reduced the lung Pa238 concentrations (-2.37log10CFU/g, P=0.1, or -1.35log10CFU/g, P=0.75). For Pa39, no statistically significant difference was observed in the PS and pneumonia models between combined therapy and monotherapy. Moreover, LPC+imipenem and LPC+ceftazidime significantly decreased and increased the TNF-α and IL-10 levels, respectively, in comparison with the untreated controls and monotherapies. CONCLUSIONS These results demonstrate the impact of immune response modification by LPC plus antibiotics on the prognosis of infections induced by ceftazidime-resistant P. aeruginosa.
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Affiliation(s)
- Raquel Parra-Millán
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Manuel E Jiménez-Mejías
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.
| | - Rafael Ayerbe-Algaba
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Juan Domínguez-Herrera
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Caridad Díaz
- Fundación Centro De Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Fundación MEDINA, Granada, Spain
| | - José Pérez Del Palacio
- Fundación Centro De Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Fundación MEDINA, Granada, Spain
| | - Jerónimo Pachón
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Younes Smani
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain
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15
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Ma J, He JJ, Hou JL, Zhou CX, Elsheikha HM, Zhu XQ. Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Metabolomics Reveals Metabolic Alterations in the Mouse Cerebellum During Toxoplasma gondii Infection. Front Microbiol 2020; 11:1555. [PMID: 32765450 PMCID: PMC7381283 DOI: 10.3389/fmicb.2020.01555] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Toxoplasma gondii is a protozoan parasite with a remarkable neurotropism. We recently showed that T. gondii infection can alter the global metabolism of the cerebral cortex of mice. However, the impact of T. gondii infection on the metabolism of the cerebellum remains unknown. Here we apply metabolomic profiling to discover metabolic changes associated with T. gondii infection of the mouse cerebellum using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Multivariate statistics revealed differences in the metabolic profiles between the infected and control mouse groups and between the infected mouse groups as infection advanced. We also detected 10, 22, and 42 significantly altered metabolites (SAMs) in the infected cerebellum at 7, 14, and 21 days post infection (dpi), respectively. Four metabolites [tabersonine, arachidonic acid (AA), docosahexaenoic acid, and oleic acid] were identified as potential biomarker or responsive metabolites to T. gondii infection in the mouse cerebellum. Three of these metabolites (AA, docosahexaenoic acid, and oleic acid) play roles in the regulation of host behavior and immune response. Pathway analysis showed that T. gondii infection of the cerebellum involves reprogramming of amino acid and lipid metabolism. These results showcase temporal metabolomic changes during cerebellar infection by T. gondii in mice. The study provides new insight into the neuropathogenesis of T. gondii infection and reveals new metabolites and pathways that mediate the interplay between T. gondii and the mouse cerebellum.
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Affiliation(s)
- Jun Ma
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jun-Jun He
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jun-Ling Hou
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Chun-Xue Zhou
- Department of Parasitology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Hany M Elsheikha
- Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom
| | - Xing-Quan Zhu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
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16
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Knuplez E, Marsche G. An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System. Int J Mol Sci 2020; 21:E4501. [PMID: 32599910 PMCID: PMC7350010 DOI: 10.3390/ijms21124501] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/14/2022] Open
Abstract
Lysophosphatidylcholines are a group of bioactive lipids heavily investigated in the context of inflammation and atherosclerosis development. While present in plasma during physiological conditions, their concentration can drastically increase in certain inflammatory states. Lysophosphatidylcholines are widely regarded as potent pro-inflammatory and deleterious mediators, but an increasing number of more recent studies show multiple beneficial properties under various pathological conditions. Many of the discrepancies in the published studies are due to the investigation of different species or mixtures of lysophatidylcholines and the use of supra-physiological concentrations in the absence of serum or other carrier proteins. Furthermore, interpretation of the results is complicated by the rapid metabolism of lysophosphatidylcholine (LPC) in cells and tissues to pro-inflammatory lysophosphatidic acid. Interestingly, most of the recent studies, in contrast to older studies, found lower LPC plasma levels associated with unfavorable disease outcomes. Being the most abundant lysophospholipid in plasma, it is of utmost importance to understand its physiological functions and shed light on the discordant literature connected to its research. LPCs should be recognized as important homeostatic mediators involved in all stages of vascular inflammation. In this review, we want to point out potential pro- and anti-inflammatory activities of lysophospholipids in the vascular system and highlight recent discoveries about the effect of lysophosphatidylcholines on immune cells at the endothelial vascular interface. We will also look at their potential clinical application as biomarkers.
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Affiliation(s)
- Eva Knuplez
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Gunther Marsche
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
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17
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Levites EV, Kirikovich SS, Dolgova EV, Proskurina AS, Ritter GS, Ostanin АA, Chernykh ER, Bogachev SS. <i>In vitro</i> assay of biological activity of a national preparation of macrophage activating factor (GcMAF-RF). Vavilovskii Zhurnal Genet Selektsii 2020; 24:284-291. [PMID: 33659810 PMCID: PMC7905294 DOI: 10.18699/vj20.621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
В статье сообщается о разработанном оригинальном способе получения витамин D3-связывающего
белка (DBP) и его конвертации в макрофаг-активирующий фактор GcMAF-RF. Согласно разработанному
регламенту, DBP получали из плазмы крови человека, применяя аффинную колоночную хроматографию, очи-
щали и модифицировали до GcMAF-RF с использованием цитоиммобилизованных гликозидаз (бета-галакто-
зидаза и нейраминидаза). Принадлежность полученного полипептида к Gc-группе глобулинов плазмы крови
подтверждали вестерн-блотом с использованием специфических антител. Полученный полипептид по своим
молекулярным свойствам соответствует описанному в литературе белку GсMAF, находящемуся на стадии кли-
нических испытаний в США, Британии, Израиле и Японии (Saisei Mirai, Reno Integrative Medical Center, Immuno
Biotech Ltd, Efranat, Catalytic Longevity). Биологическую активность препарата GcMAF-RF определяли по индук-
ции у перитонеальных макрофагов мыши фагоцитарной активности и способности продуцировать моноок-
сид азота (NO) in vitro. Фагоцитарную активность макрофагов оценивали по эффективности захвата магнитных
шариков. Степень активации макрофагов рассчитывали по отношению числа захваченных шариков к общему
числу макрофагов. Уровень продукции NO оценивали по накоплению монооксида азота в культуральных су-
пернатантах перитонеальных макрофагов колориметрическим методом с использованием реактива Грисса.
Показано, что GcMAF-RF кратно увеличивает фагоцитарную активность макрофагов и достоверно увеличивает
продукцию ими монооксида азота. Выделенный оригинальным способом активатор макрофагов GcMAF-RF по
своим характеристикам (согласно материалам, опубликованным в печати) соответствует препаратам GcMAF,
представляемым на рынке зарубежными компаниями, и может рассматриваться как новый отечественный био-
логически активный препарат с широким спектром действия. Наибольший интерес вызывает его способность
через активацию макрофагов усиливать адаптивный иммунитет организма. В этой связи предполагаются два
направления терапевтического применения препарата GcMAF-RF. Препарат может быть востребован в области
лечения онкологических заболеваний и, кроме того, может быть использован при лечении ряда нейродегене-
ративных патологий и иммунодефицитных состояний.
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Affiliation(s)
- E. V. Levites
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - S. S. Kirikovich
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - E. V. Dolgova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - A. S. Proskurina
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
| | - G. S. Ritter
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University
| | | | | | - S. S. Bogachev
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences
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18
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Boontiam W, Hyun YK, Jung B, Kim YY. Effects of lysophospholipid supplementation to reduced energy, crude protein, and amino acid diets on growth performance, nutrient digestibility, and blood profiles in broiler chickens. Poult Sci 2020; 98:6693-6701. [PMID: 31801309 PMCID: PMC6869753 DOI: 10.3382/ps/pex005] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 01/04/2017] [Indexed: 01/13/2023] Open
Abstract
Two experiments investigated the effects of lysophospholipid (LPL) supplementation on low-energy and low-nitrogenous diets for broilers. A total of 300 one-day-old male chicks (Ross 308) was allotted to 5 treatments in a completely randomized design. Each group consisted of 6 replicates with 10 birds each. Experimental diet I included positive control (PC) having 3,025 (starter), 3,150 (grower), and 3,200 kcal/kg (finisher) of ME; negative control (NC) was 150 kcal/kg of ME lower than PC, and LPL-05, LPL-10, and LPL-15 treatments were NC + 0.05%, 0.10%, and 0.15% of LPL supplementation, respectively. Experimental diet II included positive control (PC) having a formulated amount of crude protein including Lys and Met + Cys that met the Ross 308 standards; negative control (NC) was 4% lower CP and AA than PC; other treatments were supplemented with LPL at 0.05% (LPL-05), 0.10% (LPL-10), and 0.15% (LPL-15) into the NC, respectively. Experiment I showed that growth performance linearly increased as the LPL inclusion increased (P < 0.001). Broilers fed LPL-10 and LPL-15 increased digestibility of DM (P < 0.05), crude protein (P < 0.01), and total amino acids (P < 0.01) compared to NC. Serum glucose (P < 0.01) and high-density lipoprotein (P < 0.05) concentrations were greater in groups fed LPL-10 than those fed PC. Furthermore, leg muscle increased in birds fed LPL-10 compared with NC (P < 0.05). Experiment II observed a linear response to LPL supplementation in the whole period, in terms of body weight gain (P = 0.015) and feed conversion ratio (P = 0.027). Feeding of 0.15% LPL had promising effects on digestibility of crude protein and ether extract compared with NC (P < 0.01 and P < 0.05, respectively). Overall, LPL could be considered as a feed additive to reduced energy (−150 kcal/kg) or nitrogenous diets (−5%) in order to improve growth performance and nutrient digestibility without adverse effects on lymphoid organs and hepatic enzyme of broilers.
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Affiliation(s)
- W Boontiam
- School of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, South Korea.,Faculty of Agriculture, Department of Animal Science, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Y K Hyun
- School of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, South Korea.,Easy Bio Inc., 310 Gangnam-daero, Gangnam-gu, Seoul 135-754, South Korea
| | - B Jung
- Easy Bio Inc., 310 Gangnam-daero, Gangnam-gu, Seoul 135-754, South Korea
| | - Y Y Kim
- School of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-921, South Korea
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19
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Miao R, Lung SC, Li X, Li XD, Chye ML. Thermodynamic insights into an interaction between ACYL-CoA-BINDING PROTEIN2 and LYSOPHOSPHOLIPASE2 in Arabidopsis. J Biol Chem 2019; 294:6214-6226. [PMID: 30782848 DOI: 10.1074/jbc.ra118.006876] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/12/2019] [Indexed: 12/17/2022] Open
Abstract
Lysophospholipids (LPLs) are important lipid-signaling molecules in plants, of which lysophosphatidylcholine (lysoPC) is one of the most well-characterized LPLs, having important roles in plant stress responses. It is broken down by lysophospholipases, but the molecular mechanism involved in lysoPC degradation is unclear. Recombinant Arabidopsis thaliana ACYL-CoA-BINDING PROTEIN2 (AtACBP2) has been reported to bind lysoPC via its acyl-CoA-binding domain and also LYSOPHOSPHOLIPASE 2 (AtLYSOPL2) via its ankyrin repeats in vitro To investigate the interactions of AtACBP2 with AtLYSOPL2 and lysoPC in more detail, we conducted isothermal titration calorimetry with AtACBP270-354, an AtACBP2 derivative consisting of amino acids 70-354, containing both the acyl-CoA-binding domain and ankyrin repeats. We observed that the interactions of AtACBP270-354 with AtLYSOPL2 and lysoPC were both endothermic, favored by solvation entropy and opposed by enthalpy, with dissociation constants in the micromolar range. Of note, three AtLYSOPL2 catalytic triad mutant proteins (S147A, D268A, and H298A) bound lysoPC only weakly, with an exothermic burst and dissociation constants in the millimolar range. Furthermore, the binding affinity of lysoPC-premixed AtACBP270-354 to AtLYSOPL2 was 10-fold higher than that of AtACBP270-354 alone to AtLYSOPL2. We conclude that AtACBP2 may play a role in facilitating a direct interaction between AtLYSOPL2 and lysoPC. Our results suggest that AtACBP270-354 probably binds to lysoPC through a hydrophobic interface that enhances a hydrotropic interaction of AtACBP270-354 with AtLYSOPL2 and thereby facilitates AtLYSOPL2's lysophospholipase function.
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Affiliation(s)
- Rui Miao
- From the School of Biological Sciences and
| | | | - Xin Li
- Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong and
| | - Xiang David Li
- Department of Chemistry, University of Hong Kong, Pokfulam Road, Hong Kong and
| | - Mee-Len Chye
- From the School of Biological Sciences and .,the State Key Laboratory of Agrobiotechnology, Chinese University of Hong Kong, Shatin N.T., Hong Kong, China
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20
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Batista WR, Fernandes FC, Neves MHCB, Nascimento TS, Lopes RSC, Lopes CC, Ziegler GP, Soler-Figueroa BM, Sparks D, Fontaine DN, Carney KJ, Quiñones-Oquendo LE, Ruiz GM. Synthetic lipids as a biocide candidate for disinfection of ballast water. MARINE POLLUTION BULLETIN 2018; 137:702-710. [PMID: 30503487 DOI: 10.1016/j.marpolbul.2018.11.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/06/2018] [Accepted: 11/09/2018] [Indexed: 06/09/2023]
Abstract
The objective of this study is to propose the use of specific synthetic lipid as an active substance (biocide) in the control of harmful aquatic microorganisms, such as pathogens and non-indigenous species, transported in ships' ballast water. The biocide candidate, without metal or halogen components, was produced from a sub-product of the edible oil industry, the lecithin. Laboratory assays were conducted with phytoplankton, zooplankton, and marine bacteria to evaluate the efficiency of the biocide. The study also considers specific biocide's characteristics related to environmental risks, such as chemical composition, persistence, bioaccumulation, and toxicity. Results showed that, in the first 24 h of treatment, the biocide effectively reduced the concentration of the planktonic micro-organisms to very low levels. Additionally, a preliminary risk evaluation pointed that biocide candidate has a low residual toxicity, also a low potential for persistence and bioaccumulation in the environment.
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Affiliation(s)
- William R Batista
- Instituto de Estudos do Mar Almirante Paulo Moreira, Marinha do Brasil, Rua Kioto 253, Praia dos Anjos, Arraial do Cabo, RJ 28930-000, Brazil.
| | - Flavio C Fernandes
- Instituto de Estudos do Mar Almirante Paulo Moreira, Marinha do Brasil, Rua Kioto 253, Praia dos Anjos, Arraial do Cabo, RJ 28930-000, Brazil
| | - Maria H C B Neves
- Instituto de Estudos do Mar Almirante Paulo Moreira, Marinha do Brasil, Rua Kioto 253, Praia dos Anjos, Arraial do Cabo, RJ 28930-000, Brazil
| | - Thiana S Nascimento
- Laboratório de Síntese e Análise de Produtos Estratégicos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Bloco A, s.508, Cidade Universitária, RJ 21941-909, Brazil
| | - Rosangela S C Lopes
- Laboratório de Síntese e Análise de Produtos Estratégicos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Bloco A, s.508, Cidade Universitária, RJ 21941-909, Brazil
| | - Claudio C Lopes
- Laboratório de Síntese e Análise de Produtos Estratégicos, Universidade Federal do Rio de Janeiro (UFRJ), Av. Athos da Silveira Ramos, 149, Bloco A, s.508, Cidade Universitária, RJ 21941-909, Brazil
| | - Gregory P Ziegler
- Wye Research and Education Center, University of Maryland, 124 Wye Narrows Drive, Queenstown, MD 21658-0169, USA
| | - Brenda M Soler-Figueroa
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
| | - Darrick Sparks
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
| | - Diana N Fontaine
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
| | - Katharine J Carney
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
| | - Luz E Quiñones-Oquendo
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
| | - Gregory M Ruiz
- Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, MD 21037-0028, USA
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21
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Wang R, Gu X, Dai W, Ye J, Lu F, Chai Y, Fan G, Gonzalez FJ, Duan G, Qi Y. A lipidomics investigation into the intervention of celastrol in experimental colitis. MOLECULAR BIOSYSTEMS 2017; 12:1436-44. [PMID: 27021137 DOI: 10.1039/c5mb00864f] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Celastrol is well known for its anti-inflammatory and anti-cancer effects. In this study, the efficacy of celastrol against dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mice was established and the mechanism was investigated using lipidomics. Celastrol treatment significantly alleviated DSS-induced colitis in mice, as revealed by the body weight, colon length, scores of rectal bleeding and diarrhea, serum TNF-α level, and histological analysis results. Lipidomics analysis based on UPLC/MS revealed characteristic changes in the metabolic profiles of the colitis mice, with altered levels of lipid markers associated with IBD, including LPC18 : 0, LPC18 : 1, LPC18 : 2, sphingomyelin (SM), and increased LPC18 : 0/LPC18 : 1 and LPC18 : 0/LPC18 : 2 ratios. For the celastrol-treated colitis mice, however, levels of the above lipid markers were restored, together with recovered saturated LPC/unsaturated LPC ratios. Accordingly, using GC-MS analysis, increased stearic acid (C18 : 0)/oleic acid (C18 : 1) and stearic acid (C18 : 0)/linoleic acid (C18 : 2) ratios were observed in colitis mice, which were later recovered after celastrol treatment. Quantitative real-time PCR analysis revealed that the liver expression of stearoyl-coenzyme A desaturase 1 (SCD1), the key enzyme controlling the desaturation of saturated fatty acid, was dramatically inhibited in IBD mice, and was obviously recovered after celastrol treatment. These results suggest that the increased saturated LPC/unsaturated LPC (and saturated fatty acid/unsaturated fatty acid) ratios associated with SCD1 down-regulation could be regarded as biomarkers of colitis, and celastrol alleviates DSS-induced colitis partially via up-regulation of SCD1, restoring the altered balance between stearic acid- and oleic acid-derived lipid species, which plays an important role in alleviating colitis. In all, this study provided the scientific basis for further development of celastrol in treating IBD.
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Affiliation(s)
- Renping Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Xueqin Gu
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Weiquan Dai
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Jun Ye
- Shanghai Zhabei Institute for Food and Drug Control, Shanghai 200436, China
| | - Feng Lu
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Yifeng Chai
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Guorong Fan
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Gengli Duan
- Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, Shanghai 201203, China.
| | - Yunpeng Qi
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China. and Department of Pharmaceutical Analysis, School of Pharmacy, Fudan University, Shanghai 201203, China.
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Full-Length cDNA Cloning, Molecular Characterization and Differential Expression Analysis of Lysophospholipase I from Ovis aries. Int J Mol Sci 2016; 17:ijms17081206. [PMID: 27483239 PMCID: PMC5000604 DOI: 10.3390/ijms17081206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/15/2016] [Accepted: 07/19/2016] [Indexed: 01/23/2023] Open
Abstract
Lysophospholipase I (LYPLA1) is an important protein with multiple functions. In this study, the full-length cDNA of the LYPLA1 gene from Ovis aries (OaLypla1) was cloned using primers and rapid amplification of cDNA ends (RACE) technology. The full-length OaLypla1 was 2457 bp with a 5′-untranslated region (UTR) of 24 bp, a 3′-UTR of 1740 bp with a poly (A) tail, and an open reading frame (ORF) of 693 bp encoding a protein of 230 amino acid residues with a predicted molecular weight of 24,625.78 Da. Phylogenetic analysis showed that the OaLypla1 protein shared a high amino acid identity with LYPLA1 of Bos taurus. The recombinant OaLypla1 protein was expressed and purified, and its phospholipase activity was identified. Monoclonal antibodies (mAb) against OaLypla1 that bound native OaLypla1 were generated. Real-time PCR analysis revealed that OaLypla1 was constitutively expressed in the liver, spleen, lung, kidney, and white blood cells of sheep, with the highest level in the kidney. Additionally, the mRNA levels of OaLypla1 in the buffy coats of sheep challenged with virulent or avirulent Brucella strains were down-regulated compared to untreated sheep. The results suggest that OaLypla1 may have an important physiological role in the host response to bacteria. The function of OaLypla1 in the host response to bacterial infection requires further study in the future.
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23
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Lewis ED, Richard C, Goruk S, Dellschaft NS, Curtis JM, Jacobs RL, Field CJ. The Form of Choline in the Maternal Diet Affects Immune Development in Suckled Rat Offspring. J Nutr 2016; 146:823-30. [PMID: 26936140 DOI: 10.3945/jn.115.225888] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/14/2016] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Lipid-soluble phosphatidylcholine (PC) and aqueous free choline are absorbed and metabolized differently, but the metabolic effects of feeding these 2 forms of choline have not been thoroughly investigated. OBJECTIVE We sought to compare the effects of PC and free choline in the maternal diet on the development of the offspring's immune system. METHODS During lactation, Sprague-Dawley dams (n= 10) were randomly assigned to 1 of 2 diet groups containing the same concentration of total choline (1 g/kg diet) as free choline (choline bitartrate) or PC (egg lecithin). The splenocytes of pups aged 21 d were isolated and stimulated ex vivo with concanavalin A (ConA) or lipopolysaccharide (LPS), and the choline concentrations of stomach content, plasma, and the spleen were measured. RESULTS Pups from PC-fed dams had a lower proportion of cells involved in antigen presentation but produced 54% more interleukin (IL)-2, 163% more IL-6, and 107% more IFN-γ after ConA stimulation and 110% more IL-6 and 43% more tumor necrosis factor (TNF)-α after LPS stimulation (allP< 0.05). The PC concentrations were significantly higher in the plasma and spleen of pups from PC-fed dams (P< 0.05). Increasing the supply of PC in the form of lysophosphatidylcholine to splenocytes in vitro increased the rate of proliferation and IL-2 production and the surface expression of CD25, CD28, CD71, and CD152 on CD8+ T cells, suggesting 1 possible mechanism. CONCLUSIONS The results of this study demonstrate that providing choline to rats in the form of PC (compared to free choline), possibly by increasing the supply of PC to the suckling pups, promotes maturation and improves function of the offspring's immune system.
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Affiliation(s)
- Erin D Lewis
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
| | - Caroline Richard
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
| | - Susan Goruk
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
| | - Neele S Dellschaft
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and Early Life Research Unit, Academic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Jonathan M Curtis
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
| | - René L Jacobs
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
| | - Catherine J Field
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, Canada; and
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Dudzik D, Revello R, Barbas C, Bartha JL. LC–MS-Based Metabolomics Identification of Novel Biomarkers of Chorioamnionitis and Its Associated Perinatal Neurological Damage. J Proteome Res 2015; 14:1432-44. [DOI: 10.1021/pr501087x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Danuta Dudzik
- CEMBIO
(Center for Metabolomics and Bioanalysis), Pharmacy Faculty, University San Pablo CEU, 28668 Madrid, Spain
| | - Rocio Revello
- Division
of Maternal and Fetal Medicine, University Hospital La Paz, 28046 Madrid, Spain
| | - Coral Barbas
- CEMBIO
(Center for Metabolomics and Bioanalysis), Pharmacy Faculty, University San Pablo CEU, 28668 Madrid, Spain
| | - Jose L. Bartha
- Division
of Maternal and Fetal Medicine, University Hospital La Paz, 28046 Madrid, Spain
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25
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Pieragostino D, D'Alessandro M, di Ioia M, Rossi C, Zucchelli M, Urbani A, Di Ilio C, Lugaresi A, Sacchetta P, Del Boccio P. An integrated metabolomics approach for the research of new cerebrospinal fluid biomarkers of multiple sclerosis. MOLECULAR BIOSYSTEMS 2015; 11:1563-72. [DOI: 10.1039/c4mb00700j] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
(1) Lipid profiling in MuS and OND patients. (2) Search of alterations associated with MuS. (3) Characterization of differences.
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26
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Jin S, Song C, Li S, Zhang Y, Chen C, Zhou X, Xu Y, Feng Y, Zhang Z, Jiang H. Preventive effects of turmeric on the high-fat diet-induced hyperlipidaemia in mice associated with a targeted metabolomic approach for the analysis of serum lysophosphatidylcholine using LC-MS/MS. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.09.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Cho WH, Park T, Park YY, Huh JW, Lim CM, Koh Y, Song DK, Hong SB. Clinical significance of enzymatic lysophosphatidylcholine (LPC) assay data in patients with sepsis. Eur J Clin Microbiol Infect Dis 2011; 31:1805-10. [PMID: 22167258 DOI: 10.1007/s10096-011-1505-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Accepted: 11/23/2011] [Indexed: 01/06/2023]
Abstract
Lysophosphatidylcholine (LPC) has been suggested to serve as a useful prognostic marker for sepsis. However, existing LPC assays are complicated, time-consuming, and of limited application in real clinical situations. Thus, we investigated the serum LPC levels in sepsis patients using an enzymatic assay and analyzed the correlations between the serum LPC concentration and clinical characteristics. We prospectively collected blood samples from suspected sepsis patients, commencing on day 1 of sepsis. We analyzed all samples using an enzymatic assay. Additionally, we analyzed the serum LPC concentrations in a control group of 21 healthy blood donors. A total of 105 patients who fulfilled the sepsis criteria were included. The mean serum LPC concentration was 43.49 ± 33.09 μmol/L in sepsis patients, which was much lower than that of 21 healthy controls (234.68 ± 30.33 μmol/L, p<0.001). Bacteremic sepsis was associated with a lower serum LPC concentration than non-bacteremic sepsis (34.8 ± 26.85 vs. 49.05 ± 35.63 μmol/L, p<0.05). No difference in serum LPC concentration was evident between survivors and non-survivors. The serum LPC concentration tended to decrease with the severity of sepsis. The day 1 serum LPC concentration was decreased in patients with sepsis, especially when bacteremia was present. However, the serum LPC level did not correlate with disease severity and did not predict mortality from sepsis.
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Affiliation(s)
- W H Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
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Wang Q, Wu YJ. Lysophosphatidylcholine induces Ca2+ mobilization in Jurkat human T lymphocytes and CTLL-2 mouse T lymphocytes by different pathways. Eur J Pharm Sci 2011; 44:602-9. [DOI: 10.1016/j.ejps.2011.10.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2011] [Revised: 10/04/2011] [Accepted: 10/07/2011] [Indexed: 11/16/2022]
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29
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Del Boccio P, Pieragostino D, Di Ioia M, Petrucci F, Lugaresi A, De Luca G, Gambi D, Onofrj M, Di Ilio C, Sacchetta P, Urbani A. Lipidomic investigations for the characterization of circulating serum lipids in multiple sclerosis. J Proteomics 2011; 74:2826-36. [PMID: 21757039 DOI: 10.1016/j.jprot.2011.06.023] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 06/08/2011] [Accepted: 06/24/2011] [Indexed: 11/28/2022]
Abstract
Multiple Sclerosis (MS) is a neurodegenerative autoimmune demyelinating disease affecting young adults. The aetiology still remains a mystery and diagnosis is impaired by the lack of defined molecular markers. Autoimmune response remains the main topic under investigation and recent studies suggest additional non-proteic mediators of brain inflammation such as lipids. We carried out an LC-MS based lipidomics approach to highlight serum lipids profiling in MS. Method was optimised and applied in a preliminary clinical cross-sectional investigation of MS patients vs Healthy Controls (HC) and patients with Other Neurological Diseases (OND). Ten significant metabolites were highlighted and tentatively identified by accurate mass and MS/MS experiments. Our most relevant data show altered level of lyso-glycerophosphatidylcholine (lysoPC) and glycerophosphatidylcholine (PC) species. Total lysoPC/PC ratio showed significant decrease in pathological groups (MS, OND) and, in addition, MS subjects had a relevant decrease of this ratio also in respect to OND. These findings suggest that there may be an altered phospholipid metabolism in MS that can be evaluated in serum. Some of these features are distinctive and may be considered specific for MS. Our lipidomics data show, for the first time, evidence in serum of a relationship between LysoPC/PC ratio and MS.
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Affiliation(s)
- Piero Del Boccio
- Department of Biomedical Sciences, G. d'Annunzio University, Chieti-Pescara, Italy.
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Yu S, Peng M, Ronis M, Badger T, Fang N. Analysis of polar lipids in the serum from rats fed shiitake by liquid chromatography-mass spectrometry/mass spectrometry. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2010; 58:12650-12656. [PMID: 21090619 DOI: 10.1021/jf103266c] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Consumption of a shiitake mushroom diet has been reported to have effects on serum phospholipids. However, much less is known about the effect on serum polar lipids including lysophospholipids and free fatty acids. In the present study, the effects of a shiitake diet were evaluated on the basis of identification and quantification of individual polar lipid components in rat serum using liquid chromatography-mass spectrometry/mass spectrometry. By comparison with standards and published data, 50 lysophospholipids and 32 free fatty acids were identified, and the concentrations of 27 polar lipids in rat serum were determined. Shiitake diets decreased the levels of all individual polar lipid components in the serum of male rat. The total level of serum polar lipids in males fed 4% shiitake diets (1365.71 mol/L) was significantly lower than that of the control (2270.26 mol/L). However, shiitake diets did not significantly affect the levels of serum polar lipids in female rats.
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Affiliation(s)
- Shanggong Yu
- Key Laboratory of Chinese Medicine Resource and Compound Prescription (Hubei University of Chinese Medicine), Ministry of Education, 1 Huang-jia-hu, Wuhan, China, 430065
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SOFI MHANIEF, BHATNAGAR ARCHANA, SAPRA SAVEETA, MAHMOOD AKHTAR, MAJUMDAR SIDHARTHA. INFLUENCE OF INTESTINAL SURFACTANT LIKE PARTICLES ON DIFFERENTIAL ACTIVATION OF SECONDARY SIGNALING MOLECULES DURING SALMONELLA TYPHIMURIUM INFECTION. J Food Saf 2010. [DOI: 10.1111/j.1745-4565.2010.00219.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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32
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Quantitative Analysis of Polar Lipids in the Nanoliter Level of Rat Serum by Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Exp Biol Med (Maywood) 2009; 234:157-63. [DOI: 10.3181/0807-rm-224] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Polar lipids in serum, including lysophospholipids (LPLs) and free fatty acids (FFAs), have a broad range of biological activities and require a suitable method for their quantitative analysis. Conventional methods use multistep procedures to simultaneously purify and analyze polar lipids and non-polar lipids in serum. However, the methods could result in inaccurate quantifications of polar and/or non-polar lipids because compounds with different polarities have different behaviors in solvent extraction and mass spectrometric ionization. In this study, a method was designed to analyze polar lipids in serum based on the polarities of LPLs and FFAs. The method consisted of extraction without filtration and analysis of the crude extract without multistep purification. Fifty LPLs and 32 FFAs were detected in rat serum. The concentrations of LPLs (1272.1 μmole/L in female and 999.8 μmole/L in male) and FFAs (1910.9 μmole/L in female and 1651.4 μmole/L in male) were determined. Peak areas of MS ion in Extract Ion Chromatogram (EIC) were used for the quantification in this study. The approach of quantification should be perfectly suitable for precise quantification of a specific serum component by adding its isotope standard to the serum before extraction.
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Foulds LM, Boysen RI, Crane M, Yang Y, Muir JA, Smith AI, de Kretser DM, Hearn MTW, Hedger MP. Molecular identification of lyso-glycerophosphocholines as endogenous immunosuppressives in bovine and rat gonadal fluids. Biol Reprod 2008; 79:525-36. [PMID: 18509166 DOI: 10.1095/biolreprod.107.064386] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
The ability of the gametes to escape detection by the immune system is vital to successful human reproduction. Furthermore, the observed capacity of the testis in some species to support tissue grafts without rejection (immunological privilege) indicates that spermatogenic cells are protected by local immunoregulatory mechanisms. One of these mechanisms involves targeting T cells for inactivation and destruction within the testicular environment. Although the fluids of the testis and ovary surrounding the developing gametes contain soluble factors that inhibit T cells, the identity of the molecule(s) responsible for this activity has been unknown. Using a specific T-cell proliferation assay to monitor bioactivity, these molecules were purified from bovine ovarian follicular fluid by methanol extraction and sequential reverse-phase HPLC (RP-HPLC). All purified active fractions coincided with the elution position on RP-HPLC of several small molecules ranging in size from 496 to 522 Da. The same molecules were localized to the immunosuppressive fractions of rat testicular interstitial fluid. The active molecules were identified, using capillary electrophoresis electrospray ionization mass spectroscopy, as lyso-glycerophosphocholines (lyso-GPCs), namely, 1-palmitoyl-sn-glycero-3-phosphocholine, 1-oleoyl-sn-glycero-3-phosphocholine, a 18:2a/lyso-GPC (putatively, 1-linoleoyl-sn-glycero-3-phosphocholine), and a 20:4a/lyso-GPC (putatively, 1-arachidonyl-sn-glycero-3-phosphocholine). Comparison of the bioactivity and mass spectroscopy profiles of two of the purified molecules with their synthetic standards confirmed the identification. These molecules inhibit T-cell proliferation in response to activation and induce apoptosis of these cells in a time- and dose-dependent manner. The emergence of gonadal lyso-GPCs as potential regulators of critical immune events opens up new avenues of inquiry into the origins of autoimmune infertility and more generally into mechanisms of peripheral immunoregulation and the development of novel immunosuppressives.
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Affiliation(s)
- Lynda M Foulds
- Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia
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Chen C, Shah YM, Morimura K, Krausz KW, Miyazaki M, Richardson TA, Morgan ET, Ntambi JM, Idle JR, Gonzalez FJ. Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab 2008; 7:135-47. [PMID: 18249173 PMCID: PMC2276699 DOI: 10.1016/j.cmet.2007.12.003] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 10/23/2007] [Accepted: 12/14/2007] [Indexed: 02/08/2023]
Abstract
To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases.
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Affiliation(s)
- Chi Chen
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Hara Y, Kusumi Y, Mitsumata M, Li XK, Fujino M. Lysophosphatidylcholine upregulates LOX-1, chemokine receptors, and activation-related transcription factors in human T-cell line Jurkat. J Thromb Thrombolysis 2007; 26:113-8. [DOI: 10.1007/s11239-007-0158-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Accepted: 10/09/2007] [Indexed: 11/27/2022]
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Takatera A, Takeuchi A, Saiki K, Morioka I, Yokoyama N, Matsuo M. Blood lysophosphatidylcholine (LPC) levels and characteristic molecular species in neonates: prolonged low blood LPC levels in very low birth weight infants. Pediatr Res 2007; 62:477-82. [PMID: 17667851 DOI: 10.1203/pdr.0b013e31814625ca] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Lysophosphatidylcholine (LPC) has various stimulatory effects on many types of immune cells. The purpose of our study was to characterize blood LPC levels and to determine the composition of LPC molecular species (LPCs) in the neonatal period. Thirty-six neonates were enrolled in this study and then grouped according to birth-weight as follows: non-very low birth weight (NVLBW); >or=1,500 g (n=17), and very low birth weight (VLBW); <1,500 g (n=19). Sixteen healthy normal adults were used as controls. Levels of total blood LPC and LPCs (16:0-, 18:0-, 18:1-, 18:2-, and 20:4-LPC species) were measured using HPLC coupled with tandem mass spectrometry. Total blood LPC levels at birth in neonates in both groups (NVLBW and VLBW) were significantly lower than those of adult levels. In NVLBW infants, LPC levels reached adult levels at postnatal day 3 compared with VLBW infants, who attained adult levels after postnatal day 57 (around full-term). The composition of the LPCs was different not only between neonates and adults, but between NVLBW and VLBW infants. These findings may be associated with the difference of immunity among adults, NVLBW, and VLBW infants.
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Affiliation(s)
- Akihiro Takatera
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Han L, Li ZM, Gao JR. New 3-O-Lauroyl-2-O-Benzyl-Glycerol Sulfonate. JOURNAL OF CHEMICAL RESEARCH 2007. [DOI: 10.3184/030823407x240917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The hydroxy groups of D-mannitol were protected by the formation of acetals and benzylethers and then 2-O-benzyl-D-glyceraldehyde dimethylacetal was prepared after the deprotection and oxygenolysis of the protected D-mannitol. In the presence of DCC and DMAP, the lauroyl group was introduced at the primary hydroxyl group of the dimethylacetal and 3-O-lauroyl-2-O-benzyl-glycerol was obtained after the deprotection of the dimethylacetal with FeCl3·6H2O and then reduction with NaBH4. A series of new 3-O-lauroyl-2-O-benzyl-glycerol sulfonates was synthesised by the coupling of different sulfonyl groups with the 3-O-lauroyl-2-O-benzyl- glycerol. The bioactivities of the title compounds were tested and some compounds exhibited fungicidal activity against the tested fungi.
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Affiliation(s)
- Liang Han
- State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310014, China
| | - Zheng-Ming Li
- National Key Laboratory of Elemento-Organic Chemistry, Naikai University, Tianjin 300071, China
| | - Jian-Rong Gao
- State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310014, China
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Santiago MF, López-Aparicio P, Recio MN, Pérez-Albarsanz MA. Effect of aroclor 1248 and two pure PCB congeners on phospholipase D activity in rat renal tubular cell cultures. J Biochem Mol Toxicol 2007; 21:68-75. [PMID: 17427178 DOI: 10.1002/jbt.20160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This paper elucidates the effect of different polychlorinated biphenyls (PCBs) on the phospholipase D (PLD) activity in soluble and particulate fractions of rat renal proximal tubular culture cells. Treatment with Aroclor 1248 (a commercial PCB mixture) caused a marked increase in the activity of PLD in intact renal tubular cells. The PLD activity was increased by Aroclor 1248 in the particulate fraction while the enzyme activity was unaffected in the soluble fraction. This work also shows that PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl, a di-ortho-substituted nonplanar congener) can increase the activity of PLD only in the particulate fraction. The exposure of cell cultures to PCB 77 (3,3',4,4'-tetrachlorobiphenyl, a non-ortho-substituted planar congener) does not alter PLD activity. These results suggest that PCB effects are structure dependent. Therefore, in order to clarify the molecular mechanism of activation of PLD by PCBs, the contents of immunoreactive PLD were examined by immunoblot analysis. Renal tubular cells expressed a PLD protein of 120 kDa corresponding with the PLD1 mammalian isoform in both the particulate and the soluble fraction. Aroclor 1248, PCB 153, and PCB 77 do not induce changes in the levels of PLD protein. These data indicate that PCBs, particularly nonplanar congeners, increase PLD activity. Moreover, these changes could not be demonstrated in the enzyme content in rat renal tubular cell cultures.
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Affiliation(s)
- Mercedes Fernández Santiago
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain
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Santiago MF, Pérez-Reyes PL, López-Aparicio P, Recio MN, Pérez-Albarsanz MA. Differential effects of PCBs on the induction of apoptosis machinery and PKCα translocation in rat renal tubular cell cultures. Toxicol Lett 2006; 163:91-100. [PMID: 16263226 DOI: 10.1016/j.toxlet.2005.09.032] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2005] [Revised: 09/22/2005] [Accepted: 09/22/2005] [Indexed: 10/25/2022]
Abstract
We have demonstrated previously [Pérez-Reyes, P.L., Sánchez-Alonso, J.A., López-Aparicio, P., Recio, M.N., Pérez-Albarsanz, M.A., 2001. Different molecular capacity in the induction of apoptosis by polychlorinated biphenyl congeners in rat renal tubular cell cultures. Biosci. Rep. 6, 765-778] that the polychlorinated biphenyls (PCBs) cause loss of cell viability and accelerate apoptosis in cell kidney cultures. Further investigations are necessary to elucidate the mechanism of apoptosis induction. In this way, we have analyzed in the present work the effects of PCBs on protein kinase C (PKC, a protein family intimately involved in the regulation of cell survival) and the expression of two proapoptotic (caspase-3 and Bax) and one antiapoptotic (Bcl-2) proteins. Aroclor 1248 (a commercial PCB mixture with 48% chlorine by weight), PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl, a di-ortho-substituted nonplanar congener) and PCB 77 (3,3',4,4'-tetrachlorobiphenyl, a non-ortho-substituted planar congener), significantly increased PKCalpha activity compared to control cells in the cytosolic and particulate cell fractions, and increased the PKCalpha protein content in the particulate fraction. The nonplanar PCB 153 showed stronger effects than the coplanar congener PCB 77. In addition, Aroclor 1248 decreased both, procaspase-3 levels and the Bcl-2/Bax protein ratio. These findings indicate that PCBs, particularly nonplanar congeners, can induce apoptosis in primary renal tubular cells through the PKCalpha, caspase-3 and Bcl-2/Bax pathway.
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Affiliation(s)
- Mercedes Fernández Santiago
- Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain
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Takatera A, Takeuchi A, Saiki K, Morisawa T, Yokoyama N, Matsuo M. Quantification of lysophosphatidylcholines and phosphatidylcholines using liquid chromatography-tandem mass spectrometry in neonatal serum. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 838:31-6. [PMID: 16603422 DOI: 10.1016/j.jchromb.2006.03.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2005] [Revised: 01/14/2006] [Accepted: 03/05/2006] [Indexed: 10/24/2022]
Abstract
We established an improved method for quantification of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) molecular species in neonatal serum using high-performance liquid chromatography coupled tandem mass spectrometry (LC-MS/MS). A multiple reaction monitoring (MRM) mode of positive ionization for MS/MS was used. The method involved purification of phospholipids by solid phase extraction (SPE) from a 20-microl minimum specimen of serum. The assayed values of authentic 16:0-LPC and 18:0-LPC showed a linear response, and our quantitative results showed high precision for the all species of PC and LPC. Then, we quantified PC and LPC in adult and neonatal serum and compared them. Day 0-1 neonatal serum 16:0-, 18:0-, 18:1-, 18:2-LPC levels were significantly lower than adult ones. All species LPC levels in the day 0-1 neonates were significantly lower than day 4-8 neonates. Day 0-1 neonatal serum 16:0/18:2-, 18:0/18:2-PC levels were significantly lower than adult ones. Our method is advantageous for precise assessments of the relationships between PCs/LPCs levels and neonatal infectious diseases.
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Affiliation(s)
- Akihiro Takatera
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
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Fasoli E, Arnone A, Caligiuri A, D'Arrigo P, de Ferra L, Servi S. Tin-mediated synthesis of lyso-phospholipids. Org Biomol Chem 2006; 4:2974-8. [PMID: 16855747 DOI: 10.1039/b604636c] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
1-O-Acyl-sn-glycero-3-phosphocholine and 1-O-acyl-sn-glycero-3-phosphoric acid have been prepared selectively and with high yields from the corresponding diols, glycerophosphoryl choline and glycerol-3-phosphate. Starting from the diols, the activated tin ketals were prepared in 2-propanol by reaction with dialkyltin oxide. The intermediates were acylated in the same solvent with long-chain fatty acid chlorides, giving the corresponding 1-acyl-lyso-phospholipids in high yield and with complete regioselectivity. The catalytic nature of the tin-mediated acylation and the relevance of the solvent are discussed.
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Affiliation(s)
- Ezio Fasoli
- Dipartimento di Chimica, Materiali e Ingegneria Chimica, G. Natta Politecnico di Milano, Italy
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Maghazachi AA. Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells. Pharmacol Rev 2005; 57:339-57. [PMID: 16109839 DOI: 10.1124/pr.57.3.5] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Human natural killer (NK) cells are important cells of the innate immune system. These cells perform two prominent functions: the first is recognizing and destroying virally infected cells and transformed cells; the second is secreting various cytokines that shape up the innate and adaptive immune re-sponses. For these cells to perform these activities, they express different sets of receptors. The receptors used by NK cells to extravasate into sites of injury belong to the seven transmembrane (7TM) family of receptors, which characteristically bind heterotrimeric G proteins. These receptors allow NK cells to sense the chemotactic gradients and activate second messengers, which aid NK cells in polarizing and migrating toward the sites of injured tissues. In addition, these receptors determine how and why human resting NK cells are mainly found in the bloodstream, whereas activated NK cells extravasate into inflammatory sites. Receptors for chemokines and lysophospholipids belong to the 7TM family. On the other hand, NK cells recognize invading or transformed cells through another set of receptors that belong to the single transmembrane-spanning domain family. These receptors are either inhibitory or activating. Inhibitory receptors contain the immune receptor tyrosine-based inhibitory motif, and activating receptors belong to either those that associate with adaptor molecules containing the immune receptor tyrosine-based activating motif (ITAM) or those that associate with adaptor molecules containing motifs other than ITAM. This article will describe the nature of these receptors and examine the intracellular signaling pathways induced in NK cells after ligating both types of receptors. These pathways are crucial for NK cell biology, development, and functions.
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Kostenis E. A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol Ther 2004; 102:243-57. [PMID: 15246248 DOI: 10.1016/j.pharmthera.2004.04.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A plethora of lipid-like molecules known to act as intracellular second messengers are now recognized to signal cells through plasma membrane 7 transmembrane G-protein-coupled receptors (GPCRs). This has been the result of a decade-long genetic hunt for novel sequences encoding 7 transmembrane receptor proteins and the efforts to pair novel sequences with biologically active substances of (partly) unknown molecular mechanism of action. Identification of novel GPCR ligand pairs represents the first step to shed more light into the mode of action of novel cellular signaling molecules in human health and disease and might represent a fruitful source for the development of new drugs, judged on the successful history of GPCR as drug targets. Since 2000, more than 16 reports became available on lipid mediators--as diverse as lysophospholipids, arachidonic acid metabolites, short-, medium-, and long-chain fatty acids as well as steroid-like molecules--exerting their effects as extracellular mediators via rhodopsin-like family GPCRs. These reports have opened new avenues for research in human lipid receptor physiology and pharmacology. Here, the current knowledge on the recently deorphanized lipid receptors, including their isolation, expression pattern, function, and possible physiological or pathological roles will be reviewed.
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Affiliation(s)
- Evi Kostenis
- 7TM Pharma A/S, 3 Fremtidsvej, 2970 Hoersholm, Denmark.
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Légrádi A, Chitu V, Szukacsov V, Fajka-Boja R, Székely Szücs K, Monostori E. Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca(2+) level in Jurkat T cell line. Immunol Lett 2004; 91:17-21. [PMID: 14757365 DOI: 10.1016/j.imlet.2003.10.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Lysophospholipids, particularly lysophosphatidylcholine (lyso-PC), have been implicated in modulating T cell functions at the sites of inflammation and atherosclerosis. Although the chemotactic and immunomodulatory effects are well documented, the exact signaling pathway of lyso-PC action is poorly defined. In this work, we studied the earliest biochemical events in T cells triggered by lyso-PC. A marked and immediate tyrosine phosphorylation was induced in the leukemic T cell line, Jurkat. Phosphorylation of cellular substrates included src family kinase, p56(lck) and syk family kinase, ZAP70. The lyso-PC induced tyrosine phosphorylation was largely dependent on the presence of functional p56(lck). Tyrosine phosphorylation was followed by the elevation of intracellular Ca(2+) concentration. The magnitude of the mobilization of the intracellular Ca(2+) was similar in the absence of the p56(lck) activity in JCaM1.6 cells as in Jurkat cells, however, it was slightly but reproducibly delayed compared to that in the wild type cells. Inhibition of the Ser/Thr kinases and tyrosine kinases with staurosporine and genistein, respectively, decreased the rise in the intracellular Ca(2+) content. Moreover, pertussis toxin completely blocked the Ca(2+) signal supporting the role of the G-protein coupled LPC receptor in this event.
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Affiliation(s)
- Adám Légrádi
- Lymphocyte Signal Transduction Laboratory, Institute of Genetics, Biological Research Center of Hungarian Academy of Sciences, PO Box 521, Temesvári krt. 62, H-6726 Szeged, Hungary
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Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, Kim YH, Song DK. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med 2004; 10:161-7. [PMID: 14716308 DOI: 10.1038/nm989] [Citation(s) in RCA: 266] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2003] [Accepted: 12/15/2003] [Indexed: 12/13/2022]
Abstract
Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.
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Affiliation(s)
- Ji-Jing Yan
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, 1 Okchon-dong, Chunchon, Gangwon-do, 200-702, South Korea
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Fei GZ, Huang YH, Swedenborg J, Frostegård J. Oxidised LDL modulates immune-activation by an IL-12 dependent mechanism. Atherosclerosis 2003; 169:77-85. [PMID: 12860253 DOI: 10.1016/s0021-9150(03)00146-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Oxidised low density lipoprotein (oxLDL) is one factor that may cause the immune reaction in the artery wall characteristic of atherosclerosis. OxLDL can promote immune activation as determined by enhanced secretion of IFN-gamma and TNF by immune competent cells. We previously demonstrated that Platelet-activating factor (PAF)-like lipids and/or lysophosphatidylcholine (LPC) in OxLDL contribute significantly to this immune activation, but these factors may also inhibit immune activation, at higher concentrations. We here demonstrate that IL-12 induces enhanced IFN-gamma secretion in peripheral blood mononuclear cells (PBMC), with no addition of a specific antigen, as determined by ELISPOT. Antibodies to IL-12 and to MHC class II inhibited both IL-12- and oxLDL-induced IFN-gamma secretion. OxLDL induced IL-12 production in PBMC. In the presence of IL-10, a T helper 2 cytokine, oxLDL induced a decreased IFN-gamma secretion, indicating that the local cytokine-milieu may determine the immunological properties of oxLDL. IL-10 could also be induced by OxLDL. Mononuclear leukocytes were prepared directly from human atherosclerotic plaques obtained at carotid operations. OxLDL had the capacity to induce IL-12, IL-10 and TNF from plaque cells using ELISPOT. Taken together, our data indicate that oxLDL can modulate immune reactivity in atherosclerosis by a nonspecific mechanism. OxLDL can be inhibitory, especially at higher concentrations. However, oxLDL can also promote immune activation by functioning as an adjuvant, potentiating and/or modulating immune-reactions via IL-12 and other cytokines including IL-10. This suggests that a specific T cell epitope in oxLDL is not necessary for oxLDL-induced T cell activation.
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Affiliation(s)
- Guo-Zhong Fei
- Department of Medicine, Karolinska Hospital, Karolinska Institute, S-17176 Stockholm, Sweden
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Kim YA, Park MS, Kim YH, Han SY. Synthesis of 1-lyso-2-palmitoyl-rac-glycero-3-phosphocholine and its regioisomers and structural elucidation by NMR spectroscopy and FAB tandem mass spectrometry. Tetrahedron 2003. [DOI: 10.1016/s0040-4020(03)00282-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Abstract
Despite the recognized effects of lysophosphatidylcholine upon cells of the immune system and its association with inflammatory processes, its mechanism of action has remained poorly characterized. Our recent identification of the first lysophosphatidylcholine receptor as an immunoregulatory G protein-coupled receptor named G2A whose genetic ablation results in the development of inflammatory autoimmune disease has, therefore, provided a new perspective on the role of this lysophospholipid as a modulator of immune responses. This commentary discusses the biological properties of lysophosphatidylcholine as an immunoregulatory ligand for cells of the innate and adaptive arms of the immune system. Although we focus primarily on ligand interactions with G2A, we also discuss the issue of possible functional redundancy with other receptors with recently established ligand specificities towards phosphorylcholine-containing lysolipids including lysophosphatidylcholine.
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Affiliation(s)
- Janusz H S Kabarowski
- Department of Microbiology, Immunology & Molecular Genetics, University of California-Los Angeles, 5-748 MRL, 675 Charles E. Young Drive South, Box 951662, Los Angeles, CA 90095-1662, USA.
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Abstract
We observed that human (Jurkat) T-cells constitutively expressed the mRNA, encoding for the four isoforms of phospholipase A(2) (PLA(2)), i.e. two secretory (type IB and type V), and two cytosolic (type IV, Ca(2+)-dependent and type VI, Ca(2+)-independent). In order to assess whether these PLA(2) isoforms are active, we labeled Jurkat T-cells with [(3)H]arachidonic acid ([(3)H]AA) and determined its release into the extracellular medium in the presence of phorbol 12-myristate 13-acetate (PMA) and ionomycin. The three PLA(2) isoforms seem functional as aristolochic acid and bromoenol lactone (BEL), the respective inhibitors of type IB/type V and type VI PLA(2)s, significantly inhibited the release of free [(3)H]AA. On the other hand, arachidonyl trifluoromethyl ketone (AACOCF(3)), an inhibitor of type IV PLA(2), failed to curtail significantly the release of free [(3)H]AA into the extracellular medium. We assessed the implication of these PLA(2) isoforms in transcription of the interleukin-2 (IL-2) gene, involved in T-cell proliferation. Hence, aristolochic acid and BEL, but not AACOCF(3), significantly inhibited the PMA and ionomycin-induced induction of mRNA of IL-2. Similarly, aristolochic acid and BEL, but not AACOCF(3), significantly inhibited the PMA and ionomycin-induced secretion of IL-2 in the culture supernatants. Together these results suggest that human Jurkat T-cells possess two secretory and two cytosolic PLA(2) isoforms and only three of them (type IB, type V and type VI) are implicated in T-cell proliferation.
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Affiliation(s)
- Christian Tessier
- UPRES Lipides and Nutrition, Université de Bourgogne, Faculté des Sciences de la Vie, 6 Boulevard Gabriel, 21000 Dijon, France
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