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Li W, Xu G, Chai GW, Ball A, Zhang Q, Kutryk MJB. The MiR-139-5p and CXCR4 axis may play a role in high glucose-induced inflammation by regulating monocyte migration. Sci Rep 2025; 15:6738. [PMID: 40000897 PMCID: PMC11861593 DOI: 10.1038/s41598-025-91100-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/18/2025] [Indexed: 02/27/2025] Open
Abstract
MicroRNAs, a class of small non-coding RNA molecules that regulate gene expression post-transcriptionally, are implicated in various pathological conditions including diabetes mellitus (DM). DM has been increasingly recognized as an inflammatory disease and monocytes play a key role in propagating inflammation under hyperglycemic conditions. We hypothesize that high glucose dysregulates microRNAs to promote monocyte inflammatory activity, which may contribute to the pathogenesis of DM. THP-1 monocytes were cultured in normal (5 mM) and high (25 mM) glucose conditions. RT-qPCR and Western blotting were performed to assay microRNAs and proteins, respectively. Monocytes were transfected with microRNA mimics using Lipofectamine RNAiMAX reagent. THP-1 monocyte growth was assessed using Calcein-AM dye and a Boyden chamber assay was applied to measure monocyte migration. The results showed that high glucose downregulated miR-139-5p associated with increased protein expression of CXCR4, an experimentally validated target of miR-139-5p. Correspondingly, treatment with high glucose resulted in a significant increase in THP-1 cell migration towards SDF-1, a cognate ligand for CXCR4. MiR-139-5p overexpression inhibited high glucose-induced CXCR4 expression, leading to reduced cell migration towards SDF-1. High glucose did not affect THP-1 monocyte growth. In conclusion, the miR-139-5p-CXCR4 axis may play a role in high glucose-induced inflammation by regulating monocyte migration.
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Affiliation(s)
- Weifang Li
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Gengchen Xu
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Gregory W Chai
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Alexander Ball
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada
| | - Qiuwang Zhang
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada.
| | - Michael J B Kutryk
- Division of Cardiology, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, ON, Canada.
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Caron L, Vdovenko D, Lombard-Vadnais F, Lesage S. NOD alleles at Idd1 and Idd2 loci drive exocrine pancreatic inflammation. Immunogenetics 2024; 76:323-333. [PMID: 39207501 DOI: 10.1007/s00251-024-01352-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas.
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Affiliation(s)
- Laurence Caron
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
- Immunologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada
| | - Daria Vdovenko
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
- Immunologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada
| | - Félix Lombard-Vadnais
- Immunologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada
| | - Sylvie Lesage
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada.
- Immunologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Canada.
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Manzoor T, Farooq N, Sharma A, Shiekh PA, Hassan A, Dar LA, Nazir J, Godha M, Sheikh FA, Gugjoo MB, Saleem S, Ahmad SM. Exosomes in nanomedicine: a promising cell-free therapeutic intervention in burn wounds. Stem Cell Res Ther 2024; 15:355. [PMID: 39385310 PMCID: PMC11462792 DOI: 10.1186/s13287-024-03970-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024] Open
Abstract
Burn injuries are serious injuries that have a big impact on a person's health and can even cause death. Incurring severe burns can incite an immune response and inflammation within the body, alongside metabolic changes. It is of utmost importance to grasp the fact that the effects of the burn injury extend beyond the body, affecting the mind and overall well-being. Burn injuries cause long-lasting changes that need to be taken care of in order to improve their quality of life. The intricate process of skin regeneration at the site of a burn wound involves a complex and dynamic interplay among diverse cells, growth factors, nerves, and blood vessels. Exciting opportunities have arisen in the field of stem cells and regenerative medicine, allowing us to explore the development of cell-free-based alternatives that can aid in the treatment of burn injuries. These cell-free-based therapies have emerged as a promising facet within regenerative medicine. Exosomes, also referred to as naturally occurring nanoparticles, are small endosome-derived vesicles that facilitate the delivery of molecular cargo between the cells, thus allowing intercellular communication. The knowledge gained in this field has continued to support their therapeutic potential, particularly in the domains of wound healing and tissue regeneration. Notably, exosomes derived from mesenchymal stem cells (MSCs) can be safely administered in the system, which is then adeptly uptaken and internalized by fibroblasts/epithelial cells, subsequently accelerating essential processes such as migration, proliferation, and collagen synthesis. Furthermore, exosomes released by immune cells, specifically macrophages, possess the capability to modulate inflammation and effectively diminish it in adjacent cells. Exosomes also act as carriers when integrated with a scaffold, leading to scarless healing of cutaneous wounds. This comprehensive review examines the role of exosomes in burn wound healing and their potential utility in regeneration and repair.
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Affiliation(s)
- Tasaduq Manzoor
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
- School of Life and Basic Sciences, Jaipur National University, Jagatpura, Jaipur, India
| | - Nida Farooq
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Arushi Sharma
- Centre for Biomedical Engineering, Indian Institute of Technology-Delhi, New Delhi, India
| | - Parvaiz A Shiekh
- Centre for Biomedical Engineering, Indian Institute of Technology-Delhi, New Delhi, India
| | - Amreena Hassan
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Lateef Ahmad Dar
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Junaid Nazir
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Meena Godha
- School of Life and Basic Sciences, Jaipur National University, Jagatpura, Jaipur, India
| | - Faheem A Sheikh
- Department of Nanotechnology, University of Kashmir, Srinagar, Kashmir, India
| | - Mudasir Bashir Gugjoo
- Veterinary Clinical Services Complex, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST- Srinagar, Kashmir, India
| | - Sahar Saleem
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST, Srinagar, Kashmir, 190006, India.
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Jaffey JA, Backus RC, Kreisler R, Graves TK, Al-Nakkash L, Allison L. Evaluation of serum vitamin D metabolites, phagocytosis, and biomarkers of inflammation in dogs with naturally occurring diabetes mellitus. Front Vet Sci 2024; 11:1441993. [PMID: 39234180 PMCID: PMC11371797 DOI: 10.3389/fvets.2024.1441993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 08/12/2024] [Indexed: 09/06/2024] Open
Abstract
Naturally occurring diabetes mellitus (NODM) is one of the most common endocrine disorders in dogs and its etiology closely resembles type 1 diabetes mellitus (T1DM) in people. Human patients with T1DM commonly have cellular derangements consistent with inflammation, impaired immune function, and hypovitaminosis D. There is little information available regarding inflammatory biomarkers, immune function, and vitamin D status in diabetic dogs. Therefore, our objectives were to assess inflammatory biomarkers, vitamin D metabolites, and phagocytic capacity in diabetic dogs and determine whether associations exist with these variables and the level of clinical control or vitamin D metabolites. This was a prospective case-control study that included 20 otherwise healthy diabetic dogs (clinically controlled, n = 10; uncontrolled, n = 10) and 20 non-diabetic, healthy, age (± 2 years), breed, and sex matched controls. Complete blood count, biochemical panel, urinalysis, and fructosamine were performed at a single commercial reference laboratory. Basal plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured using a canine-specific multiplex bead-based assay. Serum C-reactive protein (CRP) was measured using a commercially available ELISA kit. Serum 25-hydroxyvitamin (OH)D3 and 24,25-dihydroxyvitamin (OH)2D3 were measured with HPLC. Phagocytosis of opsonized-Escherichia coli (E. coli) was evaluated with flow cytometry. Diabetic dogs had higher serum CRP concentrations than controls (p = 0.02). Plasma IL-8 concentrations were higher in diabetic dogs with uncontrolled clinical disease compared to controls (p = 0.02). Diabetic dogs had a lower percentage of leukocytes that phagocytized opsonized-E. coli (p = 0.02), but an increased number of bacteria phagocytized per cell (p < 0.001) compared to controls. No between-group differences were identified in vitamin D metabolites, nor were associations found between vitamin D and any variables. Fructosamine had a positive association with serum CRP concentration (rho = 0.35, p = 0.03) and number of bacteria phagocytized per cell (rho = 0.45, p = 0.004) in our cohort (n = 40). Like people with T1DM, diabetic dogs have a proinflammatory phenotype and phagocytic dysregulation that may be correlated with glycemic control.
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Affiliation(s)
- Jared A Jaffey
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, AZ, United States
| | - Robert C Backus
- Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, United States
| | - Rachael Kreisler
- Department of Pathology and Population Medicine, College of Veterinary Medicine, Midwestern University, Glendale, AZ, United States
| | - Thomas K Graves
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, AZ, United States
| | - Layla Al-Nakkash
- Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ,United States
| | - Lauren Allison
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, AZ, United States
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Heger LA, Schommer N, Van Bruggen S, Sheehy CE, Chan W, Wagner DD. Neutrophil NLRP3 promotes cardiac injury following acute myocardial infarction through IL-1β production, VWF release and NET deposition in the myocardium. Sci Rep 2024; 14:14524. [PMID: 38914598 PMCID: PMC11196583 DOI: 10.1038/s41598-024-64710-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 06/12/2024] [Indexed: 06/26/2024] Open
Abstract
NLRP3 inflammasome has been implicated in neutrophil polarization and extrusion of neutrophil extracellular traps (NETs) in vitro and facilitates secretion of Il1-beta (IL-1β). Permanent ligation of the left anterior descending artery was used to induce MI in WT and NLRP3-/- mice as well as in NLRP3-/- recipient mice transfused with either WT or NLRP3-/- neutrophils. NLRP3 deficiency reduced infarct size to roughly a third of WT heart injury and preserved left ventricular (LV) function at 12 h after MI as assessed by echocardiography and triphenyltetrazolium chloride staining of live tissue. Transfusion of WT but not NLRP3-/- neutrophils after MI increased infarct size in NLRP3-/- mice and significantly reduced LV function. The key features of myocardial tissue in WT neutrophil transfused recipients were increased H3Cit-positive deposits with NET-like morphology and increased tissue levels of IL-1β and plasma levels of von Willebrand Factor (VWF). Flow cytometry analysis also revealed that neutrophil NLRP3 increased the number of labeled and transfused neutrophils in the bone marrow of recipient mice following MI. Our data suggest a key role for neutrophil NLRP3 in the production of IL-1β and deposition of NETs in cardiac tissue exacerbating injury following MI. We provide evidence for a link between neutrophil NLRP3 and VWF release likely enhancing thromboinflammation in the heart. Neutrophil NLRP3 deficiency conferred similar cardioprotective effects to general NLRP3 deletion in MI rendering anti-neutrophil NLRP3 therapy a promising target for early cardioprotective treatment.
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Affiliation(s)
- Lukas A Heger
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
- Departement of Cardiology and Angiology, University Hospital Freiburg Bad Krozingen, 79106, Freiburg, Germany
| | - Nicolas Schommer
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA
- Departement of Cardiology and Angiology, University Hospital Freiburg Bad Krozingen, 79106, Freiburg, Germany
| | - Stijn Van Bruggen
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA
- Center of Molecular and Vascular Biology, Department of Cardiovascular Science, KU Leuven, 3000, Leuven, Belgium
| | - Casey E Sheehy
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA
| | - William Chan
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA
| | - Denisa D Wagner
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 1 Blackfan Circle, Ninth Floor, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
- Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.
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Ghelich P, Samandari M, Hassani Najafabadi A, Tanguay A, Quint J, Menon N, Ghanbariamin D, Saeedinejad F, Alipanah F, Chidambaram R, Krawetz R, Nuutila K, Toro S, Barnum L, Jay GD, Schmidt TA, Tamayol A. Dissolvable Immunomodulatory Microneedles for Treatment of Skin Wounds. Adv Healthc Mater 2024; 13:e2302836. [PMID: 38299437 DOI: 10.1002/adhm.202302836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/21/2023] [Indexed: 02/02/2024]
Abstract
Sustained inflammation can halt or delay wound healing, and macrophages play a central role in wound healing. Inflammatory macrophages are responsible for the removal of pathogens, debris, and neutrophils, while anti-inflammatory macrophages stimulate various regenerative processes. Recombinant human Proteoglycan 4 (rhPRG4) is shown to modulate macrophage polarization and to prevent fibrosis and scarring in ear wound healing. Here, dissolvable microneedle arrays (MNAs) carrying rhPRG4 are engineered for the treatment of skin wounds. The in vitro experiments suggest that rhPRG4 modulates the inflammatory function of bone marrow-derived macrophages. Degradable and detachable microneedles are developed from gelatin methacryloyl (GelMA) attach to a dissolvable gelatin backing. The developed MNAs are able to deliver a high dose of rhPRG4 through the dissolution of the gelatin backing post-injury, while the GelMA microneedles sustain rhPRG4 bioavailability over the course of treatment. In vivo results in a murine model of full-thickness wounds with impaired healing confirm a decrease in inflammatory biomarkers such as TNF-α and IL-6, and an increase in angiogenesis and collagen deposition. Collectively, these results demonstrate rhPRG4-incorporating MNA is a promising platform in skin wound healing applications.
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Affiliation(s)
- Pejman Ghelich
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Mohamadmahdi Samandari
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Alireza Hassani Najafabadi
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Adam Tanguay
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Jacob Quint
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Nikhil Menon
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Delaram Ghanbariamin
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Farnoosh Saeedinejad
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Fatemeh Alipanah
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Ramaswamy Chidambaram
- Center for Comparative Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Roman Krawetz
- McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Department of Surgery, University of Calgary, Calgary, AB, T2N 1N4, Canada
| | - Kristo Nuutila
- US Army Institute of Surgical Research, Fort Sam Houston, Texas, 78234, USA
| | - Steven Toro
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Lindsay Barnum
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Gregory D Jay
- Emergency Medicine, Brown University, Providence, RI, 02908, USA
| | - Tannin A Schmidt
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
| | - Ali Tamayol
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, 06030, USA
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Jaffey JA, Kreisler R, Graves TK, Al-Nakkash L, Backus RC, Allison L. Ex Vivo Immune Function and Modulatory Effects of Calcitriol in Dogs with Naturally Occurring Diabetes Mellitus. Vet Sci 2024; 11:193. [PMID: 38787165 PMCID: PMC11125998 DOI: 10.3390/vetsci11050193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/10/2024] [Accepted: 04/21/2024] [Indexed: 05/25/2024] Open
Abstract
Human patients with type 1 diabetes mellitus (T1DM) are susceptible to several long-term complications that are related to glycemic control and immune dysregulation. Immune function remains relatively unexplored in dogs with naturally occurring diabetes mellitus (NODM). Calcitriol improves various aspects of immune function in a variety of species, but its effect in diabetic dogs remains unexplored. Therefore, the objectives of this study were to (i) evaluate immune function in dogs with NODM and determine if differences exist based on the level of clinical control and (ii) assess the immunomodulatory effects of calcitriol. Twenty diabetic dogs (clinically controlled, n = ten, not controlled, n = ten) and 20 non-diabetic, healthy control dogs were included in this prospective, case-control study. Whole blood was incubated with calcitriol (10-7 M) or negative control, after which the samples were divided for phagocytosis and leukocyte cytokine response experiments. The phagocytosis of opsonized Escherichia coli (E. coli) was evaluated with flow cytometry. The samples for leukocyte cytokine response evaluations were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or phosphate buffer solution (PBS; negative control), and tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10 were measured in supernatant using a canine-specific multiplex bead-based assay. The leukocytes from diabetic dogs produced higher concentrations of IL-10 (p = 0.01), IL-6 (p < 0.0001), and IL-8 (p < 0.0001) than the control dogs while controlling for the intervention and stimulant. Calcitriol decreased the supernatant concentrations of TNF-α (p < 0.001) and IL-8 (p = 0.04) with concomitant increases in IL-6 (p = 0.005). Diabetic dogs had a lower percentage of leukocytes undergoing phagocytosis (p < 0.0001) but a higher number of bacteria phagocytized per cell (p = 0.001) when compared to the control dogs. Calcitriol had no effect on phagocytic capacity. Lastly, the status of clinical control in diabetic dogs did not yield differences in immune function. These results support that dogs with NODM exhibit immune dysregulation and warrant additional investigation.
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Affiliation(s)
- Jared A. Jaffey
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
| | - Rachael Kreisler
- Department of Pathology and Population Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA;
| | - Thomas K. Graves
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
| | - Layla Al-Nakkash
- Department of Physiology, Midwestern University, College of Graduate Studies, Glendale, AZ 85308, USA;
| | - Robert C. Backus
- Department of Veterinary Medicine and Surgery, University of Missouri, College of Veterinary Medicine, Columbia, MO 65211, USA;
| | - Lauren Allison
- Department of Specialty Medicine, Midwestern University, College of Veterinary Medicine, Glendale, AZ 85308, USA; (T.K.G.); (L.A.)
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Sun Y, Sun B, Ren Z, Xue M, Zhu C, Liu Q. Heparin-binding protein as a predictor of mortality in patients with diabetes mellitus and community-acquired pneumonia in intensive care unit : a propensity score matched study. World J Emerg Med 2024; 15:263-272. [PMID: 39050224 PMCID: PMC11265634 DOI: 10.5847/wjem.j.1920-8642.2024.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 11/20/2023] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Patients with diabetes mellitus (DM) are vulnerable to community-acquired pneumonia (CAP), which have a high mortality rate. We aimed to investigate the value of heparin-binding protein (HBP) as a prognostic marker of mortality in patients with DM and CAP. METHODS This retrospective study included CAP patients who were tested for HBP at intensive care unit (ICU) admission from January 2019 to April 2020. Patients were allocated to the DM or non-DM group and paired with propensity score matching. Baseline characteristics and clinical outcomes up to 90 days were evaluated. The primary outcome was the 10-day mortality. Receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox regression were used for statistical analysis. RESULTS Among 152 enrolled patients, 60 pairs were successfully matched. There was no significant difference in 10-day mortality, while more patients in the DM group died within 28 d (P=0.024) and 90 d (P=0.008). In the DM group, HBP levels at ICU admission were higher in 10-day non-survivors than in 10-day survivors (median 182.21 [IQR: 55.43-300] ng/ml vs. median 66.40 [IQR: 34.13-107.85] ng/mL, P=0.019), and HBP levels could predict the 10-day mortality with an area under the ROC curve of 0.747. The cut-off value, sensitivity, and specificity were 160.6 ng/mL, 66.7%, and 90.2%, respectively. Multivariate Cox regression analysis indicated that HBP was an independent prognostic factor for 10-day (HR 7.196, 95%CI: 1.596-32.455, P=0.01), 28-day (HR 4.381, 95%CI: 1.449-13.245, P=0.009), and 90-day mortality (HR 4.581, 95%CI: 1.637-12.819, P=0.004) in patients with DM. CONCLUSION Plasma HBP at ICU admission was associated with the 10-day, 28-day, and 90-day mortality, and might be a prognostic factor in patients with DM and CAP.
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Affiliation(s)
- Yuhan Sun
- Translational Medicine Center, Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Baoqing Sun
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China
| | - Zhigang Ren
- Department of Infectious Disease, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Mingshan Xue
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China
| | - Changju Zhu
- Henan Medical Key Laboratory of Emergency and Trauma Research, Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Qi Liu
- Translational Medicine Center, Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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9
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Gašparini D, Wensveen FM, Turk Wensveen T. Inflammageing mediated by cytotoxic lymphocytes is associated with diabetes duration. Diabetes Res Clin Pract 2024; 207:111056. [PMID: 38104904 DOI: 10.1016/j.diabres.2023.111056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/19/2023]
Abstract
AIMS Inflammageing, the age-related systemic increase of proinflammatory factors, has been linked to the development of cardiovascular disease, chronic kidney disease and cancer in the elderly. Chronic inflammation is believed to be a causative factor in the development of diabetic complications. However, exactly how type 2 diabetes impacts the inflammatory state of the immune system is incompletely characterised. METHODS Blood collection and anthropometric measurements were performed in patients with type 2 diabetes (n = 49) and control subjects (n = 30). The phenotype, proliferation capacity and cytokine production by cytotoxic lymphocytes were analysed using multiparametric flow cytometry. RESULTS Type 2 diabetes did not impact the phenotype or proliferation of the investigated cells. However, we observed a significantly increased production of tumour necrosis factor-α by CD8+ T cells and Granzyme B by natural killer cells and γδ T cells compared to controls. Hyperresponsiveness of cytotoxic blood lymphocytes did not correlate with glycaemia or body mass index, but instead was associated with older age and longer diabetes duration. CONCLUSIONS Type 2 diabetes is associated with an increased pro-inflammatory potential of cytotoxic blood lymphocytes correlating with age and diabetes duration. Further research is necessary to explore potential benefits of diabetes medications in reverting this effect.
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Affiliation(s)
- Dora Gašparini
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20/1, 51000 Rijeka, Croatia; Center for Diabetes, Endocrinology and Cardiometabolism, Hospital for Medical Rehabilitation of the Heart and Lung Diseases and Rheumatism Thalassotherapia Opatija, Maršala Tita 188/1, 51410 Opatija, Croatia.
| | - Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20/1, 51000 Rijeka, Croatia.
| | - Tamara Turk Wensveen
- Center for Diabetes, Endocrinology and Cardiometabolism, Hospital for Medical Rehabilitation of the Heart and Lung Diseases and Rheumatism Thalassotherapia Opatija, Maršala Tita 188/1, 51410 Opatija, Croatia; Department of Internal Medicine, Faculty of Medicine, University of Rijeka, Tome Strižića 3, 51000 Rijeka, Croatia; Department of Endocrinology, Diabetes and Metabolic Diseases, Clinic of Internal Medicine, Clinical Hospital Center Rijeka, Krešimirova 42, 51000 Rijeka, Croatia.
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10
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Zhang XJ, Han XW, Jiang YH, Wang YL, He XL, Liu DH, Huang J, Liu HH, Ye TC, Li SJ, Li ZR, Dong XM, Wu HY, Long WJ, Ni SH, Lu L, Yang ZQ. Impact of inflammation and anti-inflammatory modalities on diabetic cardiomyopathy healing: From fundamental research to therapy. Int Immunopharmacol 2023; 123:110747. [PMID: 37586299 DOI: 10.1016/j.intimp.2023.110747] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/18/2023] [Accepted: 07/29/2023] [Indexed: 08/18/2023]
Abstract
Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.
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Affiliation(s)
- Xiao-Jiao Zhang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Xiao-Wei Han
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Yan-Hui Jiang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Ya-Le Wang
- Shanghai University of Traditional Chinese Medicine, 1200 Cai lun Road, Pudong New District, Shanghai 201203, China; Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, 16 Xian tong Road, Luo hu District, Shenzhen, Guangdong 518004, China
| | - Xing-Ling He
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Dong-Hua Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Jie Huang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Hao-Hui Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Tao-Chun Ye
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Si-Jing Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Zi-Ru Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Xiao-Ming Dong
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China
| | - Hong-Yan Wu
- Shanghai University of Traditional Chinese Medicine, 1200 Cai lun Road, Pudong New District, Shanghai 201203, China; Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, 16 Xian tong Road, Luo hu District, Shenzhen, Guangdong 518004, China.
| | - Wen-Jie Long
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Shi-Hao Ni
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Lu Lu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
| | - Zhong-Qi Yang
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510407, China; University Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangdong Province 510407, China; Guangzhou Key Laboratory for Chinese Medicine Prevention and Treatment of Chronic Heart Failure, Guangzhou University of Chinese Medicine, Guangzhou 510407, China.
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11
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Chen VY, Siegfried LG, Tomic-Canic M, Stone RC, Pastar I. Cutaneous changes in diabetic patients: Primed for aberrant healing? Wound Repair Regen 2023; 31:700-712. [PMID: 37365017 PMCID: PMC10966665 DOI: 10.1111/wrr.13108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 06/28/2023]
Abstract
Cutaneous manifestations affect most patients with diabetes mellitus, clinically presenting with numerous dermatologic diseases from xerosis to diabetic foot ulcers (DFUs). Skin conditions not only impose a significantly impaired quality of life on individuals with diabetes but also predispose patients to further complications. Knowledge of cutaneous biology and the wound healing process under diabetic conditions is largely limited to animal models, and studies focusing on biology of the human condition of DFUs remain limited. In this review, we discuss the critical molecular, cellular, and structural changes to the skin in the hyperglycaemic and insulin-resistant environment of diabetes with a focus specifically on human-derived data. Elucidating the breadth of the cutaneous manifestations coupled with effective diabetes management is important for improving patient quality of life and averting future complications including wound healing disorders.
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Affiliation(s)
- Vivien Y Chen
- Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Lindsey G Siegfried
- Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Rivka C Stone
- Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
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12
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Li M, Nguyen L, Ferens D, Spizzo I, Wang Y, Denton KM, Del Borgo M, Kulkarni K, Aguilar MI, Qin CH, Samuel CS, Gaspari TA, Widdop RE. Novel AT 2R agonist, β-Pro 7Ang III, is cardio- and vaso-protective in diabetic spontaneously hypertensive rats. Biomed Pharmacother 2023; 165:115238. [PMID: 37536036 DOI: 10.1016/j.biopha.2023.115238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/15/2023] [Accepted: 07/25/2023] [Indexed: 08/05/2023] Open
Abstract
Stimulation of the angiotensin II type 2 receptor (AT2R) evokes protective effects in various cardiovascular diseases. Thus, this study aimed to investigate the effects of AT2R stimulation, with or without AT1R blockade, in a model of hypertension with concomitant type 1 diabetes mellitus (T1DM). Spontaneously hypertensive rats (SHRs) were given either citrate or a single dose of streptozotocin (STZ; 55 mg/kg, i.p.) to induce diabetes. After 4 weeks of diabetes, animals were administered either a vehicle (saline), AT2R agonist, β-Pro7Ang III (0.1 mg/kg/day via osmotic mini-pump), AT1R blocker, candesartan (2 mg/kg/day via drinking water), or a combination of both for a further 8 weeks. β-Pro7Ang III treatment had no effect on blood pressure, but attenuated the significant increase in cardiac interstitial collagen and protein expression of fibrotic and inflammatory markers, and superoxide levels that was evident in diabetic SHRs. These effects were not observed with candesartan, despite its blood pressure lowering effects. Although β-Pro7Ang III had no effect on aortic fibrosis, it significantly attenuated MCP-1 protein expression and superoxide levels when compared to both the non-diabetic and diabetic SHRs, to a similar extent as candesartan. In both the heart and vasculature, the effects of β-Pro7Ang III in combination with candesartan were similar to those of β-Pro7Ang III alone, and superior to candesartan alone. It was concluded that in hypertension with concomitant diabetes, AT2R stimulation with a novel ligand alone, or in combination with AT1R blockade, improved the cardiac and vascular structural changes that were strongly associated with inflammation and oxidative stress, independent of blood pressure regulation.
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Affiliation(s)
- Mandy Li
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Levi Nguyen
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Dorota Ferens
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Iresha Spizzo
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Yan Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Kate M Denton
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Physiology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Mark Del Borgo
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Ketav Kulkarni
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Marie-Isabel Aguilar
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Chengxue Helena Qin
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Tracey A Gaspari
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia.
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13
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Zakeri A, Khaseb S, Akhavan Rahnama M, Hajaliaskari A, Soufi Zomorrod M. Exosomes derived from mesenchymal stem cells: A promising cell-free therapeutic tool for cutaneous wound healing. Biochimie 2023; 209:73-84. [PMID: 36681232 DOI: 10.1016/j.biochi.2023.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Skin wound healing is a multifaceted process involving a cascade of molecular and cellular procedures that occur in four different phases: (a) hemostasis, (b) inflammation, (c) proliferation, and (d) tissue remodeling. Prolonged wound healing in skin is still a major challenge in treatment of wounds. Mesenchymal stem cells (MSCs) accelerate cutaneous wound healing through their paracrine activity. Exosomes are one of the key secretory products of MSCs, mimicking the effects of parental MSCs in skin wound healing process. Exosomes are small membrane vesicles (30-150 nm in diameter) that originate from endosomal pathways and transport numerous biomolecules, including DNAs, messenger RNAs, microRNAs, lipids, and proteins. They can be taken up by target cells and release their contents to modulate the activity of recipient cells. Exosomes derived from mesenchymal stem cells (MSC-Exo) reduce inflammation, promote proliferation, inhibit apoptosis, and enhance angiogenesis in skin wound healing process. Therefore, exosomes are emerging as novel cell-cell communication mediators and have opened a novel viewpoint for developing cell-free therapies. This review aims to demonstrate the roles of exosomes in each step of skin wound healing through a comprehensive literature search.
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Affiliation(s)
- Armin Zakeri
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Sanaz Khaseb
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Mahshid Akhavan Rahnama
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Akram Hajaliaskari
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
| | - Mina Soufi Zomorrod
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University (TMU), Tehran, Iran.
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14
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Zhang KF, Shi CX, Chen SY, Wei W. Progress in Multidisciplinary Treatment of Fournier's Gangrene. Infect Drug Resist 2022; 15:6869-6880. [PMID: 36465810 PMCID: PMC9717591 DOI: 10.2147/idr.s390008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/10/2022] [Indexed: 07/27/2023] Open
Abstract
Fournier's gangrene (FG) is a life-threatening and special form of necrotizing fasciitis, characterized by occult onset, rapid progress and high mortality, occurring mainly in men over 50 years of age. Risk factors of FG include diabetes, HIV infection, chronic alcoholism and other immunosuppressive state. FG was previously considered as an idiopathic disease, but in fact, three quarters of the infections originated from the skin, urethra and gastrointestinal tract. Initial symptoms of FG are often inconsistent with severity and can progress promptly to fatal infection. Although the treatment measures of FG have been improved in recent years, the mortality does not seem to have decreased significantly and remains at 20% - 30%. The time to identify FG and the waiting period before surgical debridement are directly related to the prognosis. Therefore, in addition to the combination of intensive fluid resuscitation and broad-spectrum antibiotics, treatment of FG should particularly emphasize the importance of early surgical debridement assisted with fecal diversion and skin reconstruction when necessary. This paper is to briefly summarize the progress in the definition, epidemiology, clinical manifestations, diagnosis, treatment and prognosis of Fournier's gangrene in recent years, more importantly, illustrates the importance of multidisciplinary cooperation in the management of FG.
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Affiliation(s)
- Ke-Fan Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Chuan-Xin Shi
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Si-Yu Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wei Wei
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
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15
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Son KH, Kim WH, Kwak JG, Choi CH, Lee SI, Ko UW, Kim HS, Lee H, Chung ES, Kim JB, Jang WS, Jung JS, Kim J, Yoon YK, Song S, Sung M, Jang MH, Kim YS, Jeong IS, Kim DW, Kim TY, Kim SJ, Kim SW, Hong J, An H. Hyperglycemia and Hypoglycemia Are Associated with In-Hospital Mortality among Patients with Coronavirus Disease 2019 Supported with Extracorporeal Membrane Oxygenation. J Clin Med 2022; 11:jcm11175106. [PMID: 36079032 PMCID: PMC9457381 DOI: 10.3390/jcm11175106] [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: 07/19/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Metabolic abnormalities, such as preexisting diabetes or hyperglycemia or hypoglycemia during hospitalization aggravated the severity of COVID-19. We evaluated whether diabetes history, hyperglycemia before and during extracorporeal membrane oxygenation (ECMO) support, and hypoglycemia were risk factors for mortality in patients with COVID-19. This study included data on 195 patients with COVID-19, who were aged ≥19 years and were treated with ECMO. The proportion of patients with diabetes history among nonsurvivors was higher than that among survivors. Univariate Cox regression analysis showed that in-hospital mortality after ECMO support was associated with diabetes history, renal replacement therapy (RRT), and body mass index (BMI) < 18.5 kg/m2. Glucose at admission >200 mg/dL and glucose levels before ventilator >200 mg/dL were not associated with in-hospital mortality. However, glucose levels before ECMO >200 mg/dL and minimal glucose levels during hospitalization <70 mg/dL were associated with in-hospital mortality. Multivariable Cox regression analysis showed that glucose >200 mg/dL before ECMO and minimal glucose <70 mg/dL during hospitalization remained risk factors for in-hospital mortality after adjustment for age, BMI, and RRT. In conclusion, glucose >200 mg/dL before ECMO and minimal glucose level <70 mg/dL during hospitalization were risk factors for in-hospital mortality among COVID-19 patients who underwent ECMO.
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Affiliation(s)
- Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea
| | - Woong-Han Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-2072-3637
| | - Jae Gun Kwak
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Chang-Hyu Choi
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea
| | - Seok In Lee
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea
| | - Ui Won Ko
- Pulmonary and Allergy Division, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Korea
| | - Hyoung Soo Kim
- Department of Thoracic and Cardiovascular Surgery, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Haeyoung Lee
- Department of Thoracic and Cardiovascular Surgery, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan 49267, Korea
| | - Euy Suk Chung
- Department of Thoracic and Cardiovascular Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul 03181, Korea
| | - Jae-Bum Kim
- Department of Thoracic and Cardiovascular Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, Korea
| | - Woo Sung Jang
- Department of Thoracic and Cardiovascular Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, Korea
| | - Jae Seung Jung
- Department of Thoracic and Cardiovascular Surgery, Korea University College of Medicine, Seoul 02841, Korea
| | - Jieon Kim
- Department of Thoracic and Cardiovascular Surgery, Korea University College of Medicine, Seoul 02841, Korea
| | - Young Kyung Yoon
- Division of Infectious Disease, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Korea
| | - Seunghwan Song
- Department of Thoracic and Cardiovascular Surgery, Pusan National University Hospital, Biomedical Research Institute, Pusan National University School of Medicine, Busan 49241, Korea
| | - Minji Sung
- Health Convergence Medicine Laboratory, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea
| | - Myung Hun Jang
- Department of Rehabilitation Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea
| | - Young Sam Kim
- Department of Thoracic and Cardiovascular Surgery, Inha University Hospital, Inha University School of Medicine, Incheon 22332, Korea
| | - In-Seok Jeong
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 61649, Korea
| | - Do Wan Kim
- Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 61649, Korea
| | - Tae Yun Kim
- Department of Thoracic and Cardiovascular Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea
| | - Soon Jin Kim
- Department of Thoracic and Cardiovascular Surgery, Jeonbuk National University Hospital, Jeonju 54907, Korea
| | - Su Wan Kim
- Department of Thoracic and Cardiovascular Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju 63241, Korea
| | - Joonhwa Hong
- Department of Thoracic and Cardiovascular Surgery, Chung-Ang University Hospital, Seoul 06973, Korea
| | - Hyungmi An
- Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Korea
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16
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Biswas M, Suvarna R, Krishnan S V, Devasia T, Shenoy Belle V, Prabhu K. The mechanistic role of neutrophil lymphocyte ratio perturbations in the leading non communicable lifestyle diseases. F1000Res 2022; 11:960. [PMID: 36619602 PMCID: PMC9780608 DOI: 10.12688/f1000research.123245.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/08/2022] [Indexed: 01/13/2023] Open
Abstract
Inflammation plays a critical role in the development and progression of chronic diseases like type 2 diabetes mellitus, coronary artery disease, and chronic obstructive pulmonary disease. Inflammatory responses are indispensable for pathogen control and tissue repair, but they also cause collateral damage. A chronically activated immune system and the resultant immune dysregulation mediated inflammatory surge may cause multiple negative effects, requiring tight regulation and dampening of the immune response to minimize host injury. While chronic diseases are characterized by systemic inflammation, the mechanistic relationship of neutrophils and lymphocytes to inflammation and its correlation with the clinical outcomes is yet to be elucidated. The neutrophil to lymphocyte ratio (NLR) is an easy-to-measure laboratory marker used to assess systemic inflammation. Understanding the mechanisms of NLR perturbations in chronic diseases is crucial for risk stratification, early intervention, and finding novel therapeutic targets. We investigated the correlation between NLR and prevalent chronic conditions as a measure of systemic inflammation. In addition to predicting the risk of impending chronic conditions, NLR may also provide insight into their progression. This review summarizes the mechanisms of NLR perturbations at cellular and molecular levels, and the key inflammatory signaling pathways involved in the progression of chronic diseases. We have also explored preclinical studies investigating these pathways and the effect of quelling inflammation in chronic disease as reported by a few in vitro, in vivo studies, and clinical trials.
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Affiliation(s)
- Monalisa Biswas
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Renuka Suvarna
- Division of Ayurveda, Center for Integrative Medicine and Research, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Vimal Krishnan S
- Department of Emergency Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Tom Devasia
- Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Vijetha Shenoy Belle
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India,
| | - Krishnananda Prabhu
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India,
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Uribe-Querol E, Rosales C. Neutrophils Actively Contribute to Obesity-Associated Inflammation and Pathological Complications. Cells 2022; 11:1883. [PMID: 35741012 PMCID: PMC9221045 DOI: 10.3390/cells11121883] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/02/2022] [Accepted: 06/08/2022] [Indexed: 02/01/2023] Open
Abstract
Obesity is characterized by an increase in body weight associated with an exaggerated enlargement of the adipose tissue. Obesity has serious negative effects because it is associated with multiple pathological complications such as type 2 diabetes mellitus, cardiovascular diseases, cancer, and COVID-19. Nowadays, 39% of the world population is obese or overweight, making obesity the 21st century epidemic. Obesity is also characterized by a mild, chronic, systemic inflammation. Accumulation of fat in adipose tissue causes stress and malfunction of adipocytes, which then initiate inflammation. Next, adipose tissue is infiltrated by cells of the innate immune system. Recently, it has become evident that neutrophils, the most abundant leukocytes in blood, are the first immune cells infiltrating the adipose tissue. Neutrophils then get activated and release inflammatory factors that recruit macrophages and other immune cells. These immune cells, in turn, perpetuate the inflammation state by producing cytokines and chemokines that can reach other parts of the body, creating a systemic inflammatory condition. In this review, we described the recent findings on the role of neutrophils during obesity and the initiation of inflammation. In addition, we discuss the involvement of neutrophils in the generation of obesity-related complications using diabetes as a prime example.
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Affiliation(s)
- Eileen Uribe-Querol
- Laboratorio de Biología del Desarrollo, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Carlos Rosales
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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18
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Platelet-Neutrophil Interactions and Thrombo-inflammatory Complications in Type 2 Diabetes Mellitus. CURRENT PATHOBIOLOGY REPORTS 2022. [DOI: 10.1007/s40139-022-00229-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Xiao Z, Shen D, Lan T, Wei C, Wu W, Sun Q, Luo Z, Chen W, Zhang Y, Hu L, Zhang C, Wang Y, Lu Y, Wang P, Yang F, Li Q. Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice. Redox Biol 2022; 50:102256. [PMID: 35131600 PMCID: PMC8829351 DOI: 10.1016/j.redox.2022.102256] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 11/28/2022] Open
Abstract
Diabetic hyperglycemia aggravates the prognosis of intracerebral hemorrhagic stroke (ICH) in the clinic. In addition to hematoma expansion and increased inflammation, how diabetic hyperglycemia affects the outcomes of ICH is still unclear. We found that streptozotocin-induced diabetic hyperglycemia not only increased neutrophil infiltration, but also changed the gene expression profile of neutrophils, including lactoferrin (Ltf) encoding gene Ltf. Peroxisome proliferator-activated receptor γ (PPARγ) transcribed Ltf and the lack of neutrophilic Ltf transcription and secretion exacerbated neuronal ferroptosis by accumulating intraneuronal iron. Furthermore, the administration of recombinant Ltf protected against neuronal ferroptosis and improved neurobehavior in hyperglycemic ICH mice, and vice versa. These results indicate that supplementing Ltf or inhibiting neuronal ferroptosis are promising potential strategies to improve the acute outcomes of diabetic ICH in the clinic.
Neutrophil infiltration and ICH prognosis are aggravated in hyperglycemic mice. Hyperglycemia impairs PPAR-γ activity and decreases Ltf expression in neutrophils. The lack of neutrophilic Ltf fails to decrease intraneuronal iron and ferroptosis. rLtf eases neuronal ferroptosis and neurologic deficits in hyperglycemic ICH mice.
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Affiliation(s)
- Zhongnan Xiao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, China
| | - Danmin Shen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Ting Lan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Chao Wei
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Weihua Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Qingyu Sun
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Zhaoli Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wen Chen
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yurui Zhang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Liye Hu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Chenguang Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yamei Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yabin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Peipei Wang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Fei Yang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China
| | - Qian Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China.
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20
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Giovenzana A, Carnovale D, Phillips B, Petrelli A, Giannoukakis N. Neutrophils and their role in the aetiopathogenesis of type 1 and type 2 diabetes. Diabetes Metab Res Rev 2022; 38:e3483. [PMID: 34245096 DOI: 10.1002/dmrr.3483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 05/12/2021] [Accepted: 06/19/2021] [Indexed: 12/25/2022]
Abstract
Multiple and complex aetiological processes underlie diabetes mellitus, which invariably result in the development of hyperglycaemia. Although there are two prevalent distinct forms of the disease, that is, type 1 and type 2 diabetes, accumulating evidence indicates that these syndromes share more aetiopathological mechanisms than originally thought. This compels a rethinking of the approaches to prevent and treat the different manifestations of what eventually becomes a hyperglycaemic state. This review aims to address the involvement of neutrophils, the most abundant type of granulocytes involved in the initiation of the acute phase of inflammation, in the aetiopathogenesis of diabetes mellitus, with a focus on type 1 and type 2 diabetes. We review the evidence that neutrophils are the first leucocytes to react to and accumulate inside target tissues of diabetes, such as the pancreas and insulin-sensitive tissues. We then review available data on the role of neutrophils and their functional alteration, with a focus on NETosis, in the progression towards clinical disease. Finally, we review potential approaches as secondary and adjunctive treatments to limit neutrophil-mediated damage in the prevention of the progression of subclinical disease to clinical hyperglycaemia.
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Affiliation(s)
- Anna Giovenzana
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
| | - Debora Carnovale
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
| | - Brett Phillips
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
| | - Alessandra Petrelli
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, Pennsylvania, USA
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21
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Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs. Toxins (Basel) 2021; 13:toxins13120873. [PMID: 34941711 PMCID: PMC8709190 DOI: 10.3390/toxins13120873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/28/2021] [Accepted: 12/04/2021] [Indexed: 11/28/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications.
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22
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Reshad RAI, Riana SH, Chowdhury MAB, Moin AT, Miah F, Sarkar B, Jewel NA. Diabetes in COVID-19 patients: challenges and possible management strategies. THE EGYPTIAN JOURNAL OF BRONCHOLOGY 2021. [PMCID: PMC8642747 DOI: 10.1186/s43168-021-00099-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background The recent pandemic of coronavirus disease 19 (COVID-19) has been causing intense stress among the global population. In the case of hospitalized and ICU-admitted COVID-19 patients with comorbidities, it has been observed that a major portion of them are diabetic. Therefore, researchers had indicated a link between diabetes mellitus (DM) and COVID-19. Furthermore, DM is a potential risk factor for the severity of COVID-19 cases. Thus, in this study, the correlation existing between diabetic patients and COVID-19 was summarized. Main body of the abstract Diabetic patients have a weaker immune system, less viral clearance rate, malfunctions of metabolic activity due to their high blood glucose level, and other associated problems. This does not increase the susceptibility for the patients to be infected with COVID-19. However, the severity of COVID-19 can worsen due to the comorbidity of DM. Short conclusion Proper management, appropriate use of drugs that do not increase the ACE2 expression, lowering blood glucose level, decreasing the susceptibility of SARS-CoV-2, and maintaining a healthy lifestyle could be effective.
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23
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Klaile E, Prada Salcedo JP, Klassert TE, Besemer M, Bothe AK, Durotin A, Müller MM, Schmitt V, Luther CH, Dittrich M, Singer BB, Dandekar T, Slevogt H. Antibody ligation of CEACAM1, CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses to Candida albicans. Cell Immunol 2021; 371:104459. [PMID: 34847408 DOI: 10.1016/j.cellimm.2021.104459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 11/30/2022]
Abstract
Invasive candidiasis is a healthcare-associated fungal infection with a high mortality rate. Neutrophils, the first line of defense during fungal infections, express the immunoregulatory Candida albicans receptors CEACAM1, CEACAM3, and CEACAM6. We analyzed the effects of specific antibodies on C. albicans-induced neutrophil responses. CEACAM6 ligation by 1H7-4B and to some extent CEACAM1 ligation by B3-17, but not CEACAM3 ligation by 308/3-3, resulted in the immediate release of stored CXCL8 and altered transcriptional responses of the C. albicans-stimulated neutrophils. Integrated network analyses and dynamic simulations of signaling cascades predicted alterations in apoptosis and cytokine secretion. We verified that CEACAM6 ligation enhanced Candida-induced neutrophil apoptosis and increased long-term IL-1β/IL-6 release in responses to C. albicans. CEACAM3 ligation, but not CEACAM1 ligation, increased the long-term release of pro-inflammatory IL-1β/IL-6. Taken together, we demonstrated for the first time that ligation of CEACAM receptors differentially affects the regulation of C. albicans-induced immune functions in human neutrophils.
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Affiliation(s)
- Esther Klaile
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Juan P Prada Salcedo
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Tilman E Klassert
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Matthias Besemer
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Anne-Katrin Bothe
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Adrian Durotin
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Mario M Müller
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
| | - Verena Schmitt
- Institute of Anatomy, University Hospital, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
| | - Christian H Luther
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Marcus Dittrich
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany; Dept. of Human Genetics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Bernhard B Singer
- Institute of Anatomy, University Hospital, University Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany.
| | - Thomas Dandekar
- Dept. of Bioinformatics, University of Würzburg, Biocenter/Am Hubland, 97074 Würzburg, Germany.
| | - Hortense Slevogt
- ZIK Septomics, University Hospital Jena, Albert-Einstein-Straße 10, 07749 Jena, Germany.
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24
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Fernandes ER, Pires GN, Andersen ML, Tufik S, Rosa DS. Oxygen saturation as a predictor of inflammation in obstructive sleep apnea. Sleep Breath 2021; 26:1613-1620. [PMID: 34792741 DOI: 10.1007/s11325-021-02521-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/04/2021] [Accepted: 10/27/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE Obstructive sleep apnea (OSA) is a chronic sleep disorder, and its prevalence is increasing worldwide. This disorder has been consistently associated with several comorbidities. Although it is clear that obstructive sleep apnea severity is associated with inflammation, the trigger for this phenomenon continues to puzzle scientists. Here, we investigated the relationship between obstructive sleep apnea severity and immune parameters. METHODS In this cross-sectional epidemiological research, we analyzed the immune profile of 461 adults according to OSA severity (mild, moderate, and severe) and oxygen saturation. RESULTS The hallmark of OSA severity - the apnea-hypopnea index (AHI) - weakly correlated with an inflammatory profile. However, individuals who experienced lower oxygen saturation were more likely to exhibit higher total leukocyte and neutrophil counts, a higher neutrophil-lymphocyte ratio (NLR), and an increased concentration of C-reactive protein. CONCLUSION Our findings indicated that oxygen saturation is a predictor of inflammation during OSA and should be considered crucial in disease diagnostic and treatment strategies.
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Affiliation(s)
- Edgar Ruz Fernandes
- Departamento de Microbiologia, Imunologia E Parasitologia, Universidade Federal de São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4° andar, Vila Clementino, São Paulo, Brazil
| | - Gabriel Natan Pires
- Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil
| | - Monica Levy Andersen
- Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil
| | - Sergio Tufik
- Departamento de Psicobiologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil
| | - Daniela Santoro Rosa
- Departamento de Microbiologia, Imunologia E Parasitologia, Universidade Federal de São Paulo (UNIFESP/EPM), Rua Botucatu, 862, 4° andar, Vila Clementino, São Paulo, Brazil. .,Institute for Investigation in Immunology (iii-INCT), São Paulo, Brazil.
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25
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Elmadbouh I, Singla DK. BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy. Cells 2021; 10:2640. [PMID: 34685620 PMCID: PMC8533936 DOI: 10.3390/cells10102640] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/22/2021] [Accepted: 09/28/2021] [Indexed: 01/15/2023] Open
Abstract
In the present study, we investigated a novel signaling target in diabetic cardiomyopathy where inflammation induces caspase-1-dependent cell death, pyroptosis, involving Nek7-GBP5 activators to activate the NLRP3 inflammasome, destabilizes cardiac structure and neovascularization. Furthermore, we explored the therapeutic ability of bone morphogenetic protein-7 (BMP-7) to attenuate these adverse effects. C57BL/6J mice (n = 16 mice/group) were divided into: control (200 mg/kg, 0.9% saline intraperitoneal injection, i.p.); Streptozotocin (STZ) and STZ-BMP-7 groups (STZ, 200 mg/kg, i.p. injection). After 6 weeks, heart function was examined with echocardiography, and mice were sacrificed. Immunostaining, Western blotting, H&E, and Masson's trichrome staining was performed on heart tissues. STZ-induced diabetic cardiomyopathy significantly increased inflammasome formation (TLR4, NLRP3, Nek7, and GBP5), pyroptosis markers (caspase-1, IL-1β, and IL-18), inflammatory cytokines (IL-6 and TNF-α), MMP9, and infiltration of monocytes (CD14), macrophage (iNOS), and dendritic cells (CD11b and CD11c) (p < 0.05). Moreover, a significant endothelial progenitor cells (EPCs) dysfunction (c-Kit/FLk-1, CD31), adverse cardiac remodeling, and reduction in left ventricular (LV) heart function were observed in STZ versus control (p < 0.05). Treatment with BMP-7 significantly reduced inflammasome formation, pyroptosis, and inflammatory cytokines and infiltrated inflammatory cells. In addition, BMP-7 treatment enhanced EPC markers and neovascularization and subsequently improved cardiac remodeling in a diabetic heart. Moreover, a significant improvement in LV heart function was achieved after BMP-7 administration relative to diabetic mice (p < 0.05). In conclusion, BMP-7 attenuated inflammation-induced pyroptosis, adverse cardiac remodeling, and improved heart function via the TLR4-NLRP3 inflammasome complex activated by novel signaling Nek7/GBP5. Our BMP-7 pre-clinical studies of mice could have significant potential as a future therapy for diabetic patients.
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Affiliation(s)
| | - Dinender K. Singla
- Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
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26
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Mohan R, Wei Lynn Goh S, Tan GW, Tan YP, Junnarkar SP, Huey CWT, Low JK, Shelat VG. Validation of Tokyo Guidelines 2007 and Tokyo Guidelines 2013/2018 Criteria for Acute Cholangitis and Predictors of In-Hospital Mortality. Visc Med 2021; 37:434-442. [PMID: 34722727 PMCID: PMC8543341 DOI: 10.1159/000516424] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute cholangitis (AC) is a common emergency with a significant mortality risk. The Tokyo Guidelines (TG) provide recommendations for diagnosis, severity stratification, and management of AC. However, validation of the TG remains poor. This study aims to validate TG07, TG13, and TG18 criteria and identify predictors of in-hospital mortality in patients with AC. METHODS This is a retrospective audit of patients with a discharge diagnosis of AC in the year 2016. Demographic, clinical, investigation, management and mortality data were documented. We performed a multinomial logistic regression analysis with stepwise variable selection to identify severity predictors for in-hospital mortality. RESULTS Two hundred sixty-two patients with a median age of 75.9 years (IQR 64.8-82.8) years were included for analysis. TG13/TG18 diagnostic criteria were more sensitive than TG07 diagnostic criteria (85.1 vs. 75.2%; p < 0.006). The majority of the patients (n = 178; 67.9%) presented with abdominal pain, pyrexia (n = 156; 59.5%), and vomiting (n = 123; 46.9%). Blood cultures were positive in 95 (36.3%) patients, and 79 (83.2%) patients had monomicrobial growth. The 30-day, 90-day, and in-hospital mortality numbers were 3 (1.1%), 11 (4.2%), and 15 (5.7%), respectively. In multivariate analysis, type 2 diabetes mellitus (OR = 12.531; 95% CI 0.354-116.015; p = 0.026), systolic blood pressure <100 mm Hg (OR = 10.108; 95% CI 1.094-93.395; p = 0.041), Glasgow coma score <15 (OR = 38.16; 95% CI 1.804-807.191; p = 0.019), and malignancy (OR = 14.135; 95% CI 1.017-196.394; p = 0.049) predicted in-hospital mortality. CONCLUSION TG13/18 diagnostic criteria are more sensitive than TG07 diagnostic criteria. Type 2 diabetes mellitus, systolic blood pressure <100 mm Hg, Glasgow coma score <15, and malignant etiology predict in-hospital mortality in patients with AC. These predictors could be considered in acute stratification and treatment of patients with AC.
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Affiliation(s)
- Ramkumar Mohan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- *Vishal G. Shelat,
| | | | - Guan Wei Tan
- Ministry of Health Holdings, Singapore, Singapore
| | - Yen Pin Tan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | | | - Cheong Wei Terence Huey
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Jee Keem Low
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Vishal G. Shelat
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
- *Vishal G. Shelat,
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27
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Chaar D, Dumont B, Vulesevic B, Neagoe PE, Rakel A, Sirois MG, White M. Neutrophils pro-inflammatory and anti-inflammatory cytokine release in patients with heart failure and reduced ejection fraction. ESC Heart Fail 2021; 8:3855-3864. [PMID: 34382750 PMCID: PMC8497194 DOI: 10.1002/ehf2.13539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 05/26/2021] [Accepted: 07/13/2021] [Indexed: 01/08/2023] Open
Abstract
AIMS Heart failure with reduced ejection fraction (HFrEF) is characterized by sub-clinical inflammation. Changes in selected biomarkers of inflammation concomitant with the release of pro-inflammatory and anti-inflammatory cytokines by neutrophils have not been investigated in patients with HFrEF. METHODS AND RESULTS Fifty-two patients, aged 68.8 ± 1.7 years, with HFrEF and left ventricular ejection fraction 28.7 ± 1.0%, and 21 healthy controls (CTL) were recruited. Twenty-five HF patients had type 2 diabetes. Venous blood samples from HF and CTL were collected once. Neutrophil-derived pro-inflammatory and anti-inflammatory cytokine levels were assessed in plasma by ELISA. Plasma biomarkers assessed included: C-reactive protein (CRP), vascular endothelial growth factor (VEGF), interleukins (IL)-6, -8, -1 receptor antagonist (-1RA), nitric oxide (NO), soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1) and E-Selectin (sE-Sel). Neutrophils were isolated and stimulated with various agonists to promote VEGF, IL-6, IL-8, and IL-1RA release. Compared with CTL, HFrEF patients showed a marked decrease in circulating VEGF [178.0 (interquartile range; IQR 99.6; 239.2) vs. 16.2 (IQR 9.3; 20.2) pg/mL, P ≤ 0.001] and NO [45.2 (IQR 42.1; 57.6) vs. 40.6 (IQR 30.4; 47.1) pg/mL, P = 0.0234]. All other circulating biomarkers were significantly elevated. Neutrophils isolated from patients with HFrEF exhibited a greater IL-8 release in response to LPS [1.2 ± 0.1 (CTL); 10.4 ± 1.6 ng/mL (HFrEF) and 12.4 ± 1.6 ng/mL (HFrEF and DM), P ≤ 0.001]. IL-6 release in response to LPS was not changed in HFrEF patients without diabetes, whereas it was significantly increased in patients with HFrEF and diabetes [46.7 ± 3.9 (CTL) vs. 165.8 ± 48.0 pg/mL (HFrEF), P = 0.1713 and vs. 397.7 ± 67.4 pg/mL (HFrEF and DM), P ≤ 0.001]. In contrast, the release of VEGF and IL-1RA was significantly reduced in HFrEF (VEGF; TNF-α: 38.6 ± 3.1 and LPS: 25.3 ± 2.6 pg/mL; IL1RA; TNF-α: 0.6 ± 0.04 and LPS: 0.3 ± 0.02 ng/mL) compared with CTL (VEGF; TNF-α: 60.0 ± 9.4 and LPS: 41.2 ± 5.9 pg/mL; IL1RA; TNF-α: 3.3 ± 0.2 and LPS: 2.3 ± 0.1 ng/mL). CONCLUSIONS Patients with HFrEF exhibit a significant decrease in circulating VEGF. The release of VEGF and both pro-inflammatory and anti-inflammatory cytokines from the stimulated neutrophils is markedly altered in these patients. The clinical significance of these findings deserves further investigation.
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Affiliation(s)
- Diana Chaar
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Benjamin Dumont
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada.,Department of Pharmacology and Physiology, Faculté de Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Branka Vulesevic
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada
| | - Paul-Eduard Neagoe
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada
| | - Agnes Rakel
- Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.,Research Center, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montreal, Québec, Canada
| | - Martin G Sirois
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada.,Department of Pharmacology and Physiology, Faculté de Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Michel White
- Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, H1T 1C8, Canada.,Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
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Nouri-Keshtkar M, Taghizadeh S, Farhadi A, Ezaddoustdar A, Vesali S, Hosseini R, Totonchi M, Kouhkan A, Chen C, Zhang JS, Bellusci S, Tahamtani Y. Potential Impact of Diabetes and Obesity on Alveolar Type 2 (AT2)-Lipofibroblast (LIF) Interactions After COVID-19 Infection. Front Cell Dev Biol 2021; 9:676150. [PMID: 34307358 PMCID: PMC8295688 DOI: 10.3389/fcell.2021.676150] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/11/2021] [Indexed: 01/14/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new emerging respiratory virus, caused evolving pneumonia outbreak around the world. In SARS-Cov-2 infected patients, diabetes mellitus (DM) and obesity are two metabolic diseases associated with higher severity of SARS-CoV-2 related complications, characterized by acute lung injury requiring assisted ventilation as well as fibrosis development in surviving patients. Different factors are potentially responsible for this exacerbated response to SARS-CoV-2 infection. In patients with DM, base-line increase in inflammation and oxidative stress represent preexisting risk factors for virus-induced damages. Such factors are also likely to be found in obese patients. In addition, it has been proposed that massive injury to the alveolar epithelial type 2 (AT2) cells, which express the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), leads to the activation of their stromal niches represented by the Lipofibroblasts (LIF). LIF are instrumental in maintaining the self-renewal of AT2 stem cells. LIF have been proposed to transdifferentiate into Myofibroblast (MYF) following injury to AT2 cells, thereby contributing to fibrosis. We hypothesized that LIF's activity could be impacted by DM or obesity in an age- and gender-dependent manner, rendering them more prone to transition toward the profibrotic MYF status in the context of severe COVID-19 pneumonia. Understanding the cumulative effects of DM and/or obesity in the context of SARS-CoV-2 infection at the cellular level will be crucial for efficient therapeutic solutions.
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Affiliation(s)
- Marjan Nouri-Keshtkar
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Sara Taghizadeh
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Excellence Cluster Cardio-Pulmonary System, Justus Liebig University Giessen, Giessen, Germany
| | - Aisan Farhadi
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | - Samira Vesali
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Roya Hosseini
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mehdi Totonchi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Azam Kouhkan
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Chengshui Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jin-San Zhang
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Saverio Bellusci
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Excellence Cluster Cardio-Pulmonary System, Justus Liebig University Giessen, Giessen, Germany
| | - Yaser Tahamtani
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
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Mzimela NC, Sosibo AM, Ngubane PS, Khathi A. The changes that occur in the immune system during immune activation in pre-diabetic patients of all ethnicities, from the age of 25 to 45 years: a protocol for systematic review and meta-analysis. (Preprint). JMIR Res Protoc 2021; 11:e31619. [DOI: 10.2196/31619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 11/09/2022] Open
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Dowey R, Iqbal A, Heller SR, Sabroe I, Prince LR. A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity. Front Immunol 2021; 12:678771. [PMID: 34149714 PMCID: PMC8209466 DOI: 10.3389/fimmu.2021.678771] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022] Open
Abstract
Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.
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Affiliation(s)
- Rebecca Dowey
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
| | - Ahmed Iqbal
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Simon R. Heller
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Ian Sabroe
- Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom
| | - Lynne R. Prince
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
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Cardoso EOC, Fine N, Glogauer M, Johnson F, Goldberg M, Golub LM, Tenenbaum HC. The Advent of COVID-19; Periodontal Research Has Identified Therapeutic Targets for Severe Respiratory Disease; an Example of Parallel Biomedical Research Agendas. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.674056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The pathophysiology of SARS-CoV-2 infection is characterized by rapid virus replication and aggressive inflammatory responses that can lead to acute respiratory distress syndrome (ARDS) only a few days after the onset of symptoms. It is suspected that a dysfunctional immune response is the main cause of SARS-CoV-2 infection-induced lung destruction and mortality due to massive infiltration of hyperfunctional neutrophils in these organs. Similarly, neutrophils are recruited constantly to the oral cavity to combat microorganisms in the dental biofilm and hyperfunctional neutrophil phenotypes cause destruction of periodontal tissues when periodontitis develops. Both disease models arise because of elevated host defenses against invading organisms, while concurrently causing host damage/disease when the immune cells become hyperfunctional. This represents a clear nexus between periodontal and medical research. As researchers begin to understand the link between oral and systemic diseases and their potential synergistic impact on general health, we argue that translational research from studies in periodontology must be recognized as an important source of information that might lead to different therapeutic options which can be effective for the management of both oral and non-oral diseases. In this article we connect concepts from periodontal research on oral inflammation while exploring host modulation therapy used for periodontitis as a potential strategy for the prevention of ARDS a deadly outcome of COVID-19. We suggest that host modulation therapy, although developed initially for management of periodontitis, and which inhibits proteases, cytokines, and the oxidative stress that underlie ARDS, will provide an effective and safe treatment for COVID-19.
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Adane T, Asrie F, Getaneh Z, Getawa S. White blood cells and platelet profiles of diabetic patients at University of Gondar specialized referral hospital: A comparative cross-sectional study. J Clin Lab Anal 2021; 35:e23808. [PMID: 33938591 PMCID: PMC8183936 DOI: 10.1002/jcla.23808] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Altered level of many hematological parameters such as white blood cells (WBC) and platelet function has been observed in diabetes mellitus (DM) patients. Therefore, this study aimed to determine the WBC and platelet profiles and their association with anthropometric measurement and blood pressure in DM patients and healthy controls. METHOD A comparative cross-sectional study was conducted on a total of 246 participants at the University of Gondar Specialized Referral Hospital. Venous blood with K2 EDTA anticoagulant was drawn and analyzed by using Sysmex KX21N hematology analyzers for WBC and platelet parameters. Data were analyzed using Statistical Package for Social Sciences (SPSS) version 20. Results were presented as frequency and mean ± standard deviation (SD). The independent sample t test was used to compare quantitative variables between DM and control groups. The bivariate (spearman's rank) correlation was used to analyze continuous variables. A p-value ˂ 0.05 was considered as statistically significant. RESULTS The mean platelet count was significantly higher among diabetics (252.77 ± 77.7) compared to non-diabetic controls (208.22 ± 68), p < 0.001. Similarly, the total WBC count was higher among DM patients (6.95 ± 2.23) than in the controls (6.15 ± 1.95), p = 0.04. A significant negative correlation was also found between neutrophil and duration of illness in DM patients. Besides, there is a significant positive correlation between WBC and lymphocyte number with systolic blood pressure (SBP) in DM patients. CONCLUSION Platelet and WBC count were significantly higher in DM patients than in the controls. Therefore, routine screening and profile checking of those abnormal indices is recommended to minimize DM-related complications.
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Affiliation(s)
- Tiruneh Adane
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Fikir Asrie
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Zegeye Getaneh
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Solomon Getawa
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Moustafa A. Chronic Exposure to Continuous Brightness or Darkness Modulates Immune Responses and Ameliorates the Antioxidant Enzyme System in Male Rats. Front Vet Sci 2021; 8:621188. [PMID: 33937367 PMCID: PMC8081841 DOI: 10.3389/fvets.2021.621188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/22/2021] [Indexed: 01/02/2023] Open
Abstract
Circadian rhythms are considered vital regulators of immune functions. This study aims to elucidate the effects of chronic circadian disruption on immune functions, clock genes expression, and antioxidant enzymes levels in lymphoid tissues. Adult male Sprague-Dawley rats were subjected to a normal light/dark cycle or either continuous light (LL) or continuous dark (DD) for 8 weeks. The results demonstrated (1) significant decreases in the circulating levels of interleukin 1β, interleukin 6 and tumor necrosis factor alpha (TNF-α) and significant increases in the levels of interleukin 10, interleukin 12, C-reactive protein (CRP) and corticosterone in both LL and DD groups; (2) upregulation in mRNA expression of core clock genes Cry1, Cry2, Per1, Per2, and Per3 in the spleen of the DD group and downregulation in Cry1 and Cry2 genes in the LL group; (3) elevation of total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide (NO) and the lipid peroxidation marker malondialdehyde (MDA) in the spleen, lymph node and bone marrow of both the LL and DD groups and decreases in the levels of the same markers in the thymus of the LL group; (4) decreased numbers of CD4+ and CD8+ cells in lymphoid tissues of both the LL and the DD groups; (5) reduced platelets count and suppressed immunoglobulin (IgM, IgE) in the LL and DD groups with marked erythropenia and leukocytosis in the DD group. Taken together, circadian misalignment leads to hematological disruptions, dysregulation of clock genes, and inflammatory mediators, which further enhances the antioxidant enzyme system that is crucial for an organism's adaptation to stresses.
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Affiliation(s)
- Amira Moustafa
- Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
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Chatzopoulos GS, Cisneros A, Sanchez M, Wolff LF. Association between Periodontal Disease and Systemic Inflammatory Conditions Using Electronic Health Records: A Pilot Study. Antibiotics (Basel) 2021; 10:antibiotics10040386. [PMID: 33916511 PMCID: PMC8066908 DOI: 10.3390/antibiotics10040386] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 11/16/2022] Open
Abstract
AIMS To investigate the association between periodontal disease and systemic inflammatory conditions and examine the link between medical conditions and the extent of missing teeth in a large population. METHODS In this retrospective study, a total of 4890 randomly selected patients who had attended the University of Minnesota dental clinics were analyzed. Severity of periodontal disease was determined based on the percentage of bone loss, evaluated through the examination of a full-mouth intraoral series of radiographs. The number of missing teeth was calculated from the examined radiographs, while ten systemic inflammatory conditions were extracted from patients' self-reported medical histories. RESULTS Moderate bone loss was observed in 730 (14.9%) and severe in 323 (6.6%) patients of the total population, while the mean number of missing teeth was 3.54 ± 3.93. The prevalence of systemic conditions and tobacco use were gender-dependent (p < 0.05). Regression analysis showed that hypertension, arthritis, asthma, diabetes and HIV were associated significantly with the severity of bone loss, while diabetes and lupus with the extent of missing teeth. CONCLUSIONS The findings reported in our study add to this body of knowledge, strengthening the association between periodontal disease with systemic inflammatory conditions.
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Zhou Y, Chi J, Lv W, Wang Y. Obesity and diabetes as high-risk factors for severe coronavirus disease 2019 (Covid-19). Diabetes Metab Res Rev 2021; 37:e3377. [PMID: 32588943 PMCID: PMC7361201 DOI: 10.1002/dmrr.3377] [Citation(s) in RCA: 302] [Impact Index Per Article: 75.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/04/2020] [Accepted: 06/22/2020] [Indexed: 01/08/2023]
Abstract
The outbreak of the coronavirus disease 2019 (Covid-19) has become an evolving worldwide health crisis. With the rising prevalence of obesity and diabetes has come an increasing awareness of their impacts on infectious diseases, including increased risk for various infections, post-infection complications and mortality from critical infections. Although epidemiological and clinical characteristics of Covid-19 have been constantly reported, no article has systematically illustrated the role of obesity and diabetes in Covid-19, or how Covid-19 affects obesity and diabetes, or special treatment in these at-risk populations. Here, we present a synthesis of the recent advances in our understanding of the relationships between obesity, diabetes and Covid-19 along with the underlying mechanisms, and provide special treatment guidance for these at-risk populations.
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Affiliation(s)
- Yue Zhou
- Department of EndocrinologyAffiliated Hospital of Medical College Qingdao UniversityQingdaoChina
| | - Jingwei Chi
- Department of EndocrinologyAffiliated Hospital of Medical College Qingdao UniversityQingdaoChina
| | - Wenshan Lv
- Department of EndocrinologyAffiliated Hospital of Medical College Qingdao UniversityQingdaoChina
| | - Yangang Wang
- Department of EndocrinologyAffiliated Hospital of Medical College Qingdao UniversityQingdaoChina
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Proinflammatory cytokine polarization in type 2 diabetes. Cent Eur J Immunol 2021; 45:170-175. [PMID: 33456327 PMCID: PMC7792447 DOI: 10.5114/ceji.2020.97904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 08/16/2017] [Indexed: 11/17/2022] Open
Abstract
Subclinical inflammatory reaction is associated with non-insulin dependent diabetes. Therefore, the aim of the present study is to describe the effect of the three cytokines: interferon γ (IFN-γ), interleukin (IL)-4 and IL-5 on the development of type 2 diabetes (T2D). Forty-five volunteers (after their permission) were participated in this work; according to their clinical examination and laboratory investigations (fasting blood sugar, 2 hours postprandial, HbA1c and lipid profile), they were divided into thirteen control (non-diabetic) (five females and eight males) and thirty-two diabetic patients (twenty-one females and eleven males). Thereafter, their sera were evaluated for C-reactive protein (CRP), IFN-γ, IL-4 and IL-5. The results revealed an increasing trend of CRP and a significant increase of IFN-γ in diabetic patients with no sex difference. A positive correlation between IFN-γ and both IL-4 and IL-5 in control, and a positive correlation between IL-4 and IL-5 in diabetic patients had been visualized. These results denoted that there may be an association of the pro-inflammatory cytokines in the etiology of diabetes mellitus type 2.
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Garciafigueroa Y, Phillips BE, Engman C, Trucco M, Giannoukakis N. Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice. Front Endocrinol (Lausanne) 2021; 12:565981. [PMID: 33776903 PMCID: PMC7988208 DOI: 10.3389/fendo.2021.565981] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 02/01/2021] [Indexed: 12/23/2022] Open
Abstract
A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting via myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.
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Affiliation(s)
- Yesica Garciafigueroa
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Brett E. Phillips
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Carl Engman
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- *Correspondence: Nick Giannoukakis,
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Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response. Genes (Basel) 2020; 12:genes12010047. [PMID: 33396192 PMCID: PMC7824036 DOI: 10.3390/genes12010047] [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: 11/25/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 12/19/2022] Open
Abstract
Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.
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Bortolon JR, Murata GM, Borges L, Weimann E, Silva MBB, Dermargos A, Hatanaka E. Recovery of Diabetic Rats After Physical Exhaustion: Kinetic Alterations in Muscle Inflammation and Muscle-Signaling Proteins to Atrophy and Hypertrophy. Front Physiol 2020; 11:573416. [PMID: 33281615 PMCID: PMC7688783 DOI: 10.3389/fphys.2020.573416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/09/2020] [Indexed: 01/16/2023] Open
Abstract
The complexity of the adaptive response of diabetics to intense exercise is still poorly understood. To optimize exercise interventions in diabetics, the chronology of inflammatory mediators in muscle and the signaling involved in muscle hypertrophy/atrophy must be understood. Herein, we studied the kinetic inflammatory profile and cellular signaling pathways modulated by physical exhaustion after the induction of type 1 diabetes by streptozotocin in rats. Soleus muscle samples were obtained from diabetic and control groups at the following moments: baseline (no exercise); immediately after exhaustive exercise; and at 2 h, 24 h, 48 h, and 72 h after a treadmill exhaustive exercise. Kinetic production of cytokines and kinetic activation of proteins related to muscle synthesis (p70S6K and Akt) and degradation (GSK3, MuRF1, and MAFbx) were measured in the soleus muscle. We observed that the muscle TNF-α (0.9-fold; p = 0.0007), IL-1β (0.8-fold; p = 0.01), IL-6 (0.8-fold; p = 0.0013), L-selectin (1.0-fold; p = 0.0019), and CINC-2α/β (0.9-fold; p = 0.04) levels were higher in almost all stages of the study in the diabetic animals compared with the control group. Our data showed that exhaustive exercise decreased MAFbx expression in diabetic animals compared to the control group in a time-dependent manner. The decreased activation ratios of MAFbx were followed by a decrease in TNF-α, IL-1β, and IL-6 levels. p70S6k phosphorylation was also decreased in the diabetic group compared to the control group after physical exhaustion. Regarding the activation of proteins related to muscle synthesis and degradation, we found that the alterations induced by exhaustive exercise in the diabetic rats might involve pathways related to synthesis and muscle breakdown. Moreover, after an exhaustive exercise session, the recovery of the inflammatory response in the diabetic animals was slower than that in the control rats while the return of inflammatory cytokines to baseline levels was more effective in the diabetic animals.
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Affiliation(s)
- José Ricardo Bortolon
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
| | - Gilson Masahiro Murata
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
| | - Leandro Borges
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
| | - Eleine Weimann
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
| | - Maysa Braga Barros Silva
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
| | | | - Elaine Hatanaka
- Instituto de Ciências da Atividade Física e Esporte (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil
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Sczepanik FSC, Grossi ML, Casati M, Goldberg M, Glogauer M, Fine N, Tenenbaum HC. Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000 2020; 84:45-68. [PMID: 32844417 DOI: 10.1111/prd.12342] [Citation(s) in RCA: 301] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Periodontitis is a highly prevalent disease. As it progresses, it causes serious morbidity in the form of periodontal abscesses and tooth loss and, in the latter stages, pain. It is also now known that periodontitis is strongly associated with several nonoral diseases. Thus, patients with periodontitis are at greater risk for the development and/or exacerbation of diabetes, chronic obstructive pulmonary disease, and cardiovascular diseases, among other conditions. Although it is without question that specific groups of oral bacteria which populate dental plaque play a causative role in the development of periodontitis, it is now thought that once this disease has been triggered, other factors play an equal, and possibly more important, role in its progression, particularly in severe cases or in cases that prove difficult to treat. In this regard, we allude to the host response, specifically the notion that the host, once infected with oral periodontal pathogenic bacteria, will mount a defense response mediated largely through the innate immune system. The most abundant cell type of the innate immune system - polymorphonuclear neutrophils - can, when protecting the host from microbial invasion, mount a response that includes upregulation of proinflammatory cytokines, matrix metalloproteinases, and reactive oxygen species, all of which then contribute to the tissue damage and loss of teeth commonly associated with periodontitis. Of the mechanisms referred to here, we suggest that upregulation of reactive oxygen species might play one of the most important roles in the establishment and progression of periodontitis (as well as in other diseases of inflammation) through the development of oxidative stress. In this overview, we discuss both innate and epigenetic factors (eg, diabetes, smoking) that lead to the development of oxidative stress. This oxidative stress then provides an environment conducive to the destructive processes observed in periodontitis. Therefore, we shall describe some of the fundamental characteristics of oxidative stress and its effects on the periodontium, discuss the diseases and other factors that cause oxidative stress, and, finally, review potentially novel therapeutic approaches for the management (and possibly even the reversal) of periodontitis, which rely on the use of therapies, such as resveratrol and other antioxidants, that provide increased antioxidant activity in the host.
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Affiliation(s)
| | - Márcio Lima Grossi
- School of Health Sciences, Dentistry, Post-Graduate Program in Dentistry, Prosthodontics, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Márcio Casati
- Dental Research Division, School of Dentistry, Paulista University (UNIP), Sao Paulo, Brazil.,Department of Prosthodontics and Periodontics, Piracicaba Dental School, University of Campinas, Piracicaba, Brazil
| | - Michael Goldberg
- Discipline of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.,Department of Dentistry, Centre for Advanced Dental Research and Care, University of Toronto, Toronto, ON, Canada.,Division of Periodontology, Mount Sinai Hospital, Toronto, ON, Canada
| | - Michael Glogauer
- Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.,Princess Margaret Cancer Centre, Toronto, ON, Canada.,Department of Dentistry, Centre for Advanced Dental Research and Care, Mount Sinai Hospital, Toronto, ON, Canada
| | - Noah Fine
- Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.,Centre for Advanced Dental Research and Care, Mount Sinai Hospital, Toronto, ON, Canada
| | - Howard C Tenenbaum
- Department of Dentistry, Mount Sinai Hospital, Thodupuzha, India.,Faculty of Dentistry, Centre for Advanced Dental Research and Care, University of Toronto, Toronto, ON, Canada
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Excessive walking exercise precipitates diabetic neuropathic foot pain: hind paw suspension treadmill exercise experiment in a rat model. Sci Rep 2020; 10:10498. [PMID: 32591628 PMCID: PMC7319951 DOI: 10.1038/s41598-020-67601-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 06/08/2020] [Indexed: 01/04/2023] Open
Abstract
The harmful effects of excessive mechanical loading on diabetic neuropathy and the reason diabetic neuropathic symptoms are common in feet are unclear. In this study, the hind paw suspension treadmill exercise model was used in rats to investigate whether mechanical loading applied to the front paws precipitates neuropathic pain, especially in diabetic conditions. Thirty-two rats were divided into six groups according to the presence of diabetes (DM) and the intensity of mechanical loading applied to the front paws: DM-Hi (high-intensity); DM-Lo (low-intensity); DM-No (non-mechanical loading); Sham-Hi; Sham-Lo; and Sham-No. DM was induced by streptozotocin injection. For high-intensity or low-intensity mechanical loading, treadmill walking exercise was conducted with or without hind paw suspension, respectively. The mechanical withdrawal threshold of the front paw decreased significantly after 8 weeks only in the DM mechanical loading groups (DM-Hi and DM-Lo), and high-intensity loading more significantly decreased the front-paw withdrawal threshold than low-intensity loading. In the DM-Hi group only, macrophage migration inhibitory factor (MIF) increased significantly, and intra-epidermal nerve fibers (IENF) in the front paws decreased significantly. In diabetic conditions, mechanical overloading such as excessive walking is likely to precipitate mechanical allodynia and damage IENF¸ which could explain why diabetic neuropathic symptoms are common in feet. This finding might be related to up-regulation of intracellular signaling cascades such as MIF, rather than inflammatory processes.
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Ibrahim S, Harris-Kawano A, Haider I, Mirmira RG, Sims EK, Anderson RM. A novel Cre-enabled tetracycline-inducible transgenic system for tissue-specific cytokine expression in the zebrafish: CETI-PIC3. Dis Model Mech 2020; 13:dmm042556. [PMID: 32457041 PMCID: PMC7328138 DOI: 10.1242/dmm.042556] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 03/17/2020] [Indexed: 01/21/2023] Open
Abstract
Maladaptive signaling by pro-inflammatory cytokines (PICs), such as TNFα, IL1β and IFNɣ, can activate downstream signaling cascades that are implicated in the development and progression of multiple inflammatory diseases. Despite playing critical roles in pathogenesis, the availability of in vivo models in which to model tissue-specific induction of PICs is limited. To bridge this gap, we have developed a novel multi-gene expression system dubbed Cre-enabled and tetracycline-inducible transgenic system for conditional, tissue-specific expression of pro-inflammatory cytokines (CETI-PIC3). This binary transgenic system permits the stoichiometric co-expression of proteins Tumor necrosis factor a (Tnfa), Interleukin-1 beta (Il1b) and Interferon gamma (Ifng1), and H2B-GFP fluorescent reporter in a dose-dependent manner. Furthermore, cytokine misexpression is enabled only in tissue domains that can be defined by Cre recombinase expression. We have validated this system in zebrafish using an insulin:cre line. In doubly transgenic fish, quantitative real-time polymerase chain reaction demonstrated increased expression levels of tnfa, il1b and ifng1 mRNA. Moreover, specific expression in pancreatic β cells was demonstrated by both Tnfa immunofluorescence and GFP fluorescence. Cytokine-overexpressing islets elicited specific responses: β cells exhibited increased expression of genes associated with reactive oxidative species-mediated stress and endoplasmic reticulum stress, surveilling and infiltrating macrophages were increased, and β cell death was promoted. This powerful and versatile model system can be used for modeling, analysis and therapy development of diseases with an underlying inflammatory etiology.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sara Ibrahim
- Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Arianna Harris-Kawano
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Isra Haider
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Raghavendra G Mirmira
- Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Emily K Sims
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Ryan M Anderson
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Kovler Diabetes Center and Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
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Kewcharoenwong C, Saenwongsa W, Willcocks SJ, Bancroft GJ, Fletcher HA, Lertmemongkolchai G. Glibenclamide alters interleukin-8 and interleukin-1β of primary human monocytes from diabetes patients against Mycobacterium tuberculosis infection. Tuberculosis (Edinb) 2020; 123:101939. [PMID: 32452426 DOI: 10.1016/j.tube.2020.101939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/25/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an important risk factor for development of tuberculosis (TB). Our previous study showed glibenclamide, an anti-diabetic drug used to control blood glucose concentration, reduced interleukin (IL)-8 secretion from primary human monocytes challenged with M. tuberculosis (Mtb). In mice infected with Mtb, IL-1β is essential for host resistance through the enhancement of cyclooxygenase that limits excessive Type I interferon (IFN) production and fosters Mtb containment. We hypothesize that glibenclamide may also interfere with monocyte mediated immune responses against Mtb and alter the balance between IL-1β and IFNα-mediated immunity. Purified monocytes from non-diabetic and diabetic individuals were infected with Mtb or M. bovis BCG. We demonstrate that monocytes from diabetes patients who were being treated with glibenclamide showed reduced IL-1β and IL-8 secretion when exposed to Mtb. Additionally, these responses also occurred when monocytes from non-diabetic individuals were pre-treated with glibenclamide in vitro. Moreover, this pre-treatment enhanced IFNa1 expression but was not involved with prostaglandin E2 (PGE2) expression in response to Mtb infection. Taken together, our data show that glibenclamide might exacerbate susceptibility of diabetes patients to Mtb infection by reducing IL-1β and IL-8 production by monocytes.
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Affiliation(s)
- Chidchamai Kewcharoenwong
- The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand
| | - Wipawee Saenwongsa
- The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand; Disease Prevention and Control Region 10th, Ubonratchathani, Ministry of Public Healthy, Thailand
| | - Samuel J Willcocks
- Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK
| | - Gregory J Bancroft
- Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK; Tuberculosis Centre, London School of Hygiene and Tropical Medicine, UK
| | - Helen A Fletcher
- Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK; Tuberculosis Centre, London School of Hygiene and Tropical Medicine, UK
| | - Ganjana Lertmemongkolchai
- The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Thailand.
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Bartlett DB, Slentz CA, Willis LH, Hoselton A, Huebner JL, Kraus VB, Moss J, Muehlbauer MJ, Spielmann G, Muoio DM, Koves TR, Wu H, Huffman KM, Lord JM, Kraus WE. Rejuvenation of Neutrophil Functions in Association With Reduced Diabetes Risk Following Ten Weeks of Low-Volume High Intensity Interval Walking in Older Adults With Prediabetes - A Pilot Study. Front Immunol 2020; 11:729. [PMID: 32431698 PMCID: PMC7214668 DOI: 10.3389/fimmu.2020.00729] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022] Open
Abstract
Neutrophil dysfunction is a common feature of aging, and is associated with the pathogenesis of many age-related diseases, including type 2 diabetes mellitus (T2DM). Although exercise training improves metabolic health, decreases risk of T2DM, and is associated with improving neutrophil functions, involvement in regular physical activity declines with age. The aim of this study was to determine if neutrophil functions could be improved in association with changes in fitness and metabolic parameters in older adults at risk for T2DM using 10-weeks of low volume high-intensity interval exercise training (HIIT). Ten older (71 ± 5 years) sedentary adults with prediabetes (HbA1c: 6.1 ± 0.3%) completed 10 weeks of a supervised HIIT program. Three 30 min sessions/week consisted of ten 60 s intervals of low intensity [50-60% heart rate reserve (HRR)] separated with similar durations of high intensity intervals (80-90% HRR). Before and after training, glucose and insulin sensitivity, neutrophil chemotaxis, bacterial phagocytosis, reactive oxygen species (ROS) production, and mitochondrial functions were assessed. Exercise-mediated changes in cardiorespiratory fitness (VO2peak) and neutrophil functions were compared to six young (23 ± 1 years) healthy adults. Following training, significant reductions in fasting glucose and insulin were accompanied by improved glucose control and insulin sensitivity (all p < 0.05). Before exercise training, VO2peak in the old participants was significantly less than that of the young controls (p < 0.001), but increased by 16 ± 11% following training (p = 0.002) resulting in a 6% improvement of the deficit. Neutrophil chemotaxis, phagocytosis and stimulated ROS production were significantly less than that of the young controls, while basal ROS were higher before training (all p < 0.05). Following training, chemotaxis, phagocytosis and stimulated ROS increased while basal ROS decreased, similar to levels observed in the young controls (all p < 0.05) and reducing the deficit of the young controls between 2 and 154%. In five of the adults with prediabetes, neutrophil mitochondrial functions were significantly poorer than the six young controls before training. Following training, mitochondrial functions improved toward those observed in young controls (all p < 0.05), reducing the deficit of the young controls between 14.3 and 451%. Ten weeks of HIIT in older adults at risk for T2DM reduced disease risk accompanied by improved primary and bioenergetic neutrophil functions. Our results are consistent with a reduced risk of infections mediated by relationships in exercise induced systemic and cellular metabolic features. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02441205, registered on May 12th, 2015.
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Affiliation(s)
- David B. Bartlett
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
- Division of Medical Oncology, School of Medicine, Duke University, Durham, NC, United States
- MRC-ARUK Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Cris A. Slentz
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Leslie H. Willis
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Andrew Hoselton
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Janet L. Huebner
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Virginia B. Kraus
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Jennifer Moss
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Michael J. Muehlbauer
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Guillaume Spielmann
- Department of Kinesiology, Louisiana State University, Baton Rouge, LA, United States
| | - Deborah M. Muoio
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Timothy R. Koves
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Helena Wu
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Kim M. Huffman
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
| | - Janet M. Lord
- MRC-ARUK Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
- NIHR Birmingham BRC in Inflammation, University Hospitals Birmingham, Birmingham, United Kingdom
| | - William E. Kraus
- Duke Molecular Physiology Institute, School of Medicine, Duke University, Durham, NC, United States
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Hughes MJ, McGettrick HM, Sapey E. Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target. Eur Respir Rev 2020; 29:190102. [PMID: 32198215 PMCID: PMC9488696 DOI: 10.1183/16000617.0102-2019] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/02/2019] [Indexed: 12/17/2022] Open
Abstract
Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting.
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Affiliation(s)
- Michael J Hughes
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Helen M McGettrick
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Elizabeth Sapey
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
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Belkina AC, Azer M, Lee JJ, Elgaali HH, Pihl R, Cleveland M, Carr J, Kim S, Habib C, Hasturk H, Snyder-Cappione JE, Nikolajczyk BS. Single-Cell Analysis of the Periodontal Immune Niche in Type 2 Diabetes. J Dent Res 2020; 99:855-862. [PMID: 32186942 DOI: 10.1177/0022034520912188] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Periodontitis (PD) is a common source of uncontrolled inflammation in obesity-associated type 2 diabetes (T2D). PD apparently fuels the inflammation of T2D and associates with poor glycemic control and increased T2D morbidity. New therapeutics are critically needed to counter the sources of periodontal infection and inflammation that are accelerated in people with T2D. The precise mechanisms underlying the relationship between PD and T2D remain poorly understood. Every major immune cell subset has been implicated in the unresolved inflammation of PD, regardless of host metabolic health. However, analyses of inflammatory cells in PD with human periodontal tissue have generally focused on mRNA quantification and immunohistochemical analyses, both of which provide limited information on immune cell function. We used a combination of flow cytometry for cell surface markers and enzyme-linked immunospot methods to assess the subset distribution and function of immune cells isolated from gingiva of people who had PD and were systemically healthy, had PD and T2D (PD/T2D), or, for flow cytometry, were systemically and orally healthy. T-cell subsets dominated the cellular immune compartment in gingiva from all groups, and B cells were relatively rare. Although immune cell frequencies were similar among groups, a higher proportion of CD11b+ or CD4+ cells secreted IFNγ/IL-10 or IL-8, respectively, in cells from PD/T2D samples as compared with PD-alone samples. Our data indicate that fundamental differences in gingival immune cell function between PD and T2D-potentiated PD may account for the increased risk and severity of PD in subjects with T2D. Such differences may suggest unexpected therapeutic targets for alleviating periodontal inflammation in people with T2D.
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Affiliation(s)
- A C Belkina
- Department of Pathology and Laboratory Medicine, School of Medicine, Boston University, Boston, MA, USA.,Flow Cytometry Core Facility, School of Medicine, Boston University, Boston, MA, USA
| | - M Azer
- Department of Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, MA, USA
| | - J J Lee
- Department of Pharmacology and Nutritional Sciences and Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY, USA
| | - H H Elgaali
- Department of Pharmacology and Nutritional Sciences and Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY, USA
| | - R Pihl
- Flow Cytometry Core Facility, School of Medicine, Boston University, Boston, MA, USA
| | - M Cleveland
- Department of Pharmacology and Nutritional Sciences and Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY, USA
| | - J Carr
- Department of Microbiology, School of Medicine, Boston University, Boston, MA, USA
| | - S Kim
- Department of Medicine, School of Medicine, Boston University, Boston, MA, USA
| | - C Habib
- Department of Medicine, School of Medicine, Boston University, Boston, MA, USA
| | - H Hasturk
- The Forsyth Institute, Cambridge, MA, USA
| | - J E Snyder-Cappione
- Flow Cytometry Core Facility, School of Medicine, Boston University, Boston, MA, USA.,Department of Microbiology, School of Medicine, Boston University, Boston, MA, USA
| | - B S Nikolajczyk
- Department of Pharmacology and Nutritional Sciences and Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, KY, USA.,Department of Microbiology, School of Medicine, Boston University, Boston, MA, USA
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Lekka K, Marangos M, Roupas N, Karakantza M, Gogos C, Velissaris D. Evaluation of the Activity of Neutrophils and Monocytes in Diabetic Patients With Sepsis, Can Surface Antigens HLA-DR and CD64 Be Useful as Prognostic Factors? J Clin Med Res 2020; 12:157-164. [PMID: 32231751 PMCID: PMC7092759 DOI: 10.14740/jocmr4068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/01/2020] [Indexed: 12/29/2022] Open
Abstract
Background Patients with diabetes mellitus (DM) exhibit alterations in their immune response when infected by several types of micro-organisms. The increased susceptibility of diabetics to infections is particularly related to abnormalities in the function of neutrophils such as chemotaxis, adhesion and intracellular killing, leading to increased mortality rates. Aims of the study were to assess the phagocytic activity and the expression of antigens HLA-DR and CD64 of monocytes and neutrophils in diabetics with sepsis and evaluate their significance as prognostic factors. Methods This is an observational prospective study conducted in a tertiary medical center, referring to a population of 51 diabetic patients who were treated for sepsis. Samples of whole blood were received from the selected patients and were evaluated for the expression of surface antigens HLA-DR and CD64 on monocytes and neutrophils, and for their phagocytic activity as well. Results Alterations in the phagocytic activity were found in the diabetic patients who developed sepsis, and these were addressed as an elevation in the expression of CD64 on monocytes (CD64M), and a reduction in the expression of HLA-DR on monocytes (HLA-DRM) at least in the initial phase of the acute infection. A significant elevation was also noticed in the phagocytosis rate of both neutrophils and monocytes on day of admission. Survivors had higher rates of both CD64 and HLA-DR on monocytes when compared to non-survivors. No correlation was found between glycemic control, values of inflammatory markers on admission, phagocytosis rate and the survival of diabetics with sepsis. A reduced expression of CD64O, HLA-DRM and the co-expression of CD64/HLA-DR on monocytes in the initial phase of sepsis and poor glycemic control (hemoglobin A1c (HbA1c) > 8.5) was found. Conclusions In the present study of diabetic patients with sepsis the phagocytic activity of neutrophils and monocytes is elevated at the initial phase of an acute infection and only the values of CD64 and HLA-DR on monocytes were significantly related to outcome. Further evaluation of these results with large prospective studies is warranted.
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Affiliation(s)
- Kalliopi Lekka
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Markos Marangos
- Department of Infectious Diseases, University Hospital of Patras, Rio, Greece
| | - Nikolaos Roupas
- Department of Endocrinology, University Hospital of Patras, Rio, Greece
| | - Marina Karakantza
- Division of Hematology, Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Charalampos Gogos
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
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Dance Training Improves Cytokine Secretion and Viability of Neutrophils in Diabetic Patients. Mediators Inflamm 2019; 2019:2924818. [PMID: 31827375 PMCID: PMC6886327 DOI: 10.1155/2019/2924818] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/14/2019] [Accepted: 10/24/2019] [Indexed: 12/13/2022] Open
Abstract
Background Evidence suggests that exercise improves neutrophil function. The decreased functional longevity of neutrophils and their increased clearance from infectious sites contribute to the increased susceptibility to infection and severity of infection observed in patients with diabetes. Objective Herein, we investigated the effects of a dance program on neutrophil number, function, and death in type 2 diabetes mellitus (T2DM) patients and healthy volunteers. Methods Ten patients with T2DM and twelve healthy individuals participated in a moderate-intensity dance training program for 4 months. The plasma levels of leptin, free fatty acids (FFAs), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-1β (IL-1β), and interleukin-1 receptor antagonist (IL-1ra); neutrophil counts; extent of DNA fragmentation; cell membrane integrity; and production of TNF-α, interleukin-8 (IL-8), interleukin-6 (IL-6), and IL-1β in neutrophils were measured before and after training. Results Training reduced plasma levels of TNF-α (1.9-fold in controls and 2.2-fold in patients with T2DM) and CRP (1.4-fold in controls and 3.4-fold in patients with T2DM). IL-1ra levels were higher in the control group (2.2-fold) after training. After training, neutrophil DNA fragmentation was decreased in patients with T2DM (90%), while the number of neutrophils increased (70% in controls and 1.1-fold in patients with T2DM). Conclusion Dance training is a nonpharmacological strategy to reduce inflammation and improve neutrophil clearance in patients with T2DM.
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Kuffler DP. Injury-Induced Effectors of Neuropathic Pain. Mol Neurobiol 2019; 57:51-66. [PMID: 31701439 DOI: 10.1007/s12035-019-01756-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 08/29/2019] [Indexed: 02/07/2023]
Abstract
Injuries typically result in the development of neuropathic pain, which decreases in parallel with wound healing. However, the pain may remain after the injury appears to have healed, which is generally associated with an ongoing underlying pro-inflammatory state. Injury induces many cells to release factors that contribute to the development of a pro-inflammatory state, which is considered an essential first step towards wound healing. However, pain elimination requires a transition of the injury site from pro- to anti-inflammatory. Therefore, developing techniques that eliminate chronic pain require an understanding of the cells resident at and recruited to injury sites, the factors they release, that promote a pro-inflammatory state, and promote the subsequent transition of that site to be anti-inflammatory. Although a relatively large number of cells, factors, and gene expression changes are involved in these processes, it may be possible to control a relatively small number of them leading to the reduction and elimination of chronic neuropathic pain. This first of two papers examines the roles of the most salient cells and mediators associated with the development and maintenance of chronic neuropathic pain. The following paper examines the cells and mediators involved in reducing and eliminating chronic neuropathic pain.
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Affiliation(s)
- Damien P Kuffler
- Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, 201 Blvd. del Valle, San Juan, PR, 00901, USA.
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Zhang F, Zhao Q, Jiang Y, Liu N, Liu Q, Shi FD, Hao J, Xu Y, Lo EH, Wang X. Augmented Brain Infiltration and Activation of Leukocytes After Cerebral Ischemia in Type 2 Diabetic Mice. Front Immunol 2019; 10:2392. [PMID: 31681285 PMCID: PMC6797587 DOI: 10.3389/fimmu.2019.02392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 09/24/2019] [Indexed: 01/16/2023] Open
Abstract
Background: Stroke patients with diabetes suffer from higher mortality rate and worsened neurological outcome. However, the responses of immune system to cerebral ischemia in the setting of diabetes remain poorly understood. Methods: In this study, we investigated the temporal profile of leukocyte mobilization and brain infiltration following distal middle cerebral artery occlusion (dMCAO) in db/db mouse model of type 2 diabetes (T2D) and its db/+ normoglycemic controls. Results: We found a significant increase of brain-infiltrating CD4+ T cell at day 3 after dMCAO, and a delayed and dramatic increase of brain-infiltrating neutrophils, CD4+ T cells, CD8+ T cells, and B cells at day 7 after dMCAO in db/db mice vs. db/+ controls. Leukocyte subsets in the circulation and spleen were also measured, however, there is no significant difference between non-diabetic and diabetic groups. Furthermore, we identified an increased expression of activation marker CD69 in brain-infiltrating neutrophils, CD4+ T and CD8+ T cells, and IFN-γ in brain-infiltrating CD4+ T cells in db/db mice at day 7 after dMCAO. Conclusions: These findings for the first time demonstrate that cerebral ischemia induces a delayed and sustained augmentation of brain infiltration and activation of neutrophils and lymphocytes in type 2 diabetic mice and these altered immune responses might contribute to the severer brain tissue damage and worse neurological outcomes of diabetes stroke, which warrants further investigation.
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Affiliation(s)
- Fang Zhang
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States,*Correspondence: Fang Zhang
| | - Qiuchen Zhao
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States,Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yinghua Jiang
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States,Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ning Liu
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States,Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States,The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiang Liu
- Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
| | - Fu-Dong Shi
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Junwei Hao
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yun Xu
- Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Eng H. Lo
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Xiaoying Wang
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States,Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA, United States,Xiaoying Wang
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