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Cacace J, Luna-Marco C, Hermo-Argibay A, Pesantes-Somogyi C, Hernández-López OA, Pelechá-Salvador M, Bañuls C, Apostolova N, de Miguel-Rodríguez L, Morillas C, Rocha M, Rovira-Llopis S, Víctor VM. Poor glycaemic control in type 2 diabetes compromises leukocyte oxygen consumption rate, OXPHOS complex content and neutrophil-endothelial interactions. Redox Biol 2025; 81:103516. [PMID: 39986115 PMCID: PMC11893319 DOI: 10.1016/j.redox.2025.103516] [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: 11/28/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/24/2025] Open
Abstract
The mitochondrial electron transport chain becomes overloaded in type 2 diabetes (T2D), which increases ROS (Reactive Oxygen Species) production and impairs mitochondrial function. Peripheral blood mononuclear cells (PBMCs) are critical players in the inflammatory process that underlies T2D. Poor glycaemic control in T2D is closely linked to the development of comorbidities. Our aim was to evaluate if glycaemic control in T2D has an impact on the oxygen consumption rates (OCR) of PBMC, OXPHOS complexes and inflammation. We recruited 181 subjects, consisting of 79 healthy controls, 64 patients with T2D and good glycaemic control (HbA1c<7 %), and 38 T2D patients with poor glycaemic control (HbA1c>7 %). We found a decrease in the basal OCR of PBMCs from patients with HbA1c>7 % with respect to controls (p < 0.05). Maximal OCR and spare respiratory capacity were lower in patients with HbA1c>7 % than in controls and patients with HbA1c<7 % (p < 0.05 for all). Mitochondrial ROS levels were higher in T2D patients, and particularly in the HbA1c > 7 group (p < 0.05 HbA1c<7 % vs control, p < 0.001 HbA1c>7 % vs control; p < 0.001 HbA1c > 7 vs HbA1c < 7). With respect to controls, poor glycaemic control in T2D patients was associated with a decrease in mitochondrial complex III and V (p < 0.05 and p < 0.01, respectively) and enhanced neutrophil-endothelial interactions (p < 0.001 vs controls). MPO levels were enhanced in T2D patients in general (p < 0.05 vs controls), and ICAM-1 and VCAM-1 were specifically increased in HbA1c > 7 patients vs controls (p < 0.01 and p < 0.001, respectively). Negative low-to-moderate correlations were found between HbA1c and basal respiration (r = -0.319, p < 0.05), maximal respiration (r = -0.350, p < 0.01) and spare respiratory capacity (r = -0.295, p < 0.05). Our findings suggest that poor glycaemic control during the progression of T2D compromises mitochondrial respiration and OXPHOS complex content in PBMCs. These alterations occur in parallel to enhanced neutrophil-endothelial interactions and adhesion molecule levels, leaving T2D patients with poor glycaemic control at a higher risk of developing vascular diseases.
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Affiliation(s)
- Julia Cacace
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Clara Luna-Marco
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; Department of Physiology, University of Valencia, INCLIVA (Biomedical Research Institute Valencia), Valencia, Spain
| | - Alberto Hermo-Argibay
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Catherine Pesantes-Somogyi
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Omar A Hernández-López
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - María Pelechá-Salvador
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Celia Bañuls
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Nadezda Apostolova
- National Network of Biomedical Research on Hepatic and Digestive Diseases (CIBERehd), Valencia, Spain; Department of Pharmacology, University of Valencia, Valencia, Spain
| | - Luis de Miguel-Rodríguez
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Carlos Morillas
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain
| | - Milagros Rocha
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; National Network of Biomedical Research on Hepatic and Digestive Diseases (CIBERehd), Valencia, Spain.
| | - Susana Rovira-Llopis
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Víctor M Víctor
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; Department of Physiology, University of Valencia, INCLIVA (Biomedical Research Institute Valencia), Valencia, Spain; National Network of Biomedical Research on Hepatic and Digestive Diseases (CIBERehd), Valencia, Spain.
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Peixoto-Rodrigues MC, Monteiro-Neto JR, Teglas T, Toborek M, Soares Quinete N, Hauser-Davis RA, Adesse D. Early-life exposure to PCBs and PFAS exerts negative effects on the developing central nervous system. JOURNAL OF HAZARDOUS MATERIALS 2025; 485:136832. [PMID: 39689563 DOI: 10.1016/j.jhazmat.2024.136832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/18/2024] [Accepted: 12/08/2024] [Indexed: 12/19/2024]
Abstract
Persistent organic pollutants (POPs) are ubiquitous in the environment and display the capacity to bioaccumulate in living organisms, constituting a hazard to both wildlife and humans. Although restrictions have been applied to prohibit the production of several POPs since the 1960s, high levels of these compounds can still be detected in many environmental and biological matrices, due to their chemical properties and significantly long half-lives. Some POPs can be passed from mother to the fetus and can gain entry to the central nervous system (CNS), by crossing the blood-brain barrier (BBB), resulting in significant deleterious effects, including neurocognitive and psychiatric abnormalities, which may lead to long-term socio-economic burdens. A growing body of evidence obtained from clinical and experimental studies has increasingly indicated that these POPs may influence neurodevelopment through several cellular and molecular mechanisms. However, studies assessing their mechanisms of action are still incipient, requiring further research. Polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PFAS) are two of the main classes of POPs associated with disturbances in different human systems, mainly the nervous and endocrine systems. This narrative review discusses the main PCB and PFAS effects on the CNS, focusing on neuroinflammation and oxidative stress and their consequences for neural development and BBB integrity. Moreover, we propose which mechanisms could be involved in POP-induced neurodevelopmental defects. In this sense, we highlight potential cellular and molecular pathways by which these POPs can affect neurodevelopment and could be further explored to propose preventive therapies and formulate public health policies.
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Affiliation(s)
- Maria Carolina Peixoto-Rodrigues
- Laboratório de Avaliação e Promoção da Saúde Ambiental, Instituto Oswaldo Cruz, Fiocruz, Brazil; Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Brazil
| | | | - Timea Teglas
- Research Institute of Sport Science, Hungarian University of Sports Science, Budapest, Hungary; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Hungarian University of Sports Science, Budapest, Hungary
| | - Michal Toborek
- Institute of Physiotherapy and Health Sciences, Blood-Brain Barrier Research Center, Jerzy Kukuczka Academy of Physical Education, Katowice, Poland
| | - Natalia Soares Quinete
- Departament of Chemistry and Biochemistry & Institute of Environment, Florida International University, Miami, Florida, United States
| | - Rachel Ann Hauser-Davis
- Laboratório de Avaliação e Promoção da Saúde Ambiental, Instituto Oswaldo Cruz, Fiocruz, Brazil
| | - Daniel Adesse
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Brazil; Laboratory of Ocular Immunology and Transplantation, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States.
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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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Shivganesh B R D, Karim HMR, Agrawal N, Kumar M. The Relation of Preoperative HbA1c Level With Intraoperative and Postoperative Complications in Type-2 Diabetic Patients: An Observational Study. Cureus 2024; 16:e64487. [PMID: 39139332 PMCID: PMC11319519 DOI: 10.7759/cureus.64487] [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] [Accepted: 07/13/2024] [Indexed: 08/15/2024] Open
Abstract
Background Perioperative dysglycemia increases morbidity and mortality, particularly among those with diabetes mellitus (DM), and elevated HbA1c levels, reflecting long-term blood glucose, are linked to poor healing and higher infection rates. This study investigates the link between preoperative HbA1c levels and perioperative outcomes in type-2 DM patients. Methodology This prospective observational study was conducted in India between January 2021 and April 2022. Sixty patients aged 18-60 with type-2 DM who underwent elective surgery under general anesthesia (GA) were included; the American Society of Anesthesiologists class >III and patients with severe organ failures were excluded. Participants were divided into two groups: A (HbA1c ≤7.5%) and B (HbA1c >7.5%). Data on preoperative vitals, intraoperative hemodynamics, and postoperative complications were collected. SPSS v23 was used for data analysis; p-value <0.05 was considered significant. Results The mean age of the participants was 48.22 years; males comprised 58.3%. Group A had a higher proportion of oral hypoglycemic agents. Group B showed higher maximum mean blood pressure and intraoperative blood sugar levels at one hour. Postoperatively, Group B had higher glucose levels, more prevalent hyperglycemia, and higher preoperative and postoperative blood urea levels. No significant differences were found in postoperative outcomes like acute kidney injury (AKI), leukocytopenia, leucocytosis, fever, and intensive care admission. Surgical site infection (SSI) incidence was higher in group B, though not statistically significant. Group B had more extended hospital stays. Conclusion Preoperative HbA1c above 7.5% was associated with impaired perioperative glycemic control and higher dysglycemic episodes. Higher preoperative HbA1c was found to be linked to increased postoperative hyperglycemia, AKI, intensive care admissions, and more extended hospital stays, though not statistically significant. SSI incidence was higher, highlighting its importance over preoperative HbA1c.
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Affiliation(s)
- Dhananj Shivganesh B R
- Anesthesiology and Critical Care, Post Graduate Institute of Medical Education and Research, Chandigarh, IND
| | - Habib Md R Karim
- Anesthesiology, Critical Care, and Pain Medicine, All India Institute of Medical Sciences, Guwahati, IND
| | - Nandkishore Agrawal
- Anesthesiology, Critical Care, and Pain Medicine, All India Institute of Medical Sciences, Raipur, IND
| | - Mayank Kumar
- Anesthesiology, Critical Care, and Pain Medicine, All India Institute of Medical Sciences, Raipur, IND
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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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Luna-Marco C, de Marañon AM, Hermo-Argibay A, Rodriguez-Hernandez Y, Hermenejildo J, Fernandez-Reyes M, Apostolova N, Vila J, Sola E, Morillas C, Rovira-Llopis S, Rocha M, Victor VM. Effects of GLP-1 receptor agonists on mitochondrial function, inflammatory markers and leukocyte-endothelium interactions in type 2 diabetes. Redox Biol 2023; 66:102849. [PMID: 37591012 PMCID: PMC10457591 DOI: 10.1016/j.redox.2023.102849] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/19/2023] Open
Abstract
OBJECTIVE Type 2 diabetes (T2D) is linked to metabolic, mitochondrial and inflammatory alterations, atherosclerosis development and cardiovascular diseases (CVDs). The aim was to investigate the potential therapeutic benefits of GLP-1 receptor agonists (GLP-1 RA) on oxidative stress, mitochondrial respiration, leukocyte-endothelial interactions, inflammation and carotid intima-media thickness (CIMT) in T2D patients. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (255) and control subjects (175) were recruited, paired by age and sex, and separated into two groups: without GLP-1 RA treatment (196) and treated with GLP-1 RA (59). Peripheral blood polymorphonuclear leukocytes (PMNs) were isolated to measure reactive oxygen species (ROS) production by flow cytometry and oxygen consumption with a Clark electrode. PMNs were also used to assess leukocyte-endothelial interactions. Circulating levels of adhesion molecules and inflammatory markers were quantified by Luminex's technology, and CIMT was measured as surrogate marker of atherosclerosis. RESULTS Treatment with GLP-1 RA reduced ROS production and recovered mitochondrial membrane potential, oxygen consumption and MPO levels. The velocity of leukocytes rolling over endothelial cells increased in PMNs from GLP-1 RA-treated patients, whereas rolling and adhesion were diminished. ICAM-1, VCAM-1, IL-6, TNFα and IL-12 protein levels also decreased in the GLP-1 RA-treated group, while IL-10 increased. CIMT was lower in GLP-1 RA-treated T2D patients than in T2D patients without GLP-1 RA treatment. CONCLUSIONS GLP-1 RA treatment improves the redox state and mitochondrial respiration, and reduces leukocyte-endothelial interactions, inflammation and CIMT in T2D patients, thereby potentially diminishing the risk of atherosclerosis and CVDs.
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Affiliation(s)
- Clara Luna-Marco
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Arantxa M de Marañon
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; Cancer Research @UCC, College of Medicine and Health, University College Cork, Ireland.
| | - Alberto Hermo-Argibay
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Yohaly Rodriguez-Hernandez
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Jonathan Hermenejildo
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Meylin Fernandez-Reyes
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Nadezda Apostolova
- Department of Pharmacology, University of Valencia, Valencia, Spain; National Network of Biomedical Research on Hepatic and Digestive Diseases (CIBERehd), Valencia, Spain.
| | - Jose Vila
- Department of Physiology, University of Valencia, INCLIVA (Biomedical Research Institute Valencia), Valencia, Spain.
| | - Eva Sola
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Carlos Morillas
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Susana Rovira-Llopis
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; Department of Physiology, University of Valencia, INCLIVA (Biomedical Research Institute Valencia), Valencia, Spain.
| | - Milagros Rocha
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain.
| | - Victor M Victor
- Service of Endocrinology and Nutrition, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), University Hospital Doctor Peset, Valencia, Spain; National Network of Biomedical Research on Hepatic and Digestive Diseases (CIBERehd), Valencia, Spain; Department of Physiology, University of Valencia, INCLIVA (Biomedical Research Institute Valencia), Valencia, Spain.
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Akkus G, Sert M. Diabetic foot ulcers: A devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities. World J Diabetes 2022; 13:1106-1121. [PMID: 36578865 PMCID: PMC9791571 DOI: 10.4239/wjd.v13.i12.1106] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/21/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic foot ulcer is a devastating complication of diabetes mellitus and significant cause of mortality and morbidity all over the world and can be complex and costly. The development of foot ulcer in a diabetic patient has been estimated to be 19%-34% through their lifetime. The pathophysiology of diabetic foot ulcer consist of neuropathy, trauma and, in many patients, additional peripheral arterial disease. In particular, diabetic neuropathy leads to foot deformity, callus formation, and insensitivity to trauma or pressure. The standard algorithms in diabetic foot ulcer management include assessing the ulcer grade classification, surgical debridement, dressing to facilitate wound healing, off-loading, vascular assessment (status and presence of a chance for interventional vascular correction), and infection and glycemic control. Although especially surgical procedures are sometimes inevitable, they are poor predictive factors for the prognosis of diabetic foot ulcer. Different novel treatment modalities such as nonsurgical debridement agents, oxygen therapies, and negative pressure wound therapy, topical drugs, cellular bioproducts, human growth factors, energy-based therapies, and systematic therapies have been available for patients with diabetic foot ulcer. However, it is uncertain whether they are effective in terms of promoting wound healing related with a limited number of randomized controlled trials. This review aims at evaluating diabetic foot ulcer with regard to all aspects. We will also focus on conventional and novel adjunctive therapy in diabetic foot management.
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Affiliation(s)
- Gamze Akkus
- Department of Endocrinology, Cukurova University, Adana 33170, Turkey
| | - Murat Sert
- Department of Internal Medicine, Cukurova University Medical Faculty, Adana 33170, Turkey
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8
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Hagde P, Pingle P, Mourya A, Katta CB, Srivastava S, Sharma R, Singh KK, Sodhi RK, Madan J. Therapeutic potential of quercetin in diabetic foot ulcer: Mechanistic insight, challenges, nanotechnology driven strategies and future prospects. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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9
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Altered Secretome of Diabetic Monocytes Could Negatively Influence Fracture Healing-An In Vitro Study. Int J Mol Sci 2021; 22:ijms22179212. [PMID: 34502120 PMCID: PMC8430926 DOI: 10.3390/ijms22179212] [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: 06/23/2021] [Revised: 08/23/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is a main risk factor for delayed fracture healing and fracture non-unions. Successful fracture healing requires stimuli from different immune cells, known to be affected in diabetics. Especially, application of mononuclear cells has been proposed to promote wound and fracture healing. Thus, aim was to investigate the effect of pre-/diabetic conditions on mononuclear cell functions essential to promote osteoprogenitor cell function. We here show that pre-/diabetic conditions suppress the expression of chemokines, e.g., CCL2 and CCL8 in osteoprogenitor cells. The associated MCP-1 and MCP-2 were significantly reduced in serum of diabetics. Both MCPs chemoattract mononuclear THP-1 cells. Migration of these cells is suppressed under hyperglycemic conditions, proposing that less mononuclear cells invade the site of fracture in diabetics. Further, we show that the composition of cytokines secreted by mononuclear cells strongly differ between diabetics and controls. Similar is seen in THP-1 cells cultured under hyperinsulinemia or hyperglycemia. The altered secretome reduces the positive effect of the THP-1 cell conditioned medium on migration of osteoprogenitor cells. In summary, our data support that factors secreted by mononuclear cells may support fracture healing by promoting migration of osteoprogenitor cells but suggest that this effect might be reduced in diabetics.
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10
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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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11
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SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages. Heliyon 2021; 7:e06187. [PMID: 33644468 PMCID: PMC7887388 DOI: 10.1016/j.heliyon.2021.e06187] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/02/2020] [Accepted: 01/31/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now spread globally. Some patients develop severe complications including multiple organ failure. It has been suggested that excessive inflammation associated with the disease plays major role in the severity and mortality of COVID-19. To elucidate the inflammatory mechanisms involved in COVID-19, we examined the effects of SARS-CoV-2 spike protein S1 subunit (hereafter S1) on the pro-inflammatory responses in murine and human macrophages. Murine peritoneal exudate macrophages produced pro-inflammatory mediators in response to S1 exposure. Exposure to S1 also activated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways. Pro-inflammatory cytokine induction by S1 was suppressed by selective inhibitors of NF-κB and JNK pathways. Treatment of murine peritoneal exudate macrophages and human THP-1 cell-derived macrophages with a toll-like receptor 4 (TLR4) antagonist attenuated pro-inflammatory cytokine induction and the activation of intracellular signaling by S1 and lipopolysaccharide. Similar results were obtained in experiments using TLR4 siRNA-transfected murine RAW264.7 macrophages. In contrast, TLR2 neutralizing antibodies could not abrogate the S1-induced pro-inflammatory cytokine induction in either RAW264.7 or THP-1 cell-derived macrophages. These results suggest that SARS-CoV-2 spike protein S1 subunit activates TLR4 signaling to induce pro-inflammatory responses in murine and human macrophages. Therefore, TLR4 signaling in macrophages may be a potential target for regulating excessive inflammation in COVID-19 patients.
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12
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East J, Piper D, Chan S. Spontaneous Intramuscular Abscesses Involving the Rotator Cuff Muscles in Two Cases Presenting During the COVID-19 Pandemic. Cureus 2020; 12:e11833. [PMID: 33274172 PMCID: PMC7707886 DOI: 10.7759/cureus.11833] [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] [Indexed: 11/10/2022] Open
Abstract
Spontaneous abscesses involving the rotator cuff muscles are a rare surgical occurrence. Patients with such abscesses are often initially misdiagnosed or there is a significant diagnostic delay. Herein, we report one case of a spontaneous intramuscular abscess involving the subscapularis muscle and a second case of an abscess involving the supraspinatus muscle. There is a multitude of predisposing risk factors to developing an intramuscular abscess formation, which includes immunodeficiency, trauma, injection drug use, concurrent infection, and malnutrition. The most significant risk factor in our cases was poorly controlled type 2 diabetes mellitus. Poorly controlled diabetes is known to cause impaired clearance of pathogens, predisposing patients to abscess formation. Both patients also delayed presenting to the hospital due to concerns surrounding the coronavirus disease of 2019 (COVID-19) pandemic. We describe the use of a deltoid-pectoral approach to access the subscapular abscess allowing surgical drainage. The supraspinatus abscess was drained by direct incision. We advocate utilising common and familiar approaches with or without arthroscopy where possible. These cases highlight the importance of early imaging in patients presenting with the physiological signs of infection and idiopathic shoulder pain.
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Affiliation(s)
- Jamie East
- Trauma and Orthopaedics, Queen Elizabeth Hospital, Birmingham, GBR
| | - Danielle Piper
- Trauma and Orthopaedics, Queen Elizabeth Hospital, Birmingham, GBR
| | - Sam Chan
- Trauma and Orthopaedics, Queen Elizabeth Hospital, Birmingham, GBR
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13
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Abstract
Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. Derangement in wound-linked cellular behaviours, as occurs with diabetes and ageing, can lead to healing impairment and the formation of chronic, non-healing wounds. These wounds are a significant socioeconomic burden due to their high prevalence and recurrence. Thus, there is an urgent requirement for the improved biological and clinical understanding of the mechanisms that underpin wound repair. Here, we review the cellular basis of tissue repair and discuss how current and emerging understanding of wound pathology could inform future development of efficacious wound therapies.
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Affiliation(s)
- Holly N Wilkinson
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, The University of Hull, Hull HU6 7RX, United Kingdom
| | - Matthew J Hardman
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, The University of Hull, Hull HU6 7RX, United Kingdom
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de Marañón AM, Iannantuoni F, Abad-Jiménez Z, Canet F, Díaz-Pozo P, López-Domènech S, Roldán-Torres I, Morillas C, Rocha M, Víctor VM. Association between Proinflammatory Markers, Leukocyte-Endothelium Interactions, and Carotid Intima-Media Thickness in Type 2 Diabetes: Role of Glycemic Control. J Clin Med 2020; 9:E2522. [PMID: 32764458 PMCID: PMC7465892 DOI: 10.3390/jcm9082522] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/23/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Glycated hemoglobin monitorization could be a tool for maintaining type 2 diabetes (T2D) under control and delaying the appearance of cardiovascular events. This cross-sectional study was designed to assess the role of glycemic control in modulating early-stage markers of cardiovascular complications. One hundred and eight healthy controls and 161 type 2 diabetic patients were recruited and distributed according to their glycemic control, setting the threshold at 6.5% (good control). Biochemical and anthropometrical parameters were registered during the initial visit, and peripheral blood was extracted to obtain polymorphonuclear cells and analyze inflammatory markers, adhesion molecules, leukocyte-endothelium interactions, and carotid intima-media thickness. Correlations between these parameters were explored. We found that inflammatory markers and adhesion molecules were augmented in type 2 diabetic subjects with poor glycemic control. Polymorphonuclear leukocytes interacted more with the endothelium in the diabetic population, and even more significantly in the poorly controlled subjects. In parallel, carotid intima-media thickness was also increased in the diabetic population, and the difference was greater among poorly controlled subjects. Finally, correlation measurement revealed that carotid intima-media thickness was related to glycemic control and lipid metabolism in diabetic patients. Our results suggest that glycemic control delays the onset of cardiovascular comorbidities in diabetic subjects.
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Affiliation(s)
- Aranzazu Martinez de Marañón
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Francesca Iannantuoni
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Zaida Abad-Jiménez
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Francisco Canet
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Pedro Díaz-Pozo
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Sandra López-Domènech
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Ildefonso Roldán-Torres
- Service of Cardiology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain;
| | - Carlos Morillas
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
| | - Milagros Rocha
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
- Centro de Investigación Biomédica en Red (CIBERehd)—Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
| | - Víctor M. Víctor
- Service of Endocrinology and Nutrition, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain; (A.M.d.M.); (F.I.); (Z.A.-J.); (F.C.); (P.D.-P.); (S.L.-D.); (C.M.)
- Centro de Investigación Biomédica en Red (CIBERehd)—Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
- Department of Physiology, University of Valencia, 46010 Valencia, Spain
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15
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Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, Modugu G, Schloss MJ, Rohde D, McAlpine CS, Iwamoto Y, Libby P, Naxerova K, Swirski FK, Dutta P, Nahrendorf M. Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus. Circulation 2020; 142:244-258. [PMID: 32316750 DOI: 10.1161/circulationaha.120.046038] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production. METHODS In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling. RESULTS In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (Cdh5Cre Egfrfl/fl). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5Cre Egfrfl/fl mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5Cre Egfrfl/fl mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5Cre Egfrfl/fl mice, leading to larger and more inflamed atherosclerotic lesions in the aorta. CONCLUSIONS In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
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Affiliation(s)
- Friedrich Felix Hoyer
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Xinyi Zhang
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (X.Z., E.C., S.B.V., G.M., P.D.).,The Third Xiangya Hospital, Central South University, Changsha, Hunan, China (X.Z.)
| | - Emilie Coppin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (X.Z., E.C., S.B.V., G.M., P.D.)
| | - Sathish Babu Vasamsetti
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (X.Z., E.C., S.B.V., G.M., P.D.)
| | - Ganesh Modugu
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (X.Z., E.C., S.B.V., G.M., P.D.)
| | - Maximilian J Schloss
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - David Rohde
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Cameron S McAlpine
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Yoshiko Iwamoto
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.L.)
| | - Kamila Naxerova
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Filip K Swirski
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.)
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA (X.Z., E.C., S.B.V., G.M., P.D.)
| | - Matthias Nahrendorf
- Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.).,Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (M.N.).,Department of Internal Medicine I, University Hospital Würzburg, Germany (M.N.)
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16
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The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes. J Clin Med 2019; 8:jcm8091322. [PMID: 31466264 PMCID: PMC6780723 DOI: 10.3390/jcm8091322] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/09/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial dysfunction has been shown to play a central role in the pathophysiology of type 2 diabetes (T2D), and mitochondria-targeted agents such as SS-31 are emerging as a promising strategy for its treatment. We aimed to study the effects of SS-31 on leukocytes from T2D patients by evaluating oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Sixty-one T2D patients and 53 controls were included. Anthropometric and analytical measurements were performed. We also assessed reactive oxygen species (ROS) production, calcium content, the expression of ER stress markers GRP78, CHOP, P-eIF2α, and autophagy-related proteins Beclin1, LC3 II/I, and p62 in leukocytes from T2D and control subjects treated or not with SS-31. Furthermore, we have evaluated the action of SS-31 on leukocyte-endothelium interactions. T2D patients exhibited elevated ROS concentration, calcium levels and presence of ER markers (GRP78 and CHOP gene expression, and GRP78 and P-eIF2α protein expression), all of which were reduced by SS-31 treatment. SS-31 also led to a drop in BECN1 gene expression, and Beclin1 and LC3 II/I protein expression in T2D patients. In contrast, the T2D group displayed reduced p62 protein levels that were restored by SS-31. SS-20 (with non-antioxidant activity) did not change any analyzed parameter. In addition, SS-31 decreased rolling flux and leukocyte adhesion, and increased rolling velocity in T2D patients. Our findings suggest that SS-31 exerts potentially beneficial effects on leukocytes of T2D patients modulating oxidative stress and autophagy, and ameliorating ER stress.
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Filardi T, Ghinassi B, Di Baldassarre A, Tanzilli G, Morano S, Lenzi A, Basili S, Crescioli C. Cardiomyopathy Associated with Diabetes: The Central Role of the Cardiomyocyte. Int J Mol Sci 2019; 20:ijms20133299. [PMID: 31284374 PMCID: PMC6651183 DOI: 10.3390/ijms20133299] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 12/18/2022] Open
Abstract
The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%–80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as “passive” targets but as “active” units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted.
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Affiliation(s)
- Tiziana Filardi
- Department of Experimental Medicine, "Sapienza" University, Viale del Policlinico 155, 00161 Rome, Italy
| | - Barbara Ghinassi
- Department of Medicine and Aging Sciences, "G. D'Annunzio" University of Chieti and Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Angela Di Baldassarre
- Department of Medicine and Aging Sciences, "G. D'Annunzio" University of Chieti and Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Gaetano Tanzilli
- Department of Cardiovascular Sciences, "Sapienza" University, Viale del Policlinico 155, 00161 Rome, Italy
| | - Susanna Morano
- Department of Experimental Medicine, "Sapienza" University, Viale del Policlinico 155, 00161 Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, "Sapienza" University, Viale del Policlinico 155, 00161 Rome, Italy
| | - Stefania Basili
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Clara Crescioli
- Department of Movement, Human and Health Sciences, Section of Health Sciences, University of Rome "Foro Italico", Piazza L. de Bosis 6, 00135 Rome, Italy.
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Oliveira SHP, Brito VGB, Frasnelli SCT, Ribeiro BDS, Ferreira MN, Queiroz DP, Beltan CT, Lara VS, Santos CF. Aliskiren Attenuates the Inflammatory Response and Wound Healing Process in Diabetic Mice With Periodontal Disease. Front Pharmacol 2019; 10:708. [PMID: 31333451 PMCID: PMC6620569 DOI: 10.3389/fphar.2019.00708] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/31/2019] [Indexed: 01/08/2023] Open
Abstract
The aim of this study was to characterize the role of local RAS (renin–angiotensin system) in the inflammatory response of normal (N) and diabetic (D) mice with periodontal disease (PD). Diabetes Mellitus (DM) was induced by peritoneal injection of streptozotocin in Balb/c mice. PD was induced by ligature around the first molar in both N and D, irrespective of whether they were treated with aliskiren (50 mg/kg, Alisk). Mandibles were harvested for histomorphometric analyses, and gingival tissue (GT) was collected to evaluate gene expression and extracellular matrix components (ECM). Immunohistochemical (IHC) analyses were used to localize RAS in GT. The production of C-reactive protein (CRP), IL-1β, CXCL2, and CCL8 was evaluated by enzyme-linked immunosorbent assay (ELISA). Renin was found to exacerbate the inflammation and periodontal bone loss at 14 days after PD, and Alisk inhibited this process in GT of N and D. PD increased CRP, CXCL2, CCL8, and IL-1β production in both animals. Alisk could inhibit CRP, CXCL2, and CCL8 primarily in D animals. However, only CCL8 was decreased in N animals after Alisk pretreatment. PD enhanced expression and production of AGT, ACE, AT1R, and AT2R in both N and D. AT1R expression was higher in D with PD, and AT2R expression was higher in N with PD. ACE2 and receptor Mas (MasR) expression and production was elevated in the control group of both animals. PD inhibited ACE2 in N but not in D. MasR expression was unaffected in both N and D with PD. Alisk reduced expression and production of all RAS components in GT of both animals, except for ACE2 in N. RAS staining was observed in all layers of epithelium, basal cell layer, and lamina propria and was higher in N with PD. Col1a1, Col1a2, Col3a1, and fibronectin (Fn1) were increased in both animals with PD. Alisk inhibited Col1a1 and Fn in both animals, Col1a2 was decreased only in D, while levels of Col3a1 remained unchanged in all animal groups. In conclusion, these data demonstrated the presence and functional role of local RAS in GT, exacerbating the inflammatory response, periodontal bone loss, and wound healing processes in both N and D animal groups. In addition, Alisk was able to significantly reduce gingival inflammation, excessive wound healing processes, and periodontal bone loss.
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Affiliation(s)
- Sandra Helena Penha Oliveira
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil.,Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Victor Gustavo Balera Brito
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil.,Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Sabrina Cruz Tfaile Frasnelli
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Bianca da Silva Ribeiro
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Milena Nunes Ferreira
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Dayane Priscilla Queiroz
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil.,Programa Multicêntrico de Pós-graduação em Ciências Fisiológicas, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Carluci Taís Beltan
- Department of Basic Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), São Paulo, Brazil
| | - Vanessa Soares Lara
- Department of Stomatology, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil
| | - Carlos Ferreira Santos
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo (USP), Bauru, Brazil
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19
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Ge T, Yu Y, Cui J, Cai L. The adaptive immune role of metallothioneins in the pathogenesis of diabetic cardiomyopathy: good or bad. Am J Physiol Heart Circ Physiol 2019; 317:H264-H275. [PMID: 31100011 DOI: 10.1152/ajpheart.00123.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes is a metabolic disorder characterized by hyperglycemia, resulting in low-grade systemic inflammation. Diabetic cardiomyopathy (DCM) is a common complication among diabetic patients, and the mechanism underlying its induction of cardiac remodeling and dysfunction remains unclear. Numerous experimental and clinical studies have suggested that adaptive immunity, especially T lymphocyte-mediated immunity, plays a potentially important role in the pathogenesis of diabetes and DCM. Metallothioneins (MTs), cysteine-rich, metal-binding proteins, have antioxidant properties. Some potential mechanisms underlying the cardioprotective effects of MTs include the role of MTs in calcium regulation, zinc homeostasis, insulin sensitization, and antioxidant activity. Moreover, metal homeostasis, especially MT-regulated zinc homeostasis, is essential for immune function. This review discusses aberrant immune regulation in diabetic heart disease with respect to endothelial insulin resistance and the effects of hyperglycemia and hyperlipidemia on tissues and the different effects of intracellular and extracellular MTs on adaptive immunity. This review shows that intracellular MTs are involved in naïve T-cell activation and reduce regulatory T-cell (Treg) polarization, whereas extracellular MTs promote proliferation and survival in naïve T cells and Treg polarization but inhibit their activation, thus revealing potential therapeutic strategies targeting the regulation of immune cell function by MTs.
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Affiliation(s)
- Tingwen Ge
- Cancer Center, First Hospital of Jilin University , Changchun, Jilin , China.,Pediatric Research Institute, Department of Pediatrics, University of Louisville, Norton Health Care, Louisville, Kentucky
| | - Youxi Yu
- Pediatric Research Institute, Department of Pediatrics, University of Louisville, Norton Health Care, Louisville, Kentucky.,Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University , Changchun, Jilin , China
| | - Jiuwei Cui
- Cancer Center, First Hospital of Jilin University , Changchun, Jilin , China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville, Norton Health Care, Louisville, Kentucky.,Departments of Radiation Oncology, Pharmacology and Toxicology, University of Louisville , Louisville, Kentucky
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20
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Dual Gene Expression Analysis Identifies Factors Associated with Staphylococcus aureus Virulence in Diabetic Mice. Infect Immun 2019; 87:IAI.00163-19. [PMID: 30833333 DOI: 10.1128/iai.00163-19] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 02/26/2019] [Indexed: 11/20/2022] Open
Abstract
Staphylococcus aureus is a major human pathogen of the skin. The global burden of diabetes is high, with S. aureus being a major complication of diabetic wound infections. We investigated how the diabetic environment influences S. aureus skin infection and observed an increased susceptibility to infection in mouse models of both type I and type II diabetes. A dual gene expression approach was taken to investigate transcriptional alterations in both the host and bacterium after infection. While analysis of the host response revealed only minor changes between infected control and diabetic mice, we observed that S. aureus isolated from diabetic mice had significant increases in the levels of genes associated with translation and posttranslational modification and chaperones and reductions in the levels of genes associated with amino acid transport and metabolism. One family of genes upregulated in S. aureus isolated from diabetic lesions encoded the Clp proteases, associated with the misfolded protein response. The Clp proteases were found to be partially glucose regulated as well as influencing the hemolytic activity of S. aureus Strains lacking the Clp proteases ClpX, ClpC, and ClpP were significantly attenuated in our animal model of skin infection, with significant reductions observed in dermonecrosis and bacterial burden. In particular, mutations in clpP and clpX were significantly attenuated and remained attenuated in both normal and diabetic mice. Our data suggest that the diabetic environment also causes changes to occur in invading pathogens, and one of these virulence determinants is the Clp protease system.
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21
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de Souza PRK, Ferreira SS, Nunes FPB, Casagrande FB, Tessaro FHG, Silva MCF, Cruz JWMC, Mamizuka EM, Martins JO. Cytokine and Adhesion Molecule Expression Induced by Different Strains of Staphylococcus aureus in Type 1 Diabetic Rats: Role of Insulin. Front Immunol 2019; 9:3165. [PMID: 30705678 PMCID: PMC6344427 DOI: 10.3389/fimmu.2018.03165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 12/21/2018] [Indexed: 12/24/2022] Open
Abstract
Introduction: Staphylococcus aureus may provoke peritonitis and death, especially in immunocompromized individuals such as diabetic patients. We evaluated the role of insulin in S. aureus-induced peritoneal infection in diabetic and non-diabetic rats. Materials/Methods: Alloxan-diabetic male Wistar rats and their respective controls received intraperitoneal injections of different strains of S. aureus or sterile phosphate-buffered saline. After 3 days of infection, the first set of diabetic and non-diabetic rats received 4 and 1 IU, respectively, of neutral protamine Hagedorn insulin and were analyzed 8 h later. The second set of diabetic and non-diabetic rats received 4 and 1 IU, respectively, of insulin 2 h before intraperitoneal infection and a half dose of insulin at 5 p.m. for the next 2 days and were analyzed 16 h later. The following measurements were performed: (a) number of cells in the peritoneal lavage fluid (PeLF), white blood cell count, and blood glucose; (b) serum insulin and corticosterone; (c) cytokine levels in the PeLF; (d) expression of adhesion molecules in the vascular endothelium; and (e) microbicidal activity. Results: Diabetic rats showed an increased number of polymorphonuclear leukocytes (PMNs) and increased concentrations of CINC-1, IL-4, and IFN-γ in the PeLF after infection with the ATCC 25923 or N315 αHL+ strain. The mesenteric expression of PECAM-1 was increased after infection with the N315 HLA+ strain. ICAM-1 expression was increased with ATCC infection. Treatment of diabetic rats with a single dose of insulin restored CINC-1 levels in the PeLF for both strains; however, PMN migration, IL-4, and IFN-γ were restored in rats infected with the ATCC strain, whereas the PeLF concentrations of CINC-2, IL-1β, and IL-4 were increased in N315-infected animals. Insulin restored PMN migration and CINC-2 levels in the PeLF in ATCC-infected rats. After multiple treatments with insulin, the levels of IL-1β, IL-6, and IFN-γ were increased in the PeLF of diabetic rats after infection with either strain, and CINC-2 levels were restored in N315-infected animals. Conclusion: These results suggest that insulin distinctively modulates cytokine production or release, PMN leukocyte migration, and adhesion molecule expression during the course of peritonitis induced by different strains of S. aureus.
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Affiliation(s)
- Paula R Knox de Souza
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil.,Universidade Paulista, São Paulo, Brazil
| | - Sabrina S Ferreira
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | - Fernanda P B Nunes
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | - Felipe B Casagrande
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | - Fernando H G Tessaro
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | - Mariana C F Silva
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | | | - Elsa M Mamizuka
- Laboratory of Microbiology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
| | - Joilson O Martins
- Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences (FCF), University of São Paulo (USP), São Paulo, Brazil
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22
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Bajpai A, Tilley DG. The Role of Leukocytes in Diabetic Cardiomyopathy. Front Physiol 2018; 9:1547. [PMID: 30443223 PMCID: PMC6221939 DOI: 10.3389/fphys.2018.01547] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/16/2018] [Indexed: 12/16/2022] Open
Abstract
Diabetes is predominant risk factor for cardiovascular diseases such as myocardial infarction and heart failure. Recently, leukocytes, particularly neutrophils, macrophages, and lymphocytes, have become targets of investigation for their potential role in a number of chronic inflammatory diseases such as diabetes and heart failure. While leukocytes contribute significantly to the progression of diabetes and heart failure individually, understanding their participation in the pathogenesis of diabetic heart failure is much less understood. The present review summarizes the role of leukocytes in the complex interplay between diabetes and heart failure, which is critical to the discovery of new targeted therapies for diabetic cardiomyopathy.
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Affiliation(s)
- Anamika Bajpai
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Douglas G Tilley
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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23
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Chang HY, Yazdani A, Li X, Douglas KAA, Mantzoros CS, Karniadakis GE. Quantifying Platelet Margination in Diabetic Blood Flow. Biophys J 2018; 115:1371-1382. [PMID: 30224049 PMCID: PMC6170725 DOI: 10.1016/j.bpj.2018.08.031] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/23/2018] [Accepted: 08/24/2018] [Indexed: 12/23/2022] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) develop thrombotic abnormalities strongly associated with cardiovascular diseases. In addition to the changes of numerous coagulation factors such as elevated levels of thrombin and fibrinogen, the abnormal rheological effects of red blood cells (RBCs) and platelets flowing in blood are crucial in platelet adhesion and thrombus formation in T2DM. An important process contributing to the latter is the platelet margination. We employ the dissipative particle dynamics method to seamlessly model cells, plasma, and vessel walls. We perform a systematic study on RBC and platelet transport in cylindrical vessels by considering different cell shapes, sizes, and RBC deformabilities in healthy and T2DM blood, as well as variable flowrates and hematocrit. In particular, we use cellular-level RBC and platelet models with parameters derived from patient-specific data and present a sensitivity study. We find T2DM RBCs, which are less deformable compared to normal RBCs, lower the transport of platelets toward the vessel walls, whereas platelets with higher mean volume (often observed in T2DM) lead to enhanced margination. Furthermore, increasing the flowrate or hematocrit enhances platelet margination. We also investigated the effect of platelet shape and observed a nonmonotonic variation with the highest near-wall concentration corresponding to platelets with a moderate aspect ratio of 0.38. We examine the role of white blood cells (WBCs), whose count is increased notably in T2DM patients. We find that WBC rolling or WBC adhesion tends to decrease platelet margination due to hydrodynamic effects. To the best of our knowledge, such simulations of blood including all blood cells have not been performed before, and our quantitative findings can help separate the effects of hydrodynamic interactions from adhesive interactions and potentially shed light on the associated pathological processes in T2DM such as increased inflammatory response, platelet activation and adhesion, and ultimately thrombus formation.
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Affiliation(s)
- Hung-Yu Chang
- Division of Applied Mathematics, Brown University, Providence, Rhode Island
| | - Alireza Yazdani
- Division of Applied Mathematics, Brown University, Providence, Rhode Island
| | - Xuejin Li
- Division of Applied Mathematics, Brown University, Providence, Rhode Island
| | - Konstantinos A A Douglas
- S. Lepida Biomedical Laboratory, Athens, Greece; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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24
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Shi R, Feng W, Zhang C, Yu T, Fan Z, Liu Z, Zhang Z, Zhu D. In vivo imaging the motility of monocyte/macrophage during inflammation in diabetic mice. JOURNAL OF BIOPHOTONICS 2018; 11:e201700205. [PMID: 29236358 DOI: 10.1002/jbio.201700205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 12/11/2017] [Indexed: 05/28/2023]
Abstract
Diabetes, as a chronic metabolic disease, can impair the immune function of monocytes/macrophages (MMs). However, it is unclear how MM immune response to inflammation with the development of diabetes, and whether immune response around the inflammatory foci depends on the depth in tissue. Footpad provides a classical physiological site for monitoring cellular behavior during inflammation, but limited to the superficial dermis due to the strong scattering of footpad. Herein, we used confocal microscopy to monitor the motility of MMs in deeper tissue around inflammatory foci with the development of type 1 diabetic (T1D) mice through a switchable footpad skin optical clearing window. Delayed-type hypersensitivity (DTH) model was elicited on the footpad of T1D. Results demonstrated that progressive T1D led to the gradually potentiated MM recruitment and increased expression of monocyte chemoattractant protein-1 during DTH, but MM migration displacement, motion velocity and motility coefficient were significantly attenuated. Besides, MMs from the deeper dermis had a much larger migration displacement than those from superficial dermis at early stages of DTH but an opposite tendency at late stages for non-T1D, while progressive T1D obscured this difference gradually. This study will be helpful for investigating the influences of progressive metabolic diseases on immune response. MM motion trajectory at depth of superficial dermis and the deeper dermis at AOVA (heat-aggregated ovalbumin)-4 hours and AOVA-72 hours on non-T1D (A) and T1D-4 weeks (B). Mean motility coefficient (C) at the 2 depths. Data were pooled from 6 mice per group. *P < .05 and **P < .01 compared among different T1D disease durations. #P < .05 compared between different depths.
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Affiliation(s)
- Rui Shi
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Feng
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Zhang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tingting Yu
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhan Fan
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zheng Liu
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhihong Zhang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dan Zhu
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
- MOE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, Hubei, China
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25
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Catanzaro DP, Mena Laura EE, Cestari TM, Arantes RVN, Garlet GP, Taga R, Assis GF. Green tea prevents vascular disturbs and attenuates periodontal breakdown in long-term hyperglycaemia in T1D rats. J Clin Periodontol 2018; 45:557-569. [PMID: 29500839 DOI: 10.1111/jcpe.12883] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2018] [Indexed: 12/11/2022]
Abstract
AIM The effects of green tea on the modulation of vascularization during the progression of spontaneous periodontitis in long-term hyperglycaemia in streptozotocin-induced type 1 diabetic (T1D) rats were evaluated. MATERIALS AND METHODS Wistar rats normoglycaemic (NG) and T1D were divided into two control groups, which received water (NG-W and T1D-W) and two experimental groups that received green tea (NG-GT and T1D-GT). Periodontal structures were evaluated by microtomographic and histological analyses. Number of immunostained cells for VEGF (NcVEGF+/mm2 ) and CD31 (NcCD31+/mm2 ), as well microvessel density (MVD) in the periodontal ligament (PDL) were evaluated. RESULTS Long-term hyperglycaemia in T1D-W rats induced vascular alterations in PDL with a reduction of 36% in MVD, a decrease of 33% in NcCD31+/mm2 and an increase of 53% in NcVEGF+/mm2 . Concomitantly, a severe degree of periodontitis with higher reduction in bone volume and periodontal bone level was observed. In T1D-GT, green tea maintained the MVD, NcCD31+/mm2 and NcVEGF+/mm2 in the PDL similar to normoglycaemic groups. Clinically, in T1D-GT rats, green tea reduced dental plaque accumulation and the degree of periodontitis when compared to T1D-W. CONCLUSION Daily green tea consumption has a therapeutic effect on the diabetic vascular disorder in PDL and the progression of periodontitis in long-term hyperglycaemia in T1D rats.
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Affiliation(s)
- Daniela Pereira Catanzaro
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Ever Elias Mena Laura
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Tania Mary Cestari
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | | | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Rumio Taga
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
| | - Gerson Francisco Assis
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Bauru, São Paulo, Brazil
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26
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Kuwabara WMT, Panveloski-Costa AC, Yokota CNF, Pereira JNB, Filho JM, Torres RP, Hirabara SM, Curi R, Alba-Loureiro TC. Comparison of Goto-Kakizaki rats and high fat diet-induced obese rats: Are they reliable models to study Type 2 Diabetes mellitus? PLoS One 2017; 12:e0189622. [PMID: 29220408 PMCID: PMC5722336 DOI: 10.1371/journal.pone.0189622] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
Type 2 Diabetes mellitus (T2DM) is an evident growing disease that affects different cultures throughout the world. T2DM occurs under the influence of three main factors: the genetic background, environmental and behavioral components. Obesity is strongly associated to the development of T2DM in the occident, while in the orient most of the diabetic patients are considered lean. Genetics may be a key factor in the development of T2DM in societies where obesity is not a recurrent public health problem. Herein, two different models of rats were used to understand their differences and reliability as experimental models to study the pathophysiology of T2DM, in two different approaches: the genetic (GK rats) and the environmental (HFD-induced obese rats) influences. GK rats were resistant to weight gain even though food/energy consumption (relative to body weight) was higher in this group. HFD, on the other hand, induced obesity in Wistar rats. White adipose tissue (WAT) expansion in this group was accompanied by immune cells infiltration, inflammation and insulin resistance. GK rats also presented WAT inflammation and insulin resistance; however, no immune cells infiltration was observed in the WAT of this group. Liver of HFD group presented fat accumulation without differences in inflammatory cytokines content, while liver of GK rats didn't present fat accumulation, but showed an increase of IL-6 and IL-10 content and glycogen. Also, GK rats showed increased plasma GOT and GPT. Soleus muscle of HFD presented normal insulin signaling, contrary to GK rats, which presented higher content of basal phosphorylation of GSK-3β. Our results demonstrated that HFD developed a mild insulin resistance in Wistar rats, but was not sufficient to develop T2DM. In contrast, GK rats presented all the typical hallmarks of T2DM, such as insulin resistance, defective insulin production, fasting hyperglycemia/hyperinsulinemia and lipid plasma alteration. Thus, on the given time point of this study, we may conclude that only GK rats shown to be a reliable model to study T2DM.
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Affiliation(s)
| | - Ana Carolina Panveloski-Costa
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | | | - Joice Naiara Bertaglia Pereira
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Cruzeiro do Sul University, São Paulo, Brazil
| | - Jorge Mancini Filho
- Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | | | | | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Cruzeiro do Sul University, São Paulo, Brazil
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27
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Abu-Gharbieh E, Shehab NG. Therapeutic potentials of Crataegus azarolus var. eu- azarolus Maire leaves and its isolated compounds. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:218. [PMID: 28420354 PMCID: PMC5395866 DOI: 10.1186/s12906-017-1729-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/06/2017] [Indexed: 12/18/2022]
Abstract
Background Hyperglycemia is a complicated condition accompanied with high incidence of infection and dyslipidemia. This study aimed to explore the phyto-constituents of Crataegus azarolus var. eu- azarolus Maire leaves, and to evaluate the therapeutic potentials particularly antimicrobial, antihyperglycemic and antihyperlipidemic of the extract and the isolated compound (3β-O-acetyl ursolic acid). Methods Total phenolics and flavonoidal contents were measured by RP-HPLC analysis. Free radicals scavenging activity of different extraction solvents was tested in-vitro on DPPH free radicals. The antimicrobial activity of the ethanolic extract and its fractions as well as the isolated compounds were evaluated in-vitro on variable microorganisms. Animal models were used to evaluate the antihyperglycemic and antihyperlipidemic activities of the ethanolic extract along with the isolated compound (3β-O acetyl ursolic acid). Results RP- HPLC analysis of the phenolics revealed high content of rutin, salicylic and ellagic acids. Six compounds belonging to triterpenes and phenolics were isolated from chloroform and n-butanol fractions namely: ursolic acid, 3β-O-acetyl ursolic acid, ellagic acid, quercetin 3-O-β methyl ether, rutin and apigenin7-O-rutinoside. Ethanolic extract showed the highest DPPH radical scavenger activity compared to other solvents. Ethanolic extract, hexane fraction, ursolic acid, 3β-O acetyl ursolic acid and quercetin 3-O-methyl ether showed variable antimicrobial activity against E. coli, P. aeruginosa, S. aureus, and C. albicans. Administration of the ethanolic extract or 3β-O acetyl ursolic acid orally to the mice reduced blood glucose significantly in a time- and dose-dependent manner. Ethanolic extract significantly reduced LDL-C, VLDL-C, TC and TG and increased HDL-C in rats. Ethanolic extract and 3β-O acetyl ursolic acid reduced in-vitro activity of pancreatic lipase. Conclusion This study reveals that Crataegus azarolus var. eu- azarolus Maire has the efficiency to control hyperglycemia with its associated complications. This study is the first to evaluate antihyperglycemic and antihyperlipidemic potentials of 3β-O acetyl ursolic acid. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1729-9) contains supplementary material, which is available to authorized users.
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Javid A, Zlotnikov N, Pětrošová H, Tang TT, Zhang Y, Bansal AK, Ebady R, Parikh M, Ahmed M, Sun C, Newbigging S, Kim YR, Santana Sosa M, Glogauer M, Moriarty TJ. Hyperglycemia Impairs Neutrophil-Mediated Bacterial Clearance in Mice Infected with the Lyme Disease Pathogen. PLoS One 2016; 11:e0158019. [PMID: 27340827 PMCID: PMC4920391 DOI: 10.1371/journal.pone.0158019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/08/2016] [Indexed: 12/15/2022] Open
Abstract
Insulin-insufficient type 1 diabetes is associated with attenuated bactericidal function of neutrophils, which are key mediators of innate immune responses to microbes as well as pathological inflammatory processes. Neutrophils are central to immune responses to the Lyme pathogen Borrelia burgdorferi. The effect of hyperglycemia on host susceptibility to and outcomes of B. burgdorferi infection has not been examined. The present study investigated the impact of sustained obesity-independent hyperglycemia in mice on bacterial clearance, inflammatory pathology and neutrophil responses to B. burgdorferi. Hyperglycemia was associated with reduced arthritis incidence but more widespread tissue colonization and reduced clearance of bacterial DNA in multiple tissues including brain, heart, liver, lung and knee joint. B. burgdorferi uptake and killing were impaired in neutrophils isolated from hyperglycemic mice. Thus, attenuated neutrophil function in insulin-insufficient hyperglycemia was associated with reduced B. burgdorferi clearance in target organs. These data suggest that investigating the effects of comorbid conditions such as diabetes on outcomes of B. burgdorferi infections in humans may be warranted.
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Affiliation(s)
- Ashkan Javid
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Nataliya Zlotnikov
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Helena Pětrošová
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Tian Tian Tang
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Yang Zhang
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Anil K. Bansal
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Rhodaba Ebady
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Maitry Parikh
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Mijhgan Ahmed
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Chunxiang Sun
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Susan Newbigging
- Mount Sinai Hospital/Research Institute, The Toronto Centre for Phenogenomics, 25 Orde Street, Toronto, Ontario, M5T 3H7, Canada
| | - Yae Ram Kim
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Marianna Santana Sosa
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Michael Glogauer
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
| | - Tara J. Moriarty
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Fitzgerald Building, Room 241, 150 College Street, Toronto, Ontario, M5S 3E2, Canada
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Gilardini Montani MS, Granato M, Cuomo L, Valia S, Di Renzo L, D'Orazi G, Faggioni A, Cirone M. High glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by inducing ROS and activating Wnt/β-catenin and p38 MAPK. Biochim Biophys Acta Mol Basis Dis 2016; 1862:805-813. [PMID: 26769359 DOI: 10.1016/j.bbadis.2016.01.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 12/14/2015] [Accepted: 01/04/2016] [Indexed: 01/08/2023]
Abstract
Type 2 is the type of diabetes with higher prevalence in contemporary time, representing about 90% of the global cases of diabetes. In the course of diabetes, several complications can occur, mostly due to hyperglycemia and increased reactive oxygen species (ROS) production. One of them is represented by an increased susceptibility to microbial infections and by a reduced capacity to clear them. Therefore, knowing the impact of hyperglycemia on immune system functionality is of utmost importance for the management of the disease. In this study, we show that medium containing high glucose reduced the in-vitro differentiation of monocytes into functional DCs and their activation mediated by PAMPs or DAMPs. Most importantly, the same effects were mediated by the hyperglycemic sera derived by type 2 diabetic patients, mimicking a more physiologic condition. DC dysfunction caused by hyperglycemia may be involved in the inefficient control of infections observed in diabetic patients, given the pivotal role of these cells in both the innate and adaptive immune response. Searching for the molecular mechanisms underlying DC dysfunction, we found that canonical Wnt/β-catenin and p38 MAPK pathways were activated in the DCs differentiated either in the presence of high glucose or of hyper-glycemic sera. Interestingly, the activation of these pathways and the DC immune dysfunction were partially counteracted by the anti-oxidant quercetin, a flavonoid already known to exert several beneficial effects in diabetes.
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Affiliation(s)
| | - Marisa Granato
- Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy
| | - Laura Cuomo
- U.O.C. Patologia Clinica, A.C.O. San Filippo Neri, Rome, Italy
| | - Sandro Valia
- Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy
| | - Livia Di Renzo
- Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy
| | - Gabriella D'Orazi
- Department of Translational Oncology, Regina Elena National Cancer Institute, Rome, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", 66013, Chieti, Italy
| | - Alberto Faggioni
- Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, viale Regina Elena 324, 00161, Rome, Italy.
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Qadri SM, Su Y, Cayabyab FS, Liu L. Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal. Cardiovasc Diabetol 2014; 13:134. [PMID: 25270604 PMCID: PMC4193979 DOI: 10.1186/s12933-014-0134-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 09/16/2014] [Indexed: 11/17/2022] Open
Abstract
Background Excessive levels of methylglyoxal (MG) encountered in diabetes foster enhanced leukocyte-endothelial cell interactions, mechanisms of which are incompletely understood. MG genomically upregulates endothelial serum- and glucocorticoid-inducible kinase 1 (SGK1) which orchestrates leukocyte recruitment by regulating the activation and expression of transcription factors and adhesion molecules. SGK1 regulates a myriad of ion channels and carriers including the Na+/H+ exchanger NHE1. Here, we explored the effect of MG on SGK1-dependent NHE1 activation and the putative role of NHE1 activation in MG-induced leukocyte recruitment and microvascular hyperpermeability. Methods Using RT-PCR and immunoblotting, we analyzed NHE1 mRNA and protein levels in murine microvascular SVEC4-10EE2 endothelial cells (EE2 ECs). NHE1 phosphorylation was detected using a specific antibody against the 14-3-3 binding motif at phospho-Ser703. SGK in EE2 ECs was silenced using targeted siRNA. ROS production was determined using DCF-dependent fluorescence. Leukocyte recruitment and microvascular permeability in murine cremasteric microvasculature were measured using intravital microscopy. The expression of endothelial adhesion molecules was determined by immunoblotting and confocal imaging analysis. Results MG treatment significantly upregulated NHE1 mRNA and dose-dependently increased total- and phospho-NHE1. Treatment with SGK1 inhibitor GSK650394, antioxidant Tempol and silencing SGK all blunted MG-triggered phospho-NHE1 upregulation in EE2 ECs. NHE1 inhibitor cariporide attenuated MG-triggered ROS production, leukocyte adhesion and emigration and microvascular hyperpermeability, without affecting leukocyte rolling. Cariporide treatment did not alter MG-triggered upregulation of P- and E-selectins, but reduced endothelial ICAM-1 expression. Conclusion MG elicits SGK1-dependent activation of endothelial Na+/H+ exchanger NHE1 which participates in MG-induced ROS production, upregulation of endothelial ICAM-1, leukocyte recruitment and microvascular hyperpermeability. Pharmacological inhibition of NHE1 attenuates the proinflammatory effects of excessive MG and may, thus, be beneficial in diabetes-associated inflammation.
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Hung LM, Huang JP, Liao JM, Yang MH, Li DE, Day YJ, Huang SS. Insulin renders diabetic rats resistant to acute ischemic stroke by arresting nitric oxide reaction with superoxide to form peroxynitrite. J Biomed Sci 2014; 21:92. [PMID: 25223305 PMCID: PMC4266964 DOI: 10.1186/s12929-014-0092-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/02/2014] [Indexed: 12/02/2022] Open
Abstract
Background The functions of free radicals on the effects of insulin that result in protection against cerebral ischemic insult in diabetes remain undefined. This present study aims to explain the contradiction among nitric oxide (NO)/superoxide/peroxynitrite of insulin in amelioration of focal cerebral ischemia–reperfusion (FC I/R) injury in streptozotocin (STZ)-diabetic rats and to delineate the underlying mechanisms. Long-Evans male rats were divided into three groups (age-matched controls, diabetic, and diabetic treated with insulin) with or without being subjected to FC I/R injury. Results Hyperglycemia exacerbated microvascular functions, increased cerebral NO production, and aggravated FC I/R-induced cerebral infarction and neurological deficits. Parallel with hypoglycemic effects, insulin improved microvascular functions and attenuated FC I/R injury in STZ-diabetic rats. Diabetes decreased the efficacy of NO and superoxide production, but NO and superoxide easily formed peroxynitrite in diabetic rats after FC I/R injury. Insulin treatment significantly rescued the phenomenon. Conclusions These results suggest that insulin renders diabetic rats resistant to acute ischemic stroke by arresting NO reaction with superoxide to form peroxynitrite.
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Affiliation(s)
| | | | | | | | | | | | - Shiang-Suo Huang
- Department of Pharmacology and Institute of Medicine, Chung Shan Medical University and Department of Pharmacy, Chung Shan Medical University Hospital, No,110, Sec, 1, Jianguo N, Rd, Taichung City 402, Taiwan.
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Close TE, Cepinskas G, Omatsu T, Rose KL, Summers K, Patterson EK, Fraser DD. Diabetic ketoacidosis elicits systemic inflammation associated with cerebrovascular endothelial cell dysfunction. Microcirculation 2014; 20:534-43. [PMID: 23441883 DOI: 10.1111/micc.12053] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 02/19/2013] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To determine if the DKA-induced inflammation in juvenile mice provokes activation and dysfunction of CVECs. METHODS DKA in juvenile mice was induced with administration of STZ and ALX. Blood from DKA mice was assessed for cytokines and soluble cell adhesion proteins, and either DKA plasma or exogenous compounds were applied to immortalized bEND3. RESULTS DKA increased circulating levels of IL-6, IL-8(KC), MCP-1, IL-10, sE-selectin, sICAM-1, and sVCAM-1. Stimulation of bEND3 with DKA plasma caused cellular activation (increased ROS and activation of NF-κΒ), upregulation of a proadhesive phenotype (E-selectin, ICAM-1, and VCAM-1), and increased leukocyte-bEND3 interaction (leukocyte rolling/adhesion). TEER, a measure of bEND3 monolayer integrity, was decreased by DKA plasma. Activation and dysfunction of bEND3 with DKA plasma were suppressed by plasma heat treatment (56°C, 1 hour) and replicated with the application of DKA recombinant cytomix (IL-6, IL-8[KC], MCP-1, and IL-10), implicating circulating inflammatory protein(s) as mediators. Treatment of bEND3 with β-OH-butyrate, the main ketone elevated in DKA, failed to mimic the DKA plasma-induced activation and dysfunction of bEND3. CONCLUSIONS DKA elicits systemic inflammation associated with CVEC activation and dysfunction, possibly contributing to DKA-associated intracranial microvascular complications.
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Affiliation(s)
- Taylor E Close
- Children's Health Research Institute, London, ON, Canada
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Okabayashi T, Shima Y. Are closed-loop systems for intensive insulin therapy ready for prime time in the ICU? Curr Opin Clin Nutr Metab Care 2014; 17:190-9. [PMID: 24378668 DOI: 10.1097/mco.0000000000000026] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Recent findings suggest that the effects of tight glycemic control (TGC) performing intensive insulin therapy (IIT) in medical and surgical ICU have had conflicting results. The purpose of this review is to summarize the current evidence in humans how closed-loop systems for IIT are ready for prime time in the ICU. RECENT FINDINGS Current evidence suggests that maintaining normoglycemia postoperatively can improve the outcome and reduce the mortality and morbidity of critically ill patients by TGC performing IIT according to the large randomized trials. However, trials examining the effects of TGC have had conflicting results. Systematic reviews and meta-analyses have also led to differing conclusions. The main reason these clinical trials and meta-analyses were negative results for TGC was because of the high incidence of hypoglycemia. This could not be prevented as there is no reliable technique currently able to avoid this condition during IIT. The development of accurate, continuous blood glucose monitoring devices, and closed-loop systems for computer-assisted blood glucose control in the ICU, will probably help avoid hypoglycemia in these situations. SUMMARY The challenge in the hospital setting demonstrated that a closed-loop glycemic control system is expected to the achievement of TGC with no occurrence of hypoglycemia induced by IIT after surgery. Closed-loop glycemic control systems for IIT are now ready for prime time in the ICU.
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Affiliation(s)
- Takehiro Okabayashi
- Department of Gastroenterological Surgery, Kochi Health Sciences Center, Kochi City, Kochi, Japan
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Su Y, Qadri SM, Hossain M, Wu L, Liu L. Uncoupling of eNOS contributes to redox-sensitive leukocyte recruitment and microvascular leakage elicited by methylglyoxal. Biochem Pharmacol 2013; 86:1762-74. [PMID: 24144633 DOI: 10.1016/j.bcp.2013.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 10/10/2013] [Accepted: 10/11/2013] [Indexed: 01/03/2023]
Abstract
Elevated levels of the glycolysis metabolite methylglyoxal (MG) have been implicated in impaired leukocyte-endothelial interactions and vascular complications in diabetes, putative mechanisms of which remain elusive. Uncoupling of endothelial nitric oxide synthase (eNOS) was shown to be involved in endothelial dysfunction in diabetes. Whether MG contributes to these effects has not been elucidated. By using intravital microscopy in vivo, we demonstrate that MG-triggered reduction in leukocyte rolling velocity and increases in rolling flux, adhesion, emigration and microvascular permeability were significantly abated by scavenging reactive oxygen species (ROS). In murine cremaster muscle, MG treatment reduced tetrahydrobiopterin (BH4)/total biopterin ratio, increased arginase expression and stimulated ROS and superoxide production. The latter was significantly blunted by ROS scavengers Tempol (300μM) or MnTBAP (300μM), by BH4 supplementation (100μM) or by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 20μM). In these tissues and cultured murine and human primary endothelial cells, MG increased eNOS monomerization and decreased BH4/total biopterin ratio, effects that were significantly mitigated by supplementation of BH4 or its precursor sepiapterin but not by L-NAME or tetrahydroneopterin, indicative of MG-triggered eNOS uncoupling. MG treatment further decreased the expression of guanosine triphosphate cyclohydrolase I in murine primary endothelial cells. MG-induced leukocyte recruitment was significantly attenuated by supplementation of BH4 or sepiapterin or suppression of superoxide by L-NAME confirming the role of eNOS uncoupling in MG-elicited leukocyte recruitment. Together, our study uncovers eNOS uncoupling as a pivotal mechanism in MG-induced oxidative stress, microvascular hyperpermeability and leukocyte recruitment in vivo.
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Affiliation(s)
- Yang Su
- Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E5
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Lovati AB, Drago L, Monti L, De Vecchi E, Previdi S, Banfi G, Romanò CL. Diabetic mouse model of orthopaedic implant-related Staphylococcus aureus infection. PLoS One 2013; 8:e67628. [PMID: 23818985 PMCID: PMC3688606 DOI: 10.1371/journal.pone.0067628] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 05/21/2013] [Indexed: 01/24/2023] Open
Abstract
Background Periprosthetic bacterial infections represent one of the most challenging orthopaedic complications that often require implant removal and surgical debridement and carry high social and economical costs. Diabetes is one of the most relevant risk factors of implant-related infection and its clinical occurrence is growing worldwide. The aim of the present study was to test a model of implant-related infection in the diabetic mouse, with a view to allow further investigation on the relative efficacy of prevention and treatment options in diabetic and non-diabetic individuals. Methodology A cohort of diabetic NOD/ShiLtJ mice was compared with non-diabetic CD1 mice as an in vivo model of S. aureus orthopaedic infection of bone and soft tissues after femur intramedullary pin implantation. We tested control and infected groups with 1×103 colony-forming units of S. aureus ATCC 25923 strain injected in the implant site. At 4 weeks post-inoculation, host response to infection, microbial biofilm formation, and bone damage were assessed by traditional diagnostic parameters (bacterial culture, C-reactive protein and white blood cell count), histological analysis and imaging techniques (micro computed tomography and scanning electron microscopy). Results Unlike the controls and the CD1 mice, all the diabetic mice challenged with a single inoculum of S. aureus displayed severe osteomyelitic changes around the implant. Conclusions Our findings demonstrate for the first time that the diabetic mouse can be successfully used in a model of orthopaedic implant-related infection. Furthermore, the same bacteria inoculum induced periprosthetic infection in all the diabetic mice but not in the controls. This animal model of implant-related infection in diabetes may be a useful tool to test in vivo treatments in diabetic and non-diabetic individuals.
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Affiliation(s)
- Arianna B Lovati
- Cell and Tissue Engineering Laboratory, Gruppo Ospedaliero San Donato Foundation, Milan, Italy.
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Montefusco-Pereira CV, de Carvalho MJ, de Araújo Boleti AP, Teixeira LS, Matos HR, Lima ES. Antioxidant, anti-inflammatory, and hypoglycemic effects of the leaf extract from Passiflora nitida Kunth. Appl Biochem Biotechnol 2013; 170:1367-78. [PMID: 23666642 DOI: 10.1007/s12010-013-0271-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 04/29/2013] [Indexed: 11/28/2022]
Abstract
Diabetes mellitus is a metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as insulin resistance, obesity, hyperlipidemia, and hypertension, also with alterations in the immune and neuronal systems. Brazilian plants have been studied as important sources for new molecules with medicinal properties. The genus Passiflora known as "Maracujá" has been used as a traditional folk medicine for a long time, so an investigation was performed regarding an endemic kind of passion fruit (Passiflora nitida Kunth) from Amazonas, Brazil. Here, we aimed to determine its potential biological activity against metabolic syndrome, oxidative stress, pain, and inflammation. The hydroethanol leaf extract revealed an in vitro α-glucosidase inhibitory activity of 50 % inhibitory concentration (IC₅₀) = 6.78 ± 0.31 μg/mL and an α-amylase inhibition of IC₅₀= 93.36 ± 4.37. In vivo, experiments of different saccharide tolerance resulted in significant glycemia control and, with alloxan-diabetic mice, resulted in a decrease of total cholesterol, a hypoglycemic effect, and an antioxidant activity by thiobarbituric acid-reactive substances measurement. Also, it decreased the carrageenan-induced edema volume and the rate of writhing as a nociceptive response. These results indicate positive effects of P. nitida extract and its potential to inhibit metabolic syndrome.
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Affiliation(s)
- Carlos Victor Montefusco-Pereira
- Laboratory of Biological Activity, Faculty of Pharmaceutical Sciences, Amazonas Federal University, Alexandre Amorim Street, 330, 69010-300 Aparecida, Manaus, Amazonas, Brazil
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Boyanova L, Mitov I. Antibiotic resistance rates in causative agents of infections in diabetic patients: rising concerns. Expert Rev Anti Infect Ther 2013; 11:411-420. [DOI: 10.1586/eri.13.19] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. Clin Sci (Lond) 2012; 124:191-202. [DOI: 10.1042/cs20120330] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.
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Azab B, Chainani V, Shah N, McGinn JT. Neutrophil-lymphocyte ratio as a predictor of major adverse cardiac events among diabetic population: a 4-year follow-up study. Angiology 2012; 64:456-65. [PMID: 22904109 DOI: 10.1177/0003319712455216] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The neutrophil-lymphocyte ratio (NLR) is an inflammatory marker of major adverse cardiac events (MACEs) in both acute coronary syndromes and stable coronary artery disease. The use of NLR as a predictive tool for MACEs among diabetic patients has not been elucidated. An observational study included 338 diabetic patients followed at our clinic between 2007 and 2011. Patients were arranged into equal tertiles according to the 2007 NLR. The MACEs included acute myocardial infarction, coronary revascularization, and mortality. The lowest NLR tertile (NLR < 1.6) had fewer MACEs compared with the highest NLR tertile (NLR > 2.36; MACEs were 6 of 113 patients vs 24 of 112 patients, respectively; P < .0001). In a multivariate model, the adjusted hazard ratio of third NLR tertile compared with first NLR tertile was 2.8 (95% confidence interval 1.12-6.98, P = .027). The NLR is a significant independent predictor of MACEs in diabetic patients. Further studies with larger numbers are needed.
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Affiliation(s)
- Basem Azab
- Department of Surgery, Staten Island University Hospital, Staten Island, NY 10305, USA.
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Boucher AA, Edeoga C, Ebenibo S, Wan J, Dagogo-Jack S. Leukocyte count and cardiometabolic risk among healthy participants with parental type 2 diabetes: the Pathobiology of Prediabetes in a Biracial Cohort study. Ethn Dis 2012; 22:445-450. [PMID: 23140075 PMCID: PMC4836614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023] Open
Abstract
OBJECTIVE White blood cell (WBC) count has been associated with cardiometabolic risk, but the data for African Americans are conflicting. We determined whether WBC count predicts subclinical inflammation and cardiometabolic risk in African Americans, despite their known lower WBC count, compared to Caucasians. RESEARCH DESIGN AND METHODS The study cohort consisted of 334 normoglycemic subjects (153 Caucasian, 181 African American) with parental type 2 diabetes (T2DM), mean (+/- SD) age 43.90 +/- 10.25 y and BMI 30.1 +/- 6.84 kg/m2. Each subject underwent clinical examination and a standard oral glucose tolerance test (OGTT) to document glycemic status. Blood specimens were obtained for determination of WBC counts, lipid profile and C-reactive protein (CRP) levels. Metabolic syndrome components were identified, using the NCEP cut-offs for waist circumference, blood pressure, HDL cholesterol and triglyceride levels. RESULTS Leukocyte counts were lower by approximately 400/cm3 (P=.04) in African Americans than Caucasians, and were significantly correlated with waist circumference, HDL cholesterol, triglycerides and 2-h OGTT plasma glucose (P=.024-.0009), but not blood pressure in both races. Leukocyte counts significantly predicted the presence of three or more components of the metabolic syndrome similarly in African Americans (P=.0076) and Caucasians (P=.0078), as did CRP levels. Leukocyte counts correlated significantly with CRP levels in African Americans (r=.30, P<.0001) and Caucasians (r=.29, P=.0003). CONCLUSIONS Our data indicate that WBC count, despite being lower in African Americans than Caucasians, predicts low-grade inflammation and cardiometabolic risk with similar magnitude in normoglycemic African Americans and Caucasians with parental T2DM.
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Affiliation(s)
- Alexander A Boucher
- Division of Endocrinology, Diabetes and Metabolism and Clinical Research Center, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
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